Gene Expression of Quaking in Sporadic Alzheimer's Disease Patients is Both Upregulated and Related to Expression Levels of Genes Involved in Amyloid Plaque and Neurofibrillary Tangle Formation. - Farnsworth, Bryn; Peuckert, Christiane; Zimmermann, Bettina; Jazin, Elena; Kettunen, Petronella; Emilsson, Lina Sors (J Alzheimers Dis, 2016)
Quaking (QKI) is a gene exclusively expressed within glial cells. QKI has previously been implicated in various neurological disorders and diseases, including Alzheimer's disease (AD), a condition for which increasing evidence suggests a central role of glia cells. The objective of the present study was to investigate the expression levels of QKI and three QKI isoforms (QKI5, QKI6, and QKI7) in AD. Genes that have previously been related to the ontogeny and progression of AD, specifically APP, PSEN1, PSEN2, and MAPT, were also investigated. A real-time PCR assay of 123 samples from human postmortem sporadic AD patients and control brains was performed. The expression values were analyzed with an analysis of covariance model and subsequent multiple regressions to explore the possibility of related expression values between QKI, QKI isoforms, and AD-related genes. Further, the sequences of AD-related genes were analyzed for the presence of QKI binding domains. QKI and all measured QKI isoforms were found to be significantly upregulated in AD samples, relative to control samples. However, APP, PSEN1, PSEN2, and MAPT were not found to be significantly different. QKI and QKI isoforms were found to be predictive for the variance of APP, PSEN1, PSEN2, and MAPT, and putative QKI binding sites suggests an interaction with QKI. Overall, these results implicate a possible role of QKI in AD, although the exact mechanism by which this occurs remains to be uncovered.

Gene Expression Profiling in the APP/PS1KI Mouse Model of Familial Alzheimer's Disease. - Weissmann, Robert; Hüttenrauch, Melanie; Kacprowski, Tim; Bouter, Yvonne; Pradier, Laurent; Bayer, Thomas A; Kuss, Andreas W; Wirths, Oliver (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by early intraneuronal amyloid-β (Aβ) accumulation, extracellular deposition of Aβ peptides, and intracellular hyperphosphorylated tau aggregates. These lesions cause dendritic and synaptic alterations and induce an inflammatory response in the diseased brain. Although the neuropathological characteristics of AD have been known for decades, the molecular mechanisms causing the disease are still under investigation. Studying gene expression changes in postmortem AD brain tissue can yield new insights into the molecular disease mechanisms. To that end, one can employ transgenic AD mouse models and the next-generation sequencing technology. In this study, a whole-brain transcriptome analysis was carried out using the well-characterized APP/PS1KI mouse model for AD. These mice display a robust phenotype reflected by working memory deficits at 6 months of age, a significant neuron loss in a variety of brain areas including the CA1 region of the hippocampus and a severe amyloid pathology. Based on deep sequencing, differentially expressed genes (DEGs) between 6-month-old WT or PS1KI and APP/PS1KI were identified and verified by qRT-PCR. Compared to WT mice, 250 DEGs were found in APP/PS1KI mice, while 186 DEGs could be found compared to PS1KI control mice. Most of the DEGs were upregulated in APP/PS1KI mice and belong to either inflammation-associated pathways or lysosomal activation, which is likely due to the robust intraneuronal accumulation of Aβ in this mouse model. Our comprehensive brain transcriptome study further highlights APP/PS1KI mice as a valuable model for AD, covering molecular inflammatory and immune responses.
Keywords: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Brain; Disease Models, Animal; Gene Expression Profiling; Male; Mice; Mice, Transgenic; Nerve Degeneration; Presenilin-1; Transcriptome

Genetic Counseling and Testing for Alzheimer's Disease and Frontotemporal Lobar Degeneration: An Italian Consensus Protocol. - Bocchetta, Martina; Mega, Anna; Bernardi, Livia; Di Maria, Emilio; Benussi, Luisa; Binetti, Giuliano; Borroni, Barbara; Colao, Rosanna; Di Fede, Giuseppe; Fostinelli, Silvia; Galimberti, Daniela; Gennarelli, Massimo; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Genetic testing of familial Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) is attracting interest thanks to innovative primary prevention clinical trials and increased request for information by at-risk individuals. However, ethical, social, and psychological implications are paramount and genetic testing must be supported by structured genetic counseling. In Italy, practice parameters and guidelines for genetic counseling in dementia are not available. OBJECTIVE: To develop a nationally harmonized protocol for genetic counseling and testing of familial AD and FTLD. METHODS: Activities were carried out in the context of the Italian Dominantly Inherited Alzheimer's and Frontotemporal Network (IT-DIAfN) project, a national network of centers of excellence with expertise in managing patients with familial AD and FTLD. A survey of the literature on genetic counseling protocols and guidelines was conducted. Local protocols for genetic counseling were surveyed. Differences and commonalities among protocols were identified and discussed among project partners. Consensus was reached following implicit aggregation methods. RESULTS: Consensus was reached on a protocol for patients with clinically diagnosed familial AD or FTLD and a distinct protocol for their at-risk relatives. Genetic counseling should be provided by a multidisciplinary team including a geneticist, a neurologist/geriatrician, and a psychologist/psychiatrist, according to the following schedule: (i) initial consultation with tailored information on the genetics of the dementias; (ii) clinical, psychological, and cognitive assessment; if deemed appropriate (iii) genetic testing following a structured decision tree for gene mutation search; (iv) genetic testing result disclosure; (v) psychological support follow-up. CONCLUSION: This genetic counseling protocol provides Italian centers with a line of shared practice for dealing with the requests for genetic testing for familial AD and FTLD from patients and at-risk relatives, who may also be eligible participants for novel prevention clinical trials.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Consensus; Female; Follow-Up Studies; Frontotemporal Lobar Degeneration; Genetic Counseling; Genetic Testing; Humans; Italy; Male; Peptide Fragments; Psychiatric Status Rating Scales

Genetic Influences on Plasma Homocysteine Levels in African Americans and Yoruba Nigerians. - Kim, Sungeun; Nho, Kwangsik; Ramanan, Vijay K; Lai, Dongbing; Foroud, Tatiana M; Lane, Katie; Murrell, Jill R; Gao, Sujuan; Hall, Kathleen S; Unverzagt, Frederick W; Baiyewu, Olusegun; Ogunniyi, Adesola; et al. (J Alzheimers Dis, 2016)
Plasma homocysteine, a metabolite involved in key cellular methylation processes seems to be implicated in cognitive functions and cardiovascular health with its high levels representing a potential modifiable risk factor for Alzheimer's disease (AD) and other dementias. A better understanding of the genetic factors regulating homocysteine levels, particularly in non-white populations, may help in risk stratification analyses of existing clinical trials and may point to novel targets for homocysteine-lowering therapy. To identify genetic influences on plasma homocysteine levels in individuals with African ancestry, we performed a targeted gene and pathway-based analysis using a priori biological information and then to identify new association performed a genome-wide association study. All analyses used combined data from the African American and Yoruba cohorts from the Indianapolis-Ibadan Dementia Project. Targeted analyses demonstrated significant associations of homocysteine and variants within the CBS (Cystathionine beta-Synthase) gene. We identified a novel genome-wide significant association of the AD risk gene CD2AP (CD2-associated protein) with plasma homocysteine levels in both cohorts. Minor allele (T) carriers of identified CD2AP variant (rs6940729) exhibited decreased homocysteine level. Pathway enrichment analysis identified several interesting pathways including the GABA receptor activation pathway. This is noteworthy given the known antagonistic effect of homocysteine on GABA receptors. These findings identify several new targets warranting further investigation in relation to the role of homocysteine in neurodegeneration.
Keywords: Adaptor Proteins, Signal Transducing; African Americans; African Continental Ancestry Group; Aged; Aged, 80 and over; Cohort Studies; Cystathionine beta-Synthase; Cytoskeletal Proteins; Female; Genetic Variation; Genome-Wide Association Study; Heterozygote; Homocysteine; Humans; Indiana; Longitudinal Studies; Male; Nigeria; Prospective Studies

The Genetic Variability of UCP4 Affects the Individual Susceptibility to Late-Onset Alzheimer's Disease and Modifies the Disease's Risk in APOE-ɛ4 Carriers. - Montesanto, Alberto; Crocco, Paolina; Anfossi, Maria; Smirne, Nicoletta; Puccio, Gianfranco; Colao, Rosanna; Maletta, Raffaele; Passarino, Giuseppe; Bruni, Amalia C; Rose, Giuseppina (J Alzheimers Dis, 2016)
Uncoupling proteins (UCPs) are a group of five mitochondrial inner membrane transporters with a tissue specific expression that uncouple biofuel oxidation from ATP synthesis and function as regulators of energy homeostasis and antioxidants. Previous data suggested that neuronal UCPs (UCP2, UCP4, and UCP5) can directly influence synaptic plasticity, neurotransmission, and neurodegenerative processes, and have a crucial role in the function and protection of the central nervous system. In fact, it has been observed that the expression of neuronal UCPs significantly decreases in Alzheimer's disease (AD) patients. Here we analyzed the variability of UCP2, -3, -4, and 5 genes in sporadic and familial cases (n = 465) of late-onset AD (LOAD) with respect to healthy controls (n = 442). We showed that a genetic variant in the human UCP4, rs9472817, not only significantly affects the individual susceptibility to LOAD, but also modulates the effect of APOE-ɛ4 on AD risk. In fact, rs9472817-C allele was significantly more frequent in both groups of patients with respect to the control group (p = 6.934*10-4 for familial and p = 1.033*10-3 for sporadic cases). In addition, gene-gene interaction analysis revealed that the effect of APOE-ɛ4 allele on LOAD risk was doubled in homozygote CC subjects; conversely, the risk conferred by the APOE-ɛ4 allele was annulled in subjects with two copies of the G allele. Our findings are further evidence that the efficiency in mitochondrial energy metabolism and oxidative stress are important factors in AD pathogenesis.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Apolipoprotein E4; Female; Genetic Association Studies; Genotype; Humans; Male; Mental Status Schedule; Mitochondrial Uncoupling Proteins; Neuroimaging; Polymorphism, Single Nucleotide

A Genetic Variant of the Sortilin 1 Gene is Associated with Reduced Risk of Alzheimer's Disease. - Andersson, Carl-Henrik; Hansson, Oskar; Minthon, Lennart; Andreasen, Niels; Blennow, Kaj; Zetterberg, Henrik; Skoog, Ingmar; Wallin, Anders; Nilsson, Staffan; Kettunen, Petronella (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is a neurodegenerative disorder represented by the accumulation of intracellular tau protein and extracellular deposits of amyloid-β (Aβ) in the brain. The gene sortilin 1 (SORT1) has previously been associated with cardiovascular disease in gene association studies. It has also been proposed to be involved in AD pathogenesis through facilitating Aβ clearance by binding apoE/Aβ complexes prior to cellular uptake. However, the neuropathological role of SORT1 in AD is not fully understood. To evaluate the associations between gene variants of SORT1 and risk of AD, we performed genetic analyses in a Swedish case-control cohort. Ten single nucleotide polymorphisms (SNPs), covering the whole SORT1 gene, were selected and genotyped in 620 AD patients and 1107 controls. The SNP rs17646665, located in a non-coding region of the SORT1 gene, remained significantly associated with decreased risk of AD after multiple testing (pc = 0.0061). In addition, other SNPs were found to be nominally associated with risk of AD, as well as altered cognitive function and the CSF biomarker Aβ42, but these associations did not survive correction for multiple testing. The fact that SORT1 has been strongly associated with risk of cardiovascular disease is intriguing as cardiovascular disease is also regarded as a risk factor for AD. Finally, increased knowledge about SORT1 function has a potential to increase our understanding of APOE, the strongest risk factor for AD.

Genetic Variations in ABCA7 Can Increase Secreted Levels of Amyloid-β40 and Amyloid-β42 Peptides and ABCA7 Transcription in Cell Culture Models. - Bamji-Mirza, Michelle; Li, Yan; Najem, Dema; Liu, Qing Yan; Walker, Douglas; Lue, Lih-Fen; Stupak, Jacek; Chan, Kenneth; Li, Jianjun; Ghani, Mahdi; Yang, Ze; Rogaeva, Ekaterina; et al. (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is characterized by extracellular deposits of amyloid-β (Aβ) in the brain. ABCA7 is highly expressed in the brain and a susceptibility gene for late-onset AD (LOAD). The minor alleles at two ABCA7 single-nucleotide polymorphisms (SNPs), rs3764650 (T>G; intron13) and rs3752246 at a predicted myristoylation site (C>G; exon33; p.Gly1527Ala), are significantly associated with LOAD risk; however, the mechanism of this association is unknown. Functional consequences of both SNPs were examined in HEK293 and CHO cells stably expressing AβPPSwe. Luciferase reporter assays in HEK293 cells suggested that intron13 carrying rs3764650 major T-allele (int13-T) possessed promoter-enhancing capabilities. Co-transfection experiments with hABCA7 and int13-T resulted in significantly increased ABCA7 protein level relative to that with int13-G. Expression of hABCA7 carrying rs3752246 risk allele led to increases in secreted Aβ40 and Aβ42 and β-secretase activity in CHO- and HEK-AβPPSwe cells. Hydroxymyristic acid treatment of cells expressing hABCA7 carrying the rs3752246 major G allele resulted in increased β-secretase activity and levels of Aβ, suggesting that lack of myristoylation contributes to the observed cell-phenotypes. Molecular weight determination, by gel-electrophoresis and mass spectrometry, of hABCA7 peptides spanning position 1527 showed loss of post-translational modification in the risk-allele peptide. These results suggest that decreased expression, or impaired function, of ABCA7 may contribute to AD pathology.

Genetics of Frontotemporal Lobar Degeneration: From the Bench to the Clinic. - Tang, Shan-Shan; Li, Jun; Tan, Lan; Yu, Jin-Tai (J Alzheimers Dis, 2016)
Frontotemporal lobar degeneration (FTLD) is a clinically heterogeneous neurodegenerative disease with a strong genetic component. In this review, we summarize most common mutations in MAPT, GRN, and C90RF72, as well as less common mutations in VCP, CHMP2B, TARDBP, FUS gene and so on. Several guidelines have been developed to help gene testing based on genotype-phenotype correlation, the underlying histopathological subtypes, and the neuroanatomic associations. Furthermore, we also summarize molecular pathways implicated by genes and novel targets for FTLD prevention and management in recent years.

Geographical Variation in Antipsychotic Drug Use in Elderly Patients with Dementia: A Nationwide Study. - Zakarias, Johanne Købstrup; Jensen-Dahm, Christina; Nørgaard, Ane; Stevnsborg, Lea; Gasse, Christiane; Andersen, Bodil Gramkow; Søren, Jakobsen; Waldorff, Frans Boch; Moos, Torben; Waldemar, Gunhild (J Alzheimers Dis, 2016)
BACKGROUND: Use of antipsychotics in elderly patients with dementia has decreased in the past decade due to safety regulations; however use is still high. Geographical variation may indicate discrepancies in clinical practice and lack of adherence to evidence-based guidelines for the management of behavioral symptoms. OBJECTIVE: To investigate potential geographical variances in use of antipsychotic drugs in dementia care. METHODS: A registry-based cross-sectional study in the entire elderly population of Denmark (≥65 years) conducted in 2012. Data included place of residence, prescriptions filled, and hospital discharge diagnoses. Antipsychotic drug use among elderly with (n = 34,536) and without (n = 931,203) a dementia diagnosis was compared across the five regions and 98 municipalities in Denmark, adjusted for age and sex. RESULTS: In 2012, the national prevalence of antipsychotic drug use was 20.7% for elderly patients with dementia, with a national incidence of 3.9%. The prevalence ranged from 17.0% to 23.3% in the five regions and from 7.5% to 33.1% in the 98 municipalities, demonstrating an over four-fold difference. CONCLUSION: The observed geographical variation was more pronounced at municipal level as compared to regional level, suggesting that the variation may be related to variances in clinical practice in primary care. This study highlights an urgent need for further educating professional carers and physicians to guide non-pharmacological as well as pharmacological management of neuropsychiatric symptoms in elderly patients with dementia.

The Gesture Imitation in Alzheimer's Disease Dementia and Amnestic Mild Cognitive Impairment. - Li, Xudong; Jia, Shuhong; Zhou, Zhi; Hou, Chunlei; Zheng, Wenjing; Rong, Pei; Jiao, Jinsong (J Alzheimers Dis, 2016)
BACKGROUND: Alzheimer's disease dementia (ADD) has become an important health problem in the world. Visuospatial deficits are considered to be an early symptom besides memory disorder. OBJECTIVES: The gesture imitation test was devised to detect ADD and amnestic mild cognitive impairment (aMCI). METHODS: A total of 117 patients with ADD, 118 with aMCI, and 95 normal controls were included in this study. All participants were administered our gesture imitation test, the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Clock Drawing Test (CDT), and the Clinical Dementia Rating Scale (CDR). RESULTS: Patients with ADD performed worse than normal controls on global scores and had a lower success rate on every item (p < 0.001). The area under the curve (AUC) for the global scores when comparing the ADD and control groups was 0.869 (p < 0.001). Item 4 was a better discriminator with a sensitivity of 84.62% and a specificity of 67.37%. The AUC for the global scores decreased to 0.621 when applied to the aMCI and control groups (p = 0.002). After controlling for age and education, the gesture imitation test scores were positively correlated with the MMSE (r = 0.637, p < 0.001), the MoCA (r = 0.572, p < 0.001), and the CDT (r = 0.514, p < 0.001) and were negatively correlated with the CDR scores (r = -0.558, p < 0.001). CONCLUSIONS: The gesture imitation test is an easy, rapid tool for detecting ADD, and is suitable for the patients suspected of mild ADD and aMCI in outpatient clinics.

Glutamine and Glutamate Complex, as Measured by Functional Magnetic Resonance Spectroscopy, Alters During Face-Name Association Task in Patients with Mild Cognitive Impairment and Alzheimer's Disease. - Jahng, Geon-Ho; Oh, Janghoon; Lee, Do-Wan; Kim, Hyug-Gi; Rhee, Hak Young; Shin, Wonchul; Paik, Jong-Woo; Lee, Kyung Mi; Park, Soonchan; Choe, Bo-Young; Ryu, Chang-Woo (J Alzheimers Dis, 2016)
BACKGROUND: The metabolite response during a memory task in Alzheimer's disease (AD) patients is unknown. OBJECTIVE: To investigate the metabolite changes in subjects with AD, amnestic mild cognitive impairment (aMCI), and cognitively normal (CN) elderly during a memory task using functional magnetic resonance spectroscopy (fMRS). METHODS: This study involved 23 young normal controls (YC), 24 CN elderly, 24 aMCI, and 24 mild and probable AD individuals. fMRS data were acquired at the precuneus and posterior cingulate brain regions during a face-name association task. Statistical analyses of quantified metabolites were performed to evaluate differences of the metabolite values between the stimulation conditions and among the four subject groups. Receiver operating curve analysis was performed to evaluate whether the metabolic changes after functional activations can differentiate the subject groups. RESULT: Glutamine and glutamate complex (Glx) was statistically significantly different between the fixation and repeat conditions in aMCI (p = 0.0492) as well as between the fixation and the novel conditions in the AD (p = 0.0412) group. The total N-acetylaspartate (tNAA) was statistically significantly different among the four subject groups in the fixation condition (DF = 3, F = 7.673, p <  0.001), the novel condition (DF = 3, F = 6.945, p <  0.001), and the repeat condition (DF = 3, F = 7.127, p <  0.001). tNAA, tCr, and mIns could be used to differentiate CN from aMCI. Furthermore, tNAA, tCr, Glx, and Glu could also differentiate CN from AD, and aMCI from AD. CONCLUSION: Glx was altered during a stimulation that may be used to evaluate neuronal dysfunction in a demented patient. tNAA and tCr were reduced in patients with AD.

Greater specificity for cerebrospinal fluid P-tau231 over P-tau181 in the differentiation of healthy controls from Alzheimer's disease. - Spiegel, Jonathan; Pirraglia, Elizabeth; Osorio, Ricardo S; Glodzik, Lidia; Li, Yi; Tsui, Wai; Saint Louis, Leslie A; Randall, Catherine; Butler, Tracy; Xu, Jinfeng; Zinkowski, Raymond P; Zetterberg, Henrik; et al. (J Alzheimers Dis, 2016)
Cerebrospinal fluid (CSF) measures of phosphorylated-tau (P-tau) 231 and P-tau181 are two biomarkers for the identification of tau pathology as related to Alzheimer's disease (AD). While both are pathologically validated, their relative diagnostic performances are not well known. This cross-sectional diagnostic study of 87 normal (NL) subjects and 28 AD subjects compared CSF P-tau231 with CSF P-tau181. Logistic regression modeling demonstrated that the P-tau231 was superior to the P-tau181 in the diagnostic classifications. At a fixed 85% sensitivity cutoff, the ROC analysis shows that P-tau231 has greater overall specificity than P-tau181. While both P-tau analytes demonstrated equivalent negative predictive accuracies, P-tau231 yielded significantly fewer false positives. Moreover, P-tau231, but not P-tau181, demonstrated sensitivity to the E4 genotype. A postmortem validation with 9 AD subjects confirmed the superiority of the CSF P-tau231 specificity. This study suggests that P-tau231 has the potential to improve the CSF tau biomarker diagnosis of AD.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Case-Control Studies; Cross-Sectional Studies; Female; Humans; Logistic Models; Male; Middle Aged; Phosphorylation; ROC Curve; Sensitivity and Specificity; tau Proteins

Greater than the Sum of Its Parts: δ can be Constructed from Item Level Data. - Royall, Donald R; Palmer, Raymond F; Matsuoka, Teruyuki; Kato, Yuka; Taniguchi, Shogo; Ogawa, Mayu; Fujimoto, Hiroshi; Okamura, Aiko; Shibata, Keisuke; Nakamura, Kaeko; Nakaaki, Shutaro; Koumi, Hiroyuki; et al. (J Alzheimers Dis, 2016)
"δ", a latent variable constructed from cognitive performance and functional status measures, can accurately diagnose dementia. The minimal assessment needed is unknown. We have constructed a δ homolog, "dTEXAS", from Telephone Executive Assessment Scale (TEXAS) items, and validated it in a convenience sample of Japanese persons (n = 176). dTEXAS scores correlated strongly with both Instrumental Activities of Daily Living (IADL) (r = -0.86, p <  0.001) and Clinical Dementia Rating Scale (CDR) (r = 0.71, p <  0.001). Constructed independently of their diagnoses, dTEXAS scores accurately distinguished dementia versus controls (area under the receiver operating curve [(AUC; ROC) = 0.92], dementia versus mild cognitive impairment (MCI) (AUC = 0.80) and controls versus MCI (AUC = 0.74). These AUCs are higher than those of multiple observed executive measures, as reported recently by Matsuoka et al., 2014. A dTEXAS score of -0.58 best discriminated between dementia versus controls with 90.1% sensitivity and 80.0% specificity.
Keywords: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Cognitive Dysfunction; Executive Function; Female; Humans; Japan; Male; Neuropsychological Tests; Psychiatric Status Rating Scales; ROC Curve; United States

GSK-3β is Dephosphorylated by PP2A in a Leu309 Methylation-Independent Manner. - Chu, Dandan; Tan, Jianxin; Xie, Shutao; Jin, Nana; Yin, Xiaomin; Gong, Cheng-Xin; Iqbal, Khalid; Liu, Fei (J Alzheimers Dis, 2016)
Hyperphosphorylation of tau is pivotally involved in the pathogenesis of Alzheimer's disease (AD) and related tauopathies. Glycogen synthase kinase-3β (GSK-3β) and protein phosphate 2A (PP2A) are crucial enzymes to regulate tau phosphorylation. GSK-3β activity is regulated by its inhibitory phosphorylation at Ser9. We previously reported the cross-talk between GSK-3β and PP2A signaling and showed that PP2A could dephosphorylate GSK-3β at Ser9. Here, we investigated the dephosphorylation of GSK-3β in brain extracts in the presence of phosphatase inhibitors and found that a PP2A-like phosphatase activity was required for dephosphorylation of GSK-3β at Ser9. PP2A interacted with GSK-3β and suppressed its Ser9 phosphorylation in vitro and in HEK-293FT cells. Activity of PP2A negatively correlated to the level of phosphorylated GSK-3β in kainic acid-induced excitotoxic mouse brain. Alteration of methylation of the catalytic subunit of PP2A (PP2Ac) at Leu309 did not affect GSK-3β phosphorylation. These findings suggest that Leu309 methylation is not required for PP2A to dephosphorylate GSK-3β at Ser9.
Keywords: Animals; Brain; Carboxylic Ester Hydrolases; Cell Line, Transformed; Dose-Response Relationship, Drug; Enzyme Inhibitors; Excitatory Amino Acid Agonists; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Kainic Acid; Leucine; Luminescent Proteins; Male; Methylation; Mice; Phosphorylation; Protein O-Methyltransferase; Protein Phosphatase 2; RNA, Small Interfering; Serine; tau Proteins

Gx-50 Inhibits Neuroinflammation via α7 nAChR Activation of the JAK2/STAT3 and PI3K/AKT Pathways. - Shi, Shi; Liang, Dongli; Bao, Min; Xie, Yilin; Xu, Wangjie; Wang, Lianyun; Wang, Zhaoxia; Qiao, Zhongdong (J Alzheimers Dis, 2016)
Recent studies have revealed that the α7 nicotinic acetylcholine receptor (α7 nAChR) is a critical link between inflammation and neurodegeneration, which is closely associated with Alzheimer's disease (AD). The JAK2/STAT3 and PI3K/AKT signaling pathways contribute to the neuroprotective and anti-inflammatory effects of α7nAChR. Our previous studies have shown that treatment with gx-50 improves cognitive function and is neuroprotective. Here, we investigated the effect of gx-50 on α7 nAChR and Aβ-induced inflammation in microglia. First, the binding affinity of gx-50 to α7 nAChR was examined using the fluorescence-based Octet RED system, and the expression of α7 nAChR was detected using real-time PCR and western blotting. We also investigated downstream events of α7 nAChR activity, including the translocation of p-STAT3 and the phosphorylation of JAK2, STAT3, PI3K, and AKT. Finally, the effect of gx-50 on Aβ-induced inflammation via α7 nAChR-mediated signaling pathways was investigated using cytokine assays. The results showed that gx-50 is able to act as a specific ligand to activate α7 nAChR, which then upregulates the JAK2/STAT3 and PI3K/AKT signaling pathways to inhibit the secretions of pro-inflammatory cytokines, such as IL-1β. In conclusion, the results suggest that gx-50 could inhibit the Aβ-induced inflammatory response in microglia via α7 nAChR activity, which might be a successful therapeutic target against AD.
Keywords: Acrylamides; alpha7 Nicotinic Acetylcholine Receptor; Amyloid beta-Peptides; Analysis of Variance; Animals; Anti-Inflammatory Agents; Cell Line, Transformed; Cytokines; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Janus Kinase 2; Mice; Microglia; Phosphatidylinositol 3-Kinases; Protein Binding; RNA, Messenger; Signal Transduction

Gypenoside XVII Enhances Lysosome Biogenesis and Autophagy Flux and Accelerates Autophagic Clearance of Amyloid-β through TFEB Activation. - Meng, Xiangbao; Luo, Yun; Liang, Tian; Wang, Mengxia; Zhao, Jingyu; Sun, Guibo; Sun, Xiaobo (J Alzheimers Dis, 2016)
A strategy for activating transcription factor EB (TFEB) to restore autophagy flux may provide neuroprotection against Alzheimer's disease. Our previous study reported that gypenoside XVII (GP-17), which is a major saponin abundant in ginseng and Panax notoginseng, ameliorated amyloid-β (Aβ)25-35-induced apoptosis in PC12 cells by regulating autophagy. In the present study, we aimed to determine whether GP-17 has neuroprotective effects on PC12 cells expressing the Swedish mutant of APP695 (APP695swe) and APP/PS1 mice. We also investigated the underlying mechanism. We found that GP-17 could significantly increase Atg5 expression and the conversion of LC3-I to LC3-II in APP695 cells, which was associated with a reduction in p62 expression. GP-17 also elevated the number of LC3 puncta in APP695 cells transduced with pCMV-GFP-LC3. GP-17 promoted the autophagy-based elimination of AβPP, Aβ40, and Aβ42 in APP695swe cells and prevented the formation of Aβ plaques in the hippocampus and cortex of APP/PS1 mice. Furthermore, spatial learning and memory deficits were cured. Atg5 knockdown could abrogate the GP-17-mediated removal of AβPP, Aβ40, and Aβ42 in APP695swe cells. GP-17 upregulated LAMP-1, increased LysoTracker staining, and augmented LAMP-1/LC3-II co-localization. GP-17 could release TFEB from TFEB/14-3-3 complexes, which led to TFEB nuclear translocation and the induction of autophagy and lysosome biogenesis and resulted in the amelioration of autophagy flux. The knockdown of TFEB could abolish these effects of GP-17. In summary, these results demonstrated that GP-17 conferred protective effects to the cellular and rodent models of Alzheimer's disease by activating TFEB.

Halting of Caspase Activity Protects Tau from MC1-Conformational Change and Aggregation. - Mead, Emma; Kestoras, Dimitra; Gibson, Yolanda; Hamilton, Lucy; Goodson, Ross; Jones, Sophie; Eversden, Sarah; Davies, Peter; O'Neill, Michael; Hutton, Michael; Szekeres, Philip; Wolak, Joanna (J Alzheimers Dis, 2016)
Intracellular neurofibrillary tangles (NFTs) are the hallmark of Alzheimer's disease and other tauopathies in which tau, a microtubule-associated protein, loses its ability to stabilize microtubules. Several post-translational modifications including phosphorylation and truncation increase tau's propensity to aggregate thus forming NFTs; however, the mechanisms underlying tau conformational change and aggregation still remain to be defined. Caspase activation and subsequent proteolytic cleavage of tau is thought to be a potential trigger of this disease-related pathological conformation. The aim of this work was to investigate the link between caspase activation and a disease-related conformational change of tau in a neuroblastoma cell-based model of spontaneous tau aggregation. We demonstrated that caspase induction initiates proteolytic cleavage of tau and generation of conformationally altered and aggregated tau recognized by the MC1 conformational antibody. Most importantly, these events were shown to be attenuated with caspase inhibitors. This implies that therapeutics aimed at inhibiting caspase-mediated tau cleavage may prove beneficial in slowing cleavage and aggregation, thus potentially halting tau pathology and disease progression.

Health-Related Quality of Life in Patients with Alzheimer's Disease in Different German Health Care Settings. - Heßmann, Philipp; Seeberg, Greta; Reese, Jens Peter; Dams, Judith; Baum, Erika; Müller, Matthias J; Dodel, Richard; Balzer-Geldsetzer, Monika (J Alzheimers Dis, 2016)
The purpose of this study is to evaluate the health-related quality of life (HrQoL) of patients with Alzheimer's disease (AD) in different care settings (institutionalized versus community-dwelling) across all severity stages of dementia. Patients were consecutively recruited with their primary caregivers (123 inpatients and 272 outpatients), and the impact of patient-related parameters such as behavioral and psychological symptoms of dementia (BPSD) (Geriatric Depression Scale [GDS] and Neuropsychiatric Inventory [NPI]) and functional capacity (Alzheimer's Disease Cooperative Study-Activities of Daily Living [ADCS-ADL]) on HrQoL was analyzed. Patients' HrQoL was assessed using self-reported and caregiver-rated generic (EuroQoL Instrument) and dementia-specific (Quality of Life-Alzheimer's Disease [Qol-AD]) scales. Patients reported a considerably higher HrQoL than their caregivers on the QoL-AD, EQ-5D, and EQ VAS (p <  0.001). Different dementia severity groups showed significantly worse results in HrQoL for patients with lower MMSE scores. The mean self-reported QoL-AD decreased from 32.3±5.7 in the group with the highest MMSE scores to 27.1±5.5 in patients with the lowest MMSE scores (p <  0.001). A considerably lower HrQoL was shown for institutionalized patients versus participants in outpatient settings (proxy-rated QoL-AD 19.7±4.6 versus 26.0±7.1, p <  0.001). Depressive symptoms (GDS), BPSD (NPI), and reduced functional capacity (ADCS-ADL) were evaluated for their impact on patients' HrQoL. Multivariate models explained between 22% and 54% of the variance in patients' HrQoL. To analyze the causative direction of the reported associations, further longitudinal studies should be conducted.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Caregivers; Depression; Female; Germany; Humans; Inpatients; Male; Multivariate Analysis; Neuropsychological Tests; Outpatients; Psychiatric Status Rating Scales; Quality of Life; Residential Facilities; Self Report; Severity of Illness Index

Heart Rate Spectra Confirm the Presence of Autonomic Dysfunction in Dementia Patients. - Struhal, Walter; Mahringer, Christoph; Lahrmann, Heinz; Mörtl, Christoph; Buhl, Peter; Huemer, Mario; Ransmayr, Gerhard (J Alzheimers Dis, 2016)
Recent data suggest autonomic dysfunction in patients suffering dementia. This study evaluated autonomic modulation in dementia patients with and without autonomic involvement, employing ECG spectral analysis in the time-frequency domain (wavelet transform) in supine resting and head-up tilt (HUT) position. Thirty-six patients were prospectively evaluated at the Department of Neurology and Psychiatry, General Hospital of the City of Linz, between 2009 and 2014. A standard cardiovascular autonomic test series (Ewing battery) was performed to screen for autonomic dysfunction. The Ewing battery diagnoses were used as reference standard and compared to the diagnostic results obtained by spectral analysis (time-frequency domain) of ECG recordings. Based on the Ewing battery results, 14 patients suffered autonomic dysfunction, while 22 did not. Time frequency domain was accessed by using the continuous wavelet transformation (CWT) with an analytical Morlet mother wavelet in supine resting and HUT position. Within each cohort the modification of spectral components from supine resting to HUT was analyzed reflecting the autonomic modulation. For patients without autonomic dysfunction, a significant increase of autonomic modulation was detected by wavelet transformed ECG recordings (8%, p < 0.05; low frequency content) during HUT compared to supine resting. There was no significant modulation between HUT and supine resting in patients suffering autonomic dysfunction. In dementia patients suffering autonomic dysfunction, CWT identified blunted autonomic regulation only by analysis of ECG recordings without the need to assess other biosignals or tests depending on the patient's cooperation. Further studies are needed to evaluate whether CWT is a suitable method to support the standard Ewing battery in demented patients.

Hemisphere Asymmetry of Response to Pharmacologic Treatment in an Alzheimer's Disease Mouse Model. - Manousopoulou, Antigoni; Saito, Satoshi; Yamamoto, Yumi; Al-Daghri, Nasser M; Ihara, Masafumi; Carare, Roxana O; Garbis, Spiros D (J Alzheimers Dis, 2016)
The aim of this study was to examine hemisphere asymmetry of response to pharmacologic treatment in an Alzheimer's disease mouse model using cilostazol as a chemical stimulus. Eight-month-old mice were assigned to vehicle or cilostazol treatment for three months and hemispheres were analyzed using quantitative proteomics. Bioinformatics interpretation showed that following treatment, aggregation of blood platelets significantly decreased in the right hemisphere whereas neurodegeneration significantly decreased and synaptic transmission increased in the left hemisphere only. Our study provides novel evidence on cerebral laterality of pharmacologic activity, with important implications in deciphering regional pharmacodynamic effects of existing drugs thus uncovering novel hemisphere-specific therapeutic targets.
Keywords: Alzheimer Disease; Animals; Brain; Disease Models, Animal; Functional Laterality; Male; Mice, Transgenic; Nootropic Agents; Proteome; Tetrazoles

Herpes and Alzheimer's Disease: Subversion in the Central Nervous System and How It Might Be Halted. - Itzhaki, Ruth F (J Alzheimers Dis, 2016)
The last 8 or so years have seen a large increase in the number of studies supporting the concept of a major role for herpes simplex virus type 1 (HSV1) in Alzheimer's disease (AD). The main advances have been made through studies in humans and in mice, investigating the likelihood of reactivation of the latent virus in brain. Others have aimed to explain the mechanisms in cells whereby the increase in amyloid-beta (Aβ) production on HSV1 infection of cells and mouse brains occurs, and the reason that infected cells make this increase. The possibility that other herpesviruses are involved in the development of AD has been explored, and human herpesvirus type 6, Epstein-Barr virus, and cytomegalovirus, in particular, have been implicated. Epidemiological studies have further supported the role specifically of HSV1 and its reactivation in the disease. Antiviral studies have continued, comparing those acting by different mechanisms, such as restricting viral replication, or blocking viral entry into cells, to treat HSV1-infected cell cultures, and then examining the extent to which the virus-induced increases in Aβ and AD-like tau are reduced. All the studies support the usage of antiviral treatment to slow or halt the progression of AD.

Heterogeneity of Cognitive Anosognosia and its Variation with the Severity of Dementia in Patients with Alzheimer's Disease. - Avondino, Emilie; Antoine, Pascal (J Alzheimers Dis, 2016)
Currently, the lack of awareness of deficits, i.e., anosognosia, is a major obstacle in the healthcare circuit that delays the diagnosis of Alzheimer's disease (AD). However, a clear framework is lacking in the literature related to this phenomenon in terms of its definition, mechanisms, and objects. The aim of this study is to assess the different levels of cognitive anosognosia using a prediction-performance procedure and to identify the potential correlates of these levels. A sample of patients with probable AD was divided into three groups according to the severity of dementia (mild (MiD), moderate (MoD), and moderately severe (MSD) dementia), ranked according to the results of the Mini-Mental State Examination. We observed the following three scores: the real score, the prediction score, and the anosognosia score. These scores were calculated based on the prediction-performance task MISAwareness from the Dementia Rating Scale for cognitive processes (i.e., Attention, Initiation, Conceptualization, Construction, and Memory). We obtained a strong plateau effect between the MiD and MoD groups for anosognosia scores for actual performance or prediction for both the level of overall functioning and for specific processes. The sole exception was the result for memory processes. Moreover, the profiles of the patients' responses on the Memory subscale were substantially different and, indeed, opposite from those for the other processes. The main results confirm the multidimensionality of anosognosia and its variability with the stage of dementia and specifically implicate memory processes that indicate a cleavage between memory and other cognitive functions.
Keywords: Agnosia; Alzheimer Disease; Attention; Chi-Square Distribution; Cognition Disorders; Dementia; Female; Humans; Male; Memory; Neuropsychological Tests; Predictive Value of Tests; Prospective Studies; Psychiatric Status Rating Scales; Severity of Illness Index

Heterogeneous Language Profiles in Patients with Primary Progressive Aphasia due to Alzheimer's Disease. - Louwersheimer, Eva; Keulen, M Antoinette; Steenwijk, Martijn D; Wattjes, Mike P; Jiskoot, Lize C; Vrenken, Hugo; Teunissen, Charlotte E; van Berckel, Bart N M; van der Flier, Wiesje M; Scheltens, Philip; van Swieten, John C; Pijnenburg, Yolande A L (J Alzheimers Dis, 2016)
BACKGROUND: The logopenic variant of Primary Progressive Aphasia (lvPPA) is associated with underlying Alzheimer's disease (AD) pathology and characterized by impaired single word retrieval and repetition of phrases and sentences. OBJECTIVE: We set out to study whether logopenic aphasia is indeed the prototypic language profile in PPA patients with biomarker evidence of underlying AD pathology and to correlate language profiles with cortical atrophy patterns on MRI. METHODS: Inclusion criteria: (I) clinical diagnosis of PPA; (II) CSF profile and/or PiB-PET scan indicative for amyloid pathology; (III) availability of expert language evaluation. Based on language evaluation, patients were classified as lvPPA (fulfilling lvPPA core criteria), lvPPA extended (fulfilling core criteria plus other language disturbances), or PPA unclassifiable (not fulfilling lvPPA core criteria). Cortical atrophy patterns on MRI were visually rated and quantitative measurements of cortical thickness were performed using FreeSurfer. RESULTS: We included 22 patients (age 67±7 years, 50% female, MMSE 21±6). 41% were classified as lvPPA, 36% as lvPPA extended with additional deficits in language comprehension and/or confrontation naming, and 23% as PPA unclassifiable. By both qualitative and quantitative measurements, patients with lvPPA showed mild global cortical atrophy on MRI, whereas patients with lvPPA extended showed more focal cortical atrophy, predominantly at the left tempo-parietal side. For PPA unclassifiable, qualitative measurements revealed a heterogeneous atrophy pattern. CONCLUSION: Although most patients fulfilled the lvPPA criteria, we found that their language profiles were heterogeneous. The clinical and radiological spectrum of PPA due to underlying AD pathology is broader than pure lvPPA.
Keywords: Aged; Alzheimer Disease; Aphasia, Primary Progressive; Atrophy; Biomarkers; Brain; Female; Humans; Language; Language Tests; Magnetic Resonance Imaging; Male; Mental Status Schedule; Organ Size; Positron-Emission Tomography; Retrospective Studies

Hierarchical Distribution of the Tau Cytoskeletal Pathology in the Thalamus of Alzheimer's Disease Patients. - Rüb, Udo; Stratmann, Katharina; Heinsen, Helmut; Del Turco, Domenico; Ghebremedhin, Estifanos; Seidel, Kay; den Dunnen, Wilfred; Korf, Horst-Werner (J Alzheimers Dis, 2016)
In spite of considerable progress in neuropathological research on Alzheimer's disease (AD), knowledge regarding the exact pathoanatomical distribution of the tau cytoskeletal pathology in the thalamus of AD patients in the advanced Braak and Braak AD stages V or VI of the cortical cytoskeletal pathology is still fragmentary. Investigation of serial 100 μm-thick brain tissue sections through the thalamus of clinically diagnosed AD patients with Braak and Braak AD stage V or VI cytoskeletal pathologies immunostained with the anti-tau AT8 antibody, along with the affection of the extraterritorial reticular nucleus of the thalamus, reveals a consistent and severe tau immunoreactive cytoskeletal pathology in the limbic nuclei of the thalamus (e.g., paraventricular, anterodorsal and laterodorsal nuclei, limitans-suprageniculate complex). The thalamic nuclei integrated into the associative networks of the human brain (e.g., ventral anterior and mediodorsal nuclei) are only mildly affected, while its motor precerebellar (ventral lateral nucleus) and sensory nuclei (e.g., lateral and medial geniculate bodies, ventral posterior medial and lateral nuclei, parvocellular part of the ventral posterior medial nucleus) are more or less spared. The highly stereotypical and characteristic thalamic distribution pattern of the AD-related tau cytoskeletal pathology represents an anatomical mirror of the hierarchical topographic distribution of the cytoskeletal pathology in the interconnected regions of the cerebral cortex of AD patients. These pathoanatomical parallels support the pathophysiological concept of a transneuronal spread of the disease process of AD along anatomical pathways. The AD-related tau cytoskeletal pathology in the thalamus most likely contributes substantially to the neuropsychiatric disease symptoms (e.g., dementia), attention deficits, oculomotor dysfunctions, altered non-discriminative aspects of pain experience of AD patients, and the disruption of their waking and sleeping patterns.
Keywords: Alzheimer Disease; Cytoskeleton; Humans; tau Proteins; Thalamus

High Risk of Dementia in Ventricular Enlargement with Normal Pressure Hydrocephalus Related Symptoms1. - Koivisto, Anne M; Kurki, Mitja I; Alafuzoff, Irina; Sutela, Anna; Rummukainen, Jaana; Savolainen, Sakari; Vanninen, Ritva; Jääskeläinen, Juha E; Soininen, Hilkka; Leinonen, Ville (J Alzheimers Dis, 2016)
BACKGROUND: Differential diagnosis of ventricular enlargement with normal pressure hydrocephalus (NPH) related symptoms is challenging. Patients with enlarged ventricles often manifest cognitive deterioration but their long-term outcome is not well known. OBJECTIVES: We aim to evaluate long-term cognitive outcome in patients with enlarged ventricles and clinically suspected NPH. METHODS: A neurologist and a neurosurgeon clinically evaluated 468 patients with enlarged ventricles and suspected NPH using radiological methods, intraventricular pressure monitoring, and frontal cortical brain biopsy. The neurologist confirmed final diagnoses after a median follow-up interval of 4.8 years. RESULTS: Altogether, 232 patients (50%) with enlarged ventricles did not fulfill the criteria for shunt surgery. The incidence of dementia among patients with enlarged ventricles, and at least one NPH-related symptom with adequate follow-up data (n = 446) was high, varying from 77 (iNPH, shunt responders) to 141/1000 person-years (non-shunted patients with enlarged ventricles). At the end of the follow-up, 59% of all these patients were demented. The demented population comprised 73% of non-shunted patients with enlarged ventricles, 63% of shunted iNPH patients that did not respond to treatment, and 46% of iNPH patients that were initially responsive to shunting. The most common cause of dementia was Alzheimer's disease (n = 94, 36%), followed by vascular dementia (n = 68, 26%). CONCLUSIONS: One-half of patients with enlarged ventricles and clinically suspected NPH were not shunted after intraventricular pressure monitoring. Dementia caused by various neurodegenerative diseases was frequently seen in patients with ventricular enlargement. Thus, careful diagnostic evaluation in collaboration with neurologists and neurosurgeons is emphasized.

Higher Fasting Plasma Glucose Levels, within the Normal Range, are Associated with Decreased Processing Speed in High Functioning Young Elderly. - Raizes, Meytal; Elkana, Odelia; Franko, Motty; Ravona Springer, Ramit; Segev, Shlomo; Beeri, Michal Schnaider (J Alzheimers Dis, 2016)
We explored the association of plasma glucose levels within the normal range with processing speed in high functioning young elderly, free of type 2 diabetes mellitus (T2DM). A sample of 41 participants (mean age = 64.7, SD = 10; glucose 94.5 mg/dL, SD = 9.3), were examined with a computerized cognitive battery. Hierarchical linear regression analysis showed that higher plasma glucose levels, albeit within the normal range (<110 mg/dL), were associated with longer reaction times (p <  0.01). These findings suggest that even in the subclinical range and in the absence of T2DM, monitoring plasma glucose levels may have an impact on cognitive function.
Keywords: Aged; Blood Glucose; Cognition; Diabetes Mellitus, Type 2; Fasting; Female; Humans; Linear Models; Male; Middle Aged; Neuropsychological Tests; Psychomotor Performance; Reaction Time; Reference Values

High-Sodium Diet Has Opposing Effects on Mean Arterial Blood Pressure and Cerebral Perfusion in a Transgenic Mouse Model of Alzheimer's Disease. - Taheri, Saeid; Yu, Jin; Zhu, Hong; Kindy, Mark S (J Alzheimers Dis, 2016)
BACKGROUND: Cerebral ionic homeostasis impairment, especially Ca2+, has been observed in Alzheimer's disease (AD) and also with hypertension. Hypertension and AD both have been implicated in impaired cerebral autoregulation. However, the relationship between the ionic homeostasis impairment in AD and hypertension and cerebral blood flow (CBF) autoregulation is not clear. OBJECTIVE: To test the hypothesis that a high-salt diet regimen influences the accumulation of amyloid-β (Aβand CBF) and CBF, exacerbates cognitive decline, and increases the propensity to AD. METHODS: Double transgenic mice harboring the amyloid-β protein precursor (APPswe), and presenilin-1 (PSEN1) along with control littermates, 2 months of age at initiation of special diet, were divided into 4 groups: Group A, APP/PS1 and Group B, controls fed a high-sodium (4.00%) chow diet for 3 months; Group C, APP/PS1 and Group D, controls fed a low-sodium (0.08%) regular chow diet for 3 months. Mean arterial blood pressure (MAP) and CBF were measured noninvasively using the tail MAP measurement device and magnetic resonance imaging, respectively. Aβ plaques numbers in the cortex and hippocampus of APP/PS1 were quantified. RESULTS: In contrary to controls, APP/PS1 mice fed a high-salt diet did not show markedly elevated mean systolic and diastolic blood pressure (134±4.8 compared with 162±2.8 mmHg, and 114±5.0 compared with 137±20 mmHg, p< 0.0001). However, a high-salt diet increased CBF in both APP/PS1 and controls and did not alter the cerebral tissue integrity. Aβ plaques were significantly reduced in the cortex and hippocampus of mice fed a high-salt diet. CONCLUSION: These data suggest that a high-salt diet differently affects MAP and CBF in APP/PS1 mice and controls.

High-Throughput Screening for Identification of Blood-Brain Barrier Integrity Enhancers: A Drug Repurposing Opportunity to Rectify Vascular Amyloid Toxicity. - Qosa, Hisham; Mohamed, Loqman A; Al Rihani, Sweilem B; Batarseh, Yazan S; Duong, Quoc-Viet; Keller, Jeffrey N; Kaddoumi, Amal (J Alzheimers Dis, 2016)
The blood-brain barrier (BBB) is a dynamic interface that maintains brain homeostasis and protects it from free entry of chemicals, toxins, and drugs. The barrier function of the BBB is maintained mainly by capillary endothelial cells that physically separate brain from blood. Several neurological diseases, such as Alzheimer's disease (AD), are known to disrupt BBB integrity. In this study, a high-throughput screening (HTS) was developed to identify drugs that rectify/protect BBB integrity from vascular amyloid toxicity associated with AD progression. Assessing Lucifer Yellow permeation across in-vitro BBB model composed from mouse brain endothelial cells (bEnd3) grown on 96-well plate inserts was used to screen 1280 compounds of Sigma LOPAC®1280 library for modulators of bEnd3 monolayer integrity. HTS identified 62 compounds as disruptors, and 50 compounds as enhancers of the endothelial barrier integrity. From these 50 enhancers, 7 FDA approved drugs were identified with EC50 values ranging from 0.76-4.56 μM. Of these 7 drugs, 5 were able to protect bEnd3-based BBB model integrity against amyloid toxicity. Furthermore, to test the translational potential to humans, the 7 drugs were tested for their ability to rectify the disruptive effect of Aβ in the human endothelial cell line hCMEC/D3. Only 3 (etodolac, granisetron, and beclomethasone) out of the 5 effective drugs in the bEnd3-based BBB model demonstrated a promising effect to protect the hCMEC/D3-based BBB model integrity. These drugs are compelling candidates for repurposing as therapeutic agents that could rectify dysfunctional BBB associated with AD.

Hippocampal Lipid Homeostasis in APP/PS1 Mice is Modulated by a Complex Interplay Between Dietary DHA and Estrogens: Relevance for Alzheimer's Disease. - Díaz, Mario; Fabelo, Noemí; Casañas-Sánchez, Verónica; Marin, Raquel; Gómez, Tomás; Quinto-Alemany, David; Pérez, José A (J Alzheimers Dis, 2016)
Current evidence suggests that lipid homeostasis in the hippocampus is affected by different genetic, dietary, and hormonal factors, and that its deregulation may be associated with the onset and progression of Alzheimer's disease (AD). However, the precise levels of influence of each of these factors and their potential interactions remain largely unknown, particularly during neurodegenerative processes. In the present study, we have performed multifactorial analyses of the combined effects of diets containing different doses of docosahexaenoic acid (DHA), estrogen status (ovariectomized animals receiving vehicle or 17β-estradiol), and genotype (wild-type or transgenic APP/PS1 mice) in hippocampal lipid profiles. We have observed that the three factors affect lipid classes and fatty acid composition to different extents, and that strong interactions between these factors exist. The most aberrant lipid profiles were observed in APP/PS1 animals receiving DHA-poor diets and deprived of estrogens. Conversely, wild-type animals under a high-DHA diet and receiving estradiol exhibited a lipid profile that closely resembled that of the hippocampus of control animals. Interestingly, though the lipid signatures of APP/PS1 hippocampi markedly differed from wild-type, administration of a high-DHA diet in the presence of estrogens gave rise to a lipid profile that approached that of control animals. Paralleling changes in lipid composition, patterns of gene expression of enzymes involved in lipid biosynthesis were also altered and affected by combination of experimental factors. Overall, these results indicate that hippocampal lipid homeostasis is strongly affected by hormonal and dietary conditions, and that manipulation of these factors might be incorporated in AD therapeutics.
Keywords: Acyl Coenzyme A; Alzheimer Disease; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Disease Models, Animal; Docosahexaenoic Acids; Dose-Response Relationship, Drug; Estrogens; Gene Expression Regulation; Hippocampus; Homeostasis; Humans; Lipid Metabolism; Mice; Mice, Transgenic; Mutation; Presenilin-1; RNA, Messenger

Hippocampal Sclerosis of Aging, a Common Alzheimer's Disease 'Mimic': Risk Genotypes are Associated with Brain Atrophy Outside the Temporal Lobe. - Nho, Kwangsik; Saykin, Andrew J; Nelson, Peter T (J Alzheimers Dis, 2016)
Hippocampal sclerosis of aging (HS-Aging) is a common brain disease in older adults with a clinical course that is similar to Alzheimer's disease. Four single-nucleotide polymorphisms (SNPs) have previously shown association with HS-Aging. The present study investigated structural brain changes associated with these SNPs using surface-based analysis. Participants from the Alzheimer's Disease Neuroimaging Initiative cohort (ADNI; n = 1,239), with both MRI scans and genotype data, were used to assess the association between brain atrophy and previously identified HS-Aging risk SNPs in the following genes: GRN, TMEM106B, ABCC9, and KCNMB2 (minor allele frequency for each is >30%). A fifth SNP (near the ABCC9 gene) was evaluated in post-hoc analysis. The GRN risk SNP (rs5848_T) was associated with a pattern of atrophy in the dorsomedial frontal lobes bilaterally, remarkable since GRN is a risk factor for frontotemporal dementia. The ABCC9 risk SNP (rs704180_A) was associated with multifocal atrophy whereas a SNP (rs7488080_A) nearby (∼50 kb upstream) ABCC9 was associated with atrophy in the right entorhinal cortex. Neither TMEM106B (rs1990622_T), KCNMB2 (rs9637454_A), nor any of the non-risk alleles were associated with brain atrophy. When all four previously identified HS-Aging risk SNPs were summed into a polygenic risk score, there was a pattern of associated multifocal brain atrophy in a predominately frontal pattern. We conclude that common SNPs previously linked to HS-Aging pathology were associated with a distinct pattern of anterior cortical atrophy. Genetic variation associated with HS-Aging pathology may represent a non-Alzheimer's disease contribution to atrophy outside of the hippocampus in older adults.

A History of In Vivo Neutron Activation Analysis in Measurement of Aluminum in Human Subjects. - Mohseni, Hedieh K; Chettle, David R (J Alzheimers Dis, 2016)
Aluminum, as an abundant metal, has gained widespread use in human life, entering the body predominantly as an additive to various foods and drinking water. Other major sources of exposure to aluminum include medical, cosmetic, and occupational routes. As a common environmental toxin, with well-known roles in several medical conditions such as dialysis encephalopathy, aluminum is considered a potential candidate in the causality of Alzheimer's disease. Aluminum mostly accumulates in the bone, which makes bone an indicator of the body burden of aluminum and an ideal organ as a proxy for the brain. Most of the techniques developed for measuring aluminum include bone biopsy, which requires invasive measures, causing inconvenience for the patients. There has been a considerable effort in developing non-invasive approaches, which allow for monitoring aluminum levels for medical and occupational purposes in larger populations. In vivo neutron activation analysis, a method based on nuclear activation of isotopes of elements in the body and their subsequent detection, has proven to be an invaluable tool for this purpose. There are definite challenges in developing in vivo non-invasive techniques capable of detecting low levels of aluminum in healthy individuals and aluminum-exposed populations. The following review examines the method of in vivo neutron activation analysis in the context of aluminum measurement in humans focusing on different neutron sources, interference from other activation products, and the improvements made in minimum detectable limits and patient dose over the past few decades.
Keywords: Aluminum; Alzheimer Disease; Humans; Neutron Activation Analysis

Homocysteine and Alzheimer's Disease: Evidence for a Causal Link from Mendelian Randomization. - Hu, Qingting; Teng, Wenhui; Li, Jiajia; Hao, Fangfang; Wang, Naidong (J Alzheimers Dis, 2016)
BACKGROUND/OBJECTIVE: The relationship between plasma homocysteine (Hcy) levels and Alzheimer's disease (AD) has been studied for many years, but remains controversial. While a recent meta-analysis of epidemiological studies, which included observational studies, indicated that homocysteine may be a risk factor for AD, there remains a need to further demonstrate this link due to the large degree of heterogeneity between studies. Epidemiological studies have certain limitations, as their results can be affected by confounding factors and reverse causation. In this study, we evaluated the relationship between plasma homocysteine and AD by using a Mendelian randomization method to avoid problems of confounding bias and reverse causality. METHODS: We searched the PubMed and EMBASE databases for reports regarding the MTHFR C677T polymorphism (rs1801133) from the time of their inception to September 2015. These reports were combined with related observational studies, and used to evaluate the effect of MTHFR C677T (rs1801133) on the risk for AD. A recent meta-analysis of genome-wide association studies had previously suggested a relationship between homocysteine and MTHFR C677T (rs 1801133). RESULTS: Our met-analysis included 34 studies with 9397 subjects, and demonstrated a significant relationship between plasma total homocysteine levels and the risk for AD (OR = 3.37; 95% CI = 1.90-5.95; p = 2.9×10-5). CONCLUSION: Our meta-analysis demonstrated a causal link between plasma total homocysteine and the risk for AD, and provides a new insight into the etiology and prevention of AD.

Homocysteine, Infections, Polyamines, Oxidative Metabolism, and the Pathogenesis of Dementia and Atherosclerosis. - McCully, Kilmer S (J Alzheimers Dis, 2016)
Hyperhomocysteinemia is a risk factor for development of dementia and Alzheimer's disease (AD), and low blood levels of folate and cobalamin are associated with hyperhomocysteinemia and AD. In elderly subjects with cognitive decline, supplementation with folate, cobalamin, and pyridoxal demonstrated reduction of cerebral atrophy in gray matter regions vulnerable to the AD process. Multiple pathogenic microbes are implicated as pathogenic factors in AD and atherosclerosis, and the deposition of amyloid-β (Aβ), phosphorylation of tau protein, neuronal injury, and apoptosis in AD are secondary to microbial infection. Glucose utilization and blood flow are reduced in AD, and these changes are accompanied by downregulation of glucose transport, Na, K-ATPase, oxidative phosphorylation, and energy consumption. Thioretinaco ozonide, the complex formed from thioretinamide, cobalamin, ozone, and oxygen is proposed to constitute the active site of oxidative phosphorylation, catalyzing synthesis of adenosine triphosphate (ATP) from nicotinamide adenine dinucleotide (NAD+) and phosphate. Pathogenic microbes cause synthesis of polyamines in host cells by increasing the transfer of aminopropyl groups from adenosyl methionine to putrescine, resulting in depletion of intracellular adenosyl methionine concentrations in host cells. Depletion of adenosyl methionine causes dysregulation of methionine metabolism, hyperhomocysteinemia, reduced biosynthesis of thioretinamide and thioretinaco ozonide, decreased oxidative phosphorylation, decreased production of nitric oxide and peroxynitrite, and impaired host response to infectious microbes, contributing to the pathogenesis of dementia and atherosclerosis.

Homotaurine Effects on Hippocampal Volume Loss and Episodic Memory in Amnestic Mild Cognitive Impairment. - Spalletta, Gianfranco; Cravello, Luca; Gianni, Walter; Piras, Federica; Iorio, Mariangela; Cacciari, Claudia; Casini, Anna Rosa; Chiapponi, Chiara; Sancesario, Giuseppe; Fratangeli, Claudia; Orfei, Maria Donata; Caltagirone, Carlo; et al. (J Alzheimers Dis, 2016)
Homotaurine supplementation may have a positive effect on early Alzheimer's disease. Here, we investigated its potential neuroprotective effect on the hippocampus structure and episodic memory performances in amnestic mild cognitive impairment (aMCI). Neuropsychological, clinical, and neuroimaging assessment in 11 treated and 22 untreated patients were performed at baseline and after 1 year. Magnetic resonance data were analyzed using voxel-based morphometry to explore significant differences (Family Wise Error corrected) between the two groups over time. Patients treated with homotaurine showed decreased volume loss in the left and right hippocampal tail, left and right fusiform gyrus, and right inferior temporal cortex which was associated with improved short-term episodic memory performance as measured by the recency effect of the Rey 15-word list learning test immediate recall. Thus, homotaurine supplementation in individuals with aMCI has a positive effect on hippocampus atrophy and episodic memory loss. Future studies should further clarify the mechanisms of its effects on brain morphometry.
Keywords: Aged; Aged, 80 and over; Analysis of Variance; Chi-Square Distribution; Cognitive Dysfunction; Female; Hippocampus; Humans; Image Processing, Computer-Assisted; Longitudinal Studies; Magnetic Resonance Imaging; Male; Memory, Episodic; Mental Status Schedule; Middle Aged; Neuroprotective Agents; Neuropsychological Tests; Taurine

Human ApoE ɛ2 Promotes Regulatory Mechanisms of Bioenergetic and Synaptic Function in Female Brain: A Focus on V-type H+-ATPase. - Woody, Sarah K; Zhou, Helen; Ibrahimi, Shaher; Dong, Yafeng; Zhao, Liqin (J Alzheimers Dis, 2016)
Humans possess three major isoforms of the apolipoprotein E (ApoE) gene encoded by three alleles: ApoE ɛ2 (ApoE2), ApoE ɛ3 (ApoE3), and ApoE ɛ4 (ApoE4). It is established that the three ApoE isoforms confer differential susceptibility to Alzheimer's disease (AD); however, an in-depth molecular understanding of the underlying mechanisms is currently unavailable. In this study, we examined the cortical proteome differences among the three ApoE isoforms using 6-month-old female, human ApoE2, ApoE3, and ApoE4 gene-targeted replacement mice and two-dimensional proteomic analyses. The results reveal that the three ApoE brains differ primarily in two areas: cellular bioenergetics and synaptic transmission. Of particular significance, we show for the first time that the three ApoE brains differentially express a key component of the catalytic domain of the V-type H+-ATPase (Atp6v), a proton pump that mediates the concentration of neurotransmitters into synaptic vesicles and thus is crucial in synaptic transmission. Specifically, our data demonstrate that ApoE2 brain exhibits significantly higher levels of the B subunit of Atp6v (Atp6v1B2) when compared to both ApoE3 and ApoE4 brains, with ApoE4 brain exhibiting the lowest expression. Our additional analyses show that Atp6v1B2 is significantly impacted by aging and AD pathology and the data suggest that Atp6v1B2 deficiency could be involved in the progressive loss of synaptic integrity during early development of AD. Collectively, our findings indicate that human ApoE isoforms differentially modulate regulatory mechanisms of bioenergetic and synaptic function in female brain. A more efficient and robust status in both areas-in which Atp6v may play a role-could serve as a potential mechanism contributing to the neuroprotective and cognition-favoring properties associated with the ApoE2 genotype.

Human Truncated Tau Induces Mature Neurofibrillary Pathology in a Mouse Model of Human Tauopathy. - Zimova, Ivana; Brezovakova, Veronika; Hromadka, Tomas; Weisova, Petronela; Cubinkova, Veronika; Valachova, Bernadeta; Filipcik, Peter; Jadhav, Santosh; Smolek, Tomas; Novak, Michal; Zilka, Norbert (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) represents the most common neurodegenerative disorder. Several animal models have been developed in order to test pathophysiological mechanisms of the disease and to predict effects of pharmacological interventions. Here we examine the molecular and behavioral features of R3m/4 transgenic mice expressing human non-mutated truncated tau protein (3R tau, aa151-391) that were previously used for efficacy testing of passive tau vaccine. The mouse model reliably recapitulated crucial histopathological features of human AD, such as pre-tangles, neurofibrillary tangles, and neuropil threads. The pathology was predominantly located in the brain stem. Transgenic mice developed mature sarkosyl insoluble tau complexes consisting of mouse endogenous and human truncated and hyperphosphorylated forms of tau protein. The histopathological and biochemical features were accompanied by significant sensorimotor impairment and reduced lifespan. The sensorimotor impairment was monitored by a highly sensitive, fully-automated tool that allowed us to assess early deficit in gait and locomotion. We suggest that the novel transgenic mouse model can serve as a valuable tool for analysis of the therapeutic efficacy of tau vaccines for AD therapy.

Hyperactivity with Agitative-Like Behavior in a Mouse Tauopathy Model. - Jul, Pia; Volbracht, Christiane; de Jong, Inge E M; Helboe, Lone; Elvang, Anders Brandt; Pedersen, Jan Torleif (J Alzheimers Dis, 2016)
Tauopathies, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), are characterized by formation of neurofibrillary tangles consisting of hyperphosphorylated tau. In addition to memory loss, patients experience behavioral symptoms such as agitation, aggression, depression, and insomnia. We explored the behavioral phenotype of a mouse model (rTg4510) carrying the human tau P301L mutation found in a familial form of FTD. We tested these mice in locomotor activity assays as well as in the Morris water maze to access spatial memory. In addition to cognitive impairments, rTg4510 mice exhibited a hyperactivity phenotype which correlated with progression of tau pathology and was dependent on P301L tau transgene expression. The hyperactive phenotype was characterized by significantly increased locomotor activity in a novel and in a simulated home cage environment together with a disturbed day/night cycle. The P301L-tau-dependent hyperactivity and agitative-like phenotype suggests that these mice may form a correlate to some of the behavioral disturbances observed in advanced AD and FTD.
Keywords: Age Factors; Analysis of Variance; Animals; Brain; Cognition Disorders; Disease Models, Animal; Doxycycline; Exploratory Behavior; Humans; Hyperkinesis; Male; Maze Learning; Mice; Mice, Transgenic; Motor Activity; Mutation; Psychomotor Agitation; tau Proteins; Tauopathies; Time Factors

"I Don't Think Of It As An Illness": Illness Representations in Mild to Moderate Dementia. - Clare, Linda; Quinn, Catherine; Jones, Ian Rees; Woods, Robert T (J Alzheimers Dis, 2016)
The self-regulatory model proposes that illness representations influence adjustment and coping in chronic conditions. Better understanding of the illness representations held by people with dementia could help with targeting information and support so as to optimize adjustment and coping. In this mixed-methods study of illness representations among people with mild to moderate Alzheimer's, vascular, or mixed dementia we aimed to clarify the nature of the representations held, to determine whether specific profiles can be identified based on perceptions of the identity and cause of the condition, and to examine associations between these profiles and other participant characteristics. Data were collected in the second wave of the Memory Impairment and Dementia Awareness Study (MIDAS). Sixty-four people with dementia, who had been told their diagnosis at a memory clinic, completed interviews and responded to questionnaires. In each case a carer was also interviewed. Cluster analysis based on responses about identity and cause identified three profiles. 'Illness' cluster participants saw themselves as living with an illness and used diagnostic labels, 'ageing' cluster participants did not use diagnostic labels and viewed their difficulties as related to ageing, and 'no problem' cluster participants considered that they did not have any difficulties. 'Illness' cluster participants had better cognition and better awareness, but lower mood, and perceived more practical consequences, than 'ageing' cluster participants. Holding an 'illness' model may not be advantageous. Rather than encouraging adoption of such a model, it may be preferable to target information and select interventions in line with the person's representation profile.
Keywords: Adaptation, Psychological; Aged; Aged, 80 and over; Aging; Awareness; Caregivers; Dementia; Female; Follow-Up Studies; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Residence Characteristics; Self Concept; Statistics, Nonparametric; Surveys and Questionnaires

The Identification of Aluminum in Human Brain Tissue Using Lumogallion and Fluorescence Microscopy. - Mirza, Ambreen; King, Andrew; Troakes, Claire; Exley, Christopher (J Alzheimers Dis, 2016)
Aluminum in human brain tissue is implicated in the etiologies of neurodegenerative diseases including Alzheimer's disease. While methods for the accurate and precise measurement of aluminum in human brain tissue are widely acknowledged, the same cannot be said for the visualization of aluminum. Herein we have used transversely-heated graphite furnace atomic absorption spectrometry to measure aluminum in the brain of a donor with Alzheimer's disease, and we have developed and validated fluorescence microscopy and the fluor lumogallion to show the presence of aluminum in the same tissue. Aluminum is observed as characteristic orange fluorescence that is neither reproduced by other metals nor explained by autofluorescence. This new and relatively simple method to visualize aluminum in human brain tissue should enable more rigorous testing of the aluminum hypothesis of Alzheimer's disease (and other neurological conditions) in the future.

Identification of Physician-Diagnosed Alzheimer's Disease and Related Dementias in Population-Based Administrative Data: A Validation Study Using Family Physicians' Electronic Medical Records. - Jaakkimainen, R Liisa; Bronskill, Susan E; Tierney, Mary C; Herrmann, Nathan; Green, Diane; Young, Jacqueline; Ivers, Noah; Butt, Debra; Widdifield, Jessica; Tu, Karen (J Alzheimers Dis, 2016)
BACKGROUND: Population-based surveillance of Alzheimer's and related dementias (AD-RD) incidence and prevalence is important for chronic disease management and health system capacity planning. Algorithms based on health administrative data have been successfully developed for many chronic conditions. The increasing use of electronic medical records (EMRs) by family physicians (FPs) provides a novel reference standard by which to evaluate these algorithms as FPs are the first point of contact and providers of ongoing medical care for persons with AD-RD. OBJECTIVE: We used FP EMR data as the reference standard to evaluate the accuracy of population-based health administrative data in identifying older adults with AD-RD over time. METHODS: This retrospective chart abstraction study used a random sample of EMRs for 3,404 adults over 65 years of age from 83 community-based FPs in Ontario, Canada. AD-RD patients identified in the EMR were used as the reference standard against which algorithms identifying cases of AD-RD in administrative databases were compared. RESULTS: The highest performing algorithm was "one hospitalization code OR (three physician claims codes at least 30 days apart in a two year period) OR a prescription filled for an AD-RD specific medication" with sensitivity 79.3% (confidence interval (CI) 72.9-85.8%), specificity 99.1% (CI 98.8-99.4%), positive predictive value 80.4% (CI 74.0-86.8%), and negative predictive value 99.0% (CI 98.7-99.4%). This resulted in an age- and sex-adjusted incidence of 18.1 per 1,000 persons and adjusted prevalence of 72.0 per 1,000 persons in 2010/11. CONCLUSION: Algorithms developed from health administrative data are sensitive and specific for identifying older adults with AD-RD.

Immunization Against Specific Fragments of Neurotrophin p75 Receptor Protects Forebrain Cholinergic Neurons in the Olfactory Bulbectomized Mice. - Bobkova, Natalia; Vorobyov, Vasily; Medvinskaya, Natalia; Nesterova, Inna; Tatarnikova, Olga; Nekrasov, Pavel; Samokhin, Alexander; Deev, Alexander; Sengpiel, Frank; Koroev, Dmitry; Volpina, Olga (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is characterized by progressive cognitive impairment associated with marked cholinergic neuron loss and amyloid-β (Aβ) peptide accumulation in the brain. The cytotoxicity in AD is mediated, at least in part, by Aβ binding with the extracellular domain of the p75 neurotrophin receptor (p75NTR), localized predominantly in the membranes of acetylcholine-producing neurons in the basal forebrain. Hypothesizing that an open unstructured loop of p75NTR might be the effective site for Aβ binding, we have immunized both olfactory bulbectomized (OBX) and sham-operated (SO) mice (n = 82 and 49, respectively) with synthetic peptides, structurally similar to different parts of the loops, aiming to block them by specific antibodies. OBX-mice have been shown in previous studies, and confirmed in the present one, to be characterized by typical behavioral, morphological, and biochemical AD hallmarks, including cholinergic deficits in forebrain neurons. Immunization of OBX- or SO-mice with KLH conjugated fragments of p75NTR induced high titers of specific serum antibodies for each of nine chosen fragments. However, maximal protective effects on spatial memory, evaluated in a Morris water maze, and on activity of choline acetyltransferase in forebrain neurons, detected by immunoreactivity to specific antibodies, were revealed only for peptides with amino acid residue sequences of 155-164 and 167-176. We conclude that the approach based on immunological blockade of specific p75NTR sites, linked with the cytotoxicity, is a useful and effective tool for study of AD-associated mechanisms and for development of highly selective therapy of cholinergic malfunctioning in AD patients.

Immunization with Small Amyloid-β-derived Cyclopeptide Conjugates Diminishes Amyloid-β-Induced Neurodegeneration in Mice. - Mulder, Cornelis K; Dong, Yun; Brugghe, Humphrey F; Timmermans, Hans A M; Tilstra, Wichard; Westdijk, Janny; van Riet, Elly; van Steeg, Harry; Hoogerhout, Peter; Eisel, Ulrich L M (J Alzheimers Dis, 2016)
BACKGROUND: Soluble oligomeric (misfolded) species of amyloid-β (Aβ) are the main mediators of toxicity in Alzheimer's disease (AD). These oligomers subsequently form aggregates of insoluble fibrils that precipitate as extracellular and perivascular plaques in the brain. Active immunization against Aβ is a promising disease modifying strategy. However, eliciting an immune response against Aβ in general may interfere with its biological function and was shown to cause unwanted side-effects. Therefore, we have developed a novel experimental vaccine based on conformational neo-epitopes that are exposed in the misfolded oligomeric Aβ, inducing a specific antibody response. OBJECTIVE: Here we investigate the protective effects of the experimental vaccine against oligomeric Aβ1-42-induced neuronal fiber loss in vivo. METHODS: C57BL/6 mice were immunized or mock-immunized. Antibody responses were measured by enzyme-linked immunosorbent assay. Next, mice received a stereotactic injection of oligomeric Aβ1-42 into the nucleus basalis of Meynert (NBM) on one side of the brain (lesion side), and scrambled Aβ1-42 peptide in the contralateral NBM (control side). The densities of choline acetyltransferase-stained cholinergic fibers origination from the NBM were measured in the parietal neocortex postmortem. The percentage of fiber loss in the lesion side was determined relative to the control side of the brain. RESULTS: Immunized responders (79%) showed 23% less cholinergic fiber loss (p = 0.01) relative to mock-immunized mice. Moreover, fiber loss in immunized responders correlated negatively with the measured antibody responses (R2 = 0.29, p = 0.02). CONCLUSION: These results may provide a lead towards a (prophylactic) vaccine to prevent or at least attenuate (early onset) AD symptoms.

Impact of Depressive Symptoms on Conversion from Mild Cognitive Impairment Subtypes to Alzheimer's Disease: A Community-Based Longitudinal Study. - Kida, Jiro; Nemoto, Kiyotaka; Ikejima, Chiaki; Bun, Shogyoku; Kakuma, Tatsuyuki; Mizukami, Katsuyoshi; Asada, Takashi (J Alzheimers Dis, 2016)
BACKGROUND: While longitudinal studies have investigated the relationships between mild cognitive impairment (MCI) subtypes and dementia subtypes, the results have been contradictory. In addition, some research shows that depression accompanied by MCI might increase the risk of Alzheimer's disease (AD). OBJECTIVE: The aim of this study is to longitudinally investigate the relationships between MCI subtypes and dementia subtypes, with special attention to the effect of comorbid depressive symptoms in a Japanese rural community. METHODS: Non-demented participants (n = 802) completed a baseline and follow-up study. Outcomes were conversion to dementia especially AD, MCI, or no conversion. A complementary log-log analysis was conducted to investigate the risk of dementia and AD in amnestic MCI (aMCI) compared to nonamnestic MCI (naMCI) groups. The impact of depressive symptoms on the transition from MCI to AD and from cognitively normal to MCI or AD was also analyzed. RESULTS: The risk of developing dementia, in particular AD, for the aMCI group was significantly higher than that for the naMCI group. In the aMCI group, the presence of depressive symptoms increased the risk of developing AD, but depressive symptoms in the naMCI group did not. In the cognitively normal group, the presence of depressive symptoms increased the risk of aMCI but not naMCI or AD. CONCLUSION: MCI subtyping could be useful in finding a prodrome for dementia and in particular for AD. The differing impacts of depressive symptoms on the development of AD suggest that the relationship between depressive symptoms and cognitive impairment could differ in aMCI and naMCI patients.
Keywords: Activities of Daily Living; Aged; Alzheimer Disease; Cognitive Dysfunction; Depression; Disease Progression; Female; Follow-Up Studies; Humans; Longitudinal Studies; Male; Neuropsychological Tests; Prodromal Symptoms; Prognosis; Risk

Impact of Depressive Symptoms on Memory for Emotional Words in Mild Cognitive Impairment and Late-Life Depression. - Callahan, Brandy L; Simard, Martine; Mouiha, Abderazzak; Rousseau, François; Laforce, Robert; Hudon, Carol (J Alzheimers Dis, 2016)
BACKGROUND: Amnestic mild cognitive impairment (aMCI) and late-life depression (LLD) are associated with increased risk of Alzheimer's disease (AD). This is also true for aMCI with concomitant depressive symptoms (aMCI/D+), but few studies have investigated this syndrome. OBJECTIVES: We aimed to clarify the association between cognitive and depressive symptoms in individuals at risk for AD by examining episodic memory for emotional stimuli in aMCI, aMCI/D+, and LLD. METHODS: Participants were 34 patients with aMCI, 20 patients with aMCI/D+, 19 patients with LLD, and 28 healthy elderly adults. In an implicit encoding task, participants rated the emotional valence of 12 positive, 12 negative, and 12 neutral words. Immediately and 20 minutes later, participants recalled as many words as possible. They were also asked to identify previously presented words during a yes/no recognition trial. RESULTS: At immediate recall, aMCI participants displayed better recall of emotional words, particularly positive words. aMCI/D+ and control participants displayed better recall of positive and negative words compared to neutral words. LLD participants recalled more negative than neutral words. At delayed recall, emotional words were generally better-remembered than neutral words by all groups. At recognition, all subjects responded more liberally to emotional than to neutral words. CONCLUSION: We find that the type of emotional information remembered by aMCI patients at immediate recall depends on the presence or absence of depressive symptoms. These findings contribute to identifying sources of heterogeneity in individuals at risk for AD, and suggest that the cognitive profile of aMCI/D+ is different from that of aMCI and LLD. Future studies should systematically consider the presence of depressive symptoms in elderly at-risk individuals.

Impact of Omega-3 Fatty Acid Supplementation on Memory Functions in Healthy Older Adults. - Külzow, Nadine; Witte, A Veronica; Kerti, Lucia; Grittner, Ulrike; Schuchardt, Jan Philipp; Hahn, Andreas; Flöel, Agnes (J Alzheimers Dis, 2016)
As the process of Alzheimer's disease (AD) begins years before disease onset, searching for prevention strategies is of major medical and economic importance. Nutritional supplementation with long-chain polyunsaturated omega-3 fatty acids (LC-n3-FA) may exert beneficial effects on brain structure and function. However, experimental evidence in older adults without clinical dementia is inconsistent, possibly due to low sensitivity of previously employed test batteries for detecting subtle improvements in cognition in healthy individuals. Here we used LOCATO, recently described as a robust and sensitive tool for assessing object-location memory (OLM) in older adults, to evaluate the impact of LC-n3-FA supplementation on learning and memory formation. In a double-blind placebo-controlled proof-of-concept study, 44 (20 female) cognitively healthy individuals aged 50-75 years received either LC-n3-FA (2,200 mg/day, n = 22) or placebo (n = 22) for 26 weeks. Before and after intervention, memory performance in the OLM-task (primary) was tested. As secondary outcome parameters, performance in Rey Auditory Verbal Learning Test (AVLT), dietary habits, omega-3-index, and other blood-derived parameters were assessed. Omega-3 index increased significantly in the LC-n3-FA group compared with the placebo group. Moreover, recall of object locations was significantly better after LC-n3-FA supplementation compared with placebo. Performance in the AVLT was not significantly affected by LC-n3-FA. This double-blind placebo-controlled proof-of-concept study provides further experimental evidence that LC-n3-FA exert positive effects on memory functions in healthy older adults. Our findings suggest novel strategies to maintain cognitive functions into old age.
Keywords: Aged; Apolipoproteins E; Auditory Perception; Blood Chemical Analysis; Cognitive Aging; Dietary Supplements; Double-Blind Method; Fatty Acids, Omega-3; Feeding Behavior; Female; Humans; Learning; Male; Memory; Middle Aged; Neuropsychological Tests; Nootropic Agents; Treatment Outcome

Impacts of High Serum Total Cholesterol Level on Brain Functional Connectivity in Non-Demented Elderly. - Zhang, Ting; Li, He; Zhang, Junying; Li, Xin; Qi, Di; Wang, Nuo; Zhang, Zhanjun (J Alzheimers Dis, 2016)
Epidemiological and clinical studies suggest that high serum cholesterol is a risk factor of dementia. However, the effects of cholesterol on cognition and brain remain largely unclear. This study aims to investigate the associations between serum total cholesterol (TC) and neuropsychological performance, and intrinsic functional networks in non-demented elderly. Among a cohort of 120 community-dwelling Beijing residents, 29 subjects in the high-TC group (1st quartile) and 31 in the low-TC group (4th quartile) were included in this study, and underwent a battery of neuropsychological tests and magnetic resonance imaging (MRI) scans, including T2- and T1-weighted imaging, and resting-state functional MRI. No significant group difference was found in any of the neuropsychological tests used. Stronger connectivity in the default mode network was observed in the high-TC group compared to that in the low-TC group (p <  0.001, uncorrected). While in the salience network (SN), the high-TC group showed lower connectivity in the anterior cingulate cortex and frontal regions, compared to the low-TC group (p <  0.05, FWE corrected). Our findings suggest that in non-demented elderly persons, high serum cholesterol is associated with disruption of functional connectivity in the SN. The results not only deepen our understanding of how cholesterol affects the brain, but are also significant for selecting sensitive indicators for monitoring the impairments of cholesterol on the neural system.
Keywords: Aged; Brain; Brain Mapping; Cholesterol; Cognition; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Nerve Net; Neuropsychological Tests

Impacts of Illiteracy on the Risk of Dementia: A Global Health Perspective. - Suh, Seung Wan; Han, Ji Won; Park, Jae Young; Hong, Jong Woo; Kim, Kayoung; Kim, Taehyun; Lee, Kyoung Hwan; Han, Guehee; Jeong, Hyeon; Seo, Jiyeong; Kim, Tae Hui; Lee, Dong Young; et al. (J Alzheimers Dis, 2016)
Despite its significance as a contributing factor for late-life dementia risk, illiteracy is frequently underappreciated in the management of dementia. In this study, we estimated the proportion of dementia cases attributable to illiteracy using the population attributable fraction (PAF), and calculated to what extent the monetary cost of dementia could be saved in the future by reducing illiteracy from the South Korean, Latin American, South Asian/Middle Eastern, and African populations. We collected necessary data from the 2011 United Nations Human Development Report and prevalence studies conducted in these regions. Additional variables not included in the above sources were estimated using a logit model under a "trend scenario"-based assumption. Around 16% of the total number of dementia cases in South Korea in 2015 can be attributed to illiteracy, with this figure predicted to decline to around 2% by 2050. This translates to a saving in dementia care costs of approximately 52 billion USD, providing we are successful in theoretically eradicating illiteracy as of 2015, in the population aged 65 years or under. Likewise, reducing illiteracy to 50% in Latin America, South Asia/The Middle East, and Africa by 2050 could generate further cost savings of between 71 and 244 billion, 13 and 94 billion, and 17 and 78 billion USD, respectively. Even public policies aimed solely at reducing illiteracy in the childhood, adolescent, or middle-aged population could potentially have a role in the primary prevention of dementia. Moving forward, governments will need to address this issue in a purposeful and systematic manner.

Impaired Autophagy in APOE4 Astrocytes. - Simonovitch, Shira; Schmukler, Eran; Bespalko, Alina; Iram, Tal; Frenkel, Dan; Holtzman, David M; Masliah, Eliezer; Michaelson, Danny M; Pinkas-Kramarski, Ronit (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is the most prevalent form of dementia in elderly. Genetic studies revealed allelic segregation of the apolipoprotein E (ApoE) gene in sporadic AD and in families with higher risk of AD. The mechanisms underlying the pathological effects of ApoE4 are not yet entirely clear. Several studies indicate that autophagy, which plays an important role in degradation pathways of proteins, organelles and protein aggregates, may be impaired in AD. In the present study, we investigated the effects of ApoE4 versus the ApoE3 isoform on the process of autophagy in mouse-derived astrocytes. The results obtained reveal that under several autophagy-inducing conditions, astrocytes expressing ApoE4 exhibit lower autophagic flux compared to astrocytes expressing ApoE3. Using an in situ model, we examined the role of autophagy and the effects thereon of ApoE4 in the elimination of Aβ plaques from isolated brain sections of transgenic 5xFAD mice. This revealed that ApoE4 astrocytes eliminate Aβ plaques less effectively than the corresponding ApoE3 astrocytes. Additional experiments showed that the autophagy inducer, rapamycin, enhances Aβ plaque degradation by ApoE4 astrocytes whereas the autophagy inhibitor, chloroquine, blocks Aβ plaque degradation by ApoE3 astrocytes. Taken together, these findings show that ApoE4 impairs autophagy in astrocyte cultures and that this effect is associated with reduced capacity to clear Aβ plaques. This suggests that impaired autophagy may play a role in mediating the pathological effects of ApoE4 in AD.
Keywords: Amyloid beta-Peptides; Animals; Apolipoprotein E3; Apolipoprotein E4; Astrocytes; Autophagy; Brain; Cells, Cultured; Central Nervous System Agents; Chloroquine; Disease Models, Animal; Humans; Mice, Transgenic; Plaque, Amyloid; Sirolimus; Time Factors

Impaired Parahippocampus Connectivity in Mild Cognitive Impairment and Alzheimer's Disease. - Liu, Jieqiong; Zhang, Xinqing; Yu, Chunshui; Duan, Yunyun; Zhuo, Junjie; Cui, Yue; Liu, Bing; Li, Kuncheng; Jiang, Tianzi; Liu, Yong (J Alzheimers Dis, 2016)
BACKGROUND: The parahippocampal gyrus (PHG) is an important region of the limbic system that plays an important role in episodic memory. Elucidation of the PHG connectivity pattern will aid in the understanding of memory deficits in neurodegenerative diseases. OBJECTIVE: To investigate if disease severity associated altered PHG connectivity in Alzheimer's disease (AD) exists. METHODS: We evaluated resting-state functional magnetic resonance imaging data from 18 patients with amnestic mild cognitive impairment (MCI), 35 patients with AD, and 21 controls. The PHG connectivity pattern was examined by calculating Pearson's correlation coefficients between the bilateral PHG and whole brain. Group comparisons were performed after controlling for the effects of age and gender. The functional connectivity strength in each identified region was correlated with the MMSE score to evaluate the relationship between connectivity and cognitive ability. RESULTS: Several brain regions of the default mode network showed reduced PHG connectivity in the AD patients, and PHG connectivity was associated with disease severity in the MCI and AD subjects. More importantly, correlation analyses showed that there were positive correlations between the connectivity strengths of the left PHG-PCC/Pcu and left PHG-left MTG and the Mini-Mental State Examination, indicating that with disease progression from MCI to severe AD, damage to the functional connectivity of the PHG becomes increasingly severe. CONCLUSIONS: These results indicate that disease severity is associated with altered PHG connectivity, contributing to knowledge about the reduction in cognitive ability and impaired brain activity that occur in AD/MCI. These early changes in the functional connectivity of the PHG might provide some potential clues for identification of imaging markers for the early detection of MCI and AD.
Keywords: Aged; Alzheimer Disease; Apolipoproteins E; Brain Mapping; Cognitive Dysfunction; Female; Hippocampus; Humans; Limbic System; Magnetic Resonance Imaging; Male; Mental Status Schedule; Neural Pathways; Rest; Severity of Illness Index

Improved Neuroprotection Provided by Drug Combination in Neurons Exposed to Cell-Derived Soluble Amyloid-β Peptide. - Colin, Julie; Allouche, Ahmad; Chauveau, Fabien; Corbier, Catherine; Pauron-Gregory, Lynn; Lanhers, Marie-Claire; Claudepierre, Thomas; Yen, Frances T; Oster, Thierry; Malaplate-Armand, Catherine (J Alzheimers Dis, 2016)
Oligomeric amyloid-β (Aβ) peptide contributes to impaired synaptic connections and neurodegenerative processes, and as such, represents a primary therapeutic target for Alzheimer's disease (AD)-modifying approaches. However, the lack of efficacy of drugs that inhibit production of Aβ demonstrates the need for a better characterization of its toxic effects, both on synaptic and neuronal function. Here, we used conditioned medium obtained from recombinant HEK-AβPP cells expressing the human amyloid-β protein precursor (Aβ-CM), to investigate Aβ-induced neurotoxic and synaptotoxic effects. Characterization of Aβ-CM revealed that it contained picomolar amounts of cell-secreted Aβ in its soluble form. Incubation of primary cortical neurons with Aβ-CM led to significant decreases in synaptic protein levels as compared to controls. This effect was no longer observed in neurons incubated with conditioned medium obtained from HEK-AβPP cells grown in presence of the γ-secretase inhibitor, Semagacestat or LY450139 (LY-CM). However, neurotoxic and pro-apoptotic effects of Aβ-CM were only partially prevented using LY-CM, which could be explained by other deleterious compounds related to chronic oxidative stress that were released by HEK-AβPP cells. Indeed, full neuroprotection was observed in cells exposed to LY-CM by additional treatment with the antioxidant resveratrol, or with the pluripotent n-3 polyunsaturated fatty acid docosahexaenoic acid. Inhibition of Aβ production appeared necessary but insufficient to prevent neurodegenerative effects associated with AD due to other neurotoxic compounds that could exert additional deleterious effects on neuronal function and survival. Therefore, association of various types of protective agents needs to be considered when developing strategies for AD treatment.

Incidence and Duration of Cumulative Bisphosphonate Use among Community-Dwelling Persons with or without Alzheimer's Disease. - Tiihonen, Miia; Taipale, Heidi; Tanskanen, Antti; Tiihonen, Jari; Hartikainen, Sirpa (J Alzheimers Dis, 2016)
We studied the incidence and duration of cumulative bisphosphonate use among older Finnish women and men with or without Alzheimer's disease (AD). The MEDALZ-2005 cohort is a nationwide sample of all persons with clinically diagnosed AD on 31 December 2005 and their age-, gender-, and region of residence-matched control persons without AD. Information on bisphosphonate use by persons with an AD diagnosis and their controls without AD during 2002-2009 was obtained from the prescription register database containing reimbursed medications. A total of 6,041 (11.8%) persons used bisphosphonates during the 8-year follow-up. Bisphosphonates were more commonly used among persons without AD (n = 3121, 12.3%) than among persons with AD (n = 2,920, 11.2%) (p = 0.001). The median duration of bisphosphonate use was 743 days (IQR). Among persons with AD, the median duration of use was 777 days (IQR) and among persons without AD, 701 days (IQR) (p = 0.011). People without AD more often used bisphosphonate combination preparations including vitamin D than did people with AD (p <  0.0001). Bisphosphonate use was more common among people without AD who had comorbidities, asthma/COPD, or rheumatoid arthritis compared with users with AD. Short-term users were more likely to be male, at least 80 years old, and not having AD. Although the incidence of bisphosphonate use was slightly higher among persons without AD, the cumulative duration of bisphosphonate use was longer in persons with AD. Short-term use was associated with male gender, older age, and not having AD.

The Incidence of Benzodiazepine and Related Drug Use in Persons with and without Alzheimer's Disease. - Saarelainen, Laura; Taipale, Heidi; Koponen, Marjaana; Tanskanen, Antti; Tolppanen, Anna-Maija; Tiihonen, Jari; Hartikainen, Sirpa (J Alzheimers Dis, 2016)
BACKGROUND: Benzodiazepines and related drugs (BZDR) are occasionally used to treat certain symptoms of Alzheimer's disease (AD). However, the risks related to BZDR use are high in older persons. Although frequent BZDR use has been reported in persons with AD, no previous study has focused specifically on the incidence of BZDR use in this population. OBJECTIVE: We investigated the incidence of BZDR use in persons with and without AD during a five-year follow-up. METHODS: The Finnish nationwide, register-based MEDALZ cohort includes all AD cases who received a clinically verified AD diagnosis in 2005-2011 (n = 70,718) and their matched comparison persons. Incidence of BZDR, including benzodiazepines (lorazepam, oxazepam, temazepam, alprazolam, chlordiazepoxide, diazepam, and nitrazepam) and Z-drugs (zolpidem and zopiclone), use was investigated in the cohort from two years before to three years after the diagnosis of AD. Further, initial BZDRs were investigated. RESULTS: The incidence of BZDR use was higher in persons with AD starting from 12 months before the diagnosis and peaked at six months after the diagnosis of AD (incidence rate ratio [IRR] = 2.6, 95% confidence interval [CI] = 2.5-2.8). Benzodiazepines were more frequently initiated by persons with AD, with the incidence peaking at six months after the diagnosis (IRR = 4.5, 95% CI = 4.1-4.9) and remaining over three times higher than in comparison persons until three years after the diagnosis. CONCLUSION: Early symptomatic treatment with BZDRs is contrary to AD treatment guidelines. As BZDRs impair cognition, the observed early treatment with BZDRs may complicate the monitoring of AD treatment effectiveness.
Keywords: Adult; Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Antipsychotic Agents; Benzodiazepines; Cohort Studies; Female; Finland; Humans; Incidence; Male; Middle Aged; Substance-Related Disorders

Increase of α-Secretase ADAM10 in Platelets Along Cognitively Healthy Aging. - Schuck, Florian; Wolf, Dominik; Fellgiebel, Andreas; Endres, Kristina (J Alzheimers Dis, 2016)
ADAM10 is one of the key players in ectodomain-shedding of the amyloid-β protein precursor (AβPP). Previous research with postmortem tissue has shown reduced expression and activity of ADAM10 within the central nervous system (CNS) of Alzheimer's disease (AD) patients. Determination of cerebral ADAM10 in living humans is hampered by its transmembrane property; only the physiological AβPP cleavage product generated by ADAM10, sAβPPα, can be assessed in cerebrospinal fluid. Establishment of surrogate markers in easily accessible material therefore is crucial. It has been demonstrated that ADAM10 is expressed in platelets and that platelet amount is decreased in AD patients. Just recently it has been shown that platelet ADAM10 and cognitive performance of AD patients positively correlate. In contrast to AD patients, to our knowledge almost no information has been published regarding ADAM10 expression during normal aging. We investigated ADAM10 amount and activity in platelets of cognitively healthy individuals from three different age groups ranging from 22-85 years. Interestingly, we observed an age-dependent increase in ADAM10 levels and activity in platelets.
Keywords: ADAM Proteins; ADAM10 Protein; Adult; Age Factors; Aged; Aged, 80 and over; Aging; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Analysis of Variance; Apolipoprotein E4; Cognition; Female; Healthy Volunteers; Humans; Integrin beta3; Male; Membrane Proteins; Middle Aged; Neuropsychological Tests; Young Adult

Increased Electron Paramagnetic Resonance Signal Correlates with Mitochondrial Dysfunction and Oxidative Stress in an Alzheimer's disease Mouse Brain. - Fang, Du; Zhang, Zhihua; Li, Hang; Yu, Qing; Douglas, Justin T; Bratasz, Anna; Kuppusamy, Periannan; Yan, Shirley ShiDu (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized clinically by cognitive decline and memory loss. The pathological features are amyloid-β peptide (Aβ) plaques and intracellular neurofibrillary tangles. Many studies have suggested that oxidative damage induced by reactive oxygen species (ROS) is an important mechanism for AD progression. Our recent study demonstrated that oxidative stress could further impair mitochondrial function. In the present study, we adopted a transgenic mouse model of AD (mAPP, overexpressing AβPP/Aβ in neurons) and performed redox measurements using in vivo electron paramagnetic resonance (EPR) imaging with methoxycarbamyl-proxyl (MCP) as a redox-sensitive probe for studying oxidative stress in an early stage of pathology in a transgenic AD mouse model. Through assessing oxidative stress, mitochondrial function and cognitive behaviors of mAPP mice at the age of 8-9 months, we found that oxidative stress and mitochondrial dysfunction appeared in the early onset of AD. Increased ROS levels were associated with defects of mitochondrial and cognitive dysfunction. Notably, the in vivo EPR method offers a unique way of assessing tissue oxidative stress in living animals under noninvasive conditions, and thus holds a potential for early diagnosis and monitoring the progression of AD.
Keywords: Adenosine Triphosphate; Age of Onset; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Brain; Cognition; Disease Models, Animal; Electron Spin Resonance Spectroscopy; Electron Transport Complex IV; Female; Humans; Male; Maze Learning; Mice, Transgenic; Mitochondria; Oxidative Stress; Reactive Oxygen Species; Spatial Memory

Increased Expression of Readthrough Acetylcholinesterase Variants in the Brains of Alzheimer's Disease Patients. - Campanari, Maria-Letizia; Navarrete, Francisco; Ginsberg, Stephen D; Manzanares, Jorge; Sáez-Valero, Javier; García-Ayllón, María-Salud (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is characterized by a decrease in the enzymatic activity of the enzyme acetylcholinesterase (AChE). AChE is expressed as multiple splice variants, which may serve both cholinergic degradative functions and non-cholinergic functions unrelated with their capacity to hydrolyze acetylcholine. We have recently demonstrated that a prominent pool of enzymatically inactive AChE protein exists in the AD brain. In this study, we analyzed protein and transcript levels of individual AChE variants in human frontal cortex from AD patients by western blot analysis using specific anti-AChE antibodies and by quantitative real-time PCR (qRT-PCR). We found similar protein and mRNA levels of the major cholinergic "tailed"-variant (AChE-T) and the anchoring subunit, proline-rich membrane anchor (PRiMA-1) in frontal cortex obtained from AD patients and non-demented controls. Interestingly, we found an increase in the protein and transcript levels of the non-cholinergic "readthrough" AChE (AChE-R) variants in AD patients compared to controls. Similar increases were detected by western blot using an antibody raised against the specific N-terminal domain, exclusive of alternative N-extended variants of AChE (N-AChE). In accordance with a subset of AChE-R monomers that display amphiphilic properties that are upregulated in the AD brain, we demonstrate that the increase of N-AChE species is due, at least in part, to N-AChE-R variants. In conclusion, we demonstrate selective alterations in specific AChE variants in AD cortex, with no correlation in enzymatic activity. Therefore, differential expression of AChE variants in AD may reflect changes in the pathophysiological role of AChE, independent of cholinergic impairment or its role in degrading acetylcholine.

Increased Intrinsic Activity of Medial-Temporal Lobe Subregions is Associated with Decreased Cortical Thickness of Medial-Parietal Areas in Patients with Alzheimer's Disease Dementia. - Pasquini, Lorenzo; Scherr, Martin; Tahmasian, Masoud; Myers, Nicholas E; Ortner, Marion; Kurz, Alexander; Förstl, Hans; Zimmer, Claus; Grimmer, Timo; Akhrif, Atae; Wohlschläger, Afra M; Riedl, Valentin; et al. (J Alzheimers Dis, 2016)
In Alzheimer's disease (AD), disrupted connectivity between medial-parietal cortices and medial-temporal lobes (MTL) is linked with increased MTL local functional connectivity, and parietal atrophy is associated with increased MTL memory activation. We hypothesized that intrinsic activity in MTL subregions is increased and associated with medial-parietal degeneration and impaired memory in AD. To test this hypothesis, resting-state-functional and structural-MRI was assessed in 22 healthy controls, 22 mild cognitive impairment patients, and 21 AD-dementia patients. Intrinsic activity was measured by power-spectrum density of blood-oxygenation-level-dependent signal, medial-parietal degeneration by cortical thinning. In AD-dementia patients, intrinsic activity was increased for several right MTL subregions. Raised intrinsic activity in dentate gyrus and cornu ammonis 1 was associated with cortical thinning in posterior cingulate cortices, and at-trend with impaired delayed recall. Critically, increased intrinsic activity in the right entorhinal cortex was associated with ipsilateral posterior cingulate degeneration. Our results provide evidence that in AD, intrinsic activity in MTL subregions is increased and associated with medial-parietal atrophy. Results fit a model in which medial-parietal degeneration contributes to MTL dysconnectivity from medial-parietal cortices, potentially underpinning disinhibition-like changes in MTL activity.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Cognitive Dysfunction; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Memory Disorders; Middle Aged; Nerve Net; Parietal Lobe; Temporal Lobe

Increased Levels of Extracellular Microvesicle Markers and Decreased Levels of Endocytic/Exocytic Proteins in the Alzheimer's Disease Brain. - Musunuri, Sravani; Khoonsari, Payam Emami; Mikus, Maria; Wetterhall, Magnus; Häggmark-Mänberg, Anna; Lannfelt, Lars; Erlandsson, Anna; Bergquist, Jonas; Ingelsson, Martin; Shevchenko, Ganna; Nilsson, Peter; Kultima, Kim (J Alzheimers Dis, 2016)
BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disorder accounting for more than 50% of all dementia cases. AD neuropathology is characterized by the formation of extracellular plaques and intracellular neurofibrillary tangles consisting of aggregated amyloid-β and tau, respectively. The disease mechanism has only been partially elucidated and is believed to also involve many other proteins. OBJECTIVE: This study intended to perform a proteomic profiling of post mortem AD brains and compare it with control brains as well as brains from other neurological diseases to gain insight into the disease pathology. METHODS: Here we used label-free shotgun mass spectrometry to analyze temporal neocortex samples from AD, other neurological disorders, and non-demented controls, in order to identify additional proteins that are altered in AD. The mass spectrometry results were verified by antibody suspension bead arrays. RESULTS: We found 50 proteins with altered levels between AD and control brains. The majority of these proteins were found at lower levels in AD. Pathway analyses revealed that several of the decreased proteins play a role in exocytic and endocytic pathways, whereas several of the increased proteins are related to extracellular vesicles. Using antibody-based analysis, we verified the mass spectrometry results for five representative proteins from this group of proteins (CD9, HSP72, PI42A, TALDO, and VAMP2) and GFAP, a marker for neuroinflammation. CONCLUSIONS: Several proteins involved in exo-endocytic pathways and extracellular vesicle functions display altered levels in the AD brain. We hypothesize that such changes may result in disturbed cellular clearance and a perturbed cell-to-cell communication that may contribute to neuronal dysfunction and cell death in AD.

Increased Total Homocysteine Levels Predict the Risk of Incident Dementia Independent of Cerebral Small-Vessel Diseases and Vascular Risk Factors. - Miwa, Kaori; Tanaka, Makiko; Okazaki, Shuhei; Yagita, Yoshiki; Sakaguchi, Manabu; Mochizuki, Hideki; Kitagawa, Kazuo (J Alzheimers Dis, 2016)
BACKGROUND: Homocysteine has been identified as a potential risk factor for stroke, cerebral small-vessel diseases (SVD), and dementia. OBJECTIVE: The present study aimed to investigate the predictive value of homocysteine levels on incident dementia while simultaneously controlling for MRI findings and vascular risk factors. METHODS: Within a Japanese cohort of participants with vascular risk factors in an observational study, we evaluated the association between baseline total homocysteine (tHcy) levels (per 1 μmol/L and the tertile of tHcy), the prevalence of MRI-findings at baseline, and incident all-cause dementia. Baseline brain MRI was used to determine SVD (lacunas, white matter hyperintensities, and cerebral microbleeds [CMBs]) and atrophy (medial-temporal lobe atrophy and bicaudate ratio). Logistic regression analyses were used to estimate the cross-sectional association between tHcy and each of MRI findings. Cox proportional hazards analyses were performed to estimate the longitudinal association between tHcy and dementia. RESULTS: In the 643 subjects (age: 67.2 ± 8.4 years, male: 59% ; education: 12.9 ± 2.6 years), multivariable analyses adjusted for several potential confounders, including estimated glomerular filtration rate (eGFR) and intima-media thickness, showed that highest tHcy tertile was associated with lacunas, CMBs, and strictly deep CMBs. During the mean 7.3-year follow-up (range: 2-13), 47 patients were diagnosed with dementia (Alzheimer's disease: 24; vascular dementia: 18; mixed-type: 3; other: 2). After adjusting for age, gender, APOE ɛ4, education, BMI, MMSE, hypertension, cerebrovascular events, eGFR, and MRI-findings, tHcy level (hazard ratios [HR]: 1.08, p = 0.043) and the highest tertile of tHcy (HR: 2.50, p = 0.047) for all-cause dementia remained significant. CONCLUSIONS: Our results provide additional evidence of tHcy that contributes to increased susceptibility to dementia risk.
Keywords: Aged; Carotid Intima-Media Thickness; Cerebral Small Vessel Diseases; Dementia; Female; Homocysteine; Humans; Incidence; Longitudinal Studies; Magnetic Resonance Imaging; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Predictive Value of Tests; Proportional Hazards Models; Risk Factors; Statistics, Nonparametric

Inequalities in Access to Treatment and Care for Patients with Dementia and Immigrant Background: A Danish Nationwide Study. - Stevnsborg, Lea; Jensen-Dahm, Christina; Nielsen, Thomas R; Gasse, Christiane; Waldemar, Gunhild (J Alzheimers Dis, 2016)
BACKGROUND: Previous studies demonstrated lower quality diagnostic assessment of dementia in immigrant populations, but knowledge about the quality of treatment and care for dementia is still lacking. OBJECTIVE: To conduct a nationwide registry-based study to determine whether inequality exists regarding access to anti-dementia treatment and care between immigrant and Danish-born patients with dementia. METHODS: A cross-sectional register-based study was conducted in the entire elderly (60≥years) population with dementia in Denmark in 2012 (n = 34,877). The use of anti-dementia drugs and residency in a nursing home were compared among Danish-born and Western and non-Western immigrants with dementia. Logistic regression analysis was done with adjustment for age, sex, comorbidity, marital status, basis of inclusion, and time since dementia diagnosis. RESULTS: Immigrant background was associated with a significantly lower likelihood of receiving anti-dementia drug therapy (odds ratio (OR) [95% confidence interval (CI)]): non-Western = 0.70 [0.56-0.87]; Western = 0.74 [0.63-0.87]). No significant differences were found in type or amount of anti-dementia medication dispensed between the population groups (proxy measure for adherence). Non-Western immigrants were significantly less likely to live in a nursing home (0.52 [0.41-0.65]). CONCLUSION: This nationwide registry-based study indicated a worrisome difference in access to anti-dementia treatment and care for dementia patients with an immigrant background, but similar levels of adherence compared with the Danish-born population. Further research is necessary to pinpoint barriers to access to suitable healthcare among elderly immigrants with dementia but also to identify and develop culturally sensitive methods for their treatment and care.

Inflammasome Involvement in Alzheimer's Disease. - Olsen, Ingar; Singhrao, Sim K (J Alzheimers Dis, 2016)
Inflammasomes are responsible for the maturation of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-18, and IL-33 and activation of inflammatory cell death, pyroptosis. They assemble in response to cellular infection and stress or to tissue damage, promote inflammatory reactions, and are important in regulating innate immunity particularly by acting as platforms for activation of caspase proteases. They appear to be involved in several pathological processes activated by microbes including Alzheimer's disease (AD). Best characterized in microbial pathogenesis is the nucleotide-binding domain and leucine-rich repeat (NLR)-protein 3 (NLRP3) inflammasome. AD is a neurodegenerative condition in which the neuropathological hallmarks are the deposition of amyloid-β (Aβ) and hyperphosphorylated tau protein coated neurofibrillary tangles. For decades, the role of the innate immune system in the etiology of AD was considered less important, but the recently discovered inflammatory genes by genome-wide association studies driving inflammation in this disease has changed this view. Innate immune inflammatory activity in the AD brain can result from the pathological hallmark protein Aβ as well as from specific bacterial infections that tend to possess weak immunostimulatory responses for peripheral blood myeloid cell recruitment to the brain. The weak immunostimulatory activity is a consequence of their immune evasion strategies and survival. In this review we discuss the possibility that inflammasomes, particularly via the NLR family of proteins NLRP3 are involved in the pathogenesis of AD. In addition, we discuss the plausible contribution of specific bacteria playing a role in influencing the activity of the NLRP3 inflammasome to AD progression.

Inflammation, Antiinflammatory Agents, and Alzheimer's Disease: The Last 22 Years. - McGeer, Patrick L; Rogers, Joseph; McGeer, Edith G (J Alzheimers Dis, 2016)
Two basic discoveries spurred research into inflammation as a driving force in the pathogenesis of Alzheimer's disease (AD). The first was the identification of activated microglia in association with the lesions. The second was the discovery that rheumatoid arthritics, who regularly consume anti-inflammatory agents, were relatively spared from the disease. These findings led to an exploration of the inflammatory pathways that were involved in AD pathogenesis. A pivotal advance was the discovery that amyloid-β protein (Aβ) activated the complement system. This focused attention on anti-inflammatories as blockers of complement activation. More than 15 epidemiological studies have since showed a sparing effect of non-steroidal anti-inflammatory drugs (NSAIDs) in AD. A consistent finding has been that the longer the NSAIDs were used prior to clinical diagnosis, the greater the sparing effect. The reason has since emerged from studies of biomarkers such as amyloid-β (Aβ) levels in the cerebrospinal fluid and Aβ deposits in brain. They have established that the onset of AD commences at least a decade before cognitive decline permits clinical diagnosis. Such biomarker studies have revealed that a huge window of opportunity exists when application of NSAIDs, other anti-inflammatory agents, or complement activation blockers, could arrest further progress of AD, thus eliminating its manifestation. It can be anticipated that this principle will apply to many other chronic neurodegenerative diseases. Neuroinflammation, discovered in AD more than 30 years ago, has now become a major field of brain research today. Inhibiting it may be the key to successful treatment of many chronic neurological disorders.

Influence of Incipient Dementia on Hospitalization for Primary Care Sensitive Conditions: A Population-Based Cohort Study. - Pimouguet, Clément; Rizzuto, Debora; Fastbom, Johan; Lagergren, Mårten; Fratiglioni, Laura; Xu, Weili (J Alzheimers Dis, 2016)
BACKGROUND: Studies have reported that moderate/severe stages of dementia are linked to increased hospitalization rates, but little is known about the influence of incipient dementia on hospitalizations for primary care sensitive conditions (PCSCs). OBJECTIVE: To examine the associations between incipient dementia and hospitalization outcomes, including all-cause and PCSC hospitalization. METHODS: A total of 2,268 dementia-free participants in the Swedish National study on Aging and Care-Kungsholmen were interviewed and clinically examined at baseline. Participants aged ≥78 years were followed for 3 years, and those aged 60-72 years, for 6 years. Number of hospitalizations was retrieved from the National Patient Register. Dementia was diagnosed in accordance with Diagnostic and Statistical Manual of Mental Disorders-IV criteria. Hospitalization outcomes were compared in participants who did and did not develop dementia. Zero-inflated Poisson regressions and logistic regressions were used in data analysis. RESULTS: During the follow-up, 175 participants developed dementia. The unadjusted PCSC admission rate was 88.2 per 1000 person-years in those who developed dementia and 25.6 per 1000 person-years in those who did not. In the fully adjusted logistic regression model, incipient dementia was associated with an increased risk of hospitalization for PCSCs (OR = 2.3, 95% CI 1.3-3.9) but not with the number of hospitalizations or with all-cause hospitalization. Risks for hospitalization for diabetes, congestive heart failure, and pyelonephritis were higher in those who developed dementia than in those who did not. About 10% participants had a PCSC hospitalization attributable to incipient dementia. CONCLUSION: People with incipient dementia are more prone to hospitalization for PCSCs but not to all-cause hospitalization.
Keywords: Acute Disease; Age Factors; Aged; Aged, 80 and over; Chronic Disease; Dementia; Female; Follow-Up Studies; Hospitalization; Humans; Logistic Models; Longitudinal Studies; Male; Primary Health Care; Registries; Risk; Sensitivity and Specificity; Socioeconomic Factors; Sweden

Influence of Low-Dose Aspirin on Cerebral Amyloid Angiopathy in Mice. - Hattori, Yorito; Maki, Takakuni; Saito, Satoshi; Yamamoto, Yumi; Nagatsuka, Kazuyuki; Ihara, Masafumi (J Alzheimers Dis, 2016)
Accumulation of amyloid-β peptide (Aβ) in the brain is one of the most important features of Alzheimer's dementia (AD). Cerebral amyloid angiopathy (CAA) is characterized by Aβ accumulation in the walls of cerebral arteries and capillaries, and is present in over 90% of patients with AD. Several novel agents for AD/CAA developed around the amyloid hypothesis have shown positive signs in animal studies but have failed in clinical trials due to adverse events and/or lack of efficiency. As CAA is presumably caused by a failure in Aβ clearance, drugs that promote Aβ clearance may hold promise in the treatment of CAA and possibly AD. With this in mind, cilostazol, an anti-platelet drug with vasodilating action, has been found to promote Aβ clearance along perivascular drainage pathway, reduce Aβ accumulation in the brain, and restore memory impairment in Tg-SwDI mice, an animal model of CAA. We therefore tested whether the most common anti-platelet agent, aspirin, also reduced Aβ and rescued cognitive impairment in Tg-SwDI mice, and also whether aspirin affected hemorrhagic complications that can occur in Tg-SwDI mice. Mice aged 4 months were assigned into vehicle-treated and low-dose aspirin-treated groups. Low-dose aspirin for 8 months did not increase hemorrhagic lesions, nor increase resting cerebral blood flow or cerebral vascular reserve in response to hypercapnia or acetylcholine. Subsequently, aspirin did not restore cognitive dysfunction. These results suggest that low-dose aspirin does not have a direct influence on cerebrovascular Aβ metabolism nor aggravate hemorrhagic complications in CAA.

Inhibition of Cholesterol Biosynthesis Reduces γ-Secretase Activity and Amyloid-β Generation. - Kim, Yoonhee; Kim, Chaeyoung; Jang, Hye Young; Mook-Jung, Inhee (J Alzheimers Dis, 2016)
Amyloid-β (Aβ) is one of major molecules contributing to the pathogenesis of Alzheimer's disease (AD). Aβ is derived from amyloid-β protein precursor (AβPP) through sequential cleavages by β- and γ-secretases. Regulation of these components is thought to be an important factor in Aβ generation during the pathogenesis of AD. AβPP, β-secretase, and γ-secretase reside in lipid rafts, where cholesterol regulates the integrity and flexibility of membrane proteins and Aβ is generated. However, the relationship between cholesterol and Aβ generation is controversial. In this study, we aimed to elucidate the direct effects of cholesterol depletion on AβPP processing using AY9944, which blocks the last step of cholesterol biosynthesis and thus minimizes the unknown side effects of upstream inhibitors, such as HMG-CoA reductase inhibitors. Treatment with AY9944 decreased γ-secretase activity and Aβ generation. These results suggested that changes in membrane composition by lowering cholesterol with AY9944 affected γ-secretase activity and Aβ generation, which is associated with AD pathogenesis.
Keywords: Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Analysis of Variance; Animals; Anticholesteremic Agents; Cell Line; Cholesterol; Cricetinae; Down-Regulation; Humans; In Situ Nick-End Labeling; Luminescent Proteins; Membrane Glycoproteins; Membrane Microdomains; Mutation; Presenilin-1; Protein Transport; trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride; Transfection

Inhibition of Histone Deacetylase 3 Restores Amyloid-β Oligomer-Induced Plasticity Deficit in Hippocampal CA1 Pyramidal Neurons. - Krishna, Kumar; Behnisch, Thomas; Sajikumar, Sreedharan (J Alzheimers Dis, 2016)
Neurodegenerative diseases such as Alzheimer's disease (AD) are associated with alterations in epigenetic factors leading to cognitive decline. Histone deacetylase 3 (HDAC3) is a known critical epigenetic negative regulator of learning and memory. In this study, attenuation of long-term potentiation by amyloid-β oligomer, and its reversal by specific HDAC3 inhibitor RGFP966, was performed in rat CA1 pyramidal neurons using whole cell voltage-clamp and field recording techniques. Our findings provide the first evidence that amyloid-β oligomer-induced synaptic plasticity impairment can be prevented by inhibition of HDAC3 enzyme both at the single neuron as well as in a population of neurons, thus identifying HDAC3 as a potential target for ameliorating AD related plasticity impairments.
Keywords: Acrylamides; Alzheimer Disease; Amyloid beta-Peptides; Animals; Excitatory Postsynaptic Potentials; Hippocampus; Histone Deacetylase Inhibitors; Histone Deacetylases; Long-Term Potentiation; Male; Patch-Clamp Techniques; Peptide Fragments; Phenylenediamines; Pyramidal Cells; Rats, Wistar; Tissue Culture Techniques

Insight into the Dissociation of Behavior from Histology in Synucleinopathies and in Related Neurodegenerative Diseases. - Sekiyama, Kazunari; Takamatsu, Yoshiki; Koike, Wakako; Waragai, Masaaki; Takenouchi, Takato; Sugama, Shuei; Hashimoto, Makoto (J Alzheimers Dis, 2016)
Recent clinical trials using immunization approaches against Alzheimer's disease (AD) have failed to demonstrate improved cognitive functions in patients, despite potent suppression in the formation of both senile plaques and other amyloid-β deposits in postmortem brains. Similarly, we observed that treatment with ibuprofen, a non-steroidal anti-inflammatory drug, was effective in improving the histopathology, such as reducing both protein aggregation and glial activation, in the brains of transgenic mice expressing dementia with Lewy bodies-linked P123H β-synuclein. In contrast, only a small improvement in cognitive functions was observed in these mice. Collectively, it is predicted that histology does not correlate with behavior that is resilient and resistant to therapeutic stimuli. Notably, such a 'discrepancy between histology and behavior' is reminiscent of AD-like pathologies and incidental Lewy bodies, which are frequently encountered in postmortem brains of the elderly who had been asymptomatic for memory loss and Parkinsonism during their lives. We suggest that 'the discrepancy between histology and behavior' may be a universal feature that is associated with various aspects of neurodegenerative diseases. Furthermore, given that the cognitive reserve is specifically observed in human brains, human behavior may be evolutionally distinct from that in other animals, thus, contributing to the differential efficiency of therapy between human and lower animals, an important issue in the therapy of neurodegenerative diseases. Overall, it is important to better understand 'the discrepancy between histology and behavior' in the mechanism of neurodegeneration for the development of effective therapies against neurodegenerative diseases.

The Instrumental Activity of Daily Living Profile in Aging: A Feasibility Study. - Bier, Nathalie; Belchior, Patricia da Cunha; Paquette, Guillaume; Beauchemin, Émilie; Lacasse-Champagne, Ariane; Messier, Chantal; Pellerin, Marie-Line; Petit, Marisol; Mioshi, Eneida; Bottari, Carolina (J Alzheimers Dis, 2016)
BACKGROUND: Dysfunctions in complex activities of daily living (ADLs) are a normal part of the aging process. However, differentiating functional decline associated with healthy aging from the subtle decline experienced by individuals with mild cognitive impairment and early dementia constitutes a challenge. Finding an appropriate tool that can capture these subtle but important functional changes represents a priority. OBJECTIVES: The aims of this study were to evaluate the feasibility of using the Instrumental Activities of Daily Living Profile (IADL Profile) with elderly participants and to describe their level of difficulty encountered in each task. METHODS: The tool was administered to a group of 40 elderly participants living in the community. RESULTS: The IADL Profile was found to be feasible to use in older individuals; the tool also showed sensitivity to the difficulties experienced by this population in everyday functioning. CONCLUSION: The IADL Profile is a promising ecological tool to evaluate independence in aging and may help to identify individuals with MCI. This tool may also contribute to the development of tailored interventions to enhance everyday functioning in the older population.

Insulin Resistance is Associated with Increased Levels of Cerebrospinal Fluid Biomarkers of Alzheimer's Disease and Reduced Memory Function in At-Risk Healthy Middle-Aged Adults. - Hoscheidt, Siobhan M; Starks, Erika J; Oh, Jennifer M; Zetterberg, Henrik; Blennow, Kaj; Krause, Rachel A; Gleason, Carey E; Puglielli, Luigi; Atwood, Craig S; Carlsson, Cynthia M; Asthana, Sanjay; Johnson, Sterling C; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Type 2 diabetes is associated with an increased risk for Alzheimer's disease (AD). Regulation of normal insulin function may be important in reducing the prevalence of dementia due to AD, particularly in individuals who harbor genetic risk for or have a parental family history of AD. The relationship between insulin resistance (IR) and AD pathology remains poorly understood, particularly in midlife prior to the onset of clinical metabolic disease or cognitive decline. OBJECTIVE: We examined associations between IR as indexed by HOMA-IR, cerebrospinal fluid (CSF) biomarkers of AD pathology, and memory in middle-aged adults enriched for AD. We postulated that higher HOMA-IR and APOEɛ4 carriage would be associated with greater CSF AD pathology and poor memory performance. METHODS: Cognitively asymptomatic middle-aged adults (N = 70, mean age = 57.7 years) from the Wisconsin Alzheimer's Disease Research Center with a parental family history of dementia due to AD underwent lumbar puncture, blood draw, and neuropsychological testing. CSF AD biomarkers including soluble amyloid-β protein precursor β (sAβPPβ), amyloid-β42 (Aβ42), and phosphorylated tau (P-tau181) were examined with respect to HOMA-IR and APOEɛ4 status. Delayed memory performance was examined with respect to HOMA-IR, CSF AD biomarkers, and APOEɛ4 status. RESULTS: Higher HOMA-IR was associated with higher sAβPPβ and Aβ42 . APOEɛ4 carriers had significantly higher levels of sAβPPα, sAβPPβ, and P-tau181/Aβ42 compared to noncarriers. The concurrent presence of higher HOMA-IR and CSF AD pathology predicted worse delayed memory performance. CONCLUSION: Overall, the findings suggest that IR and APOEɛ4 are contributing factors to the development of AD pathology in midlife, and provide support for targeting insulin function as a potentially modifiable risk factor for AD.

Integrated Analysis of Alzheimer's Disease and Schizophrenia Dataset Revealed Different Expression Pattern in Learning and Memory. - Li, Wen-Xing; Dai, Shao-Xing; Liu, Jia-Qian; Wang, Qian; Li, Gong-Hua; Huang, Jing-Fei (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) and schizophrenia (SZ) are both accompanied by impaired learning and memory functions. This study aims to explore the expression profiles of learning or memory genes between AD and SZ. We downloaded 10 AD and 10 SZ datasets from GEO-NCBI for integrated analysis. These datasets were processed using RMA algorithm and a global renormalization for all studies. Then Empirical Bayes algorithm was used to find the differentially expressed genes between patients and controls. The results showed that most of the differentially expressed genes were related to AD whereas the gene expression profile was little affected in the SZ. Furthermore, in the aspects of the number of differentially expressed genes, the fold change and the brain region, there was a great difference in the expression of learning or memory related genes between AD and SZ. In AD, the CALB1, GABRA5, and TAC1 were significantly downregulated in whole brain, frontal lobe, temporal lobe, and hippocampus. However, in SZ, only two genes CRHBP and CX3CR1 were downregulated in hippocampus, and other brain regions were not affected. The effect of these genes on learning or memory impairment has been widely studied. It was suggested that these genes may play a crucial role in AD or SZ pathogenesis. The different gene expression patterns between AD and SZ on learning and memory functions in different brain regions revealed in our study may help to understand the different mechanism between two diseases.
Keywords: Adult; Aged; Aged, 80 and over; Algorithms; Alzheimer Disease; Bayes Theorem; Brain; Datasets as Topic; Gene Expression Profiling; Humans; Learning; Memory; Microarray Analysis; Middle Aged; Schizophrenia; Schizophrenic Psychology; Young Adult

Integrating Biomarkers for Underlying Alzheimer's Disease in Mild Cognitive Impairment in Daily Practice: Comparison of a Clinical Decision Support System with Individual Biomarkers. - Rhodius-Meester, Hanneke F M; Koikkalainen, Juha; Mattila, Jussi; Teunissen, Charlotte E; Barkhof, Frederik; Lemstra, Afina W; Scheltens, Philip; Lötjönen, Jyrki; van der Flier, Wiesje M (J Alzheimers Dis, 2016)
BACKGROUND: Recent criteria allow biomarkers to provide evidence of Alzheimer's disease (AD) pathophysiology. How they should be implemented in daily practice remains unclear, especially in mild cognitive impairment (MCI) patients. OBJECTIVE: We evaluated how a clinical decision support system such as the PredictAD tool can aid clinicians to integrate biomarker evidence to support AD diagnosis. METHODS: With available data on demographics, cerebrospinal fluid (CSF), and MRI, we trained the PredictAD tool on a reference population of 246 controls and 491 AD patients. We then applied the identified algorithm to 211 MCI patients. For comparison, we also classified patients based on individual biomarkers (MRI; CSF) and the NIA-AA criteria. Progression to dementia was used as outcome measure. RESULTS: After a median follow up of 3 years, 72 (34%) MCI patients remained stable and 139 (66%) progressed to AD. The PredictAD tool assigned a likelihood of underlying AD to each patient (AUC 0.82). Excluding patients with missing data resulted in an AUC of 0.87. According to the NIA-AA criteria, half of the MCI patients had uninformative biomarkers, precluding an assignment of AD likelihood. A minority (41%) was assigned to high or low AD likelihood with good predictive value. The individual biomarkers showed best value for CSF total tau (AUC 0.86). CONCLUSION: The ability of the PredictAD tool to identify AD pathophysiology was comparable to individual biomarkers. The PredictAD tool has the advantage that it assigns likelihood to all patients, regardless of missing or conflicting data, allowing clinicians to integrate biomarker data in daily practice.
Keywords: Aged; Aged, 80 and over; Algorithms; Alzheimer Disease; Area Under Curve; Biomarkers; Cognitive Dysfunction; Cohort Studies; Decision Support Systems, Clinical; Disease Progression; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Outcome Assessment (Health Care); Predictive Value of Tests

Interaction Between Midlife Blood Glucose and APOE Genotype Predicts Later Alzheimer's Disease Pathology. - Bangen, Katherine J; Himali, Jayandra J; Beiser, Alexa S; Nation, Daniel A; Libon, David J; Fox, Caroline S; Seshadri, Sudha; Wolf, Philip A; McKee, Ann C; Au, Rhoda; Delano-Wood, Lisa (J Alzheimers Dis, 2016)
Elevated blood glucose and the apolipoprotein (APOE) ɛ4 allele have both been associated with increased dementia risk; however, the neuropathological mechanisms underlying these associations remain unclear. We examined the impact of APOE genotype and midlife blood glucose on post-mortem vascular and Alzheimer's disease (AD) neuropathology. Ninety-four participants from the Framingham Heart Study without diagnosed diabetes underwent health examination at midlife and brain autopsy at death. Histopathological measures of vascular and AD neuropathology were obtained and analyzed. Results demonstrated that, among APOE ɛ4 carriers, elevated blood glucose was associated with more severe AD pathology. There was no such relationship with vascular pathology. In a relatively healthy sample with low vascular risk burden, midlife elevated blood glucose was associated with greater AD pathology among APOE ɛ4 carriers. A better understanding of interactive effects of APOE genotype and vascular risk on neuropathology has implications for identification of individuals at risk for decline and long-term preventive treatment.

Intracerebroventricular Infusion of Angiotensin-(1-7) Ameliorates Cognitive Impairment and Memory Dysfunction in a Mouse Model of Alzheimer's Disease. - Uekawa, Ken; Hasegawa, Yu; Senju, Satoru; Nakagata, Naomi; Ma, Mingjie; Nakagawa, Takashi; Koibuchi, Nobutaka; Kim-Mitsuyama, Shokei (J Alzheimers Dis, 2016)
This work was performed to test our hypothesis that angiotensin-(1-7) can ameliorate cognitive impairment and cerebrovascular reactivity in 5XFAD mice, a useful model of Alzheimer's disease. 5XFAD mice received intracerebroventricular infusion of (1) vehicle, (2) angiotensin-(1-7), or (3) angiotensin-(1-7)+A779, a specific Mas receptor antagonist, for 4 weeks. Angiotensin-(1-7), through Mas receptor, significantly ameliorated cognitive impairment in 5XFAD mice. As estimated by acetazolamide-induced increase in cerebral blood flow, angiotensin-(1-7), through Mas receptor, enhanced cerebrovascular reactivity in 5XFAD mice. In conclusion, angiotensin-(1-7)/Mas receptor axis improves cognitive function and cerebrovascular function in a mouse model of Alzheimer's disease.

Intranasal Administration of a Polyethylenimine-Conjugated Scavenger Peptide Reduces Amyloid-β Accumulation in a Mouse Model of Alzheimer's Disease. - Lin, Chih-Yun; Cheng, Yu-Sung; Liao, Tai-Yan; Lin, Chen; Chen, Zih-Ten; Twu, Woan-Ing; Chang, Chi-Wei; Tan, David Tat-Wei; Liu, Ren-Shyan; Tu, Pang-Hsien; Chen, Rita P-Y (J Alzheimers Dis, 2016)
Amyloid-β (Aβ) aggregation in the brain plays a central and initiatory role in pathogenesis and/or progression of Alzheimer's disease (AD). Inhibiting Aβ aggregation is a potential strategy in the prevention of AD. A scavenger peptide, V24P(10-40), designed to decrease Aβ accumulation in the brain, was conjugated to polyethylenimine (PEI) and tested as a preventive/therapeutic strategy for AD in this study. This PEI-conjugated V24P(10-40) peptide was delivered intranasally, as nasal drops, to four-month-old APP/PS1 double transgenic mice for four or eight months. Compared with control values, peptide treatment for four months significantly reduced the amount of GdnHCl-extracted Aβ40 and Aβ42 in the mice's hippocampus and cortex. After treatment for eight months, amyloid load, as quantified by Pittsburgh compound B microPET imaging, was significantly decreased in the mice's hippocampus, cortex, amygdala, and olfactory bulb. Our data suggest that this intranasally delivered scavenger peptide is effective in decreasing Aβ accumulation in the brain of AD transgenic mice. Nasal application of peptide drops is easy to use and could be further developed to prevent and treat AD.

Intranasal TAT-haFGF Improves Cognition and Amyloid-β Pathology in an AβPP/PS1 Mouse Model of Alzheimer's Disease. - Lou, Guofeng; Zhang, Qihao; Xiao, Fei; Xiang, Qi; Su, Zhijian; Huang, Yadong (J Alzheimers Dis, 2016)
Neurotoxic amyloid-β (Aβ) peptide causing cognitive function disabilities is one of the most characteristic pathological features in Alzheimer's disease (AD). A novel fusion protein, TAT-haFGF, was administrated to AβPP/PS1 transgenic mice by intravenous (IV) injection and intranasal (IN) delivery, respectively, for 5 weeks to compare the pharmacodynamics between the two routes of administration. Our results showed that IN administration of TAT-haFGF improved cognition and reduced Aβ plaques more significantly in AβPP/PS1 mice, when compared with IV injection. Our new findings suggest that TAT-haFGF might be a promising new therapy to attenuate AD pathological process.
Keywords: Administration, Intranasal; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Brain; Cognition Disorders; Disease Models, Animal; Fibroblast Growth Factors; Gene Products, tat; Humans; Injections, Intraventricular; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Movement; Mutation; Peptide Fragments; Plaque, Amyloid; Presenilin-1

Intraneuronal Amylin Deposition, Peroxidative Membrane Injury and Increased IL-1β Synthesis in Brains of Alzheimer's Disease Patients with Type-2 Diabetes and in Diabetic HIP Rats. - Verma, Nirmal; Ly, Han; Liu, Miao; Chen, Jing; Zhu, Haining; Chow, Martin; Hersh, Louis B; Despa, Florin (J Alzheimers Dis, 2016)
Amylin is a hormone synthesized and co-secreted with insulin by pancreatic β-cells that crosses the blood-brain barrier and regulates satiety. Amylin from humans (but not rodents) has an increased propensity to aggregate into pancreatic islet amyloid deposits that contribute to β-cell mass depletion and development of type-2 diabetes by inducing oxidative stress and inflammation. Recent studies demonstrated that aggregated amylin also accumulates in brains of Alzheimer's disease (AD) patients, preponderantly those with type-2 diabetes. Here, we report that, in addition to amylin plaques and mixed amylin-Aβ deposits, brains of diabetic patients with AD show amylin immunoreactive deposits inside the neurons. Neuronal amylin formed adducts with 4-hydroxynonenal (4-HNE), a marker of peroxidative membrane injury, and increased synthesis of the proinflammatory cytokine interleukin (IL)-1β. These pathological changes were mirrored in rats expressing human amylin in pancreatic islets (HIP rats) and mice intravenously injected with aggregated human amylin, but not in hyperglycemic rats secreting wild-type non-amyloidogenic rat amylin. In cultured primary hippocampal rat neurons, aggregated amylin increased IL-1β synthesis via membrane destabilization and subsequent generation of 4-HNE. These effects were blocked by membrane stabilizers and lipid peroxidation inhibitors. Thus, elevated circulating levels of aggregated amylin negatively affect the neurons causing peroxidative membrane injury and aberrant inflammatory responses independent of other confounding factors of diabetes. The present results are consistent with the pathological role of aggregated amylin in the pancreas, demonstrate a novel contributing mechanism to neurodegeneration, and suggest a direct, potentially treatable link of type-2 diabetes with AD.

Iron Regulates Apolipoprotein E Expression and Secretion in Neurons and Astrocytes. - Xu, He; Perreau, Victoria M; Dent, Krista A; Bush, Ashley I; Finkelstein, David I; Adlard, Paul A (J Alzheimers Dis, 2016)
BACKGROUND: There is strong evidence that iron homeostasis is impaired in the aging and Alzheimer's disease (AD) brain and that this contributes to neurodegeneration. Apolipoprotein E (APOE) has been identified as the strongest genetic risk factor for AD. However, the interaction between the two has yet to be fully explored. OBJECTIVE: This study aimed to investigate the relationship between exogenous iron levels and ApoE in neurons and astrocytes. METHODS: Our study used primary cultured cortical neurons and astrocytes to investigate the changes in ApoE caused by iron. Western blot and RT-PCR were used to measure ApoE. RESULTS: We observed that iron upregulated intracellular ApoE levels in both neurons and astrocytes at the post-transcriptional and transcriptional level, respectively. However, there was less full-length ApoE secreted by neurons and astrocytes after iron treatment. We speculate that this might impair brain lipid metabolism and amyloid-β clearance. In terms of ApoE receptors, we observed that neuronal LRP-1 levels were increased by the addition of exogenous iron, which could contribute to AβPP endocytosis in neurons. However, there were no significant changes in neuronal LDLR, astrocyte LDLR, or astrocyte LRP-1. CONCLUSION: Our study reveals that iron may contribute to the pathogenesis of AD by affecting ApoE and its receptors and supports the notion that iron chelation should be investigated as a therapeutic strategy for AD.
Keywords: Amyloid beta-Peptides; Animals; Apolipoproteins E; Astrocytes; Blotting, Western; Cell Survival; Cells, Cultured; Cerebral Cortex; Copper; Ferritins; Immunohistochemistry; Iron; Mice, Inbred C57BL; Neurons; Polymerase Chain Reaction; Reactive Oxygen Species; Receptors, LDL; RNA, Messenger; Tumor Suppressor Proteins; Zinc

Japanese Care Location and Medical Procedures for People with Dementia in the Last Month of Life. - Nakanishi, Miharu; Nakashima, Taeko; Shindo, Yumi; Niimura, Junko; Nishida, Atsushi (J Alzheimers Dis, 2016)
BACKGROUND: Dementia-related societies worldwide have called for palliative end-of-life care for those suffering dementia; meanwhile, the Japanese dementia plan was revised on January 2015 to introduce into its objectives the support for end-of-life care via increased social and health care collaboration. OBJECTIVE: The study focus was the use of medical procedures in the last month of life among dementia patients in different care locations in Japan. METHODS: This study was conducted using a retrospective study design. Data from the Survey of Institutions and Establishments for Long-Term Care, which is a nationally representative cross-sectional survey of the public long-term care insurance services, were used. The 6,148 patients who received end-of-life care in their own home, nursing homes, or hospitals in September 2007, 2010, and 2013 were included for analysis. The primary disease of each patient was based on the ICD-10 code; a diagnosis of dementia included F00 (Alzheimer's), F01 (vascular), F02 (other), and F03 (unspecified). RESULTS: Of 6,148 patients, 886 (14.4%) had dementia as a primary disease; most received care in the last month of life in nursing homes (48.0%) or hospitals (44.8%) rather than in their own home (7.2%). Patients were less likely to undergo pain management when their primary disease was dementia (adjusted odds ratio, 0.44; 95% confidence interval, 0.21-0.91). CONCLUSION: Education and policy efforts are required to provide palliative end-of-life care to people with dementia at home. The national dementia plan should also explore possible approaches regarding pain management for dying people who have dementia.
Keywords: Aged, 80 and over; Cross-Sectional Studies; Dementia; Female; Hospitals; Housing; Humans; Japan; Male; Nursing Homes; Pain Management; Retrospective Studies; Terminal Care; Time Factors

JNK: A Putative Link Between Insulin Signaling and VGLUT1 in Alzheimer's Disease. - Rodriguez-Perdigon, Manuel; Solas, Maite; Ramirez, Maria Javier (J Alzheimers Dis, 2016)
In the present work, the involvement of JNK in insulin signaling alterations and its role in glutamatergic deficits in Alzheimer's disease (AD) has been studied. In postmortem cortical tissues, pJNK levels were increased, while insulin signaling and the expression of VGLUT1 were decreased. A significant correlation was found between reduced expression of insulin receptor and VGLUT1. The administration of a JNK inhibitor reversed the decrease in VGLUT1 expression found in a mice model of insulin resistance. It is suggested that activation of JNK in AD inhibits insulin signaling which could lead to a decreased expression of VGLUT1, therefore contributing to the glutamatergic deficit in AD.
Keywords: Aged; Alzheimer Disease; Animals; Brain; Corticosterone; Disease Models, Animal; Female; Humans; Insulin; Insulin Resistance; Male; MAP Kinase Kinase 4; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 1; Neuroprotective Agents; RNA, Messenger; Vesicular Glutamate Transport Protein 1

The Korean Size/Weight Attribute Test: A Semantic Knowledge Test for Korean Older Adults and Brain-Imaging Evidence. - Yoo, Yongjoon; Shin, Seong A; Park, Soowon; Lee, Ji-Hye; Youn, Jung-Hae; Kim, Yu Kyeong; Lee, Jun-Young (J Alzheimers Dis, 2016)
BACKGROUND: A standardized tool for evaluating semantic knowledge of the Korean population is needed. OBJECTIVE: The purpose of this study was to develop a neuropsychological test for the evaluation of semantic knowledge in the Korean elderly population. METHODS: The Korean version of the Size/Weight Attribute Test (SWAT-K) was developed in reference to the original version. The diagnostic validity of SWAT-K was evaluated with 95 elderly outpatients [67 normal controls; 18 with Alzheimer's disease (AD); 10 with semantic-variant progressive aphasia (SV-PPA)]. Voxel-based morphometry (VBM) was employed to examine associations between SWAT-K scores and morphological changes of the brain. RESULTS: SWAT-K could discriminate the three subject groups (normal >AD, p <  0.001; AD >SV-PPA, p = 0.040), whereas Boston Naming Test could not distinguish SV-PPA from AD. ROC curve analysis confirmed high levels of sensitivity (0.90) and specificity (0.93) for SWAT-K. The test's inter-rater reliability (ICC = 0.827) and test-retest reliability (ICC = 0.666) were assessed as well. VBM found a significant positive correlation (uncorrected p <  0.005, k >  100) between SWAT-K scores and gray matter volume in right inferior frontal cortex (T = 4.08, k = 191) and bilateral temporal cortices (left, T = 4.42, k = 135; right, T = 3.55, k = 253), the areas the most affected in SV-PPA. CONCLUSIONS: SWAT-K is a sensitive and reliable test for evaluating semantic knowledge in the Korean elderly population. Strong positive correlations between SWAT-K scores and the brain areas responsible for semantic processing further corroborate the validity of SWAT-K.
Keywords: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Analysis of Variance; Brain; Dementia; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Psychiatric Status Rating Scales; Republic of Korea; ROC Curve; Semantics

Lack of evidence for a role of HHV-6 in the pathogenesis of Alzheimer's disease. - Agostini, Simone; Mancuso, Roberta; Baglio, Francesca; Cabinio, Monia; Hernis, Ambra; Guerini, Franca Rosa; Calabrese, Elena; Nemni, Raffaello; Clerici, Mario (J Alzheimers Dis, 2016)
BACKGROUND: Alzheimer's disease (AD), the most common form of dementia worldwide, is associated with impairment in the mechanisms of the clearing of amyloid-β within a scenario of neuroinflammation. The etiopathogenesis of the AD is unclear, but a role for viral infection is suspected to play a role in initiating the disease. We recently described a positive correlation between high titers of HSV-1-specific antibodies (Ab) and the volumes of brain regions typically affected in disease. OBJECTIVE: The exploration of a possible role for Herpesviridae in AD was extended by analyzing HHV-6-specific humoral immunity in individuals with AD or a diagnosis of amnestic mild cognitive impairment (aMCI), a condition that is often prodromic of the development of AD. METHODS: 59 AD, 60 aMCI, and 61 age-matched healthy controls were enrolled in the study. Serum HHV-6 IgG antibody titers and avidity index were tested by ELISA. Two randomly selected subgroups of AD and aMCI in whom HHV-6 serum antibodies were detected underwent brain magnetic resonance imaging (MRI) by 1.5 T scanner. RESULTS: HHV-6 seroprevalence, antibody titers, and avidity were similar in the three groups. No correlation was found between Ab titers or avidity and brain volumes, either overall or in the regions typically affected by disease. CONCLUSIONS: The lack of any relation between humoral immune response against HHV-6 and AD and aMCI seems to rule out a role for this virus in the pathogenesis of AD.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Antibodies; Case-Control Studies; Cognitive Dysfunction; Female; Herpesvirus 1, Human; Herpesvirus 6, Human; Humans; Immunity, Humoral; Magnetic Resonance Imaging; Male; Seroepidemiologic Studies; Temporal Lobe

The Language Profile of Behavioral Variant Frontotemporal Dementia. - Hardy, Chris J D; Buckley, Aisling H; Downey, Laura E; Lehmann, Manja; Zimmerer, Vitor C; Varley, Rosemary A; Crutch, Sebastian J; Rohrer, Jonathan D; Warrington, Elizabeth K; Warren, Jason D (J Alzheimers Dis, 2016)
BACKGROUND: The language profile of behavioral variant frontotemporal dementia (bvFTD) remains to be fully defined. OBJECTIVE: We aimed to quantify the extent of language deficits in this patient group. METHODS: We assessed a cohort of patients with bvFTD (n = 24) in relation to patients with semantic variant primary progressive aphasia (svPPA; n = 14), nonfluent variant primary progressive aphasia (nfvPPA; n = 18), and healthy age-matched individuals (n = 24) cross-sectionally and longitudinally using a comprehensive battery of language and general neuropsychological tests. Neuroanatomical associations of language performance were assessed using voxel-based morphometry of patients' brain magnetic resonance images. RESULTS: Relative to healthy controls, and after accounting for nonverbal executive performance, patients with bvFTD showed deficits of noun and verb naming and single word comprehension, diminished spontaneous propositional speech, and deterioration in naming performance over time. Within the bvFTD group, patients with MAPT mutations had more severe impairments of noun naming and single word comprehension than patients with C9orf72 mutations. Overall the bvFTD group had less severe language deficits than patients with PPA, but showed a language profile that was qualitatively similar to svPPA. Neuroanatomical correlates of naming and word comprehension performance in bvFTD were identified predominantly in inferior frontal and antero-inferior temporal cortices within the dominant hemispheric language network. CONCLUSIONS: bvFTD is associated with a language profile including verbal semantic impairment that warrants further evaluation as a novel biomarker.
Keywords: Aged; Aphasia, Primary Progressive; Atrophy; Brain; Cognition; Comprehension; Female; Frontotemporal Dementia; Humans; Language; Magnetic Resonance Imaging; Male; Middle Aged; Neuroimaging; Neuropsychological Tests; Primary Progressive Nonfluent Aphasia

A Late Life Risk Index for Severe Cognitive Impairment in Mexico. - Downer, Brian; Veeranki, Sreenivas P; Wong, Rebeca (J Alzheimers Dis, 2016)
BACKGROUND: Several dementia risk indices have been developed for older adults in high-income countries. However, no index has been developed for populations in low- or middle-income countries. OBJECTIVE: To create a risk index for predicting severe cognitive impairment among adults aged ≥60 in Mexico and to compare the accuracy of this index to the Dementia Screening Indicator (DSI). METHODS: This study included 3,002 participants from the Mexican Health and Aging Study (MHAS) interviewed in 2001 and 2012. The MHAS risk index included sociodemographic, health, and functional characteristics collected in 2001. A point value based on the beta coefficients from a multivariable logistic regression model was assigned to each risk factor and the total score was calculated. RESULTS: The MHAS risk index (AUC = 0.74 95% CI = 0.70-0.77) and DSI (AUC = 0.72 95% CI = 0.69-0.77) had similar accuracy for discriminating between participants who developed severe cognitive impairment from those who did not. A score of ≥16 on the MHAS risk index had a sensitivity of 0.69 (95% CI = 0.64-0.70) and specificity of 0.67 (95% CI = 0.66-0.69). A score of ≥23 on the DSI had a sensitivity of 0.56 (95% CI = 0.50-0.63) and specificity of 0.78 (95% CI = 0.76-0.79). DISCUSSION: The MHAS risk index and DSI have moderate accuracy for predicting severe cognitive impairment among older adults in Mexico. This provides evidence that existing dementia risk indices may be applicable in low- and middle-income countries such as Mexico. Future research should seek to identify additional risk factors that can improve the accuracy of the MHAS risk index.
Keywords: Age Factors; Aged; Cognitive Dysfunction; Female; Humans; Life Style; Logistic Models; Longitudinal Studies; Male; Mexico; Middle Aged; Multivariate Analysis; Risk Factors; Social Behavior; Socioeconomic Factors

Late-Life Depressive Symptoms and Lifetime History of Major Depression: Cognitive Deficits are Largely Due to Incipient Dementia rather than Depression. - Heser, Kathrin; Bleckwenn, Markus; Wiese, Birgitt; Mamone, Silke; Riedel-Heller, Steffi G; Stein, Janine; Lühmann, Dagmar; Posselt, Tina; Fuchs, Angela; Pentzek, Michael; Weyerer, Siegfried; Werle, Jochen; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Late-life depression is frequently accompanied by cognitive impairments. OBJECTIVE: Whether these impairments indicate a prodromal state of dementia, or are a symptomatic expression of depression per se is not well-studied. METHODS: In a cohort of very old initially non-demented primary care patients (n = 2,709, mean age = 81.1 y), cognitive performance was compared between groups of participants with or without elevated depressive symptoms and with or without subsequent dementia using ANCOVA (adjusted for age, sex, and education). Logistic regression analyses were computed to predict subsequent dementia over up to six years of follow-up. The same analytical approach was performed for lifetime major depression. RESULTS: Participants with elevated depressive symptoms without subsequent dementia showed only small to medium cognitive deficits. In contrast, participants with depressive symptoms with subsequent dementia showed medium to very large cognitive deficits. In adjusted logistic regression models, learning and memory deficits predicted the risk for subsequent dementia in participants with depressive symptoms. Participants with a lifetime history of major depression without subsequent dementia showed no cognitive deficits. However, in adjusted logistic regression models, learning and orientation deficits predicted the risk for subsequent dementia also in participants with lifetime major depression. CONCLUSION: Marked cognitive impairments in old age depression should not be dismissed as "depressive pseudodementia", but require clinical attention as a possible sign of incipient dementia. Non-depressed elderly with a lifetime history of major depression, who remained free of dementia during follow-up, had largely normal cognitive performance.

The Latent Dementia Phenotype δ is Associated with Cerebrospinal Fluid Biomarkers of Alzheimer's Disease and Predicts Conversion to Dementia in Subjects with Mild Cognitive Impairment. - Koppara, Alexander; Wolfsgruber, Steffen; Kleineidam, Luca; Schmidtke, Klaus; Frölich, Lutz; Kurz, Alexander; Schulz, Stefanie; Hampel, Harald; Heuser, Isabella; Peters, Oliver; Reischies, Friedel M; Jahn, Holger; et al. (J Alzheimers Dis, 2016)
BACKGROUND: The recently proposed latent variable δ is a new tool for dementia case finding. It is built in a structural equation modeling framework of cognitive and functional data and constitutes a novel endophenotype for Alzheimer's disease (AD) research and clinical trials. OBJECTIVE: To investigate the association of δ with AD biomarkers and to compare the prediction of δ with established scales for conversion to dementia in patients with mild cognitive impairment (MCI). METHODS: Using data from a multicenter memory clinic study, we examined the external associations of the latent variable δ and compared δ with well-established cognitive and functional scales and cognitive-functional composite scores. For that purpose, logistic regressions with cerebrospinal fluid (CSF) biomarkers and conversion to dementia as dependent variables were performed with the investigated scores. The models were tested for significant differences. RESULTS: In patients with MCI, δ based on a broad range of cognitive scales (including the ADAS-cog, the MMSE, and the CERAD neuropsychological battery) predicted an abnormal CSF Aβ42/tau ratio indicative of AD (n = 340, AUC = 0.78, p <  0.001), and predicted incident dementia within 1-3 years of follow-up (n = 525, AUC = 0.84, p <  0.001). These associations were generally stronger than for any other scale or cognitive-functional composite examined. Homologs of δ based on reduced test batteries yielded somewhat lower effects. CONCLUSION: These findings support the interpretation of δ as a construct capturing the disease-related "essence" of cognitive and functional impairments in patients with MCI and dementia, and suggest that δ might become an analytical tool for dementia research.
Keywords: Activities of Daily Living; Aged; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction; Dementia; Disease Progression; Female; Humans; Logistic Models; Longitudinal Studies; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Peptide Fragments; Phenotype; Predictive Value of Tests; Retrospective Studies; tau Proteins

Late-Onset Metachromatic Leukodystrophy with Early Onset Dementia Associated with a Novel Missense Mutation in the Arylsulfatase A Gene. - Stoeck, Katharina; Psychogios, Marios Nikos; Ohlenbusch, Andreas; Steinfeld, Robert; Schmidt, Jens (J Alzheimers Dis, 2016)
A 48-year-old male patient presented with personality changes and progressive memory loss over 2 years with initially suspected Hashimoto's encephalopathy. Strategy of diagnostic workup of early onset dementia included dementia from neurodegenerative, neuroinflammatory, metabolic/toxic, and psychiatric origin. The patient's neurological exam was normal. MRI revealed a leukencephalopathy, predominantly in the frontal periventricular white matter, without notable changes over 2 years. On neurophysiological examination, prolonged central conduction times and a sensorimotor polyneuropathy were noted. Neuropsychological impairment included disorientation in place and a reduced short time memory. Behavioral alterations were predominated by sudden mood changes and disinhibition. Cerebrospinal fluid was normal. Despite presence of thyroid autoantibodies, glucocorticosteroid treatment did not improve the dementia. A metachromatic leukodystrophy was diagnosed by decreased arylsulfatase-A activity in leucocytes/fibroblasts and identification of a compound heterozygous mutation in the ARSA gene: c.542T>G (exon 3) and the novel mutation c.1013T>C (exon 6). Pathogenic function was suggested by bioinformatic mutation search. In a patient with early onset dementia, strategic diagnostic workup including genetic assessment revealed an adult-onset metachromatic leukodystrophy with a novel mutation in the arylsulfatase A gene.
Keywords: Age of Onset; Brain; Cerebroside-Sulfatase; Dementia; Diagnosis, Differential; DNA Mutational Analysis; Exons; Humans; Leukodystrophy, Metachromatic; Male; Middle Aged; Mutation, Missense; Neuropsychological Tests

Less Daily Computer Use is Related to Smaller Hippocampal Volumes in Cognitively Intact Elderly. - Silbert, Lisa C; Dodge, Hiroko H; Lahna, David; Promjunyakul, Nutta-On; Austin, Daniel; Mattek, Nora; Erten-Lyons, Deniz; Kaye, Jeffrey A (J Alzheimers Dis, 2016)
BACKGROUND: Computer use is becoming a common activity in the daily life of older individuals and declines over time in those with mild cognitive impairment (MCI). The relationship between daily computer use (DCU) and imaging markers of neurodegeneration is unknown. OBJECTIVE: The objective of this study was to examine the relationship between average DCU and volumetric markers of neurodegeneration on brain MRI. METHODS: Cognitively intact volunteers enrolled in the Intelligent Systems for Assessing Aging Change study underwent MRI. Total in-home computer use per day was calculated using mouse movement detection and averaged over a one-month period surrounding the MRI. Spearman's rank order correlation (univariate analysis) and linear regression models (multivariate analysis) examined hippocampal, gray matter (GM), white matter hyperintensity (WMH), and ventricular cerebral spinal fluid (vCSF) volumes in relation to DCU. A voxel-based morphometry analysis identified relationships between regional GM density and DCU. RESULTS: Twenty-seven cognitively intact participants used their computer for 51.3 minutes per day on average. Less DCU was associated with smaller hippocampal volumes (r = 0.48, p = 0.01), but not total GM, WMH, or vCSF volumes. After adjusting for age, education, and gender, less DCU remained associated with smaller hippocampal volume (p = 0.01). Voxel-wise analysis demonstrated that less daily computer use was associated with decreased GM density in the bilateral hippocampi and temporal lobes. CONCLUSIONS: Less daily computer use is associated with smaller brain volume in regions that are integral to memory function and known to be involved early with Alzheimer's pathology and conversion to dementia. Continuous monitoring of daily computer use may detect signs of preclinical neurodegeneration in older individuals at risk for dementia.

The Level of NMDA Receptor in the Membrane Modulates Amyloid-β Association and Perforation. - Peters, Christian; Sepúlveda, Fernando J; Fernández-Pérez, Eduardo J; Peoples, Robert W; Aguayo, Luis G (J Alzheimers Dis, 2016)
Alzheimer's disease is a neurodegenerative disorder that affects mostly the elderly. The main histopathological markers are the senile plaques formed by amyloid-β peptide (Aβ) aggregates that can perforate the plasma membrane of cells, increasing the intracellular calcium levels and releasing synaptic vesicles that finally lead to a delayed synaptic failure. Several membrane proteins and lipids interact with Aβ affecting its toxicity in neurons. Here, we focus on NMDA receptors (NMDARs) as proteins that could be modulating the association and neurotoxic perforation induced by Aβ on the plasma membrane. In fact, our results showed that decreasing NMDARs, using enzymatic or siRNA approaches, increased the association of Aβ to the neurons. Furthermore, overexpression of NMDARs also resulted in an enhanced association between NMDA and Aβ. Functionally, the reduction in membrane NMDARs augmented the process of membrane perforation. On the other hand, overexpressing NMDARs had a protective effect because Aβ was now unable to cause membrane perforation, suggesting a complex relationship between Aβ and NMDARs. Because previous studies have recognized that Aβ oligomers are able to increase membrane permeability and produce amyloid pores, the present study supports the conclusion that NMDARs play a critical protective role on Aβ actions in hippocampal neurons. These results could explain the lack of correlation between brain Aβ burden and clinically observed dementia.

Lewy Bodies, Vascular Risk Factors, and Subcortical Arteriosclerotic Leukoencephalopathy, but not Alzheimer Pathology, are Associated with Development of Psychosis in Alzheimer's Disease. - Fischer, Corinne E; Qian, Winnie; Schweizer, Tom A; Millikin, Colleen P; Ismail, Zahinoor; Smith, Eric E; Lix, Lisa M; Shelton, Paul; Munoz, David G (J Alzheimers Dis, 2016)
BACKGROUND: The neuropathological correlates of psychosis in Alzheimer's disease (AD) is unclear, with some studies reporting a correlation between psychosis and increased AD pathology while others have found no association. OBJECTIVE: To determine the demographic, clinical, and neuropathological features associated with psychotic symptoms in clinically attributed and neuropathologically proven AD. METHOD: We separately reviewed two overlapping groups of clinically diagnosed (cAD) AD patients with neuropathology data and neuropathologically definite (npAD) cases (regardless of clinical diagnosis) from the NACC database, and explored the relationships between psychosis and clinical variables, neuropathologic correlates, and vascular risk factors. Delusions and hallucinations, defined according to the NPI-Q, were analyzed separately. RESULTS: 1,073 subjects in the database fulfilled our criteria (890 cAD and 728 npAD patients). 34% of cAD and 37% of npAD had psychotic symptoms during their illness. Hallucinations were associated with greater cognitive and functional impairments on the MMSE and CDR, while delusional patients showed less impairment on CDR, consistent across cAD and npAD groups. Burden of AD pathology appears to relate to presence of psychotic symptoms in the clinical AD group, but this result is not confirmed in the neuropathologically confirmed group suggesting the findings in the clinical group were due to misdiagnosis of AD. Lewy body pathology, subcortical arteriosclerotic leukoencephalopathy, and vascular risk factors, including a history of hypertension and diabetes, were associated with the development of psychosis. METHOD: Vascular and Lewy body pathologies and vascular risk factors are important modifiers of the risk of psychosis in AD.
Keywords: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Cognition Disorders; Databases, Factual; Dementia, Vascular; Female; Hemorrhage; Humans; Lewy Bodies; Male; Middle Aged; Psychiatric Status Rating Scales; Psychotic Disorders; Retrospective Studies; Risk Factors; Severity of Illness Index; Surveys and Questionnaires

Lifelong Reading Disorder and Mild Cognitive Impairment: Implications for Diagnosis. - Lebowitz, Brian K; Weinstein, Cheryl; Beiser, Alexa; Seshadri, Sudha; Wolf, Philip A; Auerbach, Sandford; Au, Rhoda (J Alzheimers Dis, 2016)
Although neuropsychological tests are commonly used in the evaluation of possible mild cognitive impairment (MCI), poor test scores may be indicative of factors other than neurological compromise. The current study assessed the role of lifelong reading disorder on MCI classification. Community dwelling older adults with a suspected developmental reading disorder were identified by inference based on reading test performance. Individuals with a suspected reading disorder were significantly more likely to perform at a level consistent with MCI on several commonly used neuropsychological tests. The findings suggest a relationship between a history of reading disorder and MCI classification.
Keywords: Aged; Aged, 80 and over; Cognitive Dysfunction; Dyslexia; Female; Humans; Independent Living; Longitudinal Studies; Male; Neuropsychological Tests; Psychometrics; Retrospective Studies

Life's Simple 7's Cardiovascular Health Metrics are Associated with Hispanic/Latino Neurocognitive Function: HCHS/SOL Results. - González, Hector M; Tarraf, Wassim; Gouskova, Natalia; Rodríguez, Carlos J; Rundek, Tatjana; Grober, Ellen; Pirzada, Amber; González, Patricia; Lutsey, Pamela L; Camacho, Alvaro; Daviglus, Martha L; Wright, Clinton; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Hispanics/Latinos are purportedly at increased risk for neurocognitive decline and dementias. Without dementia cures, low-cost, well-tolerated public health means for mitigating neurocognitive decline are needed. OBJECTIVE: We examined associations between neurocognition and cardiovascular health (CVH) metrics (Life's Simple 7; LS7) among diverse Hispanics/Latinos. We hypothesized that higher LS7 would be associated with healthier brain function (neurocognitive performance). METHODS: We used baseline (2008-2011) Hispanic Community Health Study/Study of Latinos (HCHS/SOL; N = 9,623; ages 45-74 years) to examine neurocognition in relation to CVH LS7 scores. RESULTS: In age and sex adjusted models, a one unit LS7 score increase (range = 0-14) was associated with higher neurocognitive function on the B-SEVLT sum (0.23 [p < 0.01]; range = 3-42), B-SEVLT recall (0.12 [p < 0.01]; range = 0-15), Word Fluency (phonemic; 0.46 (p < 0.01); range = 0-49), and Digit Symbol Substitution (0.49 (p < 0.01); range = 0-83) tests, respectively. Stated differently, a change from the minimum LS7 (0) to maximum LS7 (14) score corresponded to higher scores on verbal learning (4.62) and memory (2.24), verbal fluency (7.0), and psychomotor processing speed (12). In fully adjusted models the associations were attenuated, but remained statistically significant. Incremental adjustments indicated that Latino background and, to a lesser extent, education were primary contributors to the evinced attenuations. CONCLUSIONS: We found that higher neurocognitive function was associated with better LS7 CVH metrics among middle-aged and older Hispanics/Latinos. Associations between neurocognitive function and LS7 were strongest among two at-risk groups for neurocognitive decline and dementia, women and Hispanics/Latinos with lower education. Public health efforts to reduce cardiovascular disease morbidity and mortality may have additional neurocognitive benefits among at-risk Hispanics/Latinos.

Limiting Factors of Brain Donation in Neurodegenerative Diseases: The Example of French Memory Clinics. - Le Bouc, Raphael; Marelli, Cecilia; Beaufils, Emilie; Berr, Claudine; Hommet, Caroline; Touchon, Jacques; Pasquier, Florence; Deramecourt, Vincent (J Alzheimers Dis, 2016)
Postmortem neuropathological examination of the brain is essential in neurodegenerative diseases, to ensure accurate diagnosis, to obtain an a posteriori critical assessment of the adequacy of clinical care, and to validate new biomarkers, but is only rarely performed. The purpose of this study was to assess factors limiting brain donation, such as reluctance of physicians to seek donation consent, opposition from patients and families, and organizational constraints. We conducted a survey across French memory clinics and major neuropathological centers. Few postmortem examinations were performed annually, as less than one third of the centers had performed at least five autopsies, and 41% had performed none. The main limiting factor was the lack of donation requests made by physicians, as half of them never approach patients for brain donation. Reasons for not seeking donation consent often include discomfort broaching the subject and lack of awareness of the medical and scientific benefit of postmortems (77%), organizational constraints (61%), and overestimation of families' negative reaction (51%). Family refusals represented a second major obstacle, and were often caused by misconceptions. Identifying and addressing these biases early could help improve physicians' rate of making requests and the public's awareness about the importance of brain donation.
Keywords: Autopsy; Brain; France; Health Knowledge, Attitudes, Practice; Humans; Neurodegenerative Diseases; Physicians; Retrospective Studies

Linguistic Features Identify Alzheimer's Disease in Narrative Speech. - Fraser, Kathleen C; Meltzer, Jed A; Rudzicz, Frank (J Alzheimers Dis, 2016)
BACKGROUND: Although memory impairment is the main symptom of Alzheimer's disease (AD), language impairment can be an important marker. Relatively few studies of language in AD quantify the impairments in connected speech using computational techniques. OBJECTIVE: We aim to demonstrate state-of-the-art accuracy in automatically identifying Alzheimer's disease from short narrative samples elicited with a picture description task, and to uncover the salient linguistic factors with a statistical factor analysis. METHODS: Data are derived from the DementiaBank corpus, from which 167 patients diagnosed with "possible" or "probable" AD provide 240 narrative samples, and 97 controls provide an additional 233. We compute a number of linguistic variables from the transcripts, and acoustic variables from the associated audio files, and use these variables to train a machine learning classifier to distinguish between participants with AD and healthy controls. To examine the degree of heterogeneity of linguistic impairments in AD, we follow an exploratory factor analysis on these measures of speech and language with an oblique promax rotation, and provide interpretation for the resulting factors. RESULTS: We obtain state-of-the-art classification accuracies of over 81% in distinguishing individuals with AD from those without based on short samples of their language on a picture description task. Four clear factors emerge: semantic impairment, acoustic abnormality, syntactic impairment, and information impairment. CONCLUSION: Modern machine learning and linguistic analysis will be increasingly useful in assessment and clustering of suspected AD.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Diagnosis, Computer-Assisted; Factor Analysis, Statistical; Female; Humans; Language Disorders; Linguistics; Logistic Models; Machine Learning; Male; Mental Status Schedule; Middle Aged; Narration; Photic Stimulation; Speech; Verbal Behavior

Living Alone with Dementia: Prevalence, Correlates and the Utilization of Health and Nursing Care Services. - Eichler, Tilly; Hoffmann, Wolfgang; Hertel, Johannes; Richter, Steffen; Wucherer, Diana; Michalowsky, Bernhard; Dreier, Adina; Thyrian, Jochen René (J Alzheimers Dis, 2016)
BACKGROUND: Little is known about the proportion and the characteristics of community-dwelling people with dementia (PWD) living alone in Germany. OBJECTIVES: To analyze the prevalence of PWD living alone (with and without the support of an informal caregiver) and socio-demographical and clinical characteristics as well as health and nursing care utilization associated with living alone. METHODS: DelpHi-MV (Dementia: Life- and person-centered help in Mecklenburg-Western Pomerania) is a general practitioner-based, randomized controlled intervention trial. The present analyses are based on baseline data of 511 patients (≥70 years, community-dwelling) who had screened positive for dementia (DemTect <9). RESULTS: N = 251 (51%) of the patients lived alone. PWD living alone were statistically significantly more often female, older, and more often widowed than those not living alone. About 9% of the patients (n = 24) were not supported by any informal caregiver. Regarding the clinical variables (cognitive and functional impairment, depression, falls, number of drug-related problems, malnutrition, quality of life), there were no statistically significant group differences. Patients living alone utilized professional services such as home care, help with medication, home-delivered meals, or housekeeping assistance significantly more often. Multivariate analyses confirmed these findings. CONCLUSION: Our results reveal the high proportion of PWD living alone in Germany. PWD living alone did not seem to be at an increased health risk. Our findings indicate that living alone with dementia is possible. In order to ensure the sufficient provision of health and nursing care services for PWD living alone, providers should consider the present results for future planning.

Longitudinal Alteration of Intrinsic Brain Activity in the Striatum in Mild Cognitive Impairment. - Ren, Ping; Lo, Raymond Y; Chapman, Benjamin P; Mapstone, Mark; Porsteinsson, Anton; Lin, Feng (J Alzheimers Dis, 2016)
The striatum is a critical functional hub in understanding neurological disorders. However, the Alzheimer's disease (AD)-associated striatal change is unclear, as is the relationship between striatal change and AD pathology. Three-year resting-state fMRI data from 15 healthy control (HC) and 20 mild cognitive impairment (MCI) participants were obtained. We analyzed the amplitude of low-frequency fluctuations (ALFF) (0.01-0.08 Hz) and two subdivided bands (slow-4:0.027-0.073 Hz; slow-5:0.01-0.027 Hz). We calculated Aβ/pTau ratio using baseline cerebrospinal fluid pTau and Aβ1-42 to represent AD pathology. Compared to HC, MCI participants showed greater decline in right putaminal ALFF, including the slow-4 band. Greater decline of ALFF in the right putamen was significantly related to the memory decline over time and lower baseline Aβ/pTau ratio regardless of age or group. The slow-4 band, relative to slow-5 band, showed a stronger correlation between Aβ/pTau ratio and decline of ALFF in the right putamen. The results suggest that the putaminal function declines early in the AD-associated neurodegeneration. The continuous decline in putaminal ALFF, especially slow-4 band, may be a sensitive marker of AD pathology such as Aβ/pTau ratio regardless of clinical diagnosis.

The Longitudinal Association Between a Discrepancy Measure of Anosognosia in Patients with Dementia, Caregiver Burden and Depression. - Perales, Jaime; Turró-Garriga, Oriol; Gascón-Bayarri, Jordi; Reñé-Ramírez, Ramón; Conde-Sala, Josep Lluís (J Alzheimers Dis, 2016)
BACKGROUND: According to cross-sectional studies, there is an association between anosognosia in people with dementia and caregiver's burden and depression. Anosognosia in patients may be a cause of caregiver burden and depression. However, variability in caregiver anosognosia ratings may exist as caregivers with burden and depression may have a more pessimistic view of the patients' health. OBJECTIVE: To assess the variability of caregiver anosognosia ratings of patients with dementia using a widely used anosognosia scale and its longitudinal relationship with caregiver burden and depression. METHODS: A convenience cohort of 221 consecutive dementia outpatient and caregiver dyads was followed up at 12 and 24 months. The main instruments used were the Anosognosia Questionnaire-Dementia (AQ-D), Caregiver Burden Interview, and Geriatric Depression Scale. Linear mixed models were used including time as a factor in every model. Multivariate analyses controlled for caregiver's socio-demographic and possible confounding factors. RESULTS: Attrition at 12 and 24 months was 24.9% and 42.5% respectively. Patients at baseline were on average 77.8 years of age, 63.3% were women, and 63.3% had < 5 years of education. In the bivariate analyses, caregiver burden, depression, and gender were associated with caregiver ratings of total, cognitive, and personality AQ-D of the patient at different time points. Multivariate analyses revealed burden as the caregiver variable most consistently associated with total, cognitive, and personality caregiver AQ-D ratings of the patient. CONCLUSION: Some caregiver characteristics, especially burden, are associated with caregiver ratings of AQ-D with regard to the patient.

Longitudinal Changes in Functional Brain Connectivity Predicts Conversion to Alzheimer's Disease. - Serra, Laura; Cercignani, Mara; Mastropasqua, Chiara; Torso, Mario; Spanò, Barbara; Makovac, Elena; Viola, Vanda; Giulietti, Giovanni; Marra, Camillo; Caltagirone, Carlo; Bozzali, Marco (J Alzheimers Dis, 2016)
This longitudinal study investigates the modifications in structure and function occurring to typical Alzheimer's disease (AD) brains over a 2-year follow-up, from pre-dementia stages of disease, with the aim of identifying biomarkers of prognostic value. Thirty-one patients with amnestic mild cognitive impairment were recruited and followed-up with clinical, neuropsychological, and MRI assessments. Patients were retrospectively classified as AD Converters or Non-Converters, and the data compared between groups. Cross-sectional MRI data at baseline, assessing volume and functional connectivity abnormalities, confirmed previous findings, showing a more severe pattern of regional grey matter atrophy and default-mode network disconnection in Converters than in Non-Converters. Longitudinally, Converters showed more grey matter atrophy in the frontotemporal areas, accompanied by increased connectivity in the precuneus. Discriminant analysis revealed that functional connectivity of the precuneus within the default mode network at baseline is the parameter able to correctly classify patients in Converters and Non-Converters with high sensitivity, specificity, and accuracy.
Keywords: Aged; Alzheimer Disease; Atrophy; Brain; Brain Mapping; Cognitive Dysfunction; Cross-Sectional Studies; Discriminant Analysis; Disease Progression; Female; Follow-Up Studies; Gray Matter; Humans; Image Processing, Computer-Assisted; Longitudinal Studies; Magnetic Resonance Imaging; Male; Neural Pathways; Neuropsychological Tests; Prognosis; Rest

Longitudinal Memory Profiles in Behavioral-Variant Frontotemporal Dementia and Alzheimer's Disease. - Schubert, Samantha; Leyton, Cristian E; Hodges, John R; Piguet, Olivier (J Alzheimers Dis, 2016)
BACKGROUND: Alzheimer's disease (AD) and behavioral-variant of frontotemporal dementia (bvFTD) can present with an overlapping neuropsychological profile, which often hinders their clinical differentiation. OBJECTIVE: To compare changes over time in memory, general cognition tasks, and functional scales between bvFTD and AD. METHODS: Consecutive cases diagnosed with probable bvFTD (n = 22) and typical AD (n = 31) with at least two clinical visits were selected. Of these, 13 (9 AD, 4 bvFTD) underwent Pittsburgh compound B PET scan, which supported the clinical diagnosis in all cases. Mixed-model regressions were used to estimate the differential rate of decline on selected tasks between cohorts. RESULTS: Analyses demonstrated that, despite equivalent baseline performance, bvFTD patients experienced a more rapid functional deterioration and a steeper decline in global cognition than AD patients. At baseline, both groups were impaired on executive function and memory tasks compared to controls, but these deficits were more marked in the bvFTD group. In addition, performance on these domains continued to decline more rapidly in this group. CONCLUSIONS: Neither the initial neuropsychological assessment nor projected performances can reliably distinguish the totality of bvFTD and AD individuals. Nevertheless, annual rates of progression on cognitive tasks provide valuable information and will potentially help establish the impact of future therapeutic treatments in these dementia syndromes.
Keywords: Alzheimer Disease; Aniline Compounds; Brain; Diagnosis, Differential; Disease Progression; Executive Function; Female; Follow-Up Studies; Frontotemporal Dementia; Humans; Longitudinal Studies; Male; Memory; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

Longitudinal Protein Changes in Blood Plasma Associated with the Rate of Cognitive Decline in Alzheimer's Disease. - Sattlecker, Martina; Khondoker, Mizanur; Proitsi, Petroula; Williams, Stephen; Soininen, Hilkka; Kłoszewska, Iwona; Mecocci, Patrizia; Tsolaki, Magda; Vellas, Bruno; Lovestone, Simon; Dobson, Richard Jb (J Alzheimers Dis, 2016)
Biomarkers of Alzheimer's disease (AD) progression are needed to support the development of urgently needed disease modifying drugs. We employed a SOMAscan assay for quantifying 1,001 proteins in blood samples from 90 AD subjects, 37 stable mild cognitive impaired (MCI) subjects, 39 MCI subjects converting to AD within a year and 69 controls at baseline and one year follow up. We used linear mixed effects models to identify proteins changing significantly over one year with the rate of cognitive decline, which was quantified as the reduction in Mini Mental State Examination (MMSE) scores. Additionally, we investigated proteins changing differently across disease groups and during the conversion from MCI to AD. We found that levels of proteins belonging to the complement cascade increase significantly in fast declining AD patients. Longitudinal changes in the complement cascade might be a surrogate biomarker for disease progression. We also found that members of the cytokine-cytokine receptor interaction pathway change during AD when compared to healthy aging subjects.
Keywords: Aged; Alzheimer Disease; Biomarkers; Cognition; Cognitive Dysfunction; Disease Progression; Female; Follow-Up Studies; Humans; Linear Models; Longitudinal Studies; Male; Mental Status Schedule; Neuropsychological Tests

Longitudinal Relationships between Caloric Expenditure and Gray Matter in the Cardiovascular Health Study. - Raji, Cyrus A; Merrill, David A; Eyre, Harris; Mallam, Sravya; Torosyan, Nare; Erickson, Kirk I; Lopez, Oscar L; Becker, James T; Carmichael, Owen T; Gach, H Michael; Thompson, Paul M; Longstreth, W T; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Physical activity (PA) can be neuroprotective and reduce the risk for Alzheimer's disease (AD). In assessing physical activity, caloric expenditure is a proxy marker reflecting the sum total of multiple physical activity types conducted by an individual. OBJECTIVE: To assess caloric expenditure, as a proxy marker of PA, as a predictive measure of gray matter (GM) volumes in the normal and cognitively impaired elderly persons. METHODS: All subjects in this study were recruited from the Institutional Review Board approved Cardiovascular Health Study (CHS), a multisite population-based longitudinal study in persons aged 65 and older. We analyzed a sub-sample of CHS participants 876 subjects (mean age 78.3, 57.5% F, 42.5% M) who had i) energy output assessed as kilocalories (kcal) per week using the standardized Minnesota Leisure-Time Activities questionnaire, ii) cognitive assessments for clinical classification of normal cognition, mild cognitive impairment (MCI), and AD, and iii) volumetric MR imaging of the brain. Voxel-based morphometry modeled the relationship between kcal/week and GM volumes while accounting for standard covariates including head size, age, sex, white matter hyperintensity lesions, MCI or AD status, and site. Multiple comparisons were controlled using a False Discovery Rate of 5 percent. RESULTS: Higher energy output, from a variety of physical activity types, was associated with larger GM volumes in frontal, temporal, and parietal lobes, as well as hippocampus, thalamus, and basal ganglia. High levels of caloric expenditure moderated neurodegeneration-associated volume loss in the precuneus, posterior cingulate, and cerebellar vermis. CONCLUSION: Increasing energy output from a variety of physical activities is related to larger gray matter volumes in the elderly, regardless of cognitive status.

Longitudinal Study of Impaired Intra- and Inter-Network Brain Connectivity in Subjects at High Risk for Alzheimer's Disease. - Zhan, Yafeng; Ma, Jianhua; Alexander-Bloch, Aaron F; Xu, Kaibin; Cui, Yue; Feng, Qianjin; Jiang, Tianzi; Liu, Yong (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is associated with abnormal resting-state network (RSN) architecture of the default mode network (DMN), the dorsal attention network (DAN), the executive control network (CON), the salience network (SAL), and the sensory-motor network (SMN). However, little is known about the disrupted intra- and inter-network architecture in mild cognitive impairment (MCI). Here, we employed a priori defined regions of interest to investigate the intra- and inter-network functional connectivity profiles of these RSNs in longitudinal participants, including normal controls (n = 23), participants with early MCI (n = 26), and participants with late MCI (n = 19). We found longitudinal alterations of functional connectivity within the DMN, where they were correlated with variation in cognitive ability. The SAL as well as the interaction between the DMN and the SAL were disrupted in MCI. Furthermore, our results demonstrate that longitudinal alterations of functional connectivity are more profound in earlier stages as opposed to later stages of the disease. The increased severity of cognitive impairment is associated with increasingly altered RSN connectivity patterns, suggesting that disruptions in functional connectivity may contribute to cognitive dysfunction and may represent a potential biomarker of impaired cognitive ability in MCI. Earlier prevention and treatment may help to delay disease progression to AD.

Looking for Measures of Disease Severity in the Frontotemporal Dementia Continuum. - Premi, Enrico; Gualeni, Vera; Costa, Paolo; Cosseddu, Maura; Gasparotti, Roberto; Padovani, Alessandro; Borroni, Barbara (J Alzheimers Dis, 2016)
Frontotemporal dementia (FTD) is characterized by executive dysfunctions, behavioral disturbances, language deficits and extrapyramidal symptoms. Frontotemporal lobar degeneration-modified Clinical Dementia Rating Scale (FTLD modified-CDR) has been proposed to measure disease severity in behavioral variant FTD (bvFTD). No tools of global disease severity are available in the other FTLD phenotypes [primary progressive aphasias (PPAs), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS)]. This would be strategic as outcome measures in clinical trials. To this aim, we evaluated the association between brain volume (voxel based morphometry) and available clinical scales in FTD. In 176 FTD patients (64 bvFTD, 40 PPAs, 32 PSP, 40 CBS), instrumental activities of daily living (ADLs), FTLD-modified CDR, Mini-Mental State Examination (MMSE), Frontal Behavioral Inventory (FBI), and Neuropsychiatry Inventory (NPI) were administered and MRI performed. Whole-brain linear correlation between each clinical rating scale and brain volume was performed. In bvFTD and PPAs, FTLD-modified CDR was associated with regional brain volume, thereby providing evidence for validity of the FTLD-modified CDR. In PSP, none of the clinical indicators were associated with regional brain volume. In CBS, ADLs and MMSE correlated with frontotemporal lower volume. Considering monogenic disease, FTLD-modified CDR was the best measure. In FTD continuum, different measures able to correlate with brain damage should be considered for the different clinical phenotypes or genetic traits.

Looking for Neuroimaging Markers in Frontotemporal Lobar Degeneration Clinical Trials: A Multi-Voxel Pattern Analysis Study in Granulin Disease. - Premi, Enrico; Cauda, Franco; Costa, Tommaso; Diano, Matteo; Gazzina, Stefano; Gualeni, Vera; Alberici, Antonella; Archetti, Silvana; Magoni, Mauro; Gasparotti, Roberto; Padovani, Alessandro; Borroni, Barbara (J Alzheimers Dis, 2016)
In light of future pharmacological interventions, neuroimaging markers able to assess the response to treatment would be crucial. In Granulin (GRN) disease, preclinical data will prompt pharmacological trials in the future. Two main points need to be assessed: (1) to identify target regions in different disease stages and (2) to determine the most accurate functional and structural neuroimaging index to be used. To this aim, we have taken advantage of the multivariate approach of multi-voxel pattern analysis (MVPA) to explore the information of brain activity patterns in a cohort of GRN Thr272fs carriers at different disease stages (14 frontotemporal dementia (FTD) patients and 17 asymptomatic carriers) and a group of 33 healthy controls. We studied structural changes by voxel-based morphometry (VBM), functional connectivity by assessing salience, default mode, fronto-parietal, dorsal attentional, executive networks, and local connectivity by regional homogeneity, amplitude of low frequency fluctuations (ALFF), fractional ALFF (fALFF), degree centrality, and voxel-mirrored homotopic connectivity. In FTD patients with GRN mutation, the most predictive measure was VBM structural analysis, while in asymptomatic carriers the best predictor marker was the local connectivity measure (fALFF). Altogether, all indexes demonstrated fronto-temporo-parietal damage in GRN pathology, with widespread structural damage of fronto-parietal and temporal regions when disease is overt. MVPA could be of aid in identifying the most accurate neuroimaging marker for clinical trials. This approach was able to identify both the target region and the best neuroimaging approach, which would be specific in the different disease stages. Further studies are needed to simultaneously integrate multimodal indexes in a classifier able to trace the disease progression moving from preclinical to clinical stage of the disease.
Keywords: Adult; Aged; Brain; Brain Mapping; Cohort Studies; Female; Frontotemporal Lobar Degeneration; Humans; Image Processing, Computer-Assisted; Intercellular Signaling Peptides and Proteins; Magnetic Resonance Imaging; Male; Middle Aged; Mutation; Neural Pathways; Oxygen; Phenylalanine; Threonine

Low Plasma Cholinesterase Activities are Associated with Deficits in Spatial Orientation, Reduced Ability to Perform Basic Activities of Daily Living, and Low Body Mass Index in Patients with Progressed Alzheimer's Disease. - Dingova, Dominika; Fazekas, Tomas; Okuliarova, Petra; Strbova, Jaroslava; Kucera, Matej; Hrabovska, Anna (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder characterized by a central cholinergic deficit. Non-neuronal cholinergic changes are, however, described as well. Here we focused on possible changes in the activity of the plasma cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), in hospitalized AD patients. We analyzed plasma AChE and BChE activities with regards to age, gender, body mass index (BMI), cognitive functions, and ability to perform activities of daily living in AD patients in comparison to healthy subjects. We observed lower AChE activity and trend toward lower BChE activity in AD patients, which both correlated with low BMI. AD patients unable to perform basic activities of daily living (feeding, bathing, dressing, and grooming) showed reduced plasma AChE activities, while worse spatial orientation was linked to lower BChE activities. Three out of four AD patients with the lowest BChE activities died within one year. In conclusion, progressed AD was accompanied by lower plasma AChE activity and trend toward lower BChE activity, which correlated with BMI and deficits in different components of the AD.
Keywords: Acetylcholinesterase; Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Blood Chemical Analysis; Body Mass Index; Butyrylcholinesterase; Female; Hospitalization; Humans; Male; Middle Aged; Orientation, Spatial

Low Prevalence of Mixed Dementia in a Cohort of 2,000 Elderly Patients in a Memory Clinic Setting. - Claus, Jules J; Staekenborg, Salka S; Roorda, Jelmen J; Stevens, Martijn; Herderschee, Dirk; van Maarschalkerweerd, Willy; Schuurmans, Lilly; Tielkes, Caroline E M; Koster, Pieter; Bavinck, Chris; Scheltens, Philip (J Alzheimers Dis, 2016)
BACKGROUND: It is generally assumed that with increasing age, pathology in clinically diagnosed Alzheimer's disease (AD) becomes more mixed, i.e., co-existence of amyloid plaques and cerebrovascular pathology. OBJECTIVE: To test the hypothesis of increasing prevalence of mixed dementia in late-onset clinically diagnosed Alzheimer's disease (AD) in a single-center memory clinic population. METHODS: Patients included had diagnoses of AD (n = 832), subjective cognitive impairment (SCI, n = 333), mild cognitive impairment (MCI, n = 492), vascular dementia (VaD, n = 57), other dementia (n = 53), or other diagnosis (n = 233). Prevalence of severe white matter lesions (WML) was defined as a score of 2 or higher on the Fazekas-scale on brain computed tomography to classify AD patients as having mixed dementia. We examined the effect of age on WML using multiple linear regression analysis, and AD patients were compared to SCI to determine the effect of disease on WML. RESULTS: Prevalence of severe WML was 33.6% in AD patients (mixed dementia), 11.4% in SCI, 22.7% in MCI, 75.4% in VaD, 3.8% in other dementia, and 15.5% in other diagnosis. With increasing age there was a significant and similar increase of WML scores in SCI, MCI, AD, other dementia, and other diagnosis, indicating no effect modification by AD. The difference between AD patients and SCI averaged 0.16 on the WML score and difference in percentage severe WML between AD and SCI patients was 15% across all ages. CONCLUSION: We found a low prevalence of mixed dementia. Furthermore, severe WML in AD was largely explained by age rather than effect of disease.
Keywords: Age Factors; Aged; Aged, 80 and over; Analysis of Variance; Cognitive Dysfunction; Cohort Studies; Dementia; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Prevalence; Regression Analysis; Risk Factors; Tomography Scanners, X-Ray Computed

Low Serum Insulin-Like Growth Factor-I Predicts Cognitive Decline in Alzheimer's Disease. - Vidal, Jean-Sébastien; Hanon, Olivier; Funalot, Benoît; Brunel, Nadège; Viollet, Cécile; Rigaud, Anne-Sophie; Seux, Marie-Laure; le-Bouc, Yves; Epelbaum, Jacques; Duron, Emmanuelle (J Alzheimers Dis, 2016)
BACKGROUND: The relationship between the insulin-like growth factor-I (IGF-I) system and Alzheimer's disease (AD) is mostly based on transversal studies. It remains, however, to demonstrate whether IGF-I is associated with cognitive decline over time in AD. OBJECTIVE: The objective of the study was to analyze the course of cognitive decline of AD subjects over a 24-month period in relation to serum IGF-I and insulin-like growth factor binding protein-3 (IGFBP-3) measured at baseline. METHODS: Data are from the SIGAL follow-up study. IGF-I and IGFBP-3 were measured in AD subjects who performed a Mini-Mental State Examination (MMSE) every 6 months for 2 years. MMSE course was analyzed using a mixed model with random intercept and slope function. RESULTS: Among the 200 AD participants, 146 (mean age = 81.1 (standard deviation (SD) = 5.9) years, 62.6% of women) had at least one follow-up visit. Mean IGF-I at baseline was 147.8 (74.2) ng/mL. Hundred forty-six participants (62.6%) had at least one follow-up visit. Mean MMSE was 21.7 (4.7)/30 and dropped on average by 2.28 points per year. MMSE decline was steeper among participants with lower IGF-I. For each decrease of 1 SD of IGF-I, subjects lost an additional 0.63 points per year in MMSE, e.g., participants with IGF-I level of 74 ng/mL lost 2.91 MMSE points per year whereas participants with IGF-I of 222 ng/mL lost 1.65 MMSE points per year. There was no association between IGFBP-3 and cognitive decline. CONCLUSION: Lower baseline serum IGF-I was associated with faster cognitive decline in AD over a 2-year period.

Lower Late-Life Body-Mass Index is Associated with Higher Cortical Amyloid Burden in Clinically Normal Elderly. - Hsu, David C; Mormino, Elizabeth C; Schultz, Aaron P; Amariglio, Rebecca E; Donovan, Nancy J; Rentz, Dorene M; Johnson, Keith A; Sperling, Reisa A; Marshall, Gad A (J Alzheimers Dis, 2016)
BACKGROUND: Lower body-mass index (BMI) in late life has been associated with an increased risk of dementia, and weight loss has been associated with more rapid decline in Alzheimer's disease (AD) dementia. OBJECTIVE: To explore the association between BMI and cortical amyloid burden in clinically normal (CN) elderly at risk for AD dementia. METHODS: Cross-sectional analyses were completed using baseline data from the Harvard Aging Brain Study, consisting of 280 community-dwelling CN older adults aged 62-90. Assessments included medical histories and physical exam, Pittsburgh compound B (PiB) positron emission tomography (PET) amyloid imaging, and apolipoprotein E ɛ4 (APOE4) genotyping. For the primary analysis, a general linear regression model was used to evaluate the association of BMI with PiB retention. Covariates included age, sex, years of education, and APOE4 carrier status. Secondary analyses were performed for BMI subdivisions (normal, overweight, obese), APOE4 carriers, and BMI×APOE4 interaction. RESULTS: In the primary analysis, greater PiB retention was associated with lower BMI (β  =  -0.14, p = 0.02). In the secondary analyses, APOE4 carrier status (β= -0.27, p = 0.02) and normal BMI (β= -0.25, p = 0.01), as opposed to overweight or obese BMI, were associated with greater PiB retention. The BMI×APOE4 interaction was also significant (β= -0.14, p = 0.04). CONCLUSIONS: This finding offers new insight into the role of BMI at the preclinical stage of AD, wherein lower BMI late in life is associated with greater cortical amyloid burden. Future studies are needed to elucidate the mechanism behind this association, especially in those with lower BMI who are APOE4 carriers.

Lower Prevalence of Alzheimer's Disease among Tibetans: Association with Religious and Genetic Factors. - Huang, Fukai; Shang, Ying; Luo, Yuandai; Wu, Peng; Huang, Xue; Tan, Xiaohui; Lu, Xingyi; Zhen, Lifang; Hu, Xianda (J Alzheimers Dis, 2016)
BACKGROUND: The prevalence of dementia differs among racial groups, the highest prevalence being in Latin America (8.5%) compared to sub-Saharan African regions (2-4%). The most common type of dementia is Alzheimer's disease (AD). OBJECTIVE: To estimate the prevalence of AD in the Qinghai-Tibet plateau and to investigate the related factors. METHODS: This was a cross-sectional, multistage cluster sampling design survey. Data was collected from May 2014 to September 2014 from 4,060 Tibetan aged >60 years. Participants underwent clinical examinations and neuropsychological evaluations. MALDI-TOF was used to test the genotypes of CLU, TFAM, TP53INP1, IGHV1-67, CR1, ApoE, and BIN1. Logistic regression models were used to ascertain the associations with AD. RESULTS: The prevalence of AD among Tibetan individuals aged >60 years was 1.33% (95% CI: 0.98-1.69). The CLU haplotypes AA+GA (odds ratio (OR) = 4.483; 95% CI: 1.069-18.792) of rs2279590 was correlated with AD. The CLU haplotypes GG+GC (OR = 0.184; 95% CI: 0.038-0.888) of rs9331888 and kowtow (OR = 0.203; 95% CI 0.046-0.896) were negatively correlated with AD. CONCLUSION: A low prevalence of AD was found in Tibetans from the Qinghai-Tibet plateau. Multivariate analysis might suggest that regular "mind-body" religious meditative activities may be negatively associated with AD in this population, as well as the CLU genotype at rs9331888.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Clusterin; Cognition Disorders; Cross-Sectional Studies; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Logistic Models; Male; Middle Aged; Neuropsychological Tests; Polymorphism, Single Nucleotide; Psychiatric Status Rating Scales; Religion; Risk Factors; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tibet

LRP/LR Antibody Mediated Rescuing of Amyloid-β-Induced Cytotoxicity is Dependent on PrPc in Alzheimer's Disease. - Pinnock, Emma C; Jovanovic, Katarina; Pinto, Maxine G; Ferreira, Eloise; Dias, Bianca Da Costa; Penny, Clement; Knackmuss, Stefan; Reusch, Uwe; Little, Melvyn; Schatzl, Hermann M; Weiss, Stefan F T (J Alzheimers Dis, 2016)
The neuronal perturbations in Alzheimer's disease are attributed to the formation of extracellular amyloid-β (Aβ) neuritic plaques, composed predominantly of the neurotoxic Aβ42 isoform. Although the plaques have demonstrated a role in synaptic dysfunction, neuronal cytotoxicity has been attributed to soluble Aβ42 oligomers. The 37kDa/67kDa laminin receptor has been implicated in Aβ42 shedding and Aβ42-induced neuronal cytotoxicity, as well as internalization of this neurotoxic peptide. As the cellular prion protein binds to both LRP/LR and Aβ42, the mechanism underlying this cytotoxicity may be indirectly due to the PrPc-Aβ42 interaction with LRP/LR. The effects of this interaction were investigated by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assays. PrPc overexpression significantly enhanced Aβ42 cytotoxicity in vitro, while PrP-/-  cells were more resistant to the cytotoxic effects of Aβ42 and exhibited significantly less cell death than PrPc expressing N2a cells. Although anti-LRP/LR specific antibody IgG1-iS18 significantly enhanced cell viability in both pSFV1-huPrP1-253 transfected and non-transfected cells treated with exogenous Aβ42, it failed to have any cell rescuing effect in PrP-/-  HpL3-4 cells. These results suggest that LRP/LR plays a significant role in Aβ42-PrPc mediated cytotoxicity and that anti-LRP/LR specific antibodies may serve as potential therapeutic tools for Alzheimer's disease.
Keywords: Amyloid beta-Peptides; Animals; Antibodies; Cell Line, Transformed; Cell Survival; Flow Cytometry; Gene Expression Regulation; Humans; Mice; Peptide Fragments; Prions; Receptors, Laminin; Transfection

M2 Macrophage Transplantation Ameliorates Cognitive Dysfunction in Amyloid-β-Treated Rats Through Regulation of Microglial Polarization. - Zhu, Dan; Yang, Nan; Liu, Yan-Yong; Zheng, Ji; Ji, Chao; Zuo, Ping-Ping (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly population. Neuroinflammation induced by amyloid-β (Aβ) aggregation is considered to be the critical factor underlying AD pathological mechanisms. Alternatively activated (M2) macrophages/microglia have been reported to have neuroprotective effects in neurodegenerative disease. In this study, we characterized the neuroprotective effects of M2 macrophage transplantation in AD model rats and investigated the underlying mechanisms. Intracerebroventricular injection of Aβ1 - 42 to rats was used to model AD and resulted in cognitive impairment, neuronal damage, and inflammatory changes in the brain microenvironment. We observed an increased interferon regulatory factor (IRF) 5/IRF4 ratio, resulting in greater production of classically activated (M1) versus M2 microglia. M2 macrophage transplantation attenuated inflammation in the brain, reversed Aβ1 - 42-induced changes in the IRF4-IRF5 ratio, drove endogenous microglial polarization toward the M2 phenotype, and ameliorated cognitive impairment. Nerve growth factor (NGF) treatment reduced the IRF5/IRF4 ratio and induced primary microglial polarization to the M2 phenotype in vitro; these effects were prevented by tyrosine Kinase Receptor A (TrkA) inhibition. M2 macrophage transplantation restored the balance of IRF4-IRF5 by affecting the expression of NGF and inflammatory cytokines in the brains of AD model rats. This drove microglial polarization to the M2 phenotype, promoted termination of neuroinflammation, and resulted in improved cognitive abilities.

Maintenance of Cognitive Performance and Mood for Individuals with Alzheimer's Disease Following Consumption of a Nutraceutical Formulation: A One-Year, Open-Label Study. - Remington, Ruth; Bechtel, Cynthia; Larsen, David; Samar, Annemarie; Page, Robert; Morrell, Christopher; Shea, Thomas B (J Alzheimers Dis, 2016)
Nutritional interventions have shown varied efficacy on cognitive performance during Alzheimer's disease (AD). Twenty-four individuals diagnosed with AD received a nutraceutical formulation (NF: folate, alpha-tocopherol, B12, S-adenosyl methioinine, N-acetyl cysteine, acetyl-L-carnitine) under open-label conditions (ClinicalTrials.gov NCT01320527). Primary outcome was cognitive performance. Secondary outcomes were behavioral and psychological symptoms of dementia (BPSD) and activities of daily living. Participants maintained their baseline cognitive performance and BPSD over 12 months. These findings are consistent with improvement in cognitive performance and BPSD in prior placebo-controlled studies with NF, and contrast with the routine decline for participants receiving placebo.
Keywords: Aged; Aged, 80 and over; alpha-Tocopherol; Alzheimer Disease; Cognition Disorders; Dietary Supplements; Disease Progression; Female; Folic Acid; Follow-Up Studies; Humans; Male; Mood Disorders; Neuropsychological Tests; Psychiatric Status Rating Scales; Time Factors; Vitamin B 12

MAPT H1 Haplotype is Associated with Late-Onset Alzheimer's Disease Risk in APOEɛ4 Noncarriers: Results from the Dementia Genetics Spanish Consortium. - Pastor, Pau; Moreno, Fermín; Clarimón, Jordi; Ruiz, Agustin; Combarros, Onofre; Calero, Miguel; López de Munain, Adolfo; Bullido, Maria J; de Pancorbo, Marian M; Carro, Eva; Antonell, Anna; Coto, Eliecer; et al. (J Alzheimers Dis, 2016)
The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer's disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson's disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR) = 2.03; p = 0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0005). Stratification analysis showed that this association was mainly driven by APOE ɛ4 noncarriers (OR = 1.14; p = 0.0025). MAPT H1 was also associated with risk for PD (OR = 1.30; p = 0.0003) and PSP (OR = 3.18; p = 8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE ɛ4 AD.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Apolipoprotein E4; Female; Frontotemporal Dementia; Genetic Predisposition to Disease; Haplotypes; Humans; Logistic Models; Male; Middle Aged; Polymorphism, Single Nucleotide; Spain; tau Proteins

Matrix Metalloproteinase in Blood-Brain Barrier Breakdown in Dementia. - Weekman, Erica M; Wilcock, Donna M (J Alzheimers Dis, 2016)
The neurovascular unit, which consists of astrocytic end-feet, neurons, pericytes, and endothelial cells, plays a key role in maintaining brain homeostasis by forming the blood-brain barrier and carefully controlling local cerebral blood flow. When the blood-brain barrier is disrupted, blood components can leak into the brain, damage the surrounding tissue and lead to cognitive impairment. This disruption in the blood-brain barrier and subsequent impairment in cognition are common after stroke and during cerebral amyloid angiopathy and Alzheimer's disease. Matrix metalloproteinases are proteases that degrade the extracellular matrix as well as tight junctions between endothelial cells and have been implicated in blood-brain barrier breakdown in neurodegenerative diseases. This review will focus on the roles of MMP2 and MMP9 in dementia, primarily post-stroke events that lead to dementia, cerebral amyloid angiopathy, and Alzheimer's disease.
Keywords: Animals; Blood-Brain Barrier; Dementia; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9

Measurement Error, Reliability, and Minimum Detectable Change in the Mini-Mental State Examination, Montreal Cognitive Assessment, and Color Trails Test among Community Living Middle-Aged and Older Adults. - Feeney, Joanne; Savva, George M; O'Regan, Claire; King-Kallimanis, Bellinda; Cronin, Hilary; Kenny, Rose Anne (J Alzheimers Dis, 2016)
BACKGROUND: Knowing the reliability of cognitive tests, particularly those commonly used in clinical practice, is important in order to interpret the clinical significance of a change in performance or a low score on a single test. OBJECTIVE: To report the intra-class correlation (ICC), standard error of measurement (SEM) and minimum detectable change (MDC) for the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Color Trails Test (CTT) among community dwelling older adults. METHODS: 130 participants aged 55 and older without severe cognitive impairment underwent two cognitive assessments between two and four months apart. Half the group changed rater between assessments and half changed time of day. RESULTS: Mean (standard deviation) MMSE was 28.1 (2.1) at baseline and 28.4 (2.1) at repeat. Mean (SD) MoCA increased from 24.8 (3.6) to 25.2 (3.6). There was a rater effect on CTT, but not on the MMSE or MoCA. The SEM of the MMSE was 1.0, leading to an MDC (based on a 95% confidence interval) of 3 points. The SEM of the MoCA was 1.5, implying an MDC95 of 4 points. MoCA (ICC = 0.81) was more reliable than MMSE (ICC = 0.75), but all tests examined showed substantial within-patient variation. CONCLUSION: An individual's score would have to change by greater than or equal to 3 points on the MMSE and 4 points on the MoCA for the rater to be confident that the change was not due to measurement error. This has important implications for epidemiologists and clinicians in dementia screening and diagnosis.

Measuring Information Processing Speed in Mild Cognitive Impairment: Clinical Versus Research Dichotomy. - Haworth, Judy; Phillips, Michelle; Newson, Margaret; Rogers, Peter J; Torrens-Burton, Anna; Tales, Andrea (J Alzheimers Dis, 2016)
A substantial body of research evidence is indicative of disproportionately slowed information processing speed in a wide range of multi-trial, computer-based, neuroimaging- and electroencephalography-based reaction time (RT) tests in Alzheimer's disease and mild cognitive impairment (MCI). However, in what is arguably a dichotomy between research evidence and clinical practice, RT associated with different brain functions is rarely assessed as part of their diagnosis. Indeed, often only the time taken to perform a single, specific task, commonly the Trail making test (TMT), is measured. In clinical practice therefore, there can be a failure to assess adequately the integrity of the rapid, serial information processing and response, necessary for efficient, appropriate, and safe interaction with the environment. We examined whether a typical research-based RT task could at least match the TMT in differentiating amnestic MCI (aMCI) from cognitively healthy aging at group level. As aMCI is a heterogeneous group, typically containing only a proportion of individuals for whom aMCI represents the early stages of dementia, we examined the ability of each test to provide intra-group performance variation. The results indicate that as well as significant slowing in performance of the operations involved in TMT part B (but not part A), individuals with aMCI also experience significant slowing in RT compared to controls. The results also suggest that research-typical RT tests may be superior to the TMT in differentiating between cognitively healthy aging and aMCI at group level and in revealing the performance variability one would expect from an etiologically heterogeneous disorder such as aMCI.
Keywords: Aged; Aged, 80 and over; Attention; Cognitive Dysfunction; Electroencephalography; Female; Humans; Male; Mental Processes; Mental Status Schedule; Middle Aged; Neuroimaging; Neuropsychological Tests; Photic Stimulation; Reaction Time; Residence Characteristics

The Mechanism Underlying Amyloid Polymorphism is Opened for Alzheimer's Disease Amyloid-β Peptide. - Selivanova, Olga M; Surin, Alexey K; Marchenkov, Victor V; Dzhus, Ulyana F; Grigorashvili, Elizaveta I; Suvorina, Mariya Yu; Glyakina, Anna V; Dovidchenko, Nikita V; Galzitskaya, Oxana V (J Alzheimers Dis, 2016)
It has been demonstrated using Aβ40 and Aβ42 recombinant and synthetic peptides that their fibrils are formed of complete oligomer ring structures. Such ring structures have a diameter of about 8-9 nm, an oligomer height of about 2- 4 nm, and an internal diameter of the ring of about 3-4 nm. Oligomers associate in a fibril in such a way that they interact with each other, overlapping slightly. There are differences in the packing of oligomers in fibrils of recombinant and synthetic Aβ peptides. The principal difference is in the degree of orderliness of ring-like oligomers that leads to generation of morphologically different fibrils. Most ordered association of ring-like structured oligomers is observed for a recombinant Aβ40 peptide. Less ordered fibrils are observed with the synthetic Aβ42 peptide. Fragments of fibrils the most protected from the action of proteases have been determined by tandem mass spectrometry. It was shown that unlike Aβ40, fibrils of Aβ42 are more protected, showing less ordered organization compared to that of Aβ40 fibrils. Thus, the mass spectrometry data agree with the electron microscopy data and structural models presented here.

The Memory Binding Test: Development of Two Alternate Forms into Spanish and Catalan. - Gramunt, Nina; Sánchez-Benavides, Gonzalo; Buschke, Herman; Diéguez-Vide, Faustino; Peña-Casanova, Jordi; Masramon, Xavier; Fauria, Karine; Gispert, Juan D; Molinuevo, José L (J Alzheimers Dis, 2016)
BACKGROUND: The Memory Binding Test (MBT) is emerging as a promising tool for the detection of subtle memory impairment suggestive of Alzheimer's disease (AD). For such a test to be widely accessed and used, the availability of both alternate forms and language adaptations is required. OBJECTIVES: To develop a thorough methodology for obtaining alternate forms (A and B) of the MBT in Spanish and Catalan and to assess their equivalence. METHOD: According to the original development of the test, frequency was taken as the lexical variable of reference for the Spanish and Catalan adaptations. A crossed design protocol by form and language was used to compare the MBT results in a sample of 290 cognitively normal middle-aged participants. Pairwise Intraclass Correlation Coefficients (ICCs) were calculated among the six possible combinations. RESULTS: The Spanish and Catalan lists of words for the MBT A and B resulting from the adaptation process as well as the original lists in English are presented. ICC indices for the comparisons between forms and languages ranged from 0.56 to 0.82. CONCLUSION: The MBT A and B in Spanish and Catalan showed similar outcomes and can be considered equivalent. Moreover, the thorough methodology presented here for the transcultural adaptation and equivalence study, could serve as a model for future adaptations of the MBT and other verbal tests.

Memory Binding Test Predicts Incident Amnestic Mild Cognitive Impairment. - Mowrey, Wenzhu B; Lipton, Richard B; Katz, Mindy J; Ramratan, Wendy S; Loewenstein, David A; Zimmerman, Molly E; Buschke, Herman (J Alzheimers Dis, 2016)
BACKGROUND: The Memory Binding Test (MBT), previously known as Memory Capacity Test, has demonstrated discriminative validity for distinguishing persons with amnestic mild cognitive impairment (aMCI) and dementia from cognitively normal elderly. OBJECTIVE: We aimed to assess the predictive validity of the MBT for incident aMCI. METHODS: In a longitudinal, community-based study of adults aged 70+, we administered the MBT to 246 cognitively normal elderly adults at baseline and followed them annually. Based on previous work, a subtle reduction in memory binding at baseline was defined by a Total Items in the Paired (TIP) condition score of ≤22 on the MBT. Cox proportional hazards models were used to assess the predictive validity of the MBT for incident aMCI accounting for the effects of covariates. The hazard ratio of incident aMCI was also assessed for different prediction time windows ranging from 4 to 7 years of follow-up, separately. RESULTS: Among 246 controls who were cognitively normal at baseline, 48 developed incident aMCI during follow-up. A baseline MBT reduction was associated with an increased risk for developing incident aMCI (hazard ratio (HR) = 2.44, 95% confidence interval: 1.30-4.56, p = 0.005). When varying the prediction window from 4-7 years, the MBT reduction remained significant for predicting incident aMCI (HR range: 2.33-3.12, p: 0.0007-0.04). CONCLUSION: Persons with poor performance on the MBT are at significantly greater risk for developing incident aMCI. High hazard ratios up to seven years of follow-up suggest that the MBT is sensitive to early disease.

Memory for Public Events in Mild Cognitive Impairment and Alzheimer's Disease: The Importance of Rehearsal. - Langlois, Roxane; Joubert, Sven; Benoit, Sophie; Dostie, Valérie; Rouleau, Isabelle (J Alzheimers Dis, 2016)
Ribot's law refers to the better preservation of remote memories compared with recent ones that presumably characterizes retrograde amnesia. Even if Ribot-type temporal gradient has been extensively studied in retrograde amnesia, particularly in Alzheimer's disease (AD), this pattern has not been consistently found. One explanation for these results may be that rehearsal frequency rather than remoteness accounts for the better preservation of these memories. Thus, the aim of present study was to address this question by studying retrograde semantic memory in subjects with amnestic mild cognitive impairment (aMCI) (n = 20), mild AD (n = 20) and in healthy older controls (HC; n = 19). In order to evaluate the impact of repetition as well as the impact of remoteness, we used a test assessing memory for enduring and transient public events that occurred in the recent and remote past. Results show no clear temporal gradient across time periods (1960-1975; 1976-1990; 1991-2005; 2006-2011), but a better performance was observed in all three groups for enduring compared with transient events. Moreover, although deficits were globally found in both patients groups compared with HC, more specific analyses revealed that aMCI patients were only impaired on transient events while AD patients were impaired on both transient and enduring events. Exploratory analyses also revealed a tendency suggesting preservation of remote transient events in aMCI. These findings are discussed with regards to memory consolidation models.
Keywords: Aged; Alzheimer Disease; Cognitive Dysfunction; Female; Humans; Learning; Male; Memory; Psychological Tests; Semantics

Memory Impairment at Initial Clinical Presentation in Posterior Cortical Atrophy. - Ahmed, Samrah; Baker, Ian; Husain, Masud; Thompson, Sian; Kipps, Christopher; Hornberger, Michael; Hodges, John R; Butler, Christopher R (J Alzheimers Dis, 2016)
Posterior cortical atrophy (PCA) is characterized by core visuospatial and visuoperceptual deficits, and predominant atrophy in the parieto-occipital cortex. The most common underlying pathology is Alzheimer's disease (AD). Existing diagnostic criteria suggest that episodic memory is relatively preserved. The aim of this study was to examine memory performance at initial clinical presentation in PCA, compared to early-onset AD patients (EOAD). 15 PCA patients and 32 EOAD patients, and 34 healthy controls were entered into the study. Patients were tested on the Addenbrooke's Cognitive Examination (ACE-R), consisting of subscales in memory and visuospatial skills. PCA and EOAD patients were significantly impaired compared to controls on the ACE total score (p < 0.001), visuospatial skills (p < 0.001), and memory (p < 0.001). Consistent with the salient diagnostic deficits, PCA patients were significantly more impaired on visuospatial skills compared to EOAD patients (p < 0.001). However, there was no significant difference between patient groups in memory. Further analysis of learning, recall, and recognition components of the memory subscale showed that EOAD and PCA patients were significantly impaired compared to controls on all three components (p < 0.001), however, there was no significant difference between EOAD and PCA patients. The results of this study show that memory is impaired in the majority of PCA patients at clinical presentation. The findings suggest that memory impairment must be considered in assessment and management of PCA. Further study into memory in PCA is warranted, since the ACE-R is a brief screening tool and is likely to underestimate the presence of memory impairment.

A Mercaptoacetamide-Based Class II Histone Deacetylase Inhibitor Increases Dendritic Spine Density via RasGRF1/ERK Pathway. - Song, Jung Min; Sung, You Me; Nam, Jin Han; Yoon, Hyejin; Chung, Andrew; Moffat, Emily; Jung, Mira; Pak, Daniel T S; Kim, Jungsu; Hoe, Hyang-Sook (J Alzheimers Dis, 2016)
BACKGROUND: The accumulation of amyloid-β (Aβ) leads to the loss of dendritic spines and synapses, which is hypothesized to cause cognitive impairments in Alzheimer's disease (AD) patients. In our previous study, we demonstrated that a novel mercaptoacetamide-based class II histone deacetylase inhibitor (HDACI), known as W2, decreased Aβ levels and improved learning and memory in mice. However, the underlying mechanism of this effect is unknown. OBJECTIVE: Because dendritic spine formation is associated with cognitive performance, here we investigated whether HDACI W2 regulates dendritic spine density and its molecular mechanism of action. METHODS: To examine the effect of HDACI W2 on dendritic spine density, we conducted morphological analysis of dendritic spines using GFP transfection and Golgi staining. In addition, to determine the molecular mechanism of W2 effects on spines, we measured the levels of mRNAs and proteins involved in the Ras signaling pathway using quantitative real-time PCR, immunocytochemistry, and western analysis. RESULTS: We found that HDACI W2 altered dendritic spine density and morphology in vitro and in vivo. Additionally, W2 increased the mRNA or protein levels of Ras GRF1 and phospho-ERK. Moreover, knockdown of RasGRF1 and inhibition of ERK activity prevented the W2-mediated spinogenesis in primary hippocampal neurons. CONCLUSION: Our Class II-selective HDACI W2 promotes the formation and growth of dendritic spines in a RasGRF1 and ERK dependent manner in primary hippocampal neurons.
Keywords: Acetamides; Animals; Blotting, Western; Cells, Cultured; Cerebral Cortex; Dendritic Spines; Gene Knockdown Techniques; Green Fluorescent Proteins; Hippocampus; Histone Deacetylase Inhibitors; Immunohistochemistry; MAP Kinase Signaling System; Mice, Inbred C57BL; ras-GRF1; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Thioglycolates; Transfection

A Meta-Analysis of Alzheimer's Disease Incidence and Prevalence Comparing African-Americans and Caucasians. - Steenland, Kyle; Goldstein, Felicia C; Levey, Allan; Wharton, Whitney (J Alzheimers Dis, 2016)
BACKGROUND: Several studies have shown higher Alzheimer's disease (AD) incidence rates are in African-Americans (AAs) than Caucasians (CCs). If this finding is consistent across studies, it raises important etiologic questions regarding factors responsible for this discrepancy. It also affects the likely public health burden of AD in the US in the future, as the non-Caucasian population becomes the majority. OBJECTIVE: Estimate the AA/CC rate ratio for AD incidence across all available studies. METHODS: We conducted a meta-analysis of population-based studies for the rate ratio (RR) of AD incidence for AAs versus CCs, after identifying six relevant studies from the literature. We calculated an AA/CC rate ratio across all studies using inverse-variance weighting, and assessed inter-study heterogeneity. Using these incidence data, as well as data on survival after diagnosis, and on all-cause mortality, we also estimated the US prevalence of AD among AAs and CCs. RESULTS: There were six population-based studies with data comparing AD incidence between AAs and CCs, with an estimated 370 AA and 640 CC incident cases. The meta-analysis RR showed that the AD rate for AAs was 64% higher than for CCs (RR = 1.64 (95% CI 1.35-2.00)) 1.35-2.00)), with no evidence of heterogeneity. We estimated the current US AD prevalence for ages 65-90 to be 5.5% for CCs, and 8.6% for AAs (prevalence ratio 1.56). CONCLUSION: AAs have an increased risk of incident and prevalent AD compared to CCs for reasons which are unknown, but are hypothesized to reflect biological, psychological, and socioeconomic factors.
Keywords: African Americans; Alzheimer Disease; Community Health Planning; European Continental Ancestry Group; Female; Follow-Up Studies; Humans; Incidence; Male; Prevalence

Meta-Analysis of Transcriptome Data Related to Hippocampus Biopsies and iPSC-Derived Neuronal Cells from Alzheimer's Disease Patients Reveals an Association with FOXA1 and FOXA2 Gene Regulatory Networks. - Wruck, Wasco; Schröter, Friederike; Adjaye, James (J Alzheimers Dis, 2016)
Although the incidence of Alzheimer's disease (AD) is continuously increasing in the aging population worldwide, effective therapies are not available. The interplay between causative genetic and environmental factors is partially understood. Meta-analyses have been performed on aspects such as polymorphisms, cytokines, and cognitive training. Here, we propose a meta-analysis approach based on hierarchical clustering analysis of a reliable training set of hippocampus biopsies, which is condensed to a gene expression signature. This gene expression signature was applied to various test sets of brain biopsies and iPSC-derived neuronal cell models to demonstrate its ability to distinguish AD samples from control. Thus, our identified AD-gene signature may form the basis for determination of biomarkers that are urgently needed to overcome current diagnostic shortfalls. Intriguingly, the well-described AD-related genes APP and APOE are not within the signature because their gene expression profiles show a lower correlation to the disease phenotype than genes from the signature. This is in line with the differing characteristics of the disease as early-/late-onset or with/without genetic predisposition. To investigate the gene signature's systemic role(s), signaling pathways, gene ontologies, and transcription factors were analyzed which revealed over-representation of response to stress, regulation of cellular metabolic processes, and reactive oxygen species. Additionally, our results clearly point to an important role of FOXA1 and FOXA2 gene regulatory networks in the etiology of AD. This finding is in corroboration with the recently reported major role of the dopaminergic system in the development of AD and its regulation by FOXA1 and FOXA2.
Keywords: Alzheimer Disease; Biopsy; Cells, Cultured; Gene Regulatory Networks; Hepatocyte Nuclear Factor 3-alpha; Hepatocyte Nuclear Factor 3-beta; Hippocampus; Humans; Induced Pluripotent Stem Cells; Transcriptome

Metabolic Syndrome and Mild Cognitive Impairment: A Case-Control Study among Elderly in a Shanghai Suburb. - Yao, Qian; Jiang, Guo-Xin; Zhou, Zhi-Ming; Chen, Jin-Mei; Cheng, Qi (J Alzheimers Dis, 2016)
BACKGROUND: Metabolic syndrome (MetS) maybe associated with mild cognitive impairment (MCI). OBJECTIVE: To investigate the relationship between MetS, with its individual or combined components, and MCI among elderly. METHODS: A case-control study was conducted among the elderly aged 65 years and over in a community located in the southwestern suburb of Shanghai, China. The Chinese version of the Mini-Mental Status Examination (C-MMSE) was used to screen subjects with MCI. Associations of MetS with its individual or combined components and MCI were analyzed using conditional regression analyses with or without adjustment for gender, education, current smoking, current drinking, and physical activities. RESULTS: There were 379 subjects with MCI and 379 gender- and age-matched healthy controls in the study. Compared with healthy controls in univariate analyses, subjects with MCI were more likely to have less time spent on physical activity, lower C-MMSE score, heavier weight, larger waistline and hipline, higher diastolic blood pressure, higher body mass index, higher abdominal obesity index, higher serum glycated hemoglobin, higher serum triglycerides, higher serum cholesterol, higher serum uric acid, and higher serum alanine aminotransferase. After multivariable adjustment, MetS was significantly associated with an increased risk of MCI (OR = 2.277; 95% CI: 1.086-4.773). Among MetS components, abdominal obesity (OR = 2.101; 95% CI: 1.224-3.608) and hypertension (OR = 2.075; 95% CI: 1.170-3.678) showed a significant association with MCI, respectively; while these two components were combined, the association was stronger (OR = 2.459; 95% CI: 1.360-4.447). CONCLUSION: MetS and its components, particularly abdominal obesity and hypertension, were found to be significantly associated with the risk of MCI.
Keywords: Activities of Daily Living; Aged; Aged, 80 and over; Aging; Case-Control Studies; Chi-Square Distribution; China; Cities; Cognition Disorders; Community Health Planning; Female; Humans; Male; Mental Status Schedule; Metabolic Diseases; Risk Factors

Metallothioneins in Prion- and Amyloid-Related Diseases. - Adam, Pavlína; Křížková, Soňa; Heger, Zbyněk; Babula, Petr; Pekařík, Vladimír; Vaculovičoá, Markéta; Gomes, Cláudio M; Kizek, René; Adam, Vojtěch (J Alzheimers Dis, 2016)
Prion and other amyloid-forming diseases represent a group of neurodegenerative disorders that affect both animals and humans. The role of metal ions, especially copper and zinc is studied intensively in connection with these diseases. Their involvement in protein misfolding and aggregation and their role in creation of reactive oxygen species have been shown. Recent data also show that metal ions not only bind the proteins with high affinity, but also modify their biochemical properties, making them important players in prion-related diseases. In particular, the level of zinc ions is tightly regulated by several mechanisms, including transporter proteins and the low molecular mass thiol-rich metallothioneins. From four metallothionein isoforms, metallothionein-3, a unique brain-specific metalloprotein, plays a crucial role only in this regulation. This review critically evaluates the involvement of metallothioneins in prion- and amyloid-related diseases in connection with the relationship between metallothionein isoforms and metal ion regulation of their homeostasis.
Keywords: Amyloidosis; Animals; Brain Diseases; Humans; Metallothionein; Prion Diseases

Metformin Facilitates Amyloid-β Generation by β- and γ-Secretases via Autophagy Activation. - Son, Sung Min; Shin, Hong-Joon; Byun, Jayoung; Kook, Sun Young; Moon, Minho; Chang, Yu Jin; Mook-Jung, Inhee (J Alzheimers Dis, 2016)
The evidence of strong pathological associations between type 2 diabetes and Alzheimer's disease (AD) has increased in recent years. Contrary to suggestions that anti-diabetes drugs may have potential for treating AD, we demonstrate here that the insulin sensitizing anti-diabetes drug metformin (Glucophage®) increased the generation of amyloid-β (Aβ), one of the major pathological hallmarks of AD, by promoting β- and γ-secretase-mediated cleavage of amyloid-β protein precursor (AβPP) in SH-SY5Y cells. In addition, we show that metformin caused autophagosome accumulation in Tg6799 AD model mice. Extremely high γ-secretase activity was also detected in autophagic vacuoles, apparently a novel site of Aβ peptide generation. Together, these data suggest that metformin-induced accumulation of autophagosomes resulted in increased γ-secretase activity and Aβ generation. Additional experiments indicated that metformin increased phosphorylation of AMP-activated protein kinase, which activates autophagy by suppressing mammalian target of rapamycin (mTOR). The suppression of mTOR then induces the abnormal accumulation of autophagosomes. We conclude that metformin, an anti-diabetes drug, may exacerbate AD pathogenesis by promoting amyloidogenic AβPP processing in autophagosomes.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Autophagy; Cell Line, Tumor; Disease Models, Animal; Female; Humans; Hypoglycemic Agents; Lysosomes; Metformin; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Electron; Mutation; Neuroblastoma; Signal Transduction

Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial. - Luchsinger, Jose A; Perez, Thania; Chang, Helena; Mehta, Pankaj; Steffener, Jason; Pradabhan, Gnanavalli; Ichise, Masanori; Manly, Jennifer; Devanand, Davangere P; Bagiella, Emilia (J Alzheimers Dis, 2016)
Diabetes and hyperinsulinemia may be risk factors for Alzheimer's disease (AD). We conducted a pilot study of metformin, a medication efficacious in treating and preventing diabetes while reducing hyperinsulinemia, among persons with amnestic mild cognitive impairment (aMCI) with the goal of collecting preliminary data on feasibility, safety, and efficacy. Participants were 80 men and women aged 55 to 90 years with aMCI, overweight or obese, without treated diabetes. We randomized participants to metformin 1000 mg twice a day or matching placebo for 12 months. The co-primary clinical outcomes were changes from baseline to 12 months in total recall of the Selective Reminding Test (SRT) and the score of the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). The secondary outcome was change in relative glucose uptake in the posterior cingulate-precuneus in brain fluorodeoxyglucose positron emission tomography. Change in plasma Aβ42 was an exploratory outcome. The mean age of participants was 65 years. Fifty percent of participants were women. The only baseline variable that was different between the arms was the ADAS-Cog. Metformin could not be tolerated by 7.5% of participants; 15% tolerated 500 mg/day, 35% tolerated 1000 mg/day, 32.5% tolerated 1500 mg/day, and only 10% tolerated the maximum dose. There were no serious adverse events related to metformin. The 7.5% of persons who did not tolerate metformin reported gastrointestinal symptoms. After adjusting for baseline ADAS-cog, changes in total recall of the SRT favored the metformin group (9.7±8.5 versus 5.3±8.5; p = 0.02). Differences for other outcomes were not significant. A larger trial seems warranted to evaluate the efficacy and cognitive safety of metformin in prodromal AD.
Keywords: Aged; Aged, 80 and over; Amyloid beta-Peptides; Brain; Cognitive Dysfunction; Double-Blind Method; Female; Follow-Up Studies; Glucose; Humans; Male; Metformin; Middle Aged; Nootropic Agents; Overweight; Peptide Fragments; Pilot Projects; Positron-Emission Tomography; Psychological Tests; Severity of Illness Index; Treatment Outcome

Methods for the Specific Detection and Quantitation of Amyloid-β Oligomers in Cerebrospinal Fluid. - Schuster, Judith; Funke, Susanne Aileen (J Alzheimers Dis, 2016)
Protein misfolding and aggregation are fundamental features of the majority of neurodegenerative diseases, like Alzheimer's disease (AD), Parkinson's disease, frontotemporal dementia, and prion diseases. Proteinaceous deposits in the brain of the patient, e.g., amyloid plaques consisting of the amyloid-β (Aβ) peptide and tangles composed of tau protein, are the hallmarks of AD. Soluble oligomers of Aβ and tau play a fundamental role in disease progression, and specific detection and quantification of the respective oligomeric proteins in cerebrospinal fluid may provide presymptomatically detectable biomarkers, paving the way for early diagnosis or even prognosis. Several studies on the development of techniques for the specific detection of Aβ oligomers were published, but some of the existing tools do not yet seem to be satisfactory, and the study results are contradicting. The detection of oligomers is challenging due to their polymorphous and unstable nature, their low concentration, and the presence of competing proteins and Aβ monomers in body fluids. Here, we present an overview of the current state of the development of methods for Aβ oligomer specific detection and quantitation. The methods are divided in the three subgroups: (i) enzyme linked immunosorbent assays (ELISA), (ii) methods for single oligomer detection, and (iii) others, which are mainly biosensor based methods.

MicroRNAs as Therapeutic Targets for Alzheimer's Disease. - Di Meco, Antonio; Praticò, Domenico (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is the most common cause of dementia in the elderly. With increasing longevity and the absence of a cure, AD has become not only a major health problem but also a heavy social and economic burden worldwide. Given this public health challenge, and that the current approved therapy for AD is limited to symptomatic treatment (i.e., cholinesterase inhibitors and NMDA receptor antagonists), exploration of new molecular pathways as novel therapeutic targets remains an attractive option for disease modifying drug development. microRNAs (miRNAs) are short non-coding RNA that control gene expression at the post-translational level by inhibiting translation of specific mRNAs or degrading them. Dysregulation of several miRNAs has been described in AD brains. Interestingly, their molecular targets are pathways that are well-established functional players in the onset and development of AD pathogenesis. Today several molecular tools have been developed to modulate miRNA levels in vitro and in vivo. These scientific advancements are affording us for the first time with the real possibility of targeting in vivo these dysregulated miRNAs as a novel therapeutic approach against AD.

Midlife Physical Activity and Cognition Later in Life: A Prospective Twin Study. - Iso-Markku, Paula; Waller, Katja; Vuoksimaa, Eero; Heikkilä, Kauko; Rinne, Juha; Kaprio, Jaakko; Kujala, Urho M (J Alzheimers Dis, 2016)
BACKGROUND: Physical activity has been associated with a reduced risk of cognitive decline but the nature of this association remains obscure. OBJECTIVE: To study associations between midlife physical activity and cognition in old age for a prospective cohort of Finnish twins. METHODS: Physical activity in the Finnish Twin Cohort was assessed using questionnaire responses collected in 1975 and 1981. After a mean follow-up of 25.1 years, the subjects' (n = 3050; mean age 74.2; range 66-97) cognition was evaluated with a validated telephone interview. Both participation in vigorous physical activity, and the volume of physical activity, divided into quintiles, were used as predictors of cognitive impairment. Metrics collected by TELE were used to categorize participants as: cognitively impaired, suffering mild cognitive impairment, or cognitively healthy. RESULTS: Participation in vigorous physical activity compared to non-participation for both 1975 and 1981 was associated with a lower risk of cognitive impairment in individual-based analyses (fully adjusted OR 0.50, 95% CI 0.35-0.73). Pairwise analyses yielded similar but statistically non-significant associations. In terms of the volume of physical activity, the most active quintile of individuals (OR 0.69, 95% CI 0.46-1.04) had a reduced risk of cognitive decline compared with the most sedentary quintile in the fully adjusted model although no clear dose-response was found. CONCLUSION: Vigorous midlife physical activity was associated with less cognitive impairment but without a clear dose-response association between the volume of physical activity and cognition.

Mild Cognitive Impairment and Susceptibility to Scams in Old Age. - Han, S Duke; Boyle, Patricia A; James, Bryan D; Yu, Lei; Bennett, David A (J Alzheimers Dis, 2016)
BACKGROUND: Falling victim to financial scams can have a significant impact upon social and financial wellbeing and independence. A large proportion of scam victims are older adults, but whether older victims with mild cognitive impairment (MCI) are at higher risk remains unknown. OBJECTIVE: We tested the hypothesis that older persons with MCI exhibit greater susceptibility to scams compared to those without cognitive impairment. METHODS: Seven hundred and thirty older adults without dementia were recruited from the Rush Memory and Aging Project, a community-based epidemiologic study of aging. Participants completed a five-item self-report measure of susceptibility to scams, a battery of cognitive measures, and clinical diagnostic evaluations. RESULTS: In models adjusted for age, education, and gender, the presence of MCI was associated with greater susceptibility to scams (B = 0.125, SE = 0.063, p-value = 0.047). Further, in analyses of the role of specific cognitive systems in susceptibility to scams among persons with MCI (n = 144), the level of performance in two systems, episodic memory and perceptual speed abilities, were associated with susceptibility. CONCLUSIONS: Adults with MCI may be more susceptible to scams in old age than older persons with normal cognition. Lower abilities in specific cognitive systems, particularly perceptual speed and episodic memory, may contribute to greater susceptibility to scams in those with MCI.
Keywords: Aged; Aged, 80 and over; Aging; Cognitive Dysfunction; Crime Victims; Disease Susceptibility; Female; Humans; Male; Memory, Episodic; Middle Aged; Neuropsychological Tests; Psychiatric Status Rating Scales; Residence Characteristics; Self Report

Mindfulness in the Maintenance of Cognitive Capacities in Alzheimer's Disease: A Randomized Clinical Trial. - Quintana-Hernández, Domingo J; Miró-Barrachina, María T; Ibáñez-Fernández, Ignacio J; Pino, Angelo Santana-Del; Quintana-Montesdeoca, María P; Rodríguez-de Vera, Bienvenida; Morales-Casanova, David; Pérez-Vieitez, María Del Carmen; Rodríguez-García, Javier; Bravo-Caraduje, Noelia (J Alzheimers Dis, 2016)
BACKGROUND: The Canary Islands longitudinal study on non-pharmacological treatments showed the overall effectiveness of mindfulness in Alzheimer's disease (AD). However, no specific data on the maintenance of cognitive capacities were presented. OBJECTIVE: To determine whether the practice of mindfulness modifies the course of cognitive impairment in AD. METHODS: DESIGN: Longitudinal, non-inferiority and equivalence, randomized clinical trial, repeated-measures design, with three experimental groups and one control group. PARTICIPANTS: Patients with AD who voluntarily attended the Lidia García Foundation (n = 502). Only those who were treated with donepezil and MMSE ≥18 were included (n = 120). INTERVENTION: Over a two-year period, each group carried out three weekly sessions of stimulation based on mindfulness, cognitive stimulation therapy, and progressive muscle relaxation. MEASURES: Cognitive assessment CAMDEX-R (MMSE and CAMCOG). STATISTICAL ANALYSIS: Repeated-measures ANOVA (p <  0.05) and the effect size Cohen's d were performed. RESULTS: The mindfulness group showed significant scores compared with the control and muscle relaxation groups (p <  0.05), while mindfulness and cognitive stimulation therapy were equivalent (p≥0.05). Group cognitive stimulation evolved better than the control (p <  0.05) group but not better than the muscle relaxation group (p≥0.05). The effect size compared over two years was large for the mindfulness group (p≥0.80), moderate for the relaxation group (p≥0.50), and low for the cognitive stimulation group (p≥0.20). CONCLUSION: The practice of mindfulness maintained cognitive function over a period of two years. This longitudinal study suggests that mindfulness can be used as a non-pharmacological treatment to slow cognitive impairment in AD.
Keywords: Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Cognition Disorders; Double-Blind Method; Female; Humans; Longitudinal Studies; Male; Mental Status Schedule; Mindfulness; Neuropsychological Tests; Treatment Outcome

Mindfulness Training for Older Adults with Subjective Cognitive Decline: Results from a Pilot Randomized Controlled Trial. - Smart, Colette M; Segalowitz, Sidney J; Mulligan, Bryce P; Koudys, Jacob; Gawryluk, Jodie R (J Alzheimers Dis, 2016)
INTRODUCTION: Subjective cognitive decline (SCD) in older adults is a condition with a complex phenomenology and diverse etiologies including (but not limited to) mood, personality, and health concerns, as well as biomarkers of preclinical Alzheimer's disease such as amyloid-β deposition and gray matter volume loss. Approximately 60% of affected persons are estimated to decline to Alzheimer's dementia. Regardless of etiology, persons with SCD may be optimal targets for early intervention. OBJECTIVE: To ascertain the feasibility and impact of mindfulness training (MT) as an early intervention in persons with SCD. METHODS: Using a single-blind, randomized controlled trial design, older adults with (n = 14) and without (n = 22) SCD were randomized to either MT or a control condition of psychoeducation (PE) on cognitive aging. EEG/ERP (specifically, the P3 component), structural MRI, and self-report measures of psychological functioning were obtained within 4 weeks prior to and within 2 weeks following intervention. RESULTS: MT resulted in decreased reaction time intra-individual variability for all participants, with a selective increase in the P3 event-related component for those with SCD. Compared with PE, MT also resulted in an increase in percent volume brain change in structural MRI. Finally, all SCD participants reported a decrease in cognitive complaints and increase in memory self-efficacy following intervention. DISCUSSION: Results suggest that MT is a feasible early intervention in persons with SCD. Longer-term follow-up with larger sample sizes will determine whether MT can slow the rate of decline in persons who may be at risk for Alzheimer's dementia.

Mini-Mental State Examination in Elderly Chinese: A Population-Based Normative Study. - Li, Hanzhi; Jia, Jianping; Yang, Zhiqiang (J Alzheimers Dis, 2016)
BACKGROUND: Chinese nationwide norms of the Mini-Mental State Examination (MMSE) have not been established despite its wide use. OBJECTIVE: To obtain norms for the MMSE based on age, gender, education, and rural or urban residences and to determine the optimal cut-off points of the MMSE in elderly Chinese. METHODS: A cross-sectional study was conducted in Chinese community residents aged 65 years or over selected by cluster random sampling. The MMSE was administered to 9,629 subjects (7,110 cognitively normal, 2,024 with mild cognitive impairment, and 495 with dementia). The demographic influences on MMSE scores were investigated and the norms were established considering those factors. Receiver operating characteristic (ROC) analysis was used to determine the optimal cut-off points. RESULTS: Years of education (standardized β= 0.399), rural residence (standardized β= -0.261), age (standardized β= -0.198), and being female (standardized β= -0.101) had significant effects on MMSE scores (p < 0.001). Accordingly, we presented the demographic-stratified normative data for the MMSE. The optimal cut-off points for dementia screening were 16/17 for illiterate (sensitivity 87.6% and specificity 80.8%), 19/20 for individuals with 1-6 years of education (sensitivity 93.6% and specificity 92.7%), and 23/24 for individuals with 7 or more years of education (sensitivity 94.3% and specificity 94.3%). CONCLUSION: We provide the age-, gender-, education-, and residence-specific reference norms for the MMSE derived from an investigation of a large-scale, multicenter, nationwide representative Chinese elderly population. It could be of great improvement for the use of the MMSE in dementia screening in Chinese elderly population.

miR-302 Attenuates Amyloid-β-Induced Neurotoxicity through Activation of Akt Signaling. - Li, Hsin-Hua; Lin, Shi-Lung; Huang, Chien-Ning; Lu, Fung-Jou; Chiu, Pai-Yi; Huang, Wen-Nung; Lai, Te-Jen; Lin, Chih-Li (J Alzheimers Dis, 2016)
Deficiency of insulin signaling has been linked to diabetes and ageing-related neurodegenerative diseases such as Alzheimer's disease (AD). In this regard, brains exhibit defective insulin receptor substrate-1 (IRS-1) and hence result in alteration of insulin signaling in progression of AD, the most common cause of dementia. Consequently, dysregulation of insulin signaling plays an important role in amyloid-β (Aβ)-induced neurotoxicity. As the derivation of induced pluripotent stem cells (iPSC) involves cell reprogramming, it may provide a means for regaining the control of ageing-associated dysfunction and neurodegeneration via affecting insulin-related signaling. To this, we found that an embryonic stem cell (ESC)-specific microRNA, miR-302, silences phosphatase and tensin homolog (PTEN) to activate Akt signaling, which subsequently stimulates nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) elevation and hence inhibits Aβ-induced neurotoxicity. miR-302 is predominantly expressed in iPSCs and is known to regulate several important biological processes of anti-oxidative stress, anti-apoptosis, and anti-aging through activating Akt signaling. In addition, we also found that miR-302-mediated Akt signaling further stimulates Nanog expression to suppress Aβ-induced p-Ser307 IRS-1 expression and thus enhances tyrosine phosphorylation and p-Ser 473-Akt/p-Ser 9-GSK3β formation. Furthermore, our in vivo studies revealed that the mRNA expression levels of both Nanog and miR-302-encoding LARP7 genes were significantly reduced in AD patients' blood cells, providing a novel diagnosis marker for AD. Taken together, our findings demonstrated that miR-302 is able to inhibit Aβ-induced cytotoxicity via activating Akt signaling to upregulate Nrf2 and Nanog expressions, leading to a marked restoration of insulin signaling in AD neurons.
Keywords: Aged; Aged, 80 and over; Amyloid beta-Peptides; Cell Line, Tumor; Cell Survival; Female; Glycogen Synthase Kinase 3 beta; Heme Oxygenase-1; Humans; Insulin; Male; Membrane Potential, Mitochondrial; MicroRNAs; Neurons; NF-E2-Related Factor 2; Oxidative Stress; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Reactive Oxygen Species; Ribonucleoproteins

Mismatch Negativity and Ear Laterality in Alzheimer's Disease and in Mild Cognitive Impairment. - Idrizbegovic, Esma; Hederstierna, Christina; Rosenhall, Ulf (J Alzheimers Dis, 2016)
BACKGROUND: Cortical auditory event-related potentials (ERPs) were studied in order to measure mismatch negativity (MMN). Three groups of subjects were studied: patients with Alzheimer's disease (AD, n = 32), mild cognitive impairment (MCI, n = 44), and subjective memory complaints without cognitive decline (SMC, n = 27). A bottom up strategy was applied, and the right and left ears were stimulated monaurally. OBJECTIVE: To investigate MMN in AD and MCI, and in a clinical reference group. METHODS: ERPs were carried out with 500 tone pulses at 80 dBnHL. Each sequence included 80% standard tones (500 Hz) (f), and 20% deviant tones (1000 Hz) (r). MMN measurements were carried out by comparing the amplitudes of (f) and (r) recordings and to calculate the amplitude difference in μV for each group. The right and the left ears were analyzed separately. RESULTS: A left ear advantage (LEA) of MMN amplitude was demonstrated in the two groups with better cognition (the MCI and the SMC groups), but not in the AD group. DISCUSSION: The absence of MMN asymmetry in the AD group is possibly caused by a dysfunction to apprehend changes of tonal stimuli.

"Missed" Mild Cognitive Impairment: High False-Negative Error Rate Based on Conventional Diagnostic Criteria. - Edmonds, Emily C; Delano-Wood, Lisa; Jak, Amy J; Galasko, Douglas R; Salmon, David P; Bondi, Mark W (J Alzheimers Dis, 2016)
Mild cognitive impairment (MCI) is typically diagnosed using subjective complaints, screening measures, clinical judgment, and a single memory score. Our prior work has shown that this method is highly susceptible to false-positive diagnostic errors. We examined whether the criteria also lead to "false-negative" errors by diagnostically reclassifying 520 participants using novel actuarial neuropsychological criteria. Results revealed a false-negative error rate of 7.1%. Participants' neuropsychological performance, cerebrospinal fluid biomarkers, and rate of decline provided evidence that an MCI diagnosis is warranted. The impact of "missed" cases of MCI has direct relevance to clinical practice, research studies, and clinical trials of prodromal Alzheimer's disease.

Mitochondrial Regulatory Pathways in the Pathogenesis of Alzheimer's Disease. - Adiele, Reginald C; Adiele, Chiedukam A (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is an age-associated neurodegenerative brain disorder with progressive cognitive decline that leads to terminal dementia and death. For decades, amyloid-beta (Aβ) and neurofibrillary tangle (NFT) aggregation hypotheses have dominated studies on the pathogenesis and identification of potential therapeutic targets in AD. Little attention has been paid to the mitochondrial molecular/biochemical pathways leading to AD. Mitochondria play a critical role in cell viability and death including neurons and neuroglia, not only because they regulate energy and oxygen metabolism but also because they regulate cell death pathways. Mitochondrial impairment and oxidative stress are implicated in the pathogenesis of AD. Interestingly, current therapeutics provide symptomatic benefits to AD patients resulting in the use of preventive trials on presymptomatic subjects. This review article elucidates the pathophysiology of AD and emphasizes the need to explore the mitochondrial pathways to provide solutions to unanswered questions in the prevention and treatment of AD.

A Mitochondrial Role of SV2a Protein in Aging and Alzheimer's Disease: Studies with Levetiracetam. - Stockburger, Carola; Miano, Davide; Baeumlisberger, Marion; Pallas, Thea; Arrey, Tabiwang N; Karas, Michael; Friedland, Kristina; Müller, Walter E (J Alzheimers Dis, 2016)
Aberrant neuronal network activity associated with neuronal hyperexcitability seems to be an important cause of cognitive decline in aging and Alzheimer's disease (AD). Out of many antiepileptics, only levetiracetam improved cognitive dysfunction in AD patients and AD animal models by reducing hyperexcitability. As impaired inhibitory interneuronal function, rather than overactive neurons, seems to be the underlying cause, improving impaired neuronal function rather than quieting overactive neurons might be relevant in explaining the lack of activity of the other antiepileptics. Interestingly, improvement of cognitive deficits by levetiracetam caused by small levels of soluble Aβ was accompanied by improvement of synaptic function and plasticity. As the negative effects of Aβ on synaptic plasticity strongly correlate with mitochondrial dysfunction, wehypothesized that the effect of levetiracetam on synaptic activity might be raised by an improved mitochondrial function. Accordingly, we investigated possible effects of levetiracetam on neuronal deficits associated with mitochondrial dysfunction linked to aging and AD. Levetiracetam improved several aspects of mitochondrial dysfunction including alterations of fission and fusion balance in a cell model for aging and early late-onset AD. We demonstrate for the first time, using immunohistochemistry and proteomics, that the synaptic vesicle protein 2A (SV2a), the molecular target of levetiracetam, is expressed in mitochondria. In addition, levetiracetam shows significant effect on the opening of the mitochondrial permeability transition pore. Importantly, the effects of levetiracetam were significantly abolished when SV2a was knockdown using siRNA. In conclusion, interfering with the SV2a protein at the mitochondrial level and thereby improving mitochondrial function might represent an additional therapeutic effect of levetiracetam to improve symptoms of late-onset AD.
Keywords: Adenosine Triphosphate; Aging; Alzheimer Disease; Animals; Brain; Cell Line; Cognition Disorders; Female; GAP-43 Protein; Gene Expression Regulation; Humans; Male; Membrane Glycoproteins; Mitochondria; Mitochondrial Membrane Transport Proteins; Nerve Tissue Proteins; Nitroprusside; Nootropic Agents; Piracetam; Proteomics; Rats; RNA, Small Interfering

Moderate-to-High Intensity Physical Exercise in Patients with Alzheimer's Disease: A Randomized Controlled Trial. - Hoffmann, Kristine; Sobol, Nanna A; Frederiksen, Kristian S; Beyer, Nina; Vogel, Asmus; Vestergaard, Karsten; Brændgaard, Hans; Gottrup, Hanne; Lolk, Annette; Wermuth, Lene; Jacobsen, Søren; Laugesen, Lars P; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Studies of physical exercise in patients with Alzheimer's disease (AD) are few and results have been inconsistent. OBJECTIVE: To assess the effects of a moderate-to-high intensity aerobic exercise program in patients with mild AD. METHODS: In a randomized controlled trial, we recruited 200 patients with mild AD to a supervised exercise group (60-min sessions three times a week for 16 weeks) or to a control group. Primary outcome was changed from baseline in cognitive performance estimated by Symbol Digit Modalities Test (SDMT) in the intention-to-treat (ITT) group. Secondary outcomes included changes in quality of life, ability to perform activities of daily living, and in neuropsychiatric and depressive symptoms. RESULTS: The ITT analysis showed no significant differences between intervention and control groups in change from baseline of SDMT, other cognitive tests, quality of life, or activities of daily living. The change from baseline in Neuropsychiatric Inventory differed significantly in favor of the intervention group (mean: -3.5, 95% confidence interval (CI) -5.8 to -1.3, p = 0.002). In subjects who adhered to the protocol, we found a significant effect on change from baseline in SDMT as compared with the control group (mean: 4.2, 95% CI 0.5 to 7.9, p = 0.028), suggesting a dose-response relationship between exercise and cognition. CONCLUSIONS: This is the first randomized controlled trial with supervised moderate-to-high intensity exercise in patients with mild AD. Exercise reduced neuropsychiatric symptoms in patients with mild AD, with possible additional benefits of preserved cognition in a subgroup of patients exercising with high attendance and intensity.
Keywords: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Cognition; Depression; Exercise; Exercise Therapy; Female; Humans; Male; Middle Aged; Quality of Life; Treatment Outcome

Modulation of Amyloid-β1-40 Transport by ApoA1 and ApoJ Across an in vitro Model of the Blood-Brain Barrier. - Merino-Zamorano, Cristina; Fernández-de Retana, Sofía; Montañola, Alex; Batlle, Aina; Saint-Pol, Julien; Mysiorek, Caroline; Gosselet, Fabien; Montaner, Joan; Hernández-Guillamon, Mar (J Alzheimers Dis, 2016)
Amyloid-β (Aβ) accumulation in Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) is likely caused by the impairment of its brain clearance that partly occurs through the blood-brain barrier (BBB). In this context, an in vitro BBB model is a valuable tool for studying the molecular mechanisms that regulate this process. This study assessed brain Aβ elimination across the BBB and its modulation by the natural chaperones Apolipoprotein A1 (ApoA1) and Apolipoprotein J/Clusterin (ApoJ). The model was based on primary cerebral endothelial cells that were cultured on Matrigel-coated Transwells and treated with fluorescently labeled-Aβ1-40 to track its efflux across the BBB, which corresponds to trafficking from the basolateral (brain) to apical (blood) compartments. We observed that the transport of basolateral Aβ1-40 was enhanced when it was complexed to rApoJ, whereas the complex formed with rApoA1 did not influence Aβ1-40 efflux. However, the presence of rApoA1 in the apical compartment was able to mobilize Aβ1-40 from the basolateral side. We also observed that both rApoA1 and rApoJ moderately crossed the monolayer (from blood to brain) through a mechanism involving the LDL receptor-related protein family. In contrast to the increased rApoJ efflux when complexed to Aβ1-40, rApoA1 trafficking was restricted when it was bound to the Aβ peptide. In summary, the present study highlights the role of ApoJ and ApoA1 in the in vitro modulation of Aβ elimination across the BBB.

Modulation of miR-19 in Aluminum-Induced Neural Cell Apoptosis. - Zhu, Mingming; Huang, Cong; Ma, Xiao; Wu, Rui; Zhu, Weiwei; Li, Xiaoting; Liang, Zhaofeng; Deng, Feifei; Zhu, Jianyun; Xie, Wei; Yang, Xue; Jiang, Ye; et al. (J Alzheimers Dis, 2016)
Neuronal cell death is an important feature of neurodegeneration. Aluminum is associated with neurodegenerative disorders, particularly Alzheimer's disease. However, the underlying mechanisms by which aluminum induces neuronal apoptosis remain to be elucidated. miR-19 is a key miRNA implicated in regulating cell survival process, while the role of miR-19 in Alzheimer's disease has not been investigated. In the present study, we showed that Aluminum maltolate (Al-malt), a lipophilic Al complex which is a common component of human diet with the ability to facilitate the entry of Al into the brain, induced apoptosis in human neuroblastoma SH-SY5Y cells, along with downregulation of miR-19a/miR-19b, upregulation of miR-19-targeted PTEN, and alterations of its downstream apoptosis related proteins including AKT, p53, Bax, and Bcl-2. miR-19 overexpression attenuated Al-malt-induced apoptosis as well as changes in the expression of apoptosis related proteins in SH-SY5Y cells. We further revealed that exposure of rats to Al-malt for 12 weeks at doses relevant to human exposure significantly elevated Al concentrations in serum and brain tissues. Al-malt dose-dependently induced apoptosis in rat brain, as evidenced by increased caspase activation and increased TUNEL staining. Consistent with in vitro results, Al-malt reduced miR-19 expression and altered the expression of apoptotic related proteins in rat brain. Taken together, our data suggest for the first time that miR-19 modulation is critically involved in Al-induced neural cell apoptosis. Findings from this study could provide new insight into the molecular mechanisms of Al-associated neurodegenerative pathogenesis.
Keywords: Aluminum; Animals; Apoptosis; Brain; Cell Line, Tumor; Dose-Response Relationship, Drug; Humans; Male; MicroRNAs; Neurons; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Rats, Sprague-Dawley; Tumor Suppressor Protein p53

Molecular markers of amnestic mild cognitive impairment among Mexican Americans. - Edwards, Melissa; Hall, James; Williams, Benjamin; Johnson, Leigh; O'Bryant, Sid (J Alzheimers Dis, 2016)
BACKGROUND: Mexican Americans face a significant health disparity when it comes to Alzheimer's disease (AD) as they present with higher rates of the disease and develop AD at an earlier age compared to other ethnic groups. Recent work identified a proteomic profile of AD among this population; however, no work to date has sought to examine the biological profile of pre-AD among Mexican Americans. OBJECTIVE: This study aims to identify an amnestic mild cognitive impairment (aMCI) proteomic profile among Mexican Americans. METHODS: Data were analyzed from 284 Mexican American participants (aMCI, n = 73; normal controls, n = 211) from the Health & Aging Brain among Latino Elders study. Fasting serum samples were analyzed using a multi-plex biomarker assay platform. A biomarker profile was generated using random forest analyses. RESULTS: Among aMCI cases, the biomarker profile was found to be largely inflammatory with the top three markers shown to include TNFα, IL10, and TARC. The overall diagnostic accuracy of the biomarkers in detecting aMCI was 96% (sensitivity = 0.82; specificity = 0.97). Inclusion of clinical variables with the selected biomarkers did not impact the overall detection accuracy (area under the curve = 0.96) but led to a slight improvement in specificity (specificity = 0.99) and decrease in sensitivity (sensitivity = 0.74). CONCLUSION: The biomarker profile of aMCI was shown to be different from our previously generated AD profile among Mexican Americans, which was largely metabolic in nature. The findings implicate a possible interplay between inflammatory and metabolic processes and additional work is needed to further examine this.
Keywords: Aged; Alzheimer Disease; Area Under Curve; Biomarkers; Cognitive Dysfunction; Female; Humans; Male; Mexican Americans; Middle Aged; Neuropsychological Tests; Proteome; Sensitivity and Specificity; United States

Molecular Signaling Mechanisms of Natural and Synthetic Retinoids for Inhibition of Pathogenesis in Alzheimer's Disease. - Chakrabarti, Mrinmay; McDonald, Alexander J; Will Reed, J; Moss, Melissa A; Das, Bhaskar C; Ray, Swapan K (J Alzheimers Dis, 2016)
Retinoids, which are vitamin A derivatives, interact through retinoic acid receptors (RARs) and retinoid X receptors (RXRs) and have profound effects on several physiological and pathological processes in the brain. The presence of retinoic acid signaling is extensively detected in the adult central nervous system, including the amygdala, cortex, hypothalamus, hippocampus, and other brain areas. Retinoids are primarily involved in neural patterning, differentiation, and axon outgrowth. Retinoids also play a key role in the preservation of the differentiated state of adult neurons. Impairment in retinoic acid signaling can result in neurodegeneration and progression of Alzheimer's disease (AD). Recent studies demonstrated severe deficiencies in spatial learning and memory in mice during retinoic acid (vitamin A) deprivation indicating its significance in preserving memory function. Defective cholinergic neurotransmission plays an important role in cognitive deficits in AD. All-trans retinoic acid is known to enhance the expression and activity of choline acetyltransferase in neuronal cell lines. Activation of RAR and RXR is also known to impede the pathogenesis of AD in mice by inhibiting accumulation of amyloids. In addition, retinoids have been shown to inhibit the expression of chemokines and pro-inflammatory cytokines in microglia and astrocytes, which are activated in AD. In this review article, we have described the chemistry and molecular signaling mechanisms of natural and synthetic retinoids and current understandings of their therapeutic potentials in prevention of AD pathology.
Keywords: Alzheimer Disease; Animals; Brain; Humans; Mice; Neurons; Retinoid X Receptors; Retinoids; Signal Transduction; Tretinoin

Monitoring Blood-Brain Barrier Integrity Following Amyloid-β Immunotherapy Using Gadolinium-Enhanced MRI in a PDAPP Mouse Model. - Blockx, Ines; Einstein, Steve; Guns, Pieter-Jan; Van Audekerke, Johan; Guglielmetti, Caroline; Zago, Wagner; Roose, Dimitri; Verhoye, Marleen; Van der Linden, Annemie; Bard, Frederique (J Alzheimers Dis, 2016)
BACKGROUND: Amyloid-related imaging abnormalities (ARIA) have been reported with some anti-amyloid-β (Aβ) immunotherapy trials. They are detected with magnetic resonance imaging (MRI) and thought to represent transient accumulation of fluid/edema (ARIA-E) or microhemorrhages (ARIA-H). Although the clinical significance and pathophysiology are unknown, it has been proposed that anti-Aβimmunotherapy may affect blood-brain barrier (BBB) integrity. OBJECTIVE: To examine vascular integrity in aged (12-16 months) PDAPP and wild type mice (WT), we performed a series of longitudinal in vivo MRI studies. METHODS: Mice were treated on a weekly basis using anti-Aβimmunotherapy (3D6) and follow up was done longitudinally from 1-12 weeks after treatment. BBB-integrity was assessed using both visual assessment of T1-weighted scans and repeated T1 mapping in combination with gadolinium (Gd-DOTA). RESULTS: A subset of 3D6 treated PDAPP mice displayed numerous BBB disruptions, whereas WT and saline-treated PDAPP mice showed intact BBB integrity under the conditions tested. In addition, the contrast induced decrease in T1 value was observed in the meningeal and midline area. BBB disruption events occurred early during treatment (between 1 and 5 weeks), were transient, and resolved quickly. Finally, BBB-leakages associated with microhemorrhages were confirmed by Perls'Prussian blue histopathological analysis. CONCLUSION: Our preclinical findings support the hypothesis that 3D6 leads to transient leakage from amyloid-positive vessels. The current study has provided valuable insights on the time course of vascular alterations during immunization treatment and supports further research in relation to the nature of ARIA and the utility of in vivo repeated T1 MRI as a translational tool.

Monophosphoryl Lipid-A: A Promising Tool for Alzheimer's Disease Toll. - Rego, Ângela; Viana, Sofia D; Ribeiro, Carlos A Fontes; Rodrigues-Santos, Paulo; Pereira, Frederico C (J Alzheimers Dis, 2016)
Neuroinflammation is a two-edged sword in Alzheimer's disease (AD). A certain degree of neuroinflammation is instrumental in the clearance of amyloid-β (Aβ) peptides by activated microglia, although a sustained neuroinflammation might accelerate Aβ deposition, thus fostering the neurodegenerative process and functional decline in AD. There is an increasing body of evidence suggesting that the innate immune system via Toll-like receptor 4 (TLR4) finely orchestrates the highly regulated inflammatory cascade that takes place in AD pathology. Herein we critically review pre-clinical (in vitro and in vivo approaches) and clinical studies showing that monophosphoryl lipid A (MPL), a partial TLR4 agonist, may have beneficial effect on AD physiopathology. The in vivo data elegantly showed that MPL enhanced Aβ plaque phagocytosis thus decreasing the number and the size of Aβ deposits and soluble Aβ in brain from APPswe/PS1 mice. Furthermore, MPL also improved their cognition. The mechanism underlying this MPL effect was proposed to be microglial activation by recruiting TLR4. Additionally, it was demonstrated that MPL increased the Aβ antibody titer and showed a safe profile in mice and primates, when used as a vaccine adjuvant. Clinical studies using MPL as an adjuvant in Aβ immunotherapy are currently ongoing. Overall, we argue that the TLR4 partial agonist MPL is a potentially safe and effective new pharmacological tool in AD.

Morroniside-Induced PP2A Activation Antagonizes Tau Hyperphosphorylation in a Cellular Model of Neurodegeneration. - Yang, Cui-cui; Kuai, Xue-xian; Gao, Wen-bin; Yu, Jian-chun; Wang, Qi; Li, Lin; Zhang, Lan (J Alzheimers Dis, 2016)
BACKGROUND: An accumulation of hyperphosphorylated tau in the brain is a hallmark of Alzheimer's disease (AD). Deficits in protein phosphatase 2A (PP2A) are associated with tau hyperphosphorylation in AD. OBJECTIVE: To investigate the effects of morroniside (MOR), isolated from Cornus officinalis, on tau hyperphosphorylation and its underlying mechanisms related to PP2A. METHODS: SK-N-SH cells were pretreated with 50-200 μM MOR for 24 h followed by 20 nM okadaic acid (OA) for 6 h. PP2Ac siRNA was transfected into HEK293 cells to determine the direct interaction of MOR with PP2A. Western blotting was used to measure the expression of proteins and enzymes. PP2A activity was measured by molybdenum blue spectrophotometry. RESULTS: Pretreatment with MOR improved the cellular morphological damage and inhibited tau hyperphosphorylation in SK-N-SH cells induced by OA, a PP2A inhibitor. Moreover, MOR increased PP2A activity, concurrent with a decrease in the expression of demethylated PP2A at Leu309 and phosphorylated PP2A at Tyr307. MOR decreased protein phosphatase methylesterase 1 (PME-1) expression and the ratio of PME-1/leucine carboxyl methyltransferase 1 (LCMT-1). Furthermore, MOR treatment decreased the phosphorylation of Src at Tyr416, which regulates the phosphorylation of PP2A. MOR had no effect on PP2Ac expression and tau hyperphosphorylation in PP2Ac siRNA-transfected cells. CONCLUSION: MOR attenuated OA-induced tau hyperphosphorylation via PP2A activation, and its mechanism might be related to the regulation of PP2Ac post-translational modification and upstream enzymes such as Src and PME-1.
Keywords: Analysis of Variance; Cell Line; Enzyme Inhibitors; Gene Expression Regulation; Glycogen Synthase Kinase 3 beta; Glycosides; HEK293 Cells; Humans; Neuroblastoma; Okadaic Acid; Phosphorylation; Protein Phosphatase 2; RNA, Small Interfering; tau Proteins; Transfection; Tyrosine

Mortality in Mild Cognitive Impairment: A Longitudinal Study in Memory Clinics. - Connors, Michael H; Ames, David; Boundy, Karyn; Clarnette, Roger; Kurrle, Sue; Mander, Alastair; Ward, John; Woodward, Michael; Brodaty, Henry (J Alzheimers Dis, 2016)
BACKGROUND: Patients with mild cognitive impairment (MCI) are at greater risk of mortality than the general population. Comparatively little research has examined predictors of mortality in MCI and no research has examined whether time-varying variables, such as change in cognition and function, predict survival. OBJECTIVE: To identify predictors of mortality in patients with MCI. METHODS: 185 patients with MCI were recruited from nine memory clinics around Australia. Patients completed measures of cognition, function, and neuropsychiatric symptoms over three years. Mortality data were obtained from state registries eight years after baseline. RESULTS: 55 (30%) patients died within this period. Older age, lower cognitive and functional ability at baseline, and greater decline in functional ability over six months predicted mortality. CONCLUSION: Easily measurable clinical data predict mortality in patients with MCI. Longitudinal assessment over time can provide additional information about patients' risk.

Motoric Cognitive Risk Syndrome and Falls Risk: A Multi-Center Study. - Callisaya, Michele L; Ayers, Emmeline; Barzilai, Nir; Ferrucci, Luigi; Guralnik, Jack M; Lipton, Richard B; Otahal, Petr; Srikanth, Velandai K; Verghese, Joe (J Alzheimers Dis, 2016)
BACKGROUND: The Motoric Cognitive Risk Syndrome (MCR) is characterized by slow gait speed and cognitive complaints. OBJECTIVES: The objective of this study was to determine if the presence of MCR increases the risk of falls in older people. METHODS: Individual participant data (n = 6,204) from five longitudinal studies from three countries were used for this analysis. MCR diagnosis was defined as both the presence of objectively measured slow gait speed and subjective cognitive complaints in those without dementia or mobility disability. Falls were prospectively ascertained using phone calls or questionnaires. Log binomial regression was performed to determine if MCR increased the risk of falls separately in each cohort. Random effects meta-analysis was used to pool results from all cohorts. RESULTS: The mean age of participants was 74.9 (SD 6.8) years and 44% (n = 2728) were male. Overall 33.9% (n = 2104) reported a fall over follow-up. Pooled relative risk of MCR with any falls was RR 1.44 95% CI 1.16, 1.79. The components of MCR, slow gait (RR 1.30 95% CI 1.14, 1.47) and cognitive complaint (RR 1.25, 95% CI 1.07, 1.46) were also associated with an increased risk of any falls. In sub-analyses MCR was associated with any fall independent of previous falls (RR 1.29 95% CI 1.09, 1.53) and with multiple falls (RR 1.77, 95% CI 1.25, 2.51). CONCLUSION: MCR is associated with an increased risk of falls. The increase in risk was higher than for its individual components. The simplicity of the MCR makes it an attractive falls risk screening tool for the clinic.

Moving from the Dish to the Clinical Practice: A Decade of Lessons and Perspectives from the Pre-Clinical and Clinical Stem Cell Studies for Alzheimer's Disease. - Salem, Haitham; Rocha, Natalia Pessoa; Colpo, Gabriela Delevati; Teixeira, Antonio Lucio (J Alzheimers Dis, 2016)
To date, there is no definitive treatment for Alzheimer's disease (AD). The realm of stem cells is very promising in regenerative medicine, particularly neurodegenerative disorders. Various types of stem cells have been used in multiple trials on AD models, trying to find an innovative management of this disease. In this systematic review, we trace the published preclinical and clinical data throughout the last decade, to show how much knowledge we gained so far in this field and the future perspectives of stem cells in AD treatment.

Multifunctional Effect of Human Serum Albumin Reduces Alzheimer's Disease Related Pathologies in the 3xTg Mouse Model. - Ezra, Assaf; Rabinovich-Nikitin, Inna; Rabinovich-Toidman, Polina; Solomon, Beka (J Alzheimers Dis, 2016)
Alzheimer's disease (AD), the prevalent dementia in the elderly, involves many related and interdependent pathologies that manifests simultaneously, eventually leading to cognitive impairment and death. No treatment is currently available; however, an agent addressing several key pathologies simultaneously has a better therapeutic potential. Human serum albumin (HSA) is a highly versatile protein, harboring multifunctional properties that are relevant to key pathologies underlying AD. This study provides insight into the mechanism for HSA's therapeutic effect. In vivo, a myriad of beneficial effects were observed by pumps infusing HSA intracerebroventricularly, for the first time in an AD 3xTg mice model. A significant effect on amyloid-β (Aβ) pathology was observed. Aβ1-42, soluble oligomers, and total plaque area were reduced. Neuroblastoma SHSY5Y cell line confirmed that the reduction in Aβ1-42 toxicity was due to direct binding rather than other properties of HSA. Total and hyperphosphorylated tau were reduced along with an increase in tubulin, suggesting increased microtubule stability. HSA treatment also reduced brain inflammation, affecting both astrocytes and microglia markers. Finally, evidence for blood-brain barrier and myelin integrity repair was observed. These multidimensional beneficial effects of intracranial administrated HSA, together or individually, contributed to an improvement in cognitive tests, suggesting a non-immune or Aβ efflux dependent means for treating AD.
Keywords: Albumins; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Blood-Brain Barrier; Brain; Calcium; Cell Line, Tumor; Cognition Disorders; Disease Models, Animal; Drug Delivery Systems; Encephalitis; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neuroblastoma; Neuropsychological Tests; Peptide Fragments; Presenilin-1; tau Proteins

Multimodal Classification of Mild Cognitive Impairment Based on Partial Least Squares. - Wang, Pingyue; Chen, Kewei; Yao, Li; Hu, Bin; Wu, Xia; Zhang, Jiacai; Ye, Qing; Guo, Xiaojuan (J Alzheimers Dis, 2016)
In recent years, increasing attention has been given to the identification of the conversion of mild cognitive impairment (MCI) to Alzheimer's disease (AD). Brain neuroimaging techniques have been widely used to support the classification or prediction of MCI. The present study combined magnetic resonance imaging (MRI), 18F-fluorodeoxyglucose PET (FDG-PET), and 18F-florbetapir PET (florbetapir-PET) to discriminate MCI converters (MCI-c, individuals with MCI who convert to AD) from MCI non-converters (MCI-nc, individuals with MCI who have not converted to AD in the follow-up period) based on the partial least squares (PLS) method. Two types of PLS models (informed PLS and agnostic PLS) were built based on 64 MCI-c and 65 MCI-nc from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The results showed that the three-modality informed PLS model achieved better classification accuracy of 81.40%, sensitivity of 79.69%, and specificity of 83.08% compared with the single-modality model, and the three-modality agnostic PLS model also achieved better classification compared with the two-modality model. Moreover, combining the three modalities with clinical test score (ADAS-cog), the agnostic PLS model (independent data: florbetapir-PET; dependent data: FDG-PET and MRI) achieved optimal accuracy of 86.05%, sensitivity of 81.25%, and specificity of 90.77%. In addition, the comparison of PLS, support vector machine (SVM), and random forest (RF) showed greater diagnostic power of PLS. These results suggested that our multimodal PLS model has the potential to discriminate MCI-c from the MCI-nc and may therefore be helpful in the early diagnosis of AD.

Multimodal Magnetic Resonance Imaging in Alzheimer's Disease Patients at Prodromal Stage. - Eustache, Pierre; Nemmi, Federico; Saint-Aubert, Laure; Pariente, Jérémie; Péran, Patrice (J Alzheimers Dis, 2016)
One objective of modern neuroimaging is to identify markers that can aid in diagnosis, monitor disease progression, and impact long-term drug analysis. In this study, physiopathological modifications in seven subcortical structures of patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) were characterized by simultaneously measuring quantitative magnetic resonance parameters that are sensitive to complementary tissue characteristics (e.g., volume atrophy, shape changes, microstructural damage, and iron deposition). Fourteen MCI patients and fourteen matched, healthy subjects underwent 3T-magnetic resonance imaging with whole-brain, T1-weighted, T2*-weighted, and diffusion-tensor imaging scans. Volume, shape, mean R2*, mean diffusivity (MD), and mean fractional anisotropy (FA) in the thalamus, hippocampus, putamen, amygdala, caudate nucleus, pallidum, and accumbens were compared between MCI patients and healthy subjects. Comparisons were then performed using voxel-based analyses of R2*, MD, FA maps, and voxel-based morphometry to determine which subregions showed the greatest difference for each parameter. With respect to the micro- and macro-structural patterns of damage, our results suggest that different and distinct physiopathological processes are present in the prodromal phase of AD. MCI patients had significant atrophy and microstructural changes within their hippocampi and amygdalae, which are known to be affected in the prodromal stage of AD. This suggests that the amygdala is affected in the same, direct physiopathological process as the hippocampus. Conversely, atrophy alone was observed within the thalamus and putamen, which are not directly involved in AD pathogenesis. This latter result may reflect another mechanism, whereby atrophy is linked to indirect physiopathological processes.
Keywords: Aged; Alzheimer Disease; Biomarkers; Brain; Cognitive Dysfunction; Diffusion Tensor Imaging; Female; Fluorodeoxyglucose F18; Humans; Magnetic Resonance Imaging; Male; Mental Status Schedule; Multimodal Imaging; Neuropsychological Tests; Organ Size; Positron-Emission Tomography; Prodromal Symptoms; Radiopharmaceuticals

The Multiple Object Test as a Performance Based Tool to Assess Cognitive Driven Activity of Daily Living Function in Parkinson's Disease. - Glonnegger, Hannah; Beyle, Aline; Cerff, Bernhard; Gräber, Susanne; Csoti, Ilona; Berg, Daniela; Liepelt-Scarfone, Inga (J Alzheimers Dis, 2016)
BACKGROUND: There is need for multidimensional quantitative assessment of cognitive driven activities of daily living (ADL) functions in Parkinson's disease (PD). OBJECTIVE: To determine whether there is an ADL profile related to cognitive impairment in PD assessed by the Multiple Object Test (MOT). We assumed MOT performance to be lower in PD patients versus controls and in PD patients with more severe cognitive impairment. METHODS: 50 PD patients with no cognitive impairment (PD-NC), 54 patients with PD-mild cognitive impairment (PD-MCI), 29 with Parkinson's disease dementia (PDD), and 40 healthy controls (HC) were investigated. Besides comprehensive cognitive testing, the MOT, a performance based test consisting of five routine tasks (e.g., preparing a cup of coffee), was applied. Quantitative (total errors and time) and qualitative (error type) MOT parameters were analyzed. RESULTS: Total time and number of MOT errors was increased in PD patients compared to controls (p < 0.001). These parameters also differentiated PDD patients from other cognitive groups (p < 0.05). No control subject had ≥ 4 errors in the MOT, but 30% of PD patients, especially PDD, scored above this cut-off. Omission (p < 0.001) and mislocation (p < 0.03) errors were more prominent in PDD than other cognitive groups. Perplexity errors did not differ between PD-MCI and PDD but between PD-NC and PDD (p = 0.01). MOT parameters discriminating between cognitive groups correlated mainly with lower test performance in psychomotor speed and executive function. CONCLUSION: Performance based testing is promising to identify quantitative and qualitative ADL aspects differentiating between different cognitive groups which might be helpful for an early detection of PDD.

Multi-Vitamin B Supplementation Reverses Hypoxia-Induced Tau Hyperphosphorylation and Improves Memory Function in Adult Mice. - Yu, Lixia; Chen, Yuan; Wang, Weiguang; Xiao, Zhonghai; Hong, Yan (J Alzheimers Dis, 2016)
Hypobaric hypoxia (HH) leads to reduced oxygen delivery to brain. It could trigger cognitive dysfunction and increase the risk of dementia including Alzheimer's disease (AD). The present study was undertaken in order to examine whether B vitamins (B6, B12, folate, and choline) could exert protective effects on hypoxia-induced memory deficit and AD related molecular events in mice. Adult male Kunming mice were assigned to five groups: normoxic control, hypoxic model (HH), hypoxia+vitamin B6/B12/folate (HB), hypoxia+choline (HC), hypoxia+vitamin B6/B12/folate+choline (HBC). Mice in the hypoxia, HB, HC, and HBC groups were exposed to hypobaric hypoxia for 8 h/day for 28 days in a decompression chamber mimicking 5500 meters of high altitude. Spatial and passive memories were assessed by radial arm and step-through passive test, respectively. Levels of tau and glycogen synthase kinase (GSK)-3β phosphorylation were detected by western blot. Homocysteine (Hcy) concentrations were determined using enzymatic cycling assay. Mice in the HH group exhibited significant spatial working and passive memory impairment, increased tau phosphorylation at Thr181, Ser262, Ser202/Thr205, and Ser396 in the cortex and hippocampus, and elevated Hcy levels compared with controls. Concomitantly, the levels of Ser9-phosphorylated GSK-3β were significantly decreased in brain after hypoxic treatment. Supplementations of vitamin B6/B12/folate+choline could significantly ameliorate the hypoxia-induced memory deficits, observably decreased Hcy concentrations in serum, and markedly attenuated tau hyperphosphorylation at multiple AD-related sites through upregulating inhibitory Ser9-phosphorylated GSK-3β. Our finding give further insight into combined neuroprotective effects of vitamin B6, B12, folate, and choline on brain against hypoxia.

Music and Memory in Alzheimer's Disease and The Potential Underlying Mechanisms. - Peck, Katlyn J; Girard, Todd A; Russo, Frank A; Fiocco, Alexandra J (J Alzheimers Dis, 2016)
With population aging and a projected exponential expansion of persons diagnosed with Alzheimer's disease (AD), the development of treatment and prevention programs has become a fervent area of research and discovery. A growing body of evidence suggests that music exposure can enhance memory and emotional function in persons with AD. However, there is a paucity of research that aims to identify specific underlying neural mechanisms associated with music's beneficial effects in this particular population. As such, this paper reviews existing anecdotal and empirical evidence related to the enhancing effects of music exposure on cognitive function and further provides a discussion on the potential underlying mechanisms that may explain music's beneficial effect. Specifically, this paper will outline the potential role of the dopaminergic system, the autonomic nervous system, and the default network in explaining how music may enhance memory function in persons with AD.
Keywords: Alzheimer Disease; Auditory Perception; Autonomic Nervous System; Dopamine; Humans; Memory Disorders; Music Therapy

Naphthoquinone-Tryptophan Hybrid Inhibits Aggregation of the Tau-Derived Peptide PHF6 and Reduces Neurotoxicity. - Frenkel-Pinter, Moran; Tal, Sharon; Scherzer-Attali, Roni; Abu-Hussien, Malak; Alyagor, Idan; Eisenbaum, Tal; Gazit, Ehud; Segal, Daniel (J Alzheimers Dis, 2016)
Tauopathies, such as Alzheimer's disease (AD), are a group of disorders characterized neuropathologically by intracellular toxic accumulations of abnormal protein aggregates formed by misfolding of the microtubule-associated protein tau. Since protein self-assembly appears to be an initial key step in the pathology of this group of diseases, intervening in this process can be both a prophylactic measure and a means for modifying the course of the disease for therapeutic purposes. We and others have shown that aromatic small molecules can be effective inhibitors of aggregation of various protein assemblies, by binding to the aromatic core in aggregation-prone motifs and preventing their self-assembly. Specifically, we have designed a series of small aromatic naphthoquinone-tryptophan hybrid molecules as candidate aggregation inhibitors of β -sheet based assembly and demonstrated their efficacy toward inhibiting aggregation of the amyloid-β peptide, another culprit of AD, as well as of various other aggregative proteins involved in other protein misfolding diseases. Here we tested whether a leading naphthoquinone-tryptophan hybrid molecule, namely NQTrp, can be repurposed as an inhibitor of the aggregation of the tau protein in vitro and in vivo. We show that the molecule inhibits the in vitro assembly of PHF6, the aggregation-prone fragment of tau protein, reduces hyperphosphorylated tau deposits and ameliorates tauopathy-related behavioral defect in an established transgenic Drosophila model expressing human tau. We suggest that NQTrp, or optimized versions of it, could act as novel disease modifying drugs for AD and other tauopathies.
Keywords: Animals; Carrier Proteins; Disease Models, Animal; Drosophila; Drosophila Proteins; Eye; Female; Humans; Immunoprecipitation; In Vitro Techniques; Larva; Locomotion; Mice, Transgenic; Microscopy, Electron, Scanning; Naphthoquinones; Neurotoxicity Syndromes; Protein Aggregates; Retinal Pigments; tau Proteins; Tryptophan

National Trends in Outpatient Antihypertensive Prescribing in People with Dementia in the United States. - Tan, Edwin C K; Bell, J Simon; Lu, Christine Y; Toh, Sengwee (J Alzheimers Dis, 2016)
OBJECTIVE: The objectives were to investigate national trends in outpatient antihypertensive prescribing in people with dementia in the United States between 2006 and 2012, and to investigate clinical and demographic factors associated with different antihypertensive prescribing patterns. METHODS: This was an analysis of the National Ambulatory Medical Care Survey (NAMCS) and the outpatient department component of the National Hospital Ambulatory Medical Care Survey (NHAMCS). Outpatient visits by people aged ≥65 years with documented dementia were analyzed. Complex samples multivariate logistic regression was conducted to estimate temporal trends and adjusted odds ratios (AORs) with 95% confidence intervals (CIs) for factors associated with prescribing of antihypertensives, multiple antihypertensives and different antihypertensive classes. RESULTS: There was a statistically significant increase in the proportion of physician visits by older people with dementia with a documented diagnosis of hypertension from 49.3% (95% CI: 41.3% -57.4%) in 2006 to 55.7% (95% CI: 50.2% -61.2%) in 2012. There were non-significant increases in overall antihypertensive use and the use of multiple antihypertensive classes. Male sex was associated with any antihypertensive use (AOR 1.37, 95% CI 1.02-1.84) and multiple antihypertensive class use (AOR 1.52, 95% CI 1.14-2.04). Black race (AOR 2.04, 95% CI 1.12-3.71) and Midwest residence (AOR 2.03, 95% CI 1.46-2.82) were associated with multiple antihypertensive use. CONCLUSION: There was an increase in documented hypertension in physician visits by older people with dementia from 2006 to 2012, but minimal increases in overall antihypertensive use. Various demographic and clinical factors were associated with the prescribing of antihypertensives in people with dementia.

Netrin-1 Interrupts Amyloid-β Amplification, Increases sAβPPα in vitro and in vivo, and Improves Cognition in a Mouse Model of Alzheimer's Disease. - Spilman, Patricia R; Corset, Veronique; Gorostiza, Olivia; Poksay, Karen S; Galvan, Veronica; Zhang, Junli; Rao, Rammohan; Peters-Libeu, Clare; Vincelette, Jon; McGeehan, Andrew; Dvorak-Ewell, Melita; Beyer, Janine; et al. (J Alzheimers Dis, 2016)
Recent studies have shown that inoculation of susceptible mice with amyloid-β (Aβ) peptides accelerates Aβ deposition in the brain, supporting the idea that Aβ may be self-amplifying; however, the exact mechanism is not understood. Here we provide evidence that Aβ may self-amplify, in part, by inhibiting α-secretase ADAM10 (a disintegrin and metalloprotease) cleavage of full-length Aβ precursor protein (FL AβPP) and therefore allow greater β-secretase processing, and that Aβ itself is a substrate for ADAM10. Exposure of primary neuronal cultures from PDAβPP mice to exogenous rat Aβ1- 40 resulted in increased de novo human Aβ1-42 production and exposure of cells to Aβ decreased production of ADAM10 cleavage product soluble AβPPα (sAβPPα). In a cell-free assay, Aβ decreased ADAM10 cleavage of the chimeric substrate MBP-AβPPC125 and Aβ itself was apparently cleaved by the enzyme. The axonal guidance and trophic factor netrin-1, however, reduced the Aβ1- 40-induced Aβ1-42 increase, increased sAβPPα, and reversed the Aβ-induced sAβPPα decrease in vitro. In vivo, induction of netrin-1 expression in PDAβPPSwe/Ind transgenic mice resulted in reductions in both Aβ1-42 and Aβ1- 40, and ICV delivery of netrin-1 to PDAβPPSwe/Ind mice increased sAβPPα, decreased Aβ, and improved working memory. Finally, to support further study of netrin-1's potential as a therapeutic for Alzheimer's disease, pilot gene therapy studies were performed and a netrin mimetic peptide synthesized and tested that, like netrin, can increase sAβPPα and decrease Aβ1-42in vitro. Taken together, these data provide mechanistic insights into Aβ self-amplification and the ability of netrin-1 to disrupt it.

Neuritic and Diffuse Plaque Associations with Memory in Non-Cognitively Impaired Elderly. - Malek-Ahmadi, Michael; Perez, Sylvia E; Chen, Kewei; Mufson, Elliott J (J Alzheimers Dis, 2016)
The presence of Alzheimer's disease (AD)-related neuropathology among cognitively normal individuals has been well documented. It has been proposed that these individuals may represent a pre-clinical AD population. Previous studies have demonstrated a negative association between the presence of both amyloid-β (Aβ) plaques and neurofibrillary tangles with ante-mortem cognitive performance, a relationship which is likely influenced by a number of factors including age and APOE ɛ4 carrier status. The present study determined whether the presence of neuritic plaques (NPs) and diffuse plaques (DPs) are associated with performance in a number of cognitive domains after accounting for APOE ɛ4 carrier status and neurofibrillary tangle presence in a cohort of 123 older participants from the Rush Religious Order Study who died with a premortem clinical diagnosis of no cognitive impairment (NCI). After adjusting for age at death, education, gender, Braak stage, and APOE ɛ4 carrier status, the presence of NPs was associated with lower performance in the cognitive domains of Global Cognition (p = 0.002), Episodic Memory (p = 0.03), Semantic Memory (p = 0.009), and Visuospatial performance (p = 0.006), while DPs showed no association with any cognitive domain examined. These results suggest that decreases in cognition in elderly NCI individuals are associated with an increase in NPs and not DPs when age at death, education, gender, APOE ɛ4 status, and Braak stage are taken into consideration.

Neurocognitive Deficits Distinguishing Mild Dementia with Lewy Bodies from Mild Alzheimer's Disease are Associated with Parkinsonism. - Brønnick, Kolbørn; Breitve, Monica H; Rongve, Arvid; Aarsland, Dag (J Alzheimers Dis, 2016)
BACKGROUND: The cognitive profile of mild dementia with Lewy bodies (DLB) versus mild Alzheimer's disease (AD) has not been extensively studied, and the relation of cognitive deficits to the core diagnostic criteria for DLB (fluctuations, visual hallucinations, and parkinsonism) remains poorly understood. OBJECTIVE: To compare the cognitive profile in patients with mild DLB to patients with mild AD and investigate the relation between cognitive deficits distinguishing DLB from AD and the core diagnostic features in DLB. METHODS: Patients with mild dementia were recruited from the southwestern part of Norway and patients diagnosed with probable AD (n = 113) or probable DLB (n = 77) were included. The DLB core diagnostic symptoms were assessed using standardized clinical measures, and standardized neurocognitive tests assessing attention, language, memory, and visuospatial functions were administered. Univariate and multivariate comparisons of cognitive tests were performed, and tests distinguishing between AD and DLB were subjected to correlational analyses with the core diagnostic symptoms. RESULTS: DLB patients performed worse than AD patients on test of visuoconstruction, but not visual perception and on all tests involving attention and executive functions, except verbal fluency. The multivariate model distinguished between DLB and AD with a sensitivity of 74% and a specificity of 82%. Tests where DLB performed worse than AD were highly correlated with degree of parkinsonism, but not with cognitive fluctuations or visual hallucinations. CONCLUSIONS: The cognitive profile in mild DLB can be useful in distinguishing AD from DLB. The strong relation between relative deficits in DLB and parkinsonism warrants further studies.

Neurodegeneration-Like Pathological and Behavioral Changes in an AAV9-Mediated p25 Overexpression Mouse Model. - Zhou, Xiao; Huang, Jianou; Pan, Suyue; Xu, Miaojing; He, Rongni; Ji, Zhong; Hu, Yafang (J Alzheimers Dis, 2016)
BACKGROUND: The transgenic mice models overexpressing human p25 contribute greatly to the in vivo neurotoxic mechanism of p25 in neurodegenerative diseases. However, it is time-consuming to manipulate existing transgenic mice models. OBJECTIVE: Here we aim to establish a novel mouse model of neurodegeneration by overexpressing p25 mediated by recombinant adeno-associated virus serotype 9 (rAAV9). METHODS: AAV9-GFP-p25 encoding GFP-fused p25 driven by synapsin promoter, and the control, AAV9-GFP, were delivered in mice by tail-vein injection. Assessments of p25 expression, neurodegenerative pathology, and behavioral changes were performed. RESULTS: GFP expression was detected by in vivo imaging as early as one week after virus injection. Notably, widespread expression of p25 was obviously found in cortex, hippocampus, and cerebellum in AAV9-GFP-p25 mice. Moreover, decreased hippocampus volumes in AAV9-GFP-p25 mice were detected by 7T MRI examination about one month after injection. Further, these AAV9-GFP-p25 mice exhibited progressive memory impairment from three-month to six-month after virus injection. At last, hyperphosphorylated tau, neurofibrillary tangles, activated astrocytes and microglia cells were elevated in these p25 mice at about six months after virus delivery. However, amyloid-β plaques, overt neuronal loss, and apoptosis in the hippocampus and cortex were not significantly induced by AAV9-mediated p25 overexpression. CONCLUSION: The AAV9-mediated p25 overexpression mouse model, which is a practical model exhibiting neurodegeneration-like pathological and behavioral changes, provides an easier and time-saving method to explore the functions of p25 in vivo, as well as an alternative tool for development of drugs against neurotoxic of p25.

Neuroimaging Correlates of Frontotemporal Dementia Associated with SQSTM1 Mutations. - Luis, Elkin; Ortiz, Alexandra; Eudave, Luis; Ortega-Cubero, Sara; Borroni, Barbara; van der Zee, Julie; Gazzina, Stefano; Caroppo, Paola; Rubino, Elisa; D'Agata, Federico; Le Ber, Isabelle; Santana, Isabel; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a progressive dementia characterized by focal atrophy of frontal and/or temporal lobes caused by mutations in the gene coding for sequestosome 1 (SQSTM1), among other genes. Rare SQSTM1 gene mutations have been associated with Paget's disease of bone, amyotrophic lateral sclerosis, and, more recently, frontotemporal lobar degeneration (FTLD). OBJECTIVE: The aim of the study was to determine whether a characteristic pattern of grey and white matter loss is associated with SQSTM1 dysfunction. METHODS: We performed a voxel-based morphometry (VBM) study in FTD subjects carrying SQSTM1 pathogenic variants (FTD/SQSTM1 mutation carriers; n = 10), compared with FTD subjects not carrying SQSTM1 mutations (Sporadic FTD; n = 20) and healthy controls with no SQSTM1 mutations (HC/SQSTM1 noncarriers; n = 20). The groups were matched according to current age, disease duration, and gender. RESULTS: After comparing FTD/SQSTM1 carriers with Sporadic FTD, a predominantly right cortical atrophy pattern was localized in the inferior frontal, medial orbitofrontal, precentral gyri, and the anterior insula. White matter atrophy was found in both medial and inferior frontal gyri, pallidum, and putamen. FTD/SQSTM1 carriers compared with HC/SQSTM1 noncarriers showed atrophy at frontal, temporal, and parietal lobes of both hemispheres whereas the MRI pattern found in Sporadic FTD compared with controls was frontal and left temporal lobe atrophy, extending toward parietal and occipital lobes of both hemispheres. CONCLUSIONS: These results suggest that fronto-orbito-insular regions including corticospinal projections as described in ALS are probably more susceptible to the damaging effect of SQSTM1 mutations delineatinga specific gene-linked atrophy pattern.

Neuronal activity and amyloid plaque pathology: an update. - Ovsepian, Saak V; O'Leary, Valerie B (J Alzheimers Dis, 2016)
A breakthrough in Alzheimer's disease (AD) research came with the discovery of the link between activity-dependent release of amyloid-β (Aβ) from neurons and formation of amyloid plaques. Along with elucidating the cellular basis of behavioral-dependent fluctuations in Aβ levels in the brain, insights have been gained toward understanding the mechanisms that warrant selective vulnerability of various forebrain circuits to amyloid pathology. The notion of elevated activity as a source of excessive Aβ production and plaque formation is, however, in conflict with ample electrophysiological data, which demonstrate exceedingly intense activity (both intrinsic and synaptic) of neurons in several brain regions that are spared or marginally affected by amyloid plaques of AD. Thus, the link between the functional load of brain circuits and their vulnerability to amyloidosis, while evident, is also complex and remains poorly understood. Here, we discuss emerging data suggestive of a major role for super-intense synchronous activity of cortical and limbic networks in excessive Aβ production and plaque formation. It is proposed that dense recurrent wiring of associative areas prone to epileptic seizures might be of critical relevance to their higher susceptibility to plaque pathology and related functional impairments.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Amyloidosis; Animals; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Neurons; Plaque, Amyloid; Prosencephalon; Seizures

Neurophysiological assessment of Alzheimer's disease individuals by a single electroencephalographic marker. - Lizio, Roberta; Del Percio, Claudio; Marzano, Nicola; Soricelli, Andrea; Yener, Görsev G; Başar, Erol; Mundi, Ciro; De Rosa, Salvatore; Triggiani, Antonio Ivano; Ferri, Raffaele; Arnaldi, Dario; Nobili, Flavio Mariano; et al. (J Alzheimers Dis, 2016)
Here we presented a single electroencephalographic (EEG) marker for a neurophysiological assessment of Alzheimer's disease (AD) patients already diagnosed by current guidelines. The ability of the EEG marker to classify 127 AD individuals and 121 matched cognitively intact normal elderly (Nold) individuals was tested. Furthermore, its relationship to AD patients' cognitive status and structural brain integrity was examined. Low-resolution brain electromagnetic tomography (LORETA) freeware estimated cortical sources of resting state eyes-closed EEG rhythms. The EEG marker was defined as the ratio between the activity of parieto-occipital cortical sources of delta (2-4 Hz) and low-frequency alpha (8-10.5 Hz) rhythms. Results showed 77.2% of sensitivity in the recognition of the AD individuals; 65% of specificity in the recognition of the Nold individuals; and 0.75 of area under the receiver-operating characteristic curve. Compared to the AD subgroup with the EEG maker within one standard deviation of the Nold mean (EEG-), the AD subgroup with EEG+ showed lower global cognitive status, as revealed by Mini-Mental State Evaluation score, and more abnormal values of white-matter and cerebrospinal fluid normalized volumes, as revealed by structural magnetic resonance imaging. We posit that cognitive and functional status being equal, AD patients with EEG+ should receive special clinical attention due to a neurophysiological "frailty". EEG+ label can be also used in clinical trials (i) to form homogeneous groups of AD patients diagnosed by current guidelines and (ii) as end-point to evaluate intervention effects.
Keywords: Aged; Alzheimer Disease; Biomarkers; Brain Mapping; Case-Control Studies; Cognition Disorders; Electroencephalography; Female; Humans; Italy; Magnetic Resonance Imaging; Male; Middle Aged; Occipital Lobe; Rest; ROC Curve; Turkey

Neuropsychological Features of Microbleeds and Cortical Microinfarct Detected by High Resolution Magnetic Resonance Imaging. - Ueda, Yukito; Satoh, Masayuki; Tabei, Ken-Ichi; Kida, Hirotaka; Ii, Yuichiro; Asahi, Masaru; Maeda, Masayuki; Sakuma, Hajime; Tomimoto, Hidekazu (J Alzheimers Dis, 2016)
BACKGROUND: Lobar microbleeds (MBs) and cortical microinfarct (CMI) are caused by cerebral amyloid angiopathy in the elderly and increase in number in Alzheimer's disease. OBJECTIVE: The aim of this study is to elucidate the effects of lobar MBs and CMIs on cognitive function. METHODS: The subjects were outpatients who visited the memory clinic of Mie University Hospital. Among 120 subjects, 109 patients fulfilled the inclusion criteria. We quantitatively estimated MBs and CMIs using double inversion recovery and 3D FLAIR images of 3T MRI. Neuropsychological assessments included intellectual, memory, constructional, and frontal lobe function. RESULTS: Of the 109 patients, MBs and CMIs were observed in 68 (62%) and 17 (16%) subjects, respectively. Of the 68 patients with MBs, lobar MBs were found in 28, deep MBs in 8 and mixed MBs in 31. In each age group, the number of MBs increased in patients with CMI (CMI+ group) than those without CMI (CMI- group), and MBs and CMIs additively decreased MMSE scores. In psychological screens, the MBs+ group with more than 10 MBs showed significantly lower scores of category- and letter-WF than MB- group. The CMI+ group showed significantly worse scores than CMI- group in Japanese Raven's coloured progressive matrices, Trail Making Test-A, category- and letter-word fluency and copy and drawing of figures. CONCLUSION: Lobar MBs and CMIs in the elderly frequently coexisted with each other and additively contributed to cognitive impairment, which is mainly predisposed to frontal lobe function.

Neuropsychological Markers of Medial Perirhinal and Entorhinal Cortex Functioning are Impaired Twelve Years Preceding Diagnosis of Alzheimer's Dementia. - Hirni, Daniela I; Kivisaari, Sasa L; Krumm, Sabine; Monsch, Andreas U; Berres, Manfred; Oeksuez, Fatma; Reinhardt, Julia; Ulmer, Stephan; Kressig, Reto W; Stippich, Christoph; Taylor, Kirsten I (J Alzheimers Dis, 2016)
Neurofibrillary pathology in Alzheimer's dementia (AD) is associated with cognitive impairments and cortical thinning, and begins in medial perirhinal cortex (mPRC) before entering entorhinal cortex (ERC). Thus, mPRC dysfunction (e.g., semantic object memory impairments) may predate or accompany ERC (i.e., episodic memory) dysfunction in the preclinical course of typical AD. We developed formulae estimating mPRC and ERC integrity (i.e., cortical thickness) using common neuropsychological tests in 31 healthy individuals and 58 early AD patients. These formulae estimated the longitudinal courses of mPRC and ERC functioning in independent groups of 28 optimally healthy individuals who developed AD (NC-AD) over 2.8-13.4 years and 28 pairwise-matched, stable, healthy individuals (NC-NC). Mixed models demonstrated significantly worse NC-AD than NC-NC estimated mPRC and ERC functioning at the earliest observation, 12 years preceding diagnosis, and a significant decline 4 years preceding the AD diagnosis. These findings demonstrate that specific neuropsychological impairments occur early in the course of preclinical AD and that tasks measuring mPRC functioning may serve as additional, powerful markers of preclinical AD.

Non Fluent Variant of Primary Progressive Aphasia Due to the Novel GRN g.9543delA(IVS3-2delA) Mutation. - Cioffi, Sara M G; Galimberti, Daniela; Barocco, Federica; Spallazzi, Marco; Fenoglio, Chiara; Serpente, Maria; Arcaro, Marina; Gardini, Simona; Scarpini, Elio; Caffarra, Paolo (J Alzheimers Dis, 2016)
Mutations in progranulin gene (GRN) are a common cause of autosomal dominant frontotemporal lobar degeneration syndromes and are associated with a wide phenotypic heterogeneity. The majority of genetic defects in GRN consists of loss-of-function mutations, causing haploinsufficiency, and is associated with extremely low plasma progranulin levels. Herein, we describe a patient who developed language dysfunctions and memory disturbances at 63 years of age. Considering the early onset and the positive family history (sister aged 50 with non-fluent/agrammatic variant of primary progressive aphasia, father with behavioral disturbances in his sixties), a genetic analysis was carried out, showing the presence of a novel mutation [g.9543delA (IVS3-2delA)] in a predicted splicing site of GRN. Her progranulin plasma levels were under the reference threshold, as in her sister, thus supporting the causative role of the new variant. The same genetic mutation was confirmed by sequencing in her sister. Results described enlarge current knowledge on genetic causes of the disease and clinical characteristics of carriers.

Non-Catalytic Roles of Presenilin Throughout Evolution. - Otto, Grant P; Sharma, Devdutt; Williams, Robin S B (J Alzheimers Dis, 2016)
Research into Alzheimer's disease pathology and treatment has often focused on presenilin proteins. These proteins provide the key catalytic activity of the γ-secretase complex in the cleavage of amyloid-β precursor protein and resultant amyloid tangle deposition. Over the last 25 years, screening novel drugs to control this aberrant proteolytic activity has yet to identify effective treatments for the disease. In the search for other mechanisms of presenilin pathology, several studies have demonstrated that mammalian presenilin proteins also act in a non-proteolytic role as a scaffold to co-localize key signaling proteins. This role is likely to represent an ancestral presenilin function, as it has been described in genetically distant species including non-mammalian animals, plants, and a simple eukaryotic amoeba Dictyostelium that diverged from the human lineage over a billion years ago. Here, we review the non-catalytic scaffold role of presenilin, from mammalian models to other biomedical models, and include recent insights using Dictyostelium, to suggest that this role may provide an early evolutionary function of presenilin proteins.

Non-Fibrillar Oligomeric Amyloid-β within Synapses. - Pickett, Eleanor K; Koffie, Robert M; Wegmann, Susanne; Henstridge, Christopher M; Herrmann, Abigail G; Colom-Cadena, Marti; Lleo, Alberto; Kay, Kevin R; Vaught, Melissa; Soberman, Roy; Walsh, Dominic M; Hyman, Bradley T; et al. (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is characterized by memory loss, insidious cognitive decline, profound neurodegeneration, and the extracellular accumulation of amyloid-β (Aβ) peptide in senile plaques and intracellular accumulation of tau in neurofibrillary tangles. Loss and dysfunction of synapses are believed to underlie the devastating cognitive decline in AD. A large amount of evidence suggests that oligomeric forms of Aβ associated with senile plaques are toxic to synapses, but the precise sub-synaptic localization of Aβ and which forms are synaptotoxic remain unknown. Here, we characterize the sub-synaptic localization of Aβ oligomers using three high-resolution imaging techniques, stochastic optical reconstruction microscopy, immunogold electron microscopy, and Förster resonance energy transfer in a plaque-bearing mouse model of AD. With all three techniques, we observe oligomeric Aβ inside synaptic terminals. Further, we tested a panel of Aβ antibodies using the relatively high-throughput array tomography technique to determine which forms are present in synapses. Our results show that different oligomeric Aβ species are present in synapses and highlight the potential of array tomography for rapid testing of aggregation state specific Aβ antibodies in brain tissue.

Non-Verbal Episodic Memory Deficits in Primary Progressive Aphasias are Highly Predictive of Underlying Amyloid Pathology. - Ramanan, Siddharth; Flanagan, Emma; Leyton, Cristian E; Villemagne, Victor L; Rowe, Christopher C; Hodges, John R; Hornberger, Michael (J Alzheimers Dis, 2016)
Diagnostic distinction of primary progressive aphasias (PPA) remains challenging, in particular for the logopenic (lvPPA) and nonfluent/agrammatic (naPPA) variants. Recent findings highlight that episodic memory deficits appear to discriminate these PPA variants from each other, as only lvPPA perform poorly on these tasks while having underlying amyloid pathology similar to that seen in amnestic dementias like Alzheimer's disease (AD). Most memory tests are, however, language based and thus potentially confounded by the prevalent language deficits in PPA. The current study investigated this issue across PPA variants by contrasting verbal and non-verbal episodic memory measures while controlling for their performance on a language subtest of a general cognitive screen. A total of 203 participants were included (25 lvPPA; 29 naPPA; 59 AD; 90 controls) and underwent extensive verbal and non-verbal episodic memory testing, with a subset of patients (n = 45) with confirmed amyloid profiles as assessed by Pittsburgh Compound B and PET. The most powerful discriminator between naPPA and lvPPA patients was a non-verbal recall measure (Rey Complex Figure delayed recall), with 81% of PPA patients classified correctly at presentation. Importantly, AD and lvPPA patients performed comparably on this measure, further highlighting the importance of underlying amyloid pathology in episodic memory profiles. The findings demonstrate that non-verbal recall emerges as the best discriminator of lvPPA and naPPA when controlling for language deficits in high load amyloid PPA cases.
Keywords: Aged; Alzheimer Disease; Amyloid; Aniline Compounds; Aphasia, Primary Progressive; Brain; Diagnosis, Differential; Female; Humans; Logistic Models; Male; Memory, Episodic; Neuropsychological Tests; Positron-Emission Tomography; Radiopharmaceuticals; Speech Perception; Thiazoles

Normal Amplitude of Electroretinography and Visual Evoked Potential Responses in AβPP/PS1 Mice. - Leinonen, Henri; Lipponen, Arto; Gurevicius, Kestutis; Tanila, Heikki (J Alzheimers Dis, 2016)
Alzheimer's disease has been shown to affect vision in human patients and animal models. This may pose the risk of bias in behavior studies and therefore requires comprehensive investigation. We recorded electroretinography (ERG) under isoflurane anesthesia and visual evoked potentials (VEP) in awake amyloid expressing AβPPswe/PS1dE9 (AβPP/PS1) and wild-type littermate mice at a symptomatic age. The VEPs in response to patterned stimuli were normal in AβPP/PS1 mice. They also showed normal ERG amplitude but slightly shortened ERG latency in dark-adapted conditions. Our results indicate subtle changes in visual processing in aged male AβPP/PS1 mice specifically at a retinal level.
Keywords: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Contrast Sensitivity; Disease Models, Animal; Electroencephalography; Electroretinography; Evoked Potentials, Visual; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Photic Stimulation; Presenilin-1; Reaction Time

A Novel and Intelligent Home Monitoring System for Care Support of Elders with Cognitive Impairment. - Lazarou, Ioulietta; Karakostas, Anastasios; Stavropoulos, Thanos G; Tsompanidis, Theodoros; Meditskos, Georgios; Kompatsiaris, Ioannis; Tsolaki, Magda (J Alzheimers Dis, 2016)
BACKGROUND: Assistive technology, in the form of a smart home environment, is employed to support people with dementia. OBJECTIVES: To propose a system for continuous and objective remote monitoring of problematic daily living activity areas and design personalized interventions based on system feedback and clinical observations for improving cognitive function and health-related quality of life. METHODS: The assistive technology of the proposed system, including wearable, sleep, object motion, presence, and utility usage sensors, was methodically deployed at four different home installations of people with cognitive impairment. Detection of sleep patterns, physical activity, and activities of daily living, based on the collected sensor data and analytics, was available at all times through comprehensive data visualization solutions. Combined with clinical observation, targeted psychosocial interventions were introduced to enhance the participants' quality of life and improve their cognitive functions and daily functionality. Meanwhile, participants and their caregivers were able to visualize a reduced set of information tailored to their needs. RESULTS: Overall, paired-sample t-test analysis of monitored qualities revealed improvement for all participants in neuropsychological assessment. Moreover, improvement was detected from the beginning to the end of the trial, in physical condition and in the domains of sleep. Detecting abnormalities via the system, for example in sleep quality, such as REM sleep, has proved to be critical to assess current status, drive interventions, and evaluate improvements in a reliable manner. CONCLUSION: It has been proved that the proposed system is suitable to support clinicians to reliably drive and evaluate clinical interventions toward quality of life improvement of people with cognitive impairment.

A Novel Liposomal Nanoparticle for the Imaging of Amyloid Plaque by Magnetic Resonance Imaging. - Tanifum, Eric A; Ghaghada, Ketan; Vollert, Craig; Head, Elizabeth; Eriksen, Jason L; Annapragada, Ananth (J Alzheimers Dis, 2016)
Amyloid binding molecules with greater hydrophilicity than existing ligands were synthesized. The lead candidate ET6-21 bound amyloid fibrils, and amyloid deposits in dog brain and human brain tissue ex vivo. The ligand was used to prepare novel amyloid-targeted liposomal nanoparticles. The preparation was tested in the Tg2576 and TetO/APP mouse models of amyloid deposition. Gd chelates and Indocyanine green were included in the particles for visualization by MRI and near-infrared microscopy. Upon intravenous injection, the particles successfully traversed the blood-brain barrier in these mice, and bound to the plaques. Magnetic resonance imaging (T1-MRI) conducted 4 days after injection demonstrated elevated signal in the brains of mice with amyloid plaques present. No signal was observed in amyloid-negative mice, or in amyloid-positive mice injected with an untargeted version of the same agent. The MRI results were confirmed by immunohistochemical and fluorescent microscopic examination of mouse brain sections, showing colocalization of the fluorescent tags and amyloid deposits.

Novel Mutation (Gly212Val) in the PS2 Gene Associated with Early-Onset Familial Alzheimer's Disease. - Marín-Muñoz, Juan; Noguera-Perea, Ma Fuensanta; Gómez-Tortosa, Estrella; López-Motos, David; Antequera-Torres, Martirio; Martínez-Herrada, Begoña; Manzanares-Sánchez, Salvadora; Vivancos-Moreau, Laura; Legaz-García, Agustina; Rábano-Gutiérrez Del Arroyo, Alberto; Antúnez-Almagro, Carmen (J Alzheimers Dis, 2016)
Mutations in the presenilin 2 gene (PS2) are an extremely rare cause of early-onset autosomal dominant Alzheimer's disease (AD), accounting for only 5% of these families. These cases represent a particular model of AD, and the scarcity of reports on their clinical phenotypes makes them of great interest. We report a family with early-onset autosomal dominant AD in four members, where the two living siblings were found to carry the novel PS2 mutation Gly212Val (exon 7, transmembrane domain IV) with highly predicted pathogenicity. Age at onset ranged from 60 to 65 years and three of the cases died between ages 74 and 76 years. Clinical phenotype was quite homogeneous among affected members of the family, and overall features, including cognitive decline, tau/p-tau and amyloid-β cerebrospinal fluid markers, neuroimaging, and neuropathology were consistent with typical AD. Lewy bodies were present but restricted to the amygdala.

Novel Selective Calpain 1 Inhibitors as Potential Therapeutics in Alzheimer's Disease. - Fà, Mauro; Zhang, Hong; Staniszewski, Agnieszka; Saeed, Faisal; Shen, Li W; Schiefer, Isaac T; Siklos, Marton I; Tapadar, Subhasish; Litosh, Vladislav A; Libien, Jenny; Petukhov, Pavel A; Teich, Andrew F; et al. (J Alzheimers Dis, 2016)
Alzheimer's disease, one of the most important brain pathologies associated with neurodegenerative processes, is related to overactivation of calpain-mediated proteolysis. Previous data showed a compelling efficacy of calpain inhibition against abnormal synaptic plasticity and memory produced by the excess of amyloid-β, a distinctive marker of the disease. Moreover, a beneficial effect of calpain inhibitors in Alzheimer's disease is predictable by the occurrence of calpain hyperactivation leading to impairment of memory-related pathways following abnormal calcium influxes that might ensue independently of amyloid-β elevation. However, molecules currently available as effective calpain inhibitors lack adequate selectivity. This work is aimed at characterizing the efficacy of a novel class of epoxide-based inhibitors, synthesized to display improved selectivity and potency towards calpain 1 compared to the prototype epoxide-based generic calpain inhibitor E64. Both functional and preliminary toxicological investigations proved the efficacy, potency, and safety of the novel and selective calpain inhibitors NYC438 and NYC488 as possible therapeutics against the disease.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cysteine Proteinase Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Fear; Glycoproteins; Hippocampus; Humans; In Vitro Techniques; Long-Term Potentiation; Maze Learning; Memory; Mice; Mice, Inbred ICR; Mice, Transgenic; Mutation; Patch-Clamp Techniques; Peptide Fragments; Presenilin-1; Spectrin

A Novel Small Molecule Modulator of Amyloid Pathology. - Lovell, Mark A; Lynn, Bert C; Fister, Shuling; Bradley-Whitman, Melissa; Murphy, M Paul; Beckett, Tina L; Norris, Christopher M (J Alzheimers Dis, 2016)
Because traditional approaches to drug development for Alzheimer's disease are becoming increasingly expensive and in many cases disappointingly unsuccessful, alternative approaches are required to shift the paradigm. Following leads from investigations of dihydropyridine calcium channel blockers, we observed unique properties from a class of functionalized naphthyridines and sought to develop these as novel therapeutics that minimize amyloid pathology without the adverse effects associated with current therapeutics. Our data show methyl 2,4-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridine-1-carboxylate (BNC-1) significantly decreases amyloid burden in a well-established mouse model of amyloid pathology through a unique mechanism mediated by Elk-1, a transcriptional repressor of presenilin-1. Additionally, BNC-1 treatment leads to increased levels of synaptophysin and synapsin, markers of synaptic integrity, but does not adversely impact presenilin-2 or processing of Notch-1, thus avoiding negative off target effects associated with pan-gamma secretase inhibition. Overall, our data show BNC-1 significantly decreases amyloid burden and improves markers of synaptic integrity in a well-established mouse model of amyloid deposition by promoting phosphorylation and activation of Elk-1, a transcriptional repressor of presenilin-1 but not presenilin-2. These data suggest BNC-1 might be a novel, disease-modifying therapeutic that will alter the pathogenesis of Alzheimer's disease.

A Novel Splice-Acceptor Site Mutation in GRN (c.709-2 A>T) Causes Frontotemporal Dementia Spectrum in a Large Family from Southern Italy. - Sassi, Celeste; Capozzo, Rosa; Gibbs, Raphael; Crews, Cynthia; Zecca, Chiara; Arcuti, Simona; Copetti, Massimiliano; Barulli, Maria R; Brescia, Vincenzo; Singleton, Andrew B; Logroscino, Giancarlo (J Alzheimers Dis, 2016)
Heterozygous loss of function mutations in granulin represent a significant cause of frontotemporal lobar degeneration with ubiquitin and TDP-43 inclusions (FTLD-TDP). We report a novel GRN splice site mutation (c.709-2 A>T), segregating with frontotemporal dementia spectrum in a large family from southern Italy. The GRN c.709-2 A>T is predicted to result in the skipping of exon 8, leading to non-sense mediated mRNA decay. Moreover, the PGRN plasma levels in the GRN c.709-2 A>T carriers were significantly lower (24 ng/ml) compared to controls (142.7 ng/ml) or family members non-carriers (82.0 ng/ml) (p-value = 0.005, Kruskal Wallis), suggesting progranulin haploinsufficiency. We do not report any potential pathogenic GRN mutation in a follow-up cohort composed of 6 FTD families and 43 sporadic FTD cases, from the same geographic area. Our study suggests that GRN (c.709-2 A>T) is a novel and likely very rare cause of FTD in this Italian cohort. Finally, in line with previous studies, we show that GRN haploinsufficiency leads to a heterogeneous clinical picture, and plasma progranulin levels may be a reliable tool to identify GRN loss of function mutations. However, given that a) genetic and environmental factors, gender, and age may regulate PGRN plasma levels and b) plasma progranulin levels may not reflect PGRN levels in the central nervous system, we suggest that the measurement of progranulin in the plasma should always be coupled with genetic screening of GRN for mutations.

N-Terminal Pro-B-Type Natriuretic Peptide and Risk of Future Cognitive Impairment in the REGARDS Cohort. - Cushman, Mary; Callas, Peter W; McClure, Leslie A; Unverzagt, Frederick W; Howard, Virginia J; Gillett, Sarah R; Thacker, Evan L; Wadley, Virginia G (J Alzheimers Dis, 2016)
BACKGROUND: Improved understanding of the etiology of cognitive impairment is needed to develop effective preventive interventions. Higher amino-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker of cardiac dysfunction associated with risk of cardiovascular diseases and stroke in apparently healthy people. OBJECTIVE: To study the association of NT-proBNP with risk of incident cognitive impairment. METHODS: The Reasons for Geographic and Racial Differences in Stroke is a national cohort study of 30,239 black and white Americans age 45 and older at baseline, enrolled in 2003-7. Among participants without prebaseline stroke or cognitive impairment, baseline NT-proBNP was measured in 470 cases of incident cognitive impairment and 557 controls. Cases were participants scoring below the 6th percentile of demographically-adjusted means on at least 2 of 3 serially administered tests (word list learning, word list recall and semantic fluency) over 3.5 years follow-up. RESULTS: Adjusting for age, gender, race, region of residence, education, and income, there was an increased odds ratio of incident cognitive impairment with increasing NT-proBNP; participants in the 4th versus 1st quartile (>127 versus ≤33 pg/ml) had a 1.69-fold increased odds (95% CI 1.11-2.58). Adjustment for cardiovascular risk factors and presence of an apolipoprotein E4 allele had no substantial impact on the odds ratio. Results did not differ by age, race, gender, or presence of an apolipoprotein E4 allele. CONCLUSION: Higher NT-pro-BNP was associated with incident cognitive impairment in this prospective study, independent of atherogenic and Alzheimer's disease risk factors. Future work should clarify pathophysiologic connections of NT-proBNP and cognitive dysfunction.

N-truncated Aβ2-X starting with position two in sporadic Alzheimer's disease cases and two Alzheimer mouse models. - Savastano, Adriana; Klafki, Hans; Haußmann, Ute; Oberstein, Timo Jan; Muller, Petr; Wirths, Oliver; Wiltfang, Jens; Bayer, Thomas A (J Alzheimers Dis, 2016)
According to the modified amyloid hypothesis, the key event in the pathogenesis of Alzheimer's disease (AD) is the deposition of neurotoxic amyloid β-peptides (Aβs) in plaques and cerebral blood vessels. Additionally to full-length peptides, a great diversity of N-truncated Aβ variants is derived from the larger amyloid-β protein precursor (AβPP). Vast evidence suggests that Aβx-42 isoforms play an important role in triggering neurodegeneration due to their high abundance, amyloidogenic propensity and toxicity. Although N-truncated Aβ peptides and Aβx-42 species appear to be the crucial players in AD etiology, the Aβ2-X isoforms did not receive much attention yet. The present study is the first to show immunohistochemical evidence of Aβ2-X in cases of AD and its distribution in AβPP/PS1KI and 5XFAD transgenic mouse models using a novel antibody pAB77 that has been developed using Aβ2-14 as antigen. Positive plaques and congophilic amyloid angiopathy (CAA) were observed in AD cases and in both mouse models. While in AD cases, abundant CAA and less pronounced plaque pathology was evident, the two mouse models showed predominantly extracellular Aβ deposits and minor CAA staining. Western blotting and a capillary isoelectric focusing immunoassay demonstrated the high specificity of the antibody pAb77 against Aβ-variants starting with the N-terminal Alanine-2.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Animals; Blotting, Western; Brain; Cerebral Amyloid Angiopathy; Disease Models, Animal; Female; Humans; Male; Mice; Mice, Transgenic; Plaque, Amyloid

Nutritional Status is Associated with Faster Cognitive Decline and Worse Functional Impairment in the Progression of Dementia: The Cache County Dementia Progression Study1. - Sanders, Chelsea; Behrens, Stephanie; Schwartz, Sarah; Wengreen, Heidi; Corcoran, Chris D; Lyketsos, Constantine G; Tschanz, JoAnn T (J Alzheimers Dis, 2016)
Nutritional status may be a modifiable factor in the progression of dementia. We examined the association of nutritional status and rate of cognitive and functional decline in a U.S. population-based sample. Study design was an observational longitudinal study with annual follow-ups up to 6 years of 292 persons with dementia (72% Alzheimer's disease, 56% female) in Cache County, UT using the Mini-Mental State Exam (MMSE), Clinical Dementia Rating Sum of Boxes (CDR-sb), and modified Mini Nutritional Assessment (mMNA). mMNA scores declined by approximately 0.50 points/year, suggesting increasing risk for malnutrition. Lower mMNA score predicted faster rate of decline on the MMSE at earlier follow-up times, but slower decline at later follow-up times, whereas higher mMNA scores had the opposite pattern (mMNA by time β= 0.22, p = 0.017; mMNA by time2 β= -0.04, p = 0.04). Lower mMNA score was associated with greater impairment on the CDR-sb over the course of dementia (β= 0.35, p <  0.001). Assessment of malnutrition may be useful in predicting rates of progression in dementia and may provide a target for clinical intervention.
Keywords: Age of Onset; Aged, 80 and over; Alzheimer Disease; Dementia, Vascular; Disease Progression; Female; Follow-Up Studies; Humans; Longitudinal Studies; Male; Mental Status Schedule; Nutritional Status; Severity of Illness Index; Sex Factors; Utah

Nutritional Status of Patients with Alzheimer's Disease and Their Caregivers. - Tombini, Mario; Sicari, Maura; Pellegrino, Giovanni; Ursini, Francesca; Insardá, Pasqualina; Di Lazzaro, Vincenzo (J Alzheimers Dis, 2016)
BACKGROUND: Malnutrition is one of the most important conditions that negatively affects the health of elder people, particularly in patients with dementia. OBJECTIVE: To provide an assessment of nutritional status of patients affected by Alzheimer's disease (AD) living at home and of their caregivers by means of Mini Nutritional Assessment (MNA), and to explore the influence of different factors on nutrition. METHODS: 90 patients affected by AD living at home and 90 age- and sex-matched caregivers were enrolled. Patients and caregivers, coming from an urban-rural fringe of Southern Italy, were assessed using full MNA, Mini-Mental State Examination, Geriatric Depression Scale- short form, Activity of Daily Living, and Instrumental Activities of Daily Living scales. RESULTS: Malnutrition was found with high prevalence in patients affected by AD of different severity (more than 95% of patients were malnourished or at risk of malnutrition), and associated with reduced functional status. An altered nutrition was also recognized with high rate in the group of caregivers (23.3% were malnourished and 41.1% at risk of malnutrition) and the worse nutritional condition was correlated with higher age and lower functional and cognitive status and education. A positive correlation between MNA score of AD patients and caregivers was found. CONCLUSION: Corrective measures should be taken in order to early identify nutritional deficiencies and risk of malnutrition observed with high rate in both groups of AD patients and their caregivers; in these subjects a nutrition education program and intervention policies are mandatory to restore nutritional status.

Oculodentodigital dysplasia with massive brain calcification and a new mutation of GJA1 gene. - Tumminelli, Gemma; Di Donato, Ilaria; Guida, Valentina; Rufa, Alessandra; De Luca, Alessandro; Federico, Antonio (J Alzheimers Dis, 2016)
Oculodentodigital dysplasia (ODDD) [MIM 164200] is a rare disorder caused by mutations in the gap junction alpha 1 (GJA1) gene encoding for connexin 43 (Cx43). Typical signs include type III syndactyly, microphtalmia, microdontia, and neurological disturbances. We report a 59-year-old man having clinical symptoms and signs suggestive of ODDD, with some rarely reported features, that is the presence of gross calcifications of basal ganglia and cerebellar nuclei. Mutation analysis of GJA1 gene identified an unreported heterozygous missense mutation [NM_000165.3:c.124 G>C;p.(Glu42Gln)], which may be thought to alter the brain microvessels leading to massive calcifications, as in primary familial brain calcification.
Keywords: Basal Ganglia; Calcinosis; Connexin 43; Craniofacial Abnormalities; DNA Mutational Analysis; Eye Abnormalities; Fingers; Foot Deformities, Congenital; Humans; Male; Middle Aged; Mutation, Missense; Syndactyly; Tomography, X-Ray Computed; Tooth Abnormalities

Older Adults Taking AT1-Receptor Blockers Exhibit Reduced Cerebral Amyloid Retention. - Nation, Daniel A; Ho, Jean; Yew, Belinda (J Alzheimers Dis, 2016)
BACKGROUND: Evidence suggests that angiotensin II AT1-receptor blockers (ARBs) may be protective against dementia, and studies in transgenic animals indicate that this may be due to improved amyloid-β (Aβ) clearance. OBJECTIVE: We investigated whether taking ARBs was associated with an attenuation of age-related increases in cerebral Aβ retention, and reduced progression to dementia. METHODS: Eight hundred seventy-one stroke-free and dementia-free older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study underwent baseline lumbar puncture, and a subgroup (n = 124) underwent 12 and 24 month follow-up lumbar puncture. Participants were followed at variable intervals for clinical progression to dementia. Linear mixed models and ANCOVA compared ARBs users with those taking other antihypertensives (O-antiHTN) or no antihypertensives (No-antiHTN) on cerebrospinal fluid (CSF) Aβ and phosphorylated tau (P-tau) levels. Cox regression and chi-square analyses compared groups on progression to dementia. RESULTS: ARBs users exhibited greater vascular risk and lower educational attainment than the No-antiHTN group. Longitudinal analyses indicated higher CSF Aβ and lower P-tau in ARBs users versus other groups. Cross-sectional analyses revealed age-related decreases in CSF Aβ in other groups but not ARBs users. ARBs users were less likely to progress to dementia and showed reduced rate of progression relative to the No-antiHTN group. DISCUSSION: Patients taking ARBs showed an attenuation of age-related decreases in CSF Aβ, a finding that is consistent with studies done in transgenic animals. These findings may partly explain why ARBs users show reduced progression to dementia despite their lower educational attainment and greater vascular risk burden.
Keywords: Aged; Aged, 80 and over; Aging; Amyloid beta-Peptides; Angiotensin Receptor Antagonists; Antihypertensive Agents; Chi-Square Distribution; Cross-Sectional Studies; Dementia; Female; Humans; Longitudinal Studies; Male; Middle Aged; Peptide Fragments; Psychiatric Status Rating Scales; Regression Analysis; tau Proteins; Time Factors

Omega-3 Fatty Acid Status Enhances the Prevention of Cognitive Decline by B Vitamins in Mild Cognitive Impairment. - Oulhaj, Abderrahim; Jernerén, Fredrik; Refsum, Helga; Smith, A David; de Jager, Celeste A (J Alzheimers Dis, 2016)
A randomized trial (VITACOG) in people with mild cognitive impairment (MCI) found that B vitamin treatment to lower homocysteine slowed the rate of cognitive and clinical decline. We have used data from this trial to see whether baseline omega-3 fatty acid status interacts with the effects of B vitamin treatment. 266 participants with MCI aged ≥70 years were randomized to B vitamins (folic acid, vitamins B6 and B12) or placebo for 2 years. Baseline cognitive test performance, clinical dementia rating (CDR) scale, and plasma concentrations of total homocysteine, total docosahexaenoic and eicosapentaenoic acids (omega-3 fatty acids) were measured. Final scores for verbal delayed recall, global cognition, and CDR sum-of-boxes were better in the B vitamin-treated group according to increasing baseline concentrations of omega-3 fatty acids, whereas scores in the placebo group were similar across these concentrations. Among those with good omega-3 status, 33% of those on B vitamin treatment had global CDR scores >0 compared with 59% among those on placebo. For all three outcome measures, higher concentrations of docosahexaenoic acid alone significantly enhanced the cognitive effects of B vitamins, while eicosapentaenoic acid appeared less effective. When omega-3 fatty acid concentrations are low, B vitamin treatment has no effect on cognitive decline in MCI, but when omega-3 levels are in the upper normal range, B vitamins interact to slow cognitive decline. A clinical trial of B vitamins combined with omega-3 fatty acids is needed to see whether it is possible to slow the conversion from MCI to AD.
Keywords: Aged; Aged, 80 and over; Cognition; Cognitive Dysfunction; Disease Progression; Fatty Acids, Omega-3; Female; Humans; Male; Neuropsychological Tests; Treatment Outcome; Vitamin B Complex

The Online Environment: A Key Variable in the Ethical Response to Complementary and Alternative Medicine for Alzheimer's Disease. - Robillard, Julie M (J Alzheimers Dis, 2016)
Racine et al.'s Ethics Review highlights the challenges associated with the use of complementary and alternative medicine (CAM) in the context of early diagnosis of Alzheimer's disease (AD). As CAM are increasingly promoted and sold on the Internet, the unregulated online environment has the potential to significantly impact the health and well-being of the aging demographic, and in particular of individuals concerned about AD. In this response, the ethical challenges specific to the online environment are discussed and solutions are put forward to empower the aging population to maximize the benefits of the online environment while minimizing the potential harms of misinformation, conflict of interest, and other ethical concerns.
Keywords: Alzheimer Disease; Complementary Therapies; Humans

Optimization of Statistical Single Subject Analysis of Brain FDG PET for the Prognosis of Mild Cognitive Impairment-to-Alzheimer's Disease Conversion. - Lange, Catharina; Suppa, Per; Frings, Lars; Brenner, Winfried; Spies, Lothar; Buchert, Ralph (J Alzheimers Dis, 2016)
BACKGROUND: Positron emission tomography (PET) with the glucose analog F-18-fluorodeoxyglucose (FDG) is widely used in the diagnosis of neurodegenerative diseases. Guidelines recommend voxel-based statistical testing to support visual evaluation of the PET images. However, the performance of voxel-based testing strongly depends on each single preprocessing step involved. OBJECTIVE: To optimize the processing pipeline of voxel-based testing for the prognosis of dementia in subjects with amnestic mild cognitive impairment (MCI). METHODS: The study included 108 ADNI MCI subjects grouped as 'stable MCI' (n = 77) or 'MCI-to-AD converter' according to their diagnostic trajectory over 3 years. Thirty-two ADNI normals served as controls. Voxel-based testing was performed with the statistical parametric mapping software (SPM8) starting with default settings. The following modifications were added step-by-step: (i) motion correction, (ii) custom-made FDG template, (iii) different reference regions for intensity scaling, and (iv) smoothing was varied between 8 and 18 mm. The t-sum score for hypometabolism within a predefined AD mask was compared between the different settings using receiver operating characteristic (ROC) analysis with respect to differentiation between 'stable MCI' and 'MCI-to-AD converter'. The area (AUC) under the ROC curve was used as performance measure. RESULTS: The default setting provided an AUC of 0.728. The modifications of the processing pipeline improved the AUC up to 0.832 (p = 0.046). Improvement of the AUC was confirmed in an independent validation sample of 241 ADNI MCI subjects (p = 0.048). CONCLUSION: The prognostic value of voxel-based single subject analysis of brain FDG PET in MCI subjects can be improved considerably by optimizing the processing pipeline.
Keywords: Aged; Alzheimer Disease; Area Under Curve; Brain; Cognitive Dysfunction; Disease Progression; Female; Fluorodeoxyglucose F18; Follow-Up Studies; Glucose; Humans; Image Interpretation, Computer-Assisted; Male; Positron-Emission Tomography; Prognosis; Radiopharmaceuticals; ROC Curve

An Optimized Combination of Ginger and Peony Root Effectively Inhibits Amyloid-β Accumulation and Amyloid-β-Mediated Pathology in AβPP/PS1 Double-Transgenic Mice. - Lim, Soonmin; Choi, Jin Gyu; Moon, Minho; Kim, Hyo Geun; Lee, Wonil; Bak, Hyoung-Rok; Sung, Hachang; Park, Chi Hye; Kim, Sun Yeou; Oh, Myung Sook (J Alzheimers Dis, 2016)
The progressive aggregation of amyloid-β protein (Aβ) into senile plaques is a major pathological factor of Alzheimer's disease (AD) and is believed to result in memory impairment. We aimed to investigate the effect of an optimized combination of ginger and peony root (OCGP), a standardized herbal mixture of ginger and peony root, on Aβ accumulation and memory impairment in amyloid-β protein precursor (AβPP)/presenilin 1 (PS1) double-transgenic mice. In an in vitro thioflavin T fluorescence assay, 100 μg/ml OCGP inhibited Aβ accumulation to the same extent as did 10 μM curcumin. Furthermore, AβPP/PS1 double-transgenic mice treated with OCGP (50 or 100 mg/kg/day given orally for 14 weeks) exhibited reduced Aβ plaque accumulation in the hippocampus and lower levels of glial fibrillary acid protein and cyclooxygease-2 expression compared with vehicle-treated controls. These results suggest that OCGP may prevent memory impairment in AD by inhibiting Aβ accumulation and inflammation in the brain.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Cyclooxygenase 2; Disease Models, Animal; Dose-Response Relationship, Drug; Ginger; Glial Fibrillary Acidic Protein; Humans; Male; Mice; Mice, Transgenic; Mutation; Paeonia; Phytotherapy; Plant Preparations; Plaque, Amyloid; Presenilin-1

Optimized Standard Operating Procedures for the Analysis of Cerebrospinal Fluid Aβ42 and the Ratios of Aβ Isoforms Using Low Protein Binding Tubes. - Vanderstichele, Hugo Marcel Johan; Janelidze, Shorena; Demeyer, Leentje; Coart, Els; Stoops, Erik; Herbst, Victor; Mauroo, Kimberley; Brix, Britta; Hansson, Oskar (J Alzheimers Dis, 2016)
BACKGROUND: Reduced cerebrospinal fluid (CSF) concentration of amyloid-β1-42 (Aβ1-42) reflects the presence of amyloidopathy in brains of subjects with Alzheimer's disease (AD). OBJECTIVE: To qualify the use of Aβ1-42/Aβ1-40 for improvement of standard operating procedures (SOP) for measurement of CSF Aβ with a focus on CSF collection, storage, and analysis. METHODS: Euroimmun ELISAs for CSF Aβ isoforms were used to set up a SOP with respect to recipient properties (low binding, polypropylene), volume of tubes, freeze/thaw cycles, addition of detergents (Triton X-100, Tween-20) in collection or storage tubes or during CSF analysis. Data were analyzed with linear repeated measures and mixed effects models. RESULTS: Optimization of CSF analysis included a pre-wash of recipients (e.g., tubes, 96-well plates) before sample analysis. Using the Aβ1-42/Aβ1-40 ratio, in contrast to Aβ1-42, eliminated effects of tube type, additional freeze/thaw cycles, or effect of CSF volumes for polypropylene storage tubes. 'Low binding' tubes reduced the loss of Aβ when aliquoting CSF or in function of additional freeze/thaw cycles. Addition of detergent in CSF collection tubes resulted in an almost complete absence of variation in function of collection procedures, but affected the concentration of Aβ isoforms in the immunoassay. CONCLUSION: The ratio of Aβ1-42/Aβ1-40 is a more robust biomarker than Aβ1-42 toward (pre-) analytical interfering factors. Further, 'low binding' recipients and addition of detergent in collection tubes are able to remove effects of SOP-related confounding factors. Integration of the Aβ1-42/Aβ1-40 ratio and 'low-binding tubes' into guidance criteria may speed up worldwide standardization of CSF biomarker analysis.

An Oral Aβ Vaccine Using a Recombinant Adeno-Associated Virus Vector in Aged Monkeys: Reduction in Plaque Amyloid and Increase in Aβ Oligomers. - Hara, Hideo; Ono, Fumiko; Nakamura, Shinichiro; Matsumoto, Shin-Ei; Jin, Haifeng; Hattori, Nobutaka; Tabira, Takeshi (J Alzheimers Dis, 2016)
With the objective to improve the amyloid-β (Aβ) targeting immunotherapy, we investigated the safety and efficacy of an oral vaccine with recombinant adeno-associated virus vector carrying a signal sequence and Aβ1-43 cDNA (rAAV/Aβ) in old non-human primates, 12 African green and 10 cynomolgus monkeys. The enteric-dissolving coated capsules containing rAAV/Aβ were orally administered once or twice, then monkeys' conditions were carefully observed with complete blood count and laboratory examinations of the sera. General conditions, food intake, water intake, stool conditions, body weight changes, and menstruation cycles were not significantly altered, and laboratory tests and pathological examinations of the systemic organs were unremarkable. Pathological examinations of the brain showed significant reduction of the amyloid plaque burden and intracellular Aβ without inflammatory or hemorrhagic changes in the brain. However, soluble Aβ and some Aβ oligomers were increased in rAAV-treated monkey brains without changes of the neuronal density and vascular amyloidosis. Thus, this vaccine seems to be safe in general, but we must be cautious about the increase of Aβ oligomers after vaccination. This vaccine may be recommended at a very early stage of Alzheimer's disease when little amyloid is deposited.

Oral Infections and Cytokine Levels in Patients with Alzheimer's Disease and Mild Cognitive Impairment Compared with Controls. - Cestari, José Augusto Ferrari; Fabri, Gisele Maria Campos; Kalil, Jorge; Nitrini, Ricardo; Jacob-Filho, Wilson; de Siqueira, José Tadeu Tesseroli; Siqueira, Silvia Regina D T (J Alzheimers Dis, 2016)
BACKGROUND: Oral infections are prevalent in the adult population. Their impact includes the implication as a risk factor for Alzheimer's disease (AD), altering its progression. One of the potential mechanisms involves immune mediators such as circulating cytokines. OBJECTIVE: The goal of the present study was to investigate the prevalence of oral infections and blood levels of IL-1β, TNF-α, and IL-6 in patients with AD, mild cognitive impairment (MCI), and controls. METHODS: Sixty-five elderly were evaluated (25 AD, 19 MCI, and 21 controls) by the following methods: Mini Mental State Exam, Questionnaire of Functional Activities, periodontal and oral evaluation, and blood concentrations of IL-1β, TNF-α and IL-6. RESULTS: Patients with AD had high serum IL-6 levels (p = 0.029), and patients with periodontitis had high serum TNF-α levels (p = 0.005). There was an association between IL-6 and TNF-α in patients with AD/MCI and periodontitis (p = 0.023). CONCLUSION: The increased levels of TNF-α and IL-6 in this study suggests their implication in the overlapping mechanisms between oral infections and AD. Longitudinal studies are necessary for further investigation.

The Oral Iron Chelator, Deferasirox, Reverses the Age-Dependent Alterations in Iron and Amyloid-β Homeostasis in Rat Brain: Implications in the Therapy of Alzheimer's Disease. - Banerjee, Priyanjalee; Sahoo, Arghyadip; Anand, Shruti; Bir, Aritri; Chakrabarti, Sasanka (J Alzheimers Dis, 2016)
The altered metabolism of iron impacts the brain function in multiple deleterious ways during normal aging as well as in Alzheimer's disease. We have shown in this study that chelatable iron accumulates in the aged rat brain along with overexpression of transferrin receptor 1 (TfR1) and ferritin, accompanied by significant alterations in amyloid-β (Aβ) peptide homeostasis in the aging brain, such as an increased production of the amyloid-β protein precursor, a decreased level of neprilysin, and increased accumulation of Aβ42. When aged rats are given daily the iron chelator, deferasirox, over a period of more than 4 months starting from the 18th month, the age-related accumulation of iron and overexpression of TfR1 and ferritin in the brain are significantly prevented. More interestingly, the chelator treatment also considerably reverses the altered Aβ peptide metabolism in the aging brain implying a significant role of iron in the latter phenomenon. Further, other results indicate that iron accumulation results in oxidative stress and the activation of NF-κB in the aged rat brain, which are also reversed by the deferasirox treatment. The analysis of the results together suggests that iron accumulation and oxidative stress interact at multiple levels that include transcriptional and post-transcriptional mechanisms to bring about changes in the expression levels of TfR1 and ferritin and also alterations in Aβ peptide metabolism in the aging rat brain. The efficacy of deferasirox in preventing age-related changes in iron and Aβ peptide metabolism in the aging brain, as shown here, has obvious therapeutic implications for Alzheimer's disease.
Keywords: Administration, Oral; Aging; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Benzoates; Brain; Ferritins; Gene Expression Regulation; Iron; Iron Chelating Agents; Neprilysin; NF-kappa B; Oxidative Stress; Peptide Fragments; Protein Carbonylation; Rats; Rats, Wistar; Receptors, Transferrin; Spectrophotometry; Triazoles

Outstanding Phenotypic Differences in the Profile of Amyloid-β between Tg2576 and APPswe/PS1dE9 Transgenic Mouse Models of Alzheimer's Disease. - Allué, José Antonio; Sarasa, Leticia; Izco, María; Pérez-Grijalba, Virginia; Fandos, Noelia; Pascual-Lucas, María; Ogueta, Samuel; Pesini, Pedro; Sarasa, Manuel (J Alzheimers Dis, 2016)
APPswe/PS1dE9 and Tg2576 are very common transgenic mouse models of Alzheimer's disease (AD), used in many laboratories as tools to research the mechanistic process leading to the disease. In order to augment our knowledge about the amyloid-β (Aβ) isoforms present in both transgenic mouse models, we have developed two chromatographic methods, one acidic and the other basic, for the characterization of the Aβ species produced in the brains of the two transgenic mouse models. After immunoprecipitation and micro-liquid chromatography-electrospray ionization mass spectrometry/mass spectrometry, 10 species of Aβ, surprisingly all of human origin, were detected in the brain of Tg2576 mouse, whereas 39 species, of both murine and human origin, were detected in the brain of the APP/PS1 mouse. To the best of our knowledge, this is the first study showing the identification of such a high number of Aβ species in the brain of the APP/PS1 transgenic mouse, whereas, in contrast, a much lower number of Aβ species were identified in the Tg2576 mouse. Therefore, this study brings to light a relevant phenotypic difference between these two popular mice models of AD.

Overexpression of Metallothionein-1 Modulates the Phenotype of the Tg2576 Mouse Model of Alzheimer's Disease. - Manso, Yasmina; Comes, Gemma; López-Ramos, Juan C; Belfiore, Mónica; Molinero, Amalia; Giralt, Mercedes; Carrasco, Javier; Adlard, Paul A; Bush, Ashley I; Delgado-García, José María; Hidalgo, Juan (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is the most commonly diagnosed dementia, where signs of neuroinflammation and oxidative stress are prominent. In this study we intend to further characterize the roles of the antioxidant, anti-inflammatory, and heavy metal binding protein, metallothionein-1 (MT-1), by crossing Mt1 overexpressing mice with a well-known mouse model of AD, Tg2576 mice, which express the human amyloid-β protein precursor (hAβPP) with the Swedish K670N/M671L mutations. Mt1 overexpression increased overall perinatal survival, but did not affect significantly hAβPP-induced mortality and weight loss in adult mice. Amyloid plaque burden in ∼14-month-old mice was increased by Mt1 overexpression in the hippocampus but not the cortex. Despite full length hAβPP levels and amyloid plaques being increased by Mt1 overexpression in the hippocampus of both sexes, oligomeric and monomeric forms of Aβ, which may contribute more to toxicity, were decreased in the hippocampus of females and increased in males. Several behavioral traits such as exploration, anxiety, and learning were altered in Tg2576 mice to various degrees depending on the age and the sex. Mt1 overexpression ameliorated the effects of hAβPP on exploration in young females, and potentiated those on anxiety in old males, and seemed to improve the rate of spatial learning (Morris water maze) and the learning elicited by a classical conditioning procedure (eye-blink test). These results clearly suggest that MT-1 may be involved in AD pathogenesis.
Keywords: Age Factors; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Anxiety; Disease Models, Animal; Exploratory Behavior; Female; Gene Expression Regulation; Humans; Male; Matrix Metalloproteinase 16; Maze Learning; Metallothionein; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity; Mutation; Phenotype; Psychomotor Disorders

Pain Assessment in Elderly with Behavioral and Psychological Symptoms of Dementia. - Malara, Alba; De Biase, Giuseppe Andrea; Bettarini, Francesco; Ceravolo, Francesco; Di Cello, Serena; Garo, Michele; Praino, Francesco; Settembrini, Vincenzo; Sgrò, Giovanni; Spadea, Fausto; Rispoli, Vincenzo (J Alzheimers Dis, 2016)
BACKGROUND: Pain is under-detected and undertreated in people with dementia. The present study investigates the prevalence of pain in people with dementia hospitalized in nursing homes that are members of National Association of Third Age Residences (ANASTE) Calabria, and evaluates the association among pain, mood, and behavioral and psychological symptoms of dementia (BPSD). OBJECTIVE: The aim of this study is to define the prevalence of pain in people with dementia in long term care facilities using scales of self-reporting and observational tools and, particularly, to study the relationship between pain and BPSD. METHODS: A prospective observational study was carried out on 233 patients. Pain assessment was performed using self-reporting tools such as the Numeric Rating Scale (NRS) for patients with slight cognitive impairment or no cognitive impairment and observational tools such as Pain Assessment In Advanced Dementia Scale (PAINAD) for patients with moderate or severe cognitive impairment. Mood was evaluated through the Cornell Scale for Depression in Dementia (CSDD) while behavioral problems were assessed through the Cohen-Mansfield Agitation Inventory (CMAI) and Neuropsychiatric Inventory (NPI). RESULTS: Only 42.5% of patients evaluated by NRS provided a reliable answer; of these, 20.4% reported no pain. The percentage of pain evaluated by PAINAD was 51.8% . Analysis of data showed a statistically significant correlation between diagnosis of pain and depressive symptoms, assessed with CSDD (p = 0.0113), as well as by single items of NPI, such as anxiety (p = 0.0362) and irritability (p = 0.0034), and F1 profile (Aggression) of CMAI (p = 0.01). CONCLUSION: This study confirms that self-report alone is not sufficient to assess pain in elderly people with dementia; the observational tool is a necessary and suitable way of assessing pain in patients with cognitive impairment. If not adequately treated, chronic pain can cause depression, agitation, and aggression in patients with dementia.
Keywords: Affect; Aged, 80 and over; Analgesics; Anxiety; Dementia; Depression; Female; Humans; Italy; Logistic Models; Long-Term Care; Male; Multivariate Analysis; Nursing Homes; Pain; Pain Measurement; Prevalence; Prospective Studies; Psychiatric Status Rating Scales; Self Report; Severity of Illness Index

Paired Studies Comparing Clinical Profiles of Lewy Body Dementia with Alzheimer's and Parkinson's Diseases. - Scharre, Douglas W; Chang, Shu-Ing; Nagaraja, Haikady N; Park, Ariane; Adeli, Anahita; Agrawal, Punit; Kloos, Anne; Kegelmeyer, Deb; Linder, Shannon; Fritz, Nora; Kostyk, Sandra K; Kataki, Maria (J Alzheimers Dis, 2016)
Limited data compares clinical profiles of Lewy Body Dementia (LBD) with Alzheimer's disease (AD) and Parkinson's disease (PD). Twenty-one mildly demented ambulatory LBD subjects were individually matched by MMSE score with 21 AD subjects and by UPDRS motor score with 21 PD subjects. Matched by age, gender, education, and race, pairs were compared using cognitive, functional, behavioral, and motor measures. LBD group performed worse than PD on axial motor, gait, and balance measures. AD had more amnesia and orientation impairments, but less executive and visuospatial deficits than LBD subjects. LBD group had more sleepiness, cognitive/behavioral fluctuations, hallucinations, and sleep apnea than AD or PD. Axial motor, gait, and balance disturbances correlated with executive, visuospatial, and global cognition deficits. LBD is differentiated from AD and PD by retrieval memory, visuospatial, and executive deficits; axial motor, gait and balance impairments; sleepiness, cognitive/behavioral fluctuations, hallucinations, and sleep apnea.

Palmomental Reflex a Relevant Sign in Early Alzheimer's Disease Diagnosis? - Gabelle, Audrey; Gutierrez, Laure-Anne; Dartigues, Jean-François; Ritchie, Karen; Touchon, Jacques; Berr, Claudine (J Alzheimers Dis, 2016)
BACKGROUND: Sophisticated and expensive biomarkers are proposed for the diagnostic of Alzheimer's disease (AD). The amyloid process seems to be early in AD, and brain amyloid load affects the frontal lobe. OBJECTIVE: To determine if certain simple clinical signs, especially frontal-related signs, could help reach an earlier and better diagnosis. METHODS: In the frame of the 3-City cohort, we conducted a nested case-control study comparing incident cases of AD to controls matched for age, gender, and education. The standardized neurological exam included extrapyramidal signs (akinesia, rigidity, rest tremor), pyramidal symptoms (spastic rigidity, Babinski reflex), primitive reflexes (snout, palmomental reflex grasping), and tremor (essential, intentional, head) at the time of diagnosis and two years before. RESULTS: We compared 106 incident AD subjects (mean age at diagnosis 82.2 (SD = 5.9); median MMSE at diagnosis = 23) to 208 matched controls. In patients younger than 80, palmomental reflexes were more frequent in AD than controls, two years before diagnosis (25.0 versus 7.0% , p = 0.03) and at time of diagnosis (30.3 versus 12.3% , p = 0.02). No difference was observed for other signs two years before diagnosis or for patients older than 80. CONCLUSION: Before diagnosis, the clinical examination of AD patients is not strictly normal; the primitive reflexes appear to be pathological. It might be in connection with the frontal amyloid load at an early stage of the disease. Clinical examination can reveal simple and interesting signs that deserve consideration as well as the other more invasive and expensive biomarkers.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Cohort Studies; Early Diagnosis; Female; Follow-Up Studies; France; Humans; Longitudinal Studies; Male; Neuropsychological Tests; Reflex

Parkinsonism Differentiates Idiopathic Normal Pressure Hydrocephalus from Its Mimics. - Allali, Gilles; Garibotto, Valentina; Assal, Frèdèric (J Alzheimers Dis, 2016)
BACKGROUND: Parkinsonism is frequent in neurological conditions affecting gait and cognition, such as idiopathic normal pressure hydrocephalus (iNPH) and iNPH mimics, but its discriminating value between these two groups is still unidentified. OBJECTIVE: This study aims to compare the prevalence of parkinsonism between iNPH and iNPH mimics and its discriminating value. METHODS: Among 141 patients with suspicion of iNPH (75.7±7.1 years; 31.2% women), seventy-nine presented a possible or probable iNPH according to standardized diagnostic criteria and the remaining sixty-two were classified as iNPH mimics. Presence of parkinsonism and other seminal clinical symptoms of iNPH were systematically evaluated by a board-certified neurologist. Covariates include age, gender, comorbidities, and white matter disease burden using the age-related white matter changes scale. Logistic regressions were used to assess the association between parkinsonism and diagnostic groups. RESULTS: Parkinsonism was present in 40.3% of iNPH mimics and 20.3% of iNPH (p-value: 0.015). The presence of parkinsonism, but not iNPH symptoms, was associated with the diagnosis of mimics in the adjusted model (adjusted odds ratio: 2.28; 95% CI: 1.06-4.93), even when age-related white matter changes were accounted for. CONCLUSION: Compared to iNPH, the increased prevalence of parkinsonism in patients with iNPH mimics in the absence of significant white matter disease suggest an underlying neurodegenerative mechanism.

Partial Amelioration of Synaptic and Cognitive Deficits by Inhibiting Cofilin Dephosphorylation in an Animal Model of Alzheimer's Disease. - Deng, Yulei; Wei, Jing; Cheng, Jia; Zhong, Ping; Xiong, Zhe; Liu, Aiyi; Lin, Lin; Chen, Shengdi; Yan, Zhen (J Alzheimers Dis, 2016)
The loss of synaptic structure and function has been linked to the cognitive impairment of Alzheimer's disease (AD). Dysregulation of the actin cytoskeleton, which plays a key role in regulating the integrity of synapses and the transport of synaptic proteins, has been suggested to contribute to the pathology of AD. In this study, we found that glutamate receptor surface expression and synaptic function in frontal cortical neurons were significant diminished in a familial AD (FAD) model, which was correlated with the reduction of phosphorylated cofilin, a key protein regulating the dynamics of actin filaments. Injecting a cofilin dephosphorylation inhibitory peptide to FAD mice led to the partial rescue of the surface expression of AMPA and NMDA receptor subunits, as well as the partial restoration of AMPAR- and NMDAR-mediated synaptic currents. Moreover, the impaired working memory and novel object recognition memory in FAD mice were partially ameliorated by injections of the cofilin dephosphorylation inhibitory peptide. These results suggest that targeting the cofilin-actin signaling holds promise to mitigate the physiological and behavioral abnormality in AD.

A Pathway Based Classification Method for Analyzing Gene Expression for Alzheimer's Disease Diagnosis. - Voyle, Nicola; Keohane, Aoife; Newhouse, Stephen; Lunnon, Katie; Johnston, Caroline; Soininen, Hilkka; Kloszewska, Iwona; Mecocci, Patrizia; Tsolaki, Magda; Vellas, Bruno; Lovestone, Simon; Hodges, Angela; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Recent studies indicate that gene expression levels in blood may be able to differentiate subjects with Alzheimer's disease (AD) from normal elderly controls and mild cognitively impaired (MCI) subjects. However, there is limited replicability at the single marker level. A pathway-based interpretation of gene expression may prove more robust. OBJECTIVES: This study aimed to investigate whether a case/control classification model built on pathway level data was more robust than a gene level model and may consequently perform better in test data. The study used two batches of gene expression data from the AddNeuroMed (ANM) and Dementia Case Registry (DCR) cohorts. METHODS: Our study used Illumina Human HT-12 Expression BeadChips to collect gene expression from blood samples. Random forest modeling with recursive feature elimination was used to predict case/control status. Age and APOE ɛ4 status were used as covariates for all analysis. RESULTS: Gene and pathway level models performed similarly to each other and to a model based on demographic information only. CONCLUSIONS: Any potential increase in concordance from the novel pathway level approach used here has not lead to a greater predictive ability in these datasets. However, we have only tested one method for creating pathway level scores. Further, we have been able to benchmark pathways against genes in datasets that had been extensively harmonized. Further work should focus on the use of alternative methods for creating pathway level scores, in particular those that incorporate pathway topology, and the use of an endophenotype based approach.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Apolipoproteins E; Cohort Studies; Datasets as Topic; Female; Gene Expression; Gene Expression Profiling; Humans; Male; Models, Genetic; Oligonucleotide Array Sequence Analysis; Signal Transduction

Patients that have Undergone Hemodialysis Exhibit Lower Amyloid Deposition in the Brain: Evidence Supporting a Therapeutic Strategy for Alzheimer's Disease by Removal of Blood Amyloid. - Sakai, Kazuyoshi; Senda, Takao; Hata, Ryuji; Kuroda, Makoto; Hasegawa, Midori; Kato, Masao; Abe, Masato; Kawaguchi, Kazunori; Nakai, Shigeru; Hiki, Yoshiyuki; Yuzawa, Yukio; Kitaguchi, Nobuya (J Alzheimers Dis, 2016)
As a proof of concept that removal of blood amyloid-β (Aβ) can reduce Aβ deposition in the brains of patients with Alzheimer's disease, cortices of patients who had undergone hemodialysis (HD), which removes Aβ from the blood, were histochemically analyzed; postmortem brain sections were stained with anti-Aβ antibodies. Brains from patients who had undergone HD had significantly fewer senile plaques than those of patient who had not undergone HD. This significant difference was also confirmed by silver staining. Our findings suggest that removal of blood Aβ by hemodialysis results in lower accumulation of Aβ in the brain.
Keywords: Aged; Aged, 80 and over; Amyloid beta-Peptides; Autopsy; Brain; Case-Control Studies; Humans; Kidney Diseases; Plaque, Amyloid; Renal Dialysis; Silver Staining; Statistics, Nonparametric