Early and Persistent O-GlcNAc Protein Modification in the Streptozotocin Model of Alzheimer's Disease. - Dos Santos, João Paulo Almeida; Vizuete, Adriana; Hansen, Fernanda; Biasibetti, Regina; Gonçalves, Carlos-Alberto (J Alzheimers Dis, 2018)
O-GlcNAc transferase (OGT), an enzyme highly expressed in brain tissue, catalyzes the addition of N-acetyl-glucosamine (GlcNAc) to hydroxyl residues of serine and threonine of proteins. Brain protein O-GlcNAcylation is diminished in Alzheimer's disease (AD), and OGT targets include proteins of the insulin-signaling pathway (e.g., insulin receptor susbtrate-1, IRS-1). We hypothesized that ICV streptozotocin (STZ) also affects O-GlcNAc protein modification. We investigated hippocampal metabolic changes in Wistar rats, particularly OGT levels and insulin resistance, as well as related astroglial activities, immediately after ICV STZ administration (first week) and later on (fourth week). We found an early (at one week) and persistent (at fourth week) decrease in OGT in the ICV STZ model of AD, characterized by a spatial cognitive deficit. Consistent with this observation, we observed a decrease in protein O-GlnNAc modification at both times. Increased phosphorylation at serine-307 of IRS-1, which is related to insulin resistance, was observed on the fourth week. The decrease in OGT and consequent protein O-GlnNAc modifications appear to precede the decrease in glucose uptake and increment of the glyoxalase system observed in the hippocampus. Changes in glial fibrillary acidic protein and S100B in the hippocampus, as well as the alterations in cerebrospinal fluid S100B, confirm the astrogliosis. Moreover, decreases in glutamine synthetase and glutathione content suggest astroglial dysfunction, which are likely implicated in the neurodegenerative cascade triggered in this model. Together, these data contribute to the understanding of neurochemical changes in the ICV STZ model of sporadic AD, and may explain the decreases in protein O-GlcNAc levels and insulin resistance observed in AD.
Keywords: Alzheimer Disease; Analysis of Variance; Animals; Antibiotics, Antineoplastic; Brain; Disease Models, Animal; Glial Fibrillary Acidic Protein; Glucose; Glutathione; Insulin Receptor Substrate Proteins; Lactoylglutathione Lyase; Male; Maze Learning; N-Acetylglucosaminyltransferases; Rats; Rats, Wistar; S100 Calcium Binding Protein beta Subunit; Streptozocin; Time Factors

Early Candidate Urine Biomarkers for Detecting Alzheimer's Disease Before Amyloid-β Plaque Deposition in an APP (swe)/PSEN1dE9 Transgenic Mouse Model. - Zhang, Fanshuang; Wei, Jing; Li, Xundou; Ma, Chao; Gao, Youhe (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is an incurable age-associated neurodegenerative disorder that is characterized by irreversible progressive cognitive deficits and extensive brain damage. The identification of candidate biomarkers before amyloid-β plaque deposition occurs is therefore of great importance for the early intervention of AD. Urine, which is not regulated by homeostatic mechanisms, theoretically accumulates changes associated with AD earlier than cerebrospinal fluid and blood. In this study, an APP (swe)/PSEN1dE9 transgenic mouse model was used to identify candidate biomarkers for early AD. Urine samples were collected from 4-, 6-, and 8-month-old transgenic mouse models, and the urinary proteomes were profiled using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The levels of 29 proteins differed significantly between wild type and 4-month-old mice, which had not started to accumulate amyloid-β plaques. Among these proteins, 13 have been associated with the mechanisms of AD, while 9 have been suggested as AD biomarkers. Our results indicated that urine proteins enable detection of AD before amyloid-β plaque deposition, which may present an opportunity for intervention.

Early Detection of Alzheimer's Disease Based on the Patient's Creative Drawing Process: First Results with a Novel Neuropsychological Testing Method. - Heymann, Petra; Gienger, Regine; Hett, Andreas; Müller, Stephan; Laske, Christoph; Robens, Sibylle; Ostermann, Thomas; Elbing, Ulrich (J Alzheimers Dis, 2018)
Based on the knowledge of art therapy, we developed a new neuropsychological drawing test in order to identify individuals with mild cognitive impairment (MCI) as well as dementia patients and healthy controls (HC). By observing a variety of drawing characteristics of 92 participants with a mean age of 67.7, art therapy and dementia experts discriminate HC from MCI, early dementia of the Alzheimer-type (eDAT), and moderate dementia of the Alzheimer-type (mDAT) by the process analysis of tree drawings on a digitizing tablet. The art therapist's average categorical rating of healthy and MCI or demented individuals matched the clinical diagnosis by 88%. In a first small study, we analyzed interrater reliability, sensitivity, specificity, negative and positive predicted values of our tree drawing test (TDT) in comparison with the clock drawing test (CDT). Similar values of moderate interrater reliability were found for the TDT (0.56) as well as for the CDT (0.54). A significant high sensitivity of 0.9 within this binary impairment scale (HC versus impaired or demented) can be demonstrated. Substantial values for the specificity (0.67) could be obtained that however remain under a perfect value of the CDT (1.0). Considering 31 individuals that received the clinical diagnosis "impaired or demented" the TDT shows a higher recognition rate for the MCI group than the CDT. Furthermore in 8 of 12 borderline cases of clinical diagnosis, the outcome of the TDT diagnosis was consistent with the final clinical result.

Early Emotional Attention is Impacted in Alzheimer's Disease: An Eye-Tracking Study. - Bourgin, Jessica; Guyader, Nathalie; Chauvin, Alan; Juphard, Alexandra; Sauvée, Mathilde; Moreaud, Olivier; Silvert, Laetitia; Hot, Pascal (J Alzheimers Dis, 2018)
Emotional deficits have been repetitively reported in Alzheimer's disease (AD) without clearly identifying how emotional processing is impaired in this pathology. This paper describes an investigation of early emotional processing, as measured by the effects of emotional visual stimuli on a saccadic task involving both pro (PS) and anti (AS) saccades. Sixteen patients with AD and 25 age-matched healthy controls were eye-tracked while they had to quickly move their gaze toward a positive, negative, or neutral image presented on a computer screen (in the PS condition) or away from the image (in the AS condition). The age-matched controls made more AS mistakes for negative stimuli than for other stimuli, and triggered PSs toward negative stimuli more quickly than toward other stimuli. In contrast, patients with AD showed no difference with regard to the emotional category in any of the tasks. The present study is the first to highlight a lack of early emotional attention in patients with AD. These results should be taken into account in the care provided to patients with AD, since this early impairment might seriously degrade their overall emotional functioning.

Early Stage Alterations in CA1 Extracellular Region Proteins Indicate Dysregulation of IL6 and Iron Homeostasis in the 5XFAD Alzheimer's Disease Mouse Model. - Gurel, Busra; Cansev, Mehmet; Sevinc, Cansu; Kelestemur, Seda; Ocalan, Busra; Cakir, Aysen; Aydin, Sami; Kahveci, Nevzat; Ozansoy, Mehmet; Taskapilioglu, Ozlem; Ulus, Ismail Hakki; Başar, Merve Karayel; et al. (J Alzheimers Dis, 2018)
In recent years, an increasing number of research papers revealed that the compositional and volumetric alterations in the extracellular matrix are the consequences of aging and may be related to Alzheimer's disease (AD). In this study, we aimed to demonstrate the alterations in hippocampal extracellular fluid proteins in vivo using the 5XFAD mouse model. Samples were obtained from hippocampi of 5XFAD mice (n = 6) and their non-transgenic littermates by intracerebral push-pull perfusion technique at 3 months of age, representing the pre-pathological stage of the AD. Proteins in the hippocampal perfusates were analyzed by Ultra Performance Liquid Chromatography-Electrospray Ionization Quadrupole Time-of-Flight Mass Spectrometry (UPLC-ESI-qTOF-MS/MS). 178 proteins were identified and 19 proteins of them were found to be statistically significantly altered (p≤0.05, fold change ≥40%, unique peptide count ≥3) in the hippocampal CA1 extracellular fluid of the 5XFAD mouse model. Ingenuity pathway analysis of the protein expression results identified IL6 as an upstream regulator. The upregulation of IL6 was validated by immunohistochemical staining of the hippocampus and cortex of the 5XFAD mice prior to Aβ plaque formation. Furthermore, the iron level in the hippocampus was measured by inductively coupled plasma-mass spectrometry as IL6 is mentioned in several studies to take part in iron homeostasis and inflammation and found to be increased in 5XFAD mice hippocampus. Alterations in extracellular matrix proteins in addition to increasing amount of hippocampal IL6 and iron in the early stages of AD may reveal inflammation-mediated iron dyshomeostasis in the early stages of neurodegeneration.
Keywords: Alzheimer Disease; Animals; CA1 Region, Hippocampal; Chromatography, Liquid; Disease Models, Animal; Female; Homeostasis; Interleukin-6; Iron; Mice; Mice, Transgenic; Proteomics; Tandem Mass Spectrometry

Effect of Education on Alzheimer's Disease-Related Neuroimaging Biomarkers in Healthy Controls, and Participants with Mild Cognitive Impairment and Alzheimer's Disease: A Cross-Sectional Study. - Wada, Masataka; Noda, Yoshihiro; Shinagawa, Shunichiro; Chung, Jun Ku; Sawada, Kyosuke; Ogyu, Kamiyu; Tarumi, Ryosuke; Tsugawa, Sakiko; Miyazaki, Takahiro; Yamagata, Bun; Graff-Guerrero, Ariel; Mimura, Masaru; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Cognitive reserve is the acquired capacity reflecting a functional brain adaptability/flexibility in the context of aging. Educational attainment is thought to be among the most important factors that contribute to cognitive reserve. OBJECTIVE: The aim of this study is to investigate the relationships among duration of education and Alzheimer's disease (AD) related neuroimaging biomarkers such as amyloid-β deposition, glucose metabolism, and brain volumes in each stage of AD. METHODS: We reanalyzed a part of the datasets of the Alzheimer's Disease Neuroimaging Initiative. Participants were between 55 and 90 years of age and diagnosed as one of the following: healthy controls (HC), mild cognitive impairment (MCI), or AD. Multiple regression analyses were conducted to examine the relationships among duration of education and amyloid-β deposition (n = 825), brain metabolism (n = 1,304), and brain volumes (n = 1,606) among three groups using data for 18F-Florbetapir (AV-45) imaging, fludeoxyglucose (FDG) positron emission tomography, and T1-weighted magnetic resonance imaging. RESULTS: Duration of education had no correlations with amyloid-β deposition or brain metabolism in any groups. However, duration of education was positively associated with the total brain volume only in participants with MCI. CONCLUSIONS: Our findings suggest that education may exert a protective effect on total brain volume in the MCI stage but not in HC or AD. Thus, education may play an important role in preventing the onset of dementia through brain reserve in MCI.

Effect of Fluvoxamine on Amyloid-β Peptide Generation and Memory. - Kim, Woojin Scott; Fu, YuHong; Dobson-Stone, Carol; Hsiao, Jen-Hsiang T; Shang, Kani; Hallupp, Marianne; Schofield, Peter R; Garner, Brett; Karl, Tim; Kwok, John B J (J Alzheimers Dis, 2018)
Alzheimer's disease is characterized by abnormal amyloid-β (Aβ) peptide accumulation beginning decades before symptom onset. An effective prophylactic treatment aimed at arresting the amyloidogenic pathway would therefore need to be initiated prior to the occurrence of Aβ pathology. The SIGMAR1 gene encodes a molecular chaperone that modulates processing of the amyloid-β protein precursor (AβPP). Fluvoxamine is a selective serotonin reuptake inhibitor and a potent SIGMAR1 agonist. We therefore hypothesized that fluvoxamine treatment would reduce Aβ production and improve cognition. We firstly investigated the impact of SIGMAR1 on AβPP processing, and found that overexpression and knockdown of SIGMAR1 significantly affected γ-secretase activity in SK-N-MC neuronal cells. We then tested the impact of fluvoxamine on Aβ production in an amyloidogenic cell model, and found that fluvoxamine significantly reduced Aβ production by inhibiting γ-secretase activity. Finally, we assessed the efficacy of long-term treatment (i.e., ∼8 months) of 10 mg/kg/day fluvoxamine in the J20 amyloidogenic mouse model; the treatment was initiated prior to the occurrence of predicted Aβ pathology. Physical examination of the animals revealed no overt pathology or change in weight. We conducted a series of behavioral tests to assess learning and memory, and found that the fluvoxamine treatment significantly improved memory function as measured by novel object recognition task. Two other tests revealed no significant change in memory function. In conclusion, fluvoxamine has a clear impact on γ-secretase activity and AβPP processing to generate Aβ, and may have a protective effect on cognition in the J20 mice.

Effectiveness of a Personalized Brain-Computer Interface System for Cognitive Training in Healthy Elderly: A Randomized Controlled Trial. - Yeo, Si Ning; Lee, Tih Shih; Sng, Wei Theng; Heo, Min Quan; Bautista, Dianne; Cheung, Yin Bun; Zhang, Hai Hong; Wang, Chuanchu; Chin, Zheng Yang; Feng, Lei; Zhou, Juan; Chong, Mei Sian; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Cognitive training has been demonstrated to improve cognitive performance in older adults. To date, no study has explored personalized training that targets the brain activity of each individual. OBJECTIVE: This is the first large-scale trial that examines the usefulness of personalized neurofeedback cognitive training. METHODS: We conducted a randomized-controlled trial with participants who were 60-80 years old, with Clinical Dementia Rating (CDR) score of 0-0.5, Mini-Mental State Examination (MMSE) score of 24 and above, and with no neuropsychiatric diagnosis. Participants were randomly assigned to the Intervention or Waitlist-Control group. The training system, BRAINMEM, has attention, working memory, and delayed recall game components. The intervention schedule comprised 24 sessions over eight weeks and three monthly booster sessions. The primary outcome was the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score after the 24-session training. RESULTS: There were no significant between-subjects differences in overall cognitive performance post-intervention. However, a sex moderation effect (p = 0.014) was present. Men in the intervention group performed better than those in the waitlist group (mean difference, +4.03 (95% CI 0.1 to 8.0), p = 0.046. Among females, however, both waitlist-control and intervention participants improved from baseline, although the between-group difference in improvement did not reach significance. BRAINMEM also received positive appraisal and intervention adherence from the participants. CONCLUSION: A personalized neurofeedback intervention is potentially feasible for use in cognitive training for older males. The sex moderation effect warrants further investigation and highlights the importance of taking sex into account during cognitive training.

The Effects of Music Therapy on Cognition, Psychiatric Symptoms, and Activities of Daily Living in Patients with Alzheimer's Disease. - Lyu, Jihui; Zhang, Jingnan; Mu, Haiyan; Li, Wenjie; Champ, Mei; Xiong, Qian; Gao, Tian; Xie, Lijuan; Jin, Weiye; Yang, Wan; Cui, Mengnan; Gao, Maolong; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia, affecting millions of older people worldwide. However, pharmacological therapies have not achieved desirable clinical efficacy in the past decades. Non-pharmacological therapies have been receiving increased attention to treat dementia in recent years. OBJECTIVE: This study explores the effects of music therapy on cognitive function and mental wellbeing of patients with AD. METHODS: A total number of 298 AD patients with mild, moderate, or severe dementia participated in the study. The participants with each grade of severity were randomly divided into three groups, which were a singing group, a lyric reading group, and a control group. These three groups received different interventions for three months. All participants underwent a series of tests on cognitive functions, neuropsychological symptoms, and activities of daily living at baseline, three months, and six months. RESULTS: The analysis shows that music therapy is more effective for improving verbal fluency and for alleviating the psychiatric symptoms and caregiver distress than lyrics reading in patients with AD. Stratified analysis shows that music therapy is effective for enhancing memory and language ability in patients with mild AD and reducing the psychiatric symptoms and caregiver distress in patients with moderate or severe AD. However, no significant effect was found for activities of daily living in patients with mild, moderate, or severe AD. CONCLUSION: This study suggests that music therapy is effective in enhancing cognitive function and mental wellbeing and can be recommended as an alternative approach to manage AD associated symptoms.

Effects of Physical Exercise on Alzheimer's Disease Biomarkers: A Systematic Review of Intervention Studies. - Frederiksen, Kristian Steen; Gjerum, Le; Waldemar, Gunhild; Hasselbalch, Steen Gregers (J Alzheimers Dis, 2018)
Physical exercise may be an important adjunct to pharmacological treatment of Alzheimer's disease (AD). Animal studies indicate that exercise may be disease modifying through several mechanisms including reduction of AD pathology. We carried out a systematic review of intervention studies of physical exercise with hippocampal volume (on MRI), amyloid-β, total tau, phosphorylated tau in cerebrospinal fluid (CSF), 18F-FDG-PET or amyloid PET as outcome measures in healthy subjects, patients with subjective memory complaints, mild cognitive impairment, or AD. We identified a total of 8 studies of which 6 investigated the effects of exercise on hippocampal volume in healthy subjects and 1 on CSF biomarkers and 1 on hippocampal volume in AD, and none investigating the remaining outcome measures or patient groups. Methodological quality of identified studies was generally low. One study found a detrimental effect on hippocampal volume and one found a positive effect, whereas the remaining studies did not find an effect of exercise on outcome measures. The present systematic study identified a relatively small number of studies, which did not support an effect of exercise on hippocampal volume. Methodological issues such small to moderate sample sizes and inadequate ramdomization procedures further limits conclusions. Our findings highlight the difficulties in conducting high quality studies of exercise and further studies are needed before definite conclusions may be reached.
Keywords: Alzheimer Disease; Biomarkers; Exercise; Hippocampus; Humans; Outcome Assessment (Health Care); Physical Therapy Modalities

Endocannabinoid and Muscarinic Signaling Crosstalk in the 3xTg-AD Mouse Model of Alzheimer's Disease. - Llorente-Ovejero, Alberto; Manuel, Iván; Lombardero, Laura; Giralt, Maria Teresa; Ledent, Catherine; Giménez-Llort, Lydia; Rodríguez-Puertas, Rafael (J Alzheimers Dis, 2018)
The endocannabinoid system, which modulates emotional learning and memory through CB1 receptors, has been found to be deregulated in Alzheimer's disease (AD). AD is characterized by a progressive decline in memory associated with selective impairment of cholinergic neurotransmission. The functional interplay of endocannabinoid and muscarinic signaling was analyzed in seven-month-old 3xTg-AD mice following the evaluation of learning and memory of an aversive stimulus. Neurochemical correlates were simultaneously studied with both receptor and functional autoradiography for CB1 and muscarinic receptors, and regulations at the cellular level were depicted by immunofluorescence. 3xTg-AD mice exhibited increased acquisition latencies and impaired memory retention compared to age-matched non-transgenic mice. Neurochemical analyses showed changes in CB1 receptor density and functional coupling of CB1 and muscarinic receptors to Gi/o proteins in several brain areas, highlighting that observed in the basolateral amygdala. The subchronic (seven days) stimulation of the endocannabinoid system following repeated WIN55,212-2 (1 mg/kg) or JZL184 (8 mg/kg) administration induced a CB1 receptor downregulation and CB1-mediated signaling desensitization, normalizing acquisition latencies to control levels. However, the observed modulation of cholinergic neurotransmission in limbic areas did not modify learning and memory outcomes. A CB1 receptor-mediated decrease of GABAergic tone in the basolateral amygdala may be controlling the limbic component of learning and memory in 3xTg-AD mice. CB1 receptor desensitization may be a plausible strategy to improve behavior alterations associated with genetic risk factors for developing AD.

Epitomic Characterization of the Specificity of the Anti-Amyloid Aβ Monoclonal Antibodies 6E10 and 4G8. - Baghallab, Ibtisam; Reyes-Ruiz, Jorge Mauricio; Abulnaja, Khalid; Huwait, Etimad; Glabe, Charles (J Alzheimers Dis, 2018)
The monoclonal antibodies 6E10 and 4G8 are among the first anti-amyloid monoclonal antibodies against Aβ and the most widely used antibodies in Alzheimer's disease research. Although the epitopes for 6E10 and 4G8 have been reported to correspond to residues 1-16 and 17-24, a more recent high-resolution mapping approach indicates that 6E10 maps to residues 4-10 while 4G8 maps to residues 18-23. To characterize the binding specificity of both antibodies in greater detail, we used immunoselection of random sequences from phage display library followed by deep sequencing and analysis of resulting patterns from thousands of immunoselected sequences. We found that the minimum sequence required for 6E10 binding is R-x-D with over half (53%) of the immunoselected sequences conforming to this pattern. The vast majority of these sequences contain an H at position x (R-H-D), corresponding to residues 5-7 of the Aβ target sequences, but Y is also permitted at this position in a minority of sequences. For 4G8 we found that the most frequent pattern is F-x-A contained in approximately 30% of the sequences, followed by F-A, L-x(3)-A, L-x-F, and F-F each accounting for approximately 18% of the sequences. The F-x-A motif also occurs in islet amyloid poly peptide which may explain why 4G8 also recognizes amyloid fibrils of this peptide. Immunoselection of random sequences and deep sequencing may also be a facile and efficient means of determining residues critical for antibody binding and validating the specificity of monoclonal antibodies and polyclonal antisera.

Executive Dysfunction Detected with the Frontal Assessment Battery in Alzheimer's Disease Versus Vascular Dementia. - D'Onofrio, Grazia; Panza, Francesco; Sancarlo, Daniele; Addante, Filomena; Solfrizzi, Vincenzo; Cantarini, Chiara; Mangiacotti, Antonio; Lauriola, Michele; Cascavilla, Leandro; Paris, Francesco; Lozupone, Madia; Daniele, Antonio; et al. (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) and vascular dementia (VaD) lead to progressive decline in executive function. We estimated the prevalence of executive dysfunction in AD and VaD patients, investigating cognitive, functional, and clinical correlates and also using a multidimensional approach based on a standardized comprehensive geriatric assessment (CGA). We included 215 patients (115 AD patients and 100 VaD patients) consecutively evaluated with a complete cognitive and affective assessment, a CGA, and the Frontal Assessment Battery (FAB) with six subtests investigating conceptualization, mental flexibility, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy. The prevalence of dysexecutive syndrome screened with a FAB score <12 points was high in both AD (97 patients) and VaD (77 patients) (84.3% versus 77.0%, p = 0.171). AD patients were significantly younger, with higher grade of cognitive impairment and less severe comorbidity and polypharmacy than VaD patients. AD patients showed a significantly higher impairment in FAB total score and five FAB subtests (conceptualization, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy) than VaD patients. These findings were largely confirmed in a sub-analysis conducted subdividing the sample in mild and moderate-to-severe demented patients and suggesting that in moderate-to-severe AD there was higher impairment in FAB total score and four FAB subtests (conceptualization, sensitivity to interference, inhibitory control, and environmental autonomy). Executive dysfunction could be greater in AD patients with moderate-to-severe dementia compared to VaD patients, although our groups were also not matched for age, comorbidity or polypharmacy, which could also exert an effect.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Cognitive Dysfunction; Comorbidity; Dementia, Vascular; Executive Function; Female; Frontal Lobe; Geriatric Assessment; Humans; Logistic Models; Male; Polypharmacy; Severity of Illness Index

Exploring the Role of Cognitive Factors in a New Instrument for Elders' Financial Capacity Assessment. - Giannouli, Vaitsa; Stamovlasis, Dimitrios; Tsolaki, Magda (J Alzheimers Dis, 2018)
BACKGROUND: The influence of cognitive factors on financial capacity across the dementia spectrum of cognitive aging, Alzheimer's disease (AD), and mild cognitive impairment (MCI) has been little investigated, while it has not been investigated at all in other types of dementia as well as in extended samples of elders in Greece. OBJECTIVE: The aim of this study is to investigate financial capacity, to develop a tool, test its psychometric properties, validate, and then test the tool in groups of healthy controls compared to elders with dementia, while examining other facets of their cognitive performance. METHODS: 719 elders from Greece including healthy participants and patients with different types of dementia were examined with Legal Capacity for Property Law Transactions Assessment Scale (LCPLTAS) and a battery of neuropsychological tests concerning various cognitive functions. RESULTS: Significantly different profiles in the scores and subscores of LCPLTAS for all the groups of dementia patients were found, with a general incapacity finding for all the dementia groups including the MCI patients. Logistic regression showed that Mini-Mental State Examination (MMSE), Geriatric Depression Scale, and Trail Making Part B predicted competence on LCPLTAS for the dementia patients. Persons with MCI and dementia had lower financial knowledge scores than those without cognitive impairment, with MMSE scores below 27 suggestive as an indication of financial incapacity. CONCLUSION: The LCPLTAS provides information for a strong positive correlation with MMSE, while the use both of MMSE and LCPLTAS as adequate measures of financial (in)capacity is discussed for the Greek legal procedures regarding elder guardianship cases.

Exposure to Strong Anticholinergic Medications and Dementia-Related Neuropathology in a Community-Based Autopsy Cohort. - Gray, Shelly L; Anderson, Melissa L; Hanlon, Joseph T; Dublin, Sascha; Walker, Rod L; Hubbard, Rebecca A; Yu, Onchee; Montine, Thomas J; Crane, Paul K; Sonnen, Josh A; Keene, C Dirk; Larson, Eric B (J Alzheimers Dis, 2018)
BACKGROUND: Anticholinergic medication exposure has been associated with increased risk for dementia. No study has examined the association between anticholinergic medication use and neuropathologic lesions in a community-based sample. OBJECTIVE: To examine the relationship between anticholinergic exposure and dementia-related neuropathologic changes. METHODS: Within a community-based autopsy cohort (N = 420), we ascertained use of anticholinergic medications over a 10-year period from automated pharmacy data and calculated total standardized daily doses (TSDD). We used modified Poisson regression to calculate adjusted relative risks (RRs) and 95% confidence intervals (CIs) for the association between anticholinergic exposure and dementia-associated neuropathology. Inverse probability weighting was used to account for selection into the autopsy cohort. RESULTS: Heavy anticholinergic exposure (≥1,096 TSDD) was not associated with greater neuropathologic changes of Alzheimer's disease; the adjusted RRs for heavy use of anticholinergics (≥1,096 TSDD) compared to no use were 1.22 (95% CI 0.81-1.88) for neuritic plaque scores and 0.89 (0.47-1.66) for extent of neurofibrillary degeneration. Moderate (91-1,095 TSDD) and heavy use of anticholinergics was associated with a significantly lower cerebral microinfarct burden compared with no use with adjusted RRs of 0.44 (0.21-0.89) and 0.24 (0.09-0.62), respectively. Anticholinergic exposure was not associated with macroscopic infarcts or atherosclerosis. CONCLUSIONS: Use of anticholinergic medications is not associated with Alzheimer's disease-related neuropathologic changes but is associated with lower cerebral microinfarct burden. Further research into biological mechanisms underlying the anticholinergic-dementia link is warranteds.

FDDNP-PET Tau Brain Protein Binding Patterns in Military Personnel with Suspected Chronic Traumatic Encephalopathy1. - Chen, Stephen T; Siddarth, Prabha; Merrill, David A; Martinez, Jacqueline; D Emerson, Natacha; Liu, Jie; Wong, Koon-Pong; Satyamurthy, Nagichettiar; Giza, Christopher C; Huang, Sung-Cheng; Fitzsimmons, Robert P; Bailes, Julian; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Our group has shown that in vivo tau brain binding patterns from FDDNP-PET scans in retired professional football players with suspected chronic traumatic encephalopathy differ from those of tau and amyloid aggregate binding observed in Alzheimer's disease (AD) patients and cognitively-intact controls. OBJECTIVE: To compare these findings with those from military personnel with histories of mild traumatic brain injury(mTBI). METHODS: FDDNP-PET brain scans were compared among 7 military personnel and 15 retired players with mTBI histories and cognitive and/or mood symptoms, 24 AD patients, and 28 cognitively-intact controls. Nonparametric ANCOVAs with Tukey-Kramer adjusted post-hoc comparisons were used to test for significant differences in regional FDDNP binding among subject groups. RESULTS: FDDNP brain binding was higher in military personnel compared to controls in the amygdala, midbrain, medial thalamus, pons, frontal and anterior and posterior cingulate regions (p < 0.01-0.0001). Binding patterns in the military personnel were similar to those of the players except for the amygdala and striatum (binding higher in players; p = 0.02-0.003). Compared with the AD group, the military personnel showed higher binding in the midbrain (p = 0.0008) and pons (p = 0.002) and lower binding in the medial temporal, lateral temporal, and parietal regions (all p = 0.02). CONCLUSION: This first study of in vivo tau and amyloid brain signals in military personnel with histories of mTBI shows binding patterns similar to those of retired football players and distinct from the binding patterns in AD and normal aging, suggesting the potential value of FDDNP-PET for early detection and treatment monitoring in varied at-risk populations.

Findings from the Swedish Study on Familial Alzheimer's Disease Including the APP Swedish Double Mutation. - Thordardottir, Steinunn; Graff, Caroline (J Alzheimers Dis, 2018)
This is a brief summary of the findings from the Swedish study on familial Alzheimer's disease (FAD). Similar to other FAD studies, it includes prospective assessments of cognitive function, tissue sampling, and technical analyses such as MRI and PET. This 24-year-old study involves 69 individuals with a 50% risk of inheriting a disease-causing mutation in presenilin 1 (PSEN1 H163Y or I143T), or amyloid precursor protein (the Swedish APP or the arctic APP mutation) who have made a total of 169 visits. Our results show the extraordinary power in this study design to unravel the earliest changes in preclinical AD. The Swedish FAD study will continue and future research will focus on disentangling the order of pathological change using longitudinal data as well as modeling the changes in patient derived cell systems.

The First Historically Reported Italian Family with FTD/ALS Teaches a Lesson on C9orf72 RE: Clinical Heterogeneity and Oligogenic Inheritance. - Giannoccaro, Maria Pia; Bartoletti-Stella, Anna; Piras, Silvia; Casalena, Alfonsina; Oppi, Federico; Ambrosetto, Giovanni; Montagna, Pasquale; Liguori, Rocco; Parchi, Piero; Capellari, Sabina (J Alzheimers Dis, 2018)
BACKGROUND: In 1969, Dazzi and Finizio reported the second observation of frontotemporal dementia (FTD) - amyotrophic lateral sclerosis (ALS) association in a large Italian kindred affected by an autosomal dominant form of ALS with high penetrance, frequent bulbar onset, and frequent cognitive decline. OBJECTIVE: To expand the original characterization of this family and report the link with the C9orf72 repeat expansion (RE). METHODS: We followed or reviewed the medical records of thirteen patients belonging to the original family and performed genetic analyses in four individuals. RESULTS: Eight patients presented with ALS, four with FTD, and one with schizophrenia. The C9orf72 RE was found in three patients but not in the healthy survivor. Additionally, we found a novel possible pathogenic variant in the ITM2B gene in one patient with a complex phenotype, associating movement disorders, psychiatric and cognitive features, deafness, and optic atrophy. The neuropathological examination of this patient did not show the classical features of ITM2B mutation related dementias suggesting that the putative pathogenic mechanism does not involve cellular mislocalization of the protein or the formation of amyloid plaques. CONCLUSION: We showed that the original Italian pedigree described with FTD/ALS carries the C9orf72 RE. Moreover, the finding of an additional mutation in another dementia causing gene in a patient with a more complex phenotype suggests a possible role of genetic modifiers in the disease. Together with other reports showing the coexistence of mutations in multiple ALS/FTD causative genes in the same family, our study supports an oligogenic etiology of ALS/FTD.
Keywords: Adult; Amyotrophic Lateral Sclerosis; C9orf72 Protein; Cerebral Cortex; DNA Repeat Expansion; Female; Frontotemporal Dementia; Genetic Testing; Humans; Male; Membrane Glycoproteins; Middle Aged; Multifactorial Inheritance; Mutation; Pedigree

Fragmentation of the Golgi Apparatus in Neuroblastoma Cells Is Associated with Tau-Induced Ring-Shaped Microtubule Bundles. - Rodríguez-Cruz, Fanny; Torres-Cruz, Francisco Miguel; Monroy-Ramírez, Hugo Christian; Escobar-Herrera, Jaime; Basurto-Islas, Gustavo; Avila, Jesús; Garcia-Sierra, Francisco (J Alzheimers Dis, 2018)
Abnormal fibrillary aggregation of tau protein is a pathological condition observed in Alzheimer's disease and other tauopathies; however, the presence and pathological significance of early non-fibrillary aggregates of tau remain under investigation. In cell and animal models expressing normal or modified tau, toxic effects altering the structure and function of several membranous organelles have also been reported in the absence of fibrillary structures; however, how these abnormalities are produced is an issue yet to be addressed. In order to obtain more insights into the mechanisms by which tau may disturb intracellular membranous elements, we transiently overexpressed human full-length tau and several truncated tau variants in cultured neuroblastoma cells. After 48 h of transfection, either full-length or truncated tau forms produced significant fragmentation of the Golgi apparatus (GA) with no changes in cell viability. Noteworthy is that in the majority of cells exhibiting dispersion of the GA, a ring-shaped array of cortical or perinuclear microtubule (Mt) bundles was also generated under the expression of either variant of tau. In contrast, Taxol treatment of non-transfected cells increased the amount of Mt bundles but not sufficiently to produce fragmentation of the GA. Tau-induced ring-shaped Mt bundles appeared to be well-organized and stable structures because they were resistant to Nocodazole post-treatment and displayed a high level of tubulin acetylation. These results further indicate that a mechanical force generated by tau-induced Mt-bundling may be responsible for Golgi fragmentation and that the repeated domain region of tau may be the main promoter of this effect.

A 'Framingham-like' Algorithm for Predicting 4-Year Risk of Progression to Amnestic Mild Cognitive Impairment or Alzheimer's Disease Using Multidomain Information. - Steenland, Kyle; Zhao, Liping; John, Samantha E; Goldstein, Felicia C; Levey, Allan; Alvaro, Alonso (J Alzheimers Dis, 2018)
BACKGROUND: There are no agreed-upon variables for predicting progression from unimpaired cognition to amnestic mild cognitive impairment (aMCI), or from aMCI to Alzheimer's disease (AD). OBJECTIVE: Use ADNI data to develop a 'Framingham-like' prediction model for a 4-year period. METHODS: We developed models using the strongest baseline predictors from six domains (demographics, neuroimaging, CSF biomarkers, genetics, cognitive tests, and functional ability). We chose the best predictor from each domain, which was dichotomized into more versus less harmful. RESULTS: There were 224 unimpaired individuals and 424 aMCI subjects with baseline data on all predictors, of whom 37 (17% ) and 150 (35% ) converted to aMCI and AD, respectively, during 4 years of follow-up. For the unimpaired, CSF tau/Aβ ratio, hippocampal volume, and a memory score predicted progression. For those aMCI at baseline, the same predictors plus APOE4 status and functional ability predicted progression. Demographics and family history were not important predictors for progression for either group. The fit statistic was good for the unimpaired-aMCI model (C-statistic 0.80) and very good for the aMCI-AD model (C-statistic 0.91). Among the unimpaired, those with no harmful risk factors had a 4-year predicted 2% risk of progression, while those with the most harmful risk factors had a predicted 35% risk. The aMCI subjects with no harmful risk factors had a predicted 1% risk of progression those with all six harmful risk factors had a predicted 90% risk. CONCLUSION: Our parsimonious model accurately predicted progression from unimpaired to aMCI with three variables, and from aMCI to AD with five variables.

Frequency of Cardiovascular Genetic Risk Factors in a Calabrian Population and Their Effects on Dementia. - Maletta, Raffaele; Smirne, Nicoletta; Bernardi, Livia; Anfossi, Maria; Gallo, Maura; Conidi, Maria Elena; Colao, Rosanna; Puccio, Gianfranco; Curcio, Sabrina A M; Laganà, Valentina; Frangipane, Francesca; Cupidi, Chiara; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Several genetic variants playing a key role in cholesterol levels, blood pressure, and vascular dysfunction influence the risk of Alzheimer's disease (AD) and vascular dementia (VaD). The many meta-analysis studies carried out on large numbers of samples in different populations have not provided clear results to date, because a trans-ethnic shift of risk genotypes in different populations is often observed. OBJECTIVES: To determine genotypes allele frequencies of the polymorphisms most frequently identified to be correlated with cardio-cerebrovascular disease and AD in a Southern Italy population and to investigate their possible association with dementia. METHODS: The genotype and allele frequencies of 13 cardio-cerebrovascular risk polymorphisms were assessed and their possible association with dementia was investigated in a case-control study, including 221 consecutive unrelated subjects diagnosed with dementia (120 subjects affected by AD, 55 by frontotemporal dementia, and 33 by vascular dementia) and 218 matched controls of Calabrian origin. RESULTS: Carriers of at least one APOEɛ4 allele resulted to be at higher risk of AD [OR(95% CI) = 2.721(1.477-5.011)] and VaD [OR(95% CI) = 6.205(2.356-16.342)] compared to non-carriers. Individuals with the IV genotype of the CETP polymorphism were more likely to have AD [OR(95% CI) = 2.427(1.364-4.319)] and VaD [OR(95% CI) = 3.649(1.455-9.152)] compared to subjects with the II-VV genotypes. CONCLUSION: CETP I405V polymorphism is likely a risk factor for AD and VaD in our cohort, independent of APOEɛ4 status. Unmodifiable genetic risk factors should be taken into account to promote a healthy lifestyle to prevent dementia.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Apolipoprotein E4; Case-Control Studies; Cholesterol Ester Transfer Proteins; Cohort Studies; Dementia, Vascular; Female; Frontotemporal Dementia; Gene Frequency; Humans; Italy; Male; Middle Aged; Polymorphism, Genetic; Risk Factors

Frontotemporal Dementia and Chorea Associated with a Compound Heterozygous TREM2 Mutation. - Redaelli, Veronica; Salsano, Ettore; Colleoni, Lara; Corbetta, Paola; Tringali, Giovanni; Del Sole, Angelo; Giaccone, Giorgio; Rossi, Giacomina (J Alzheimers Dis, 2018)
Frontotemporal dementia (FTD) is clinically characterized by behavioral changes, language impairment, and executive dysfunction. FTD usually belongs to the frontotemporal lobar degeneration (FTLD) disease group, and its familial forms are dominantly inherited and linked to a group of genes relevant to frontal and temporal brain pathology, such as MAPT, GRN, C9ORF72, TARDBP, CHMP2B, VCP, and FUS. However, FTD can also be associated with different clinical or pathological phenotypes caused by mutations in other genes, whose heredity can be dominant or recessive. In this work we report on a familial case of FTD characterized by behavioral changes and aphasia, very early onset and very long duration, choreic movements, and white matter lesions at magnetic resonance imaging. We performed a wide-range genetic analysis, using a next generation sequencing approach, to evaluate a number of genes involved in neurodegeneration. We found a previously unreported compound heterozygous mutation in TREM2, that is commonly associated with the recessively inherited Nasu-Hakola disease. We discuss the differential diagnosis to be taken into account in cases of FTD presenting with atypical features.

Frontotemporal Dementia Misdiagnosed for Post-Treatment Lyme Disease Syndrome or vice versa? A Treviso Dementia (TREDEM) Registry Case Report. - Di Battista, Maria Elena; Dell'Acqua, Carola; Baroni, Luciana; Fenoglio, Chiara; Galimberti, Daniela; Gallucci, Maurizio (J Alzheimers Dis, 2018)
We describe the case of a 61-year-old woman diagnosed with Borreliosis at the age of 57. Subsequently, the patient developed depression, anxiety, and behavioral disturbances. A lumbar puncture excluded the condition of Neuroborreliosis. The diagnostic workup included: an MRI scan, a 18F-FDG PET, a 123I-ioflupane-SPECT, an amyloid-β PET, a specific genetic analysis, and a neuropsychological evaluation. Based on our investigation, the patient was diagnosed with probable behavioral-frontotemporal dementia (bvFTD), whereas in the previous years, the patient had been considered firstly as a case of Post-Treatment-Lyme Disease and, secondly, a psychiatric patient. We believe that, in the present case, such initial symptoms of Borrelia infection may have superimposed on those of bvFTD rather than playing as a contributory cause.

Gait in Mild Alzheimer's Disease: Feasibility of Multi-Center Measurement in the Clinic and Home with Body-Worn Sensors: A Pilot Study. - Mc Ardle, Ríona; Morris, Rosie; Hickey, Aodhán; Del Din, Silvia; Koychev, Ivan; Gunn, Roger N; Lawson, Jennifer; Zamboni, Giovanna; Ridha, Basil; Sahakian, Barbara J; Rowe, James B; Thomas, Alan; et al. (J Alzheimers Dis, 2018)
Gait is emerging as a potential diagnostic tool for cognitive decline. The 'Deep and Frequent Phenotyping for Experimental Medicine in Dementia Study' (D&FP) is a multicenter feasibility study embedded in the United Kingdom Dementia Platform designed to determine participant acceptability and feasibility of extensive and repeated phenotyping to determine the optimal combination of biomarkers to detect disease progression and identify early risk of Alzheimer's disease (AD). Gait is included as a clinical biomarker. The tools to quantify gait in the clinic and home, and suitability for multi-center application have not been examined. Six centers from the National Institute for Health Research Translational Research Collaboration in Dementia initiative recruited 20 individuals with early onset AD. Participants wore a single wearable (tri-axial accelerometer) and completed both clinic-based and free-living gait assessment. A series of macro (behavioral) and micro (spatiotemporal) characteristics were derived from the resultant data using previously validated algorithms. Results indicate good participant acceptability, and potential for use of body-worn sensors in both the clinic and the home. Recommendations for future studies have been provided. Gait has been demonstrated to be a feasible and suitable measure, and future research should examine its suitability as a biomarker in AD.

GDF11 Rejuvenates Cerebrovascular Structure and Function in an Animal Model of Alzheimer's Disease. - Zhang, Wei; Guo, Yi; Li, Bo; Zhang, Qi; Liu, Jian-Hui; Gu, Guo-Jun; Wang, Jin-Hong; Bao, Rui-Kang; Chen, Yu-Jie; Xu, Jian-Rong (J Alzheimers Dis, 2018)
Cerebral amyloid angiopathy (CAA) is present in up to 90% of patients with Alzheimer's disease (AD), and may interact with classical neuropathology to exacerbate cognitive decline. Since growth differentiation factor 11 (GDF11) can activate vascular remodeling, we tested its effects on cognitive function and neuroinflammatory changes of AD model mice. We intravenously administered GDF11 or vehicle daily to 12-month-old transgenic mice overexpressing the amyloid-β protein precursor (AβPP)/PS1). Cognitive function was monitored using the Morris water maze, and after conclusion of the treatment, we assessed the morphology and presence of inflammatory markers in the cerebral vasculature. Subchronic treatment of adult AβPP/PS1 mice with GDF11 rescued cognitive function and ameliorated cerebrovascular function. In particular, the de novo genesis of small blood vessels and the expression of vascular-related proteins were significantly higher than in the vehicle-treated AβPP/PS1 mice, whereas the expressions of the inflammatory markers Iba-1 and GFAP significantly decreased in proportion to the lower ratio of two forms of amyloid-β (Aβ40/42). Daily intravenous treatment with GDF11-injection can rejuvenate respects of cognition and cerebrovascular changes in AD mice.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Behavior, Animal; Cerebral Amyloid Angiopathy; Disease Models, Animal; Growth Differentiation Factors; Maze Learning; Mice; Mice, Transgenic; Prefrontal Cortex; Presenilin-1

Gene Transfer Induced Hypercholesterolemia in Amyloid Mice. - Grames, Mychal S; Dayton, Robert D; Lu, Xiaohong; Schilke, Robert M; Alexander, J Steven; Orr, A Wayne; Barmada, Sami J; Woolard, Matthew D; Klein, Ronald L (J Alzheimers Dis, 2018)
A risk factor for cardiovascular disease (CVD), mutant PCSK9, was expressed in APP/PS1 mice to study the CVD-Alzheimer's disease inter-relationship. Cholesterol levels were elevated by 5-6-fold from 3 to 13 weeks after PCSK9 gene transfer. We tested whether hypercholesterolemia would increase amyloid-β plaques at a relatively early stage of plaque deposition. Plaque burden was increased in the hippocampus of PCSK9 treated mice though the increase was modest compared to the large elevation in cholesterol. Elevating cholesterol via gene transfer could be valuable in a variety of disease models compared to making crosses with germ-line transgenic mouse models of CVD.

Genotyping of the Alzheimer's Disease Genome-Wide Association Study Index Single Nucleotide Polymorphisms in the Brains for Dementia Research Cohort. - Brookes, Keeley J; McConnell, George; Williams, Kirsty; Chaudhury, Sultan; Madhan, Gaganjit; Patel, Tulsi; Turley, Christopher; Guetta-Baranes, Tamar; Bras, Jose; Guerreiro, Rita; Hardy, John; Francis, Paul T; et al. (J Alzheimers Dis, 2018)
The Brains for Dementia Research project is a recently established longitudinal cohort which aims to provide brain tissue for research purposes from neuropathologically defined samples. Here we present the findings from our analysis on the 19 established GWAS index SNPs for Alzheimer's disease, in order to demonstrate if the BDR sample also displays association to these variants. A highly significant association of the APOEɛ4 allele was identified (p = 3.99×10-12). Association tests for the 19 GWAS SNPs found that although no SNPs survive multiple testing, nominal significant findings were detected and concordance with the Lambert et al. GWAS meta-analysis was observed.

Growth Hormone-Releasing Hormone Modulation of Neuronal Exosome Biomarkers in Mild Cognitive Impairment. - Winston, Charisse N; Goetzl, Edward J; Baker, Laura D; Vitiello, Michael V; Rissman, Robert A (J Alzheimers Dis, 2018)
Age-related changes in cognition are linked to decreased expression of somatotropins, GHRH and IGF-1. Mild cognitive impairment (MCI) and Alzheimer's disease (AD) are heterogeneous conditions. The loss of GHRH signaling in the brain may be mechanistically involved in AD pathogenesis. The consequent need to identify AD at an early and perhaps more treatable stage has fueled research into blood-based, exosome biomarkers. Plasma exosomes from participants enrolled in a randomized, double-blind, placebo-controlled 20-week trial of GHRH administration, were isolated, precipitated, and enriched by immuno-absorption with anti-L1CAM antibody (neural adhesion protein) from adults with MCI and age-matched, cognitively normal controls (CNC). Extracted protein cargo from neuronally-derived exosomes (NDEs) were assessed by ELISAs for protein levels implicated in AD neuropathology and for synaptic proteins altered by AD. Plasma NDE concentrations of Aβ1-42 were significantly increased while plasma NDE concentrations of NRGN, synaptophysin, synaptotagmin, and synaptopodin were significantly decreased in patients with MCI, independent of GHRH treatment. Plasma NDE concentrations of ptau-S396 and GAP43 were not affected by cognitive status (CNC versus MCI) or by GHRH treatment. Aβ1-42, neurogranin (NRGN), synaptophysin, synaptotagmin, and synaptopodin demonstrated the highest diagnostic accuracy for distinguishing between CNC and MCI patients, while synaptophysin and synaptotagmin demonstrated moderate accuracy in distinguishing between placebo-treated and GHRH-treated, MCI patients.

Gut Microbiome is Altered in Patients with Alzheimer's Disease. - Zhuang, Zhen-Qian; Shen, Lin-Lin; Li, Wei-Wei; Fu, Xue; Zeng, Fan; Gui, Li; Lü, Yang; Cai, Min; Zhu, Chi; Tan, Yin-Ling; Zheng, Peng; Li, Hui-Yun; et al. (J Alzheimers Dis, 2018)
Previous studies suggest that gut microbiota is associated with neuropsychiatric disorders, such as Parkinson's disease, amyotrophic lateral sclerosis, and depression. However, whether the composition and diversity of gut microbiota is altered in patients with Alzheimer's disease (AD) remain largely unknown. In the present study, we collected fecal samples from 43 AD patients and 43 age- and gender-matched cognitively normal controls. 16S ribosomal RNA sequencing technique was used to analyze the microbiota composition in feces. The composition of gut microbiota was different between the two groups. Several bacteria taxa in AD patients were different from those in controls at taxonomic levels, such as Bacteroides, Actinobacteria, Ruminococcus, Lachnospiraceae, and Selenomonadales. Our findings suggest that gut microbiota is altered in AD patients and may be involved in the pathogenesis of AD.

Heme Oxygenase 1 Induces Tau Oligomer Formation and Synapse Aberrations in Hippocampal Neurons. - Si, Zizhen; Wang, Xidi; Zhang, Zhujun; Wang, Jinxin; Li, Jihong; Li, Jing; Li, Ling; Li, Yuanxin; Peng, Yahui; Sun, Chongran; Hui, Yang; Gao, Xu (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by behavioral changes and cognitive decline. Recent evidence suggests that it is the soluble forms of tau oligomers (Tau-O) and Aβ oligomers (oAβ) rather than the well-studied insoluble protein aggregates that possess the neurotoxicity, infectivity, and amplification underlying disease progression. Heme oxygenase 1 (HO-1), an inducible enzyme upregulated in the cortex and hippocampus of AD brains, was reported to damage neural structures and disrupt brain function, suggesting possible contributions to Tau-O-mediated neurodegeneration. In this study, we focused on the effects of HO-1 on Tau-O formation. In hippocampus of HO-1-overexpressing transgenic mice and neural 2a (N2a) cells, Tau-O was co-localized with HO-1 as visualized by immunofluorescence staining. Furthermore, primary cultured hippocampal neurons from HO-1 transgenic mice showed elevated Tau-O and concomitant reductions in spine density and length as well as dendritic length, diameter, and arborization. Blocking Tau-O formation by isoprenaline reversed these HO-1-induced morphological changes. These results indicated that HO-1 contributes to Tau-O formation and ensuing synaptic damage. Thus, HO-1 is a promising target for AD drug development.

The Heritability of Frontotemporal Lobar Degeneration: Validation of Pedigree Classification Criteria in a Northern Italy Cohort. - Fostinelli, Silvia; Ciani, Miriam; Zanardini, Roberta; Zanetti, Orazio; Binetti, Giuliano; Ghidoni, Roberta; Benussi, Luisa (J Alzheimers Dis, 2018)
A large portion of frontotemporal lobar degeneration (FTLD) patients has a family history of disease and the presence of a pathogenic mutation confirms the clinical diagnosis. Recently, standardized criteria to evaluate FTLD pedigree, based on first- and second-degree affected relatives, their age at onset, and clinical phenotype, were proposed and validated in an American cohort. Herein we applied these criteria to 402 Italian FTLD pedigrees and assessed mutation frequencies in GRN, C9orf72, and MAPT genes with the aim of validating these criteria. Moreover, we evaluated whether genetic counseling requests reflect the estimated family risk. 12.4% of pedigrees had high family history, 6.5% medium, 15.4% low; 39% were apparent sporadic cases and 26.6% had family history of unknown significance. Mutations frequencies were in line with the categorization proposed: the highest rate was found in the most at-risk families (74%) and decreased in other categories (medium: 15.4%; low: 9.7%; sporadic: 1.3%). Mutation carriers with unknown family history (5.6%) were mostly early-onset patients. Detected mutation frequency was comparable with the US-cohort (13.7%), but mutations distribution among genes was different, with higher frequency of GRN mutations (9.4%) in our cohort. An elevated proportion of FTLD patients belonging to "high risk" pedigrees asked for genetic counseling (42%); requests decreased according to the estimated family risk (medium: 26.9%; low: 17.7%; sporadic: 5.1%). In conclusion, the proposed pedigree classification criteria, herein further validated, should be incorporated in the FTLD diagnostic work-up. Moreover, our data suggest to extend genetic screening to early-onset patients with unknown family history.
Keywords: Age of Onset; Aged; C9orf72 Protein; Cohort Studies; Female; Frontotemporal Lobar Degeneration; Genetic Counseling; Genetic Testing; Humans; Italy; Male; Middle Aged; Mutation; Pedigree; Progranulins; tau Proteins

How Does Utilization of Health Care Services Change in People with Dementia Served by Dementia Care Networks? Results of the Longitudinal, Observational DemNet-D-Study. - Thyrian, Jochen René; Michalowsky, Bernhard; Hertel, Johannes; Wübbeler, Markus; Gräske, Johannes; Holle, Bernhard; Schäfer-Walkmann, Susanne; Wolf-Ostermann, Karin; Hoffmann, Wolfgang (J Alzheimers Dis, 2018)
BACKGROUND: There is no common definition for the Dementia Care Network (DCN). They are heterogeneous and there is no general, longitudinal evidence for the effects of DCN. OBJECTIVE: We describe changes in utilization of health services by people served by dementia care networks in Germany and factors associated with those changes over time. METHODS: Primary data was assessed in 560 people with dementia (PwD) and their caregivers supported by DCN in Germany; sociodemographic and clinical variables, utilization of services; DCN were characterized according to governance. The design: observational study with face-to-face interviews at two time points over a period of one year. Data was assessed via semi-structured interviews at the participants' homes. RESULTS: Utilization of health services in this study is consistently higher than reported for the general population and does not significantly change over time. The strongest predictor of utilization of any service after one year was the use of this service at baseline (OR from 3.23 to 44.16). Higher activities of daily functioning increased the chances to utilize specialist physicians (OR = 1.32; 95% -CI: 1.08-1.63) or occupational therapy (OR = 1.24; 95% -CI: 1.02-1.50) significantly. Being a female decreased chances to utilize specialist physicians (OR = 0.57; 95% -CI: 0.37-0.87) and increased the chances to utilize no services (OR = 2.08; 95% -CI: 1.29-3.33). CONCLUSION: While health care acknowledges the importance and benefits of dementia care networks (i.e., in Germany, the results were considered in new German legislation (SGB XI)), further research is needed to define this kind of service delivery to facilitate comparison as well as promote evidence-based implementation.

Hypercapnic and Hypoxic Respiratory Response During Wakefulness and Sleep in a Streptozotocin Model of Alzheimer's Disease in Rats. - Vicente, Mariane C; Almeida, Maria C; Bícego, Kênia C; Carrettiero, Daniel C; Gargaglioni, Luciane H (J Alzheimers Dis, 2018)
Besides the typical cognitive decline, patients with Alzheimer's disease (AD) develop disorders of the respiratory system, such as sleep apnea, shortness of breath, and arrhythmias. These symptoms are aggravated with the progression of the disease. However, the cause and nature of these disturbances are not well understood. Here, we treated animals with intracerebroventricular streptozotocin (STZ, 2 mg/kg), a drug that has been described to cause Alzheimer-like behavioral and histopathological impairments. We measured ventilation (V̇E), electroencephalography, and electromyography during normocapnia, hypercapnia, and hypoxia in Wistar rats. In addition, we performed western blot analyses for phosphorylated tau, total tau, and amyloid-β (Aβ) peptide in the locus coeruleus (LC), retrotrapezoid nucleus, medullary raphe, pre-Bötzinger/Bötzinger complex, and hippocampus, and evaluated memory and learning acquisition using the Barnes maze. STZ treatment promoted memory and learning deficits and increased the percentage of total wakefulness during normocapnia and hypercapnia due to a reduction in the length of episodes of wakefulness. CO2-drive to breathe during wakefulness was increased by 26% in STZ-treated rats due to an enhanced tidal volume, but no changes in V̇E were observed in room air or hypoxic conditions. The STZ group also showed a 70% increase of Aβ in the LC and no change in tau protein phosphorylation. In addition, no alteration in body temperature was observed. Our findings suggest that AD animals present an increased sensitivity to CO2 during wakefulness, enhanced Aβ in the LC, and sleep disruption.

Imaging Biomarkers of Neurodegeneration in Alzheimer's Disease: Distinct Contributions of Cortical MRI Atrophy and FDG-PET Hypometabolism. - Benvenutto, Agnès; Giusiano, Bernard; Koric, Lejla; Gueriot, Claude; Didic, Mira; Felician, Olivier; Guye, Maxime; Guedj, Eric; Ceccaldi, Mathieu (J Alzheimers Dis, 2018)
BACKGROUND: Neurodegeneration biomarkers are routinely used in the diagnosis of Alzheimer's disease (AD). OBJECTIVE: To evaluate the respective contributions of two neuroimaging biomarkers, structural MRI and 18FDG-PET, in the assessment of neurodegeneration in AD dementia. METHODS: Patients with mild AD dementia diagnosed based on clinical and cerebrospinal fluid criteria and cognitively healthy subjects, from the Marseille cohort ADAge with cognitive, structural MRI and 18FDG-PET assessments, were included. Extent of atrophy on MRI and of hypometabolism on 18FDG-PET were individually evaluated in each patient using a voxel-based analysis on whole-brain approach and compared to healthy subjects. Patients were divided in distinct groups according to their atrophy extent on the one hand and to their hypometabolism extent on the other, then, to their imaging profile combining the extent of the two biomarkers. RESULTS: Fifty-two patients were included. The MMSE score was significantly lower in the "Extensive hypometabolism" group than in the "Limited hypometabolism" group (respectively 19.5/30 versus 23/30). A lower Innotest Amyloid Tau Index was associated with an extensive hypometabolism (p = 0.04). There were more patients with low educational level in the "Extensive atrophy" group, while a higher educational level was more found in the "Limited atrophy" group (p = 0.005). CONCLUSION: 18FDG-PET hypometabolism extent is associated with the pathological processes and clinical severity of AD, while MRI atrophy seems to be influenced by the cognitive reserve. In the context of mild AD dementia, these two biomarkers of neurodegeneration are thus not interchangeable and require to be considered in combination rather than in isolation.

Impact of a Virtual Dementia Experience on Medical and Pharmacy Students' Knowledge and Attitudes Toward People with Dementia: A Controlled Study. - Gilmartin-Thomas, Julia F-M; McNeil, John; Powell, Anne; Malone, Daniel T; Wolfe, Rory; Larson, Ian C; O'Reilly, Claire L; Kirkpatrick, Carl M; Kipen, Eva; Petrovich, Tanya; Bell, J Simon (J Alzheimers Dis, 2018)
BACKGROUND: Clinical practice guidelines for dementia highlight the importance of providing patient-centered care. This can be achieved by improving health professionals' attitudes and knowledge toward people with dementia. OBJECTIVE: Quantitatively evaluate the impact of a virtual dementia experience on medical and pharmacy students' knowledge and attitudes toward people with dementia. METHODS: A non-randomized controlled study from September-October 2016. The intervention group received a 1.5-hour multisensory, virtual simulation of light, sound, color, and visual content to experience the cognitive and perceptual difficulties faced by people with dementia. Controls participated in the standard curriculum only. All students were invited to complete the 20-item Dementia Attitudes Scale (DAS) pre- and post-intervention. RESULTS: A total of 278 students (n = 64 medical, n = 214 pharmacy) were analyzed (n = 80 intervention, n = 198 control). The majority of students were female (n = 184, 66.2%), with an average age of 22.5 years. The intervention improved the DAS total score and subdomains of comfort and knowledge (p < 0.001). CONCLUSION: The intervention had a positive impact on medical and pharmacy students' knowledge and attitudes toward people with dementia.
Keywords: Australia; Curriculum; Dementia; Female; Health Knowledge, Attitudes, Practice; Humans; Male; Students, Medical; Students, Pharmacy; Virtual Reality; Young Adult

Impact of Amyloid PET Imaging in the Memory Clinic: A Systematic Review and Meta-Analysis. - Shea, Yat-Fung; Barker, Warren; Greig-Gusto, Maria T; Loewenstein, David A; Duara, Ranjan; DeKosky, Steven T (J Alzheimers Dis, 2018)
BACKGROUND: Patients with cognitive impairment or dementias of uncertain etiology are frequently referred to a memory disorders specialty clinic. The impact of and role for amyloid PET imaging (Aβ-PET) may be most appropriate in this clinical setting. OBJECTIVE: The primary objective of this study was to perform a systematic review and meta-analysis of the impact of Aβ-PET on etiological diagnosis and clinical management in the memory clinic setting. METHODS: A search of the literature on the impact of Aβ-PET in the memory clinic setting between 1 January 2004 and 12 February 2018 was conducted. Meta-analysis using a random effects model was performed to determine the pooled estimate of the impact of Aβ-PET in the changes of diagnoses and changes in management plan. RESULTS: After rigorous review, results from 13 studies were extracted, involving 1,489 patients. Meta-analysis revealed a pooled effect of change in diagnoses of 35.2% (95% CI 24.6-47.5). Sub-analyses showed that the pooled effect in change in diagnoses if Aβ-PET was used under the appropriate use criteria (AUC) or non-AUC criteria were 47.8% (95% CI 25.9-70.5) and 29.6% (95% CI: 21.5-39.3), respectively. The pooled effect of a change of diagnosis from Alzheimer's disease (AD) to non-AD and from non-AD to AD were 22.7% (95% CI: 17.1-29.5) and 25.6% (95% CI: 17.6-35.8), respectively. The pooled effect leading to a change of management was 59.6% (95% CI 39.4-77.0). CONCLUSIONS: Aβ-PET has a highly significant impact on both changes in diagnosis and management among patients being seen at a specialty memory clinic.

Impact of Olfactory Priming on Food Intake in an Alzheimer's Disease Unit. - Sulmont-Rossé, Claire; Gaillet, Marie; Raclot, Carine; Duclos, Michel; Servelle, Maud; Chambaron, Stéphanie (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is often associated with feeding difficulties and changes in eating behavior with may lead to malnutrition. In French nursing homes, AD patients may live in special care units that better meet dementia residents' needs. However, meals are often delivered to AD patients by using meal trays coming from central kitchens. This led to the disappearance of cues that could help residents to foresee mealtime, such as the smell of food odors. The aim of the present study was to assess the impact of odorizing the dining room of AD Units with a meat odor before lunch on subsequent food intake and eating behavior. Thirty-two residents (>75 years old) from three AD Units were included in the study. They participated in two control lunches and two primed lunches, for which a meat odor was diffused in the dining room 15 minutes before the arrival of the meal tray (olfactory priming). Results of the first replication showed a significant effect of olfactory priming, with a 25% increase in meat and vegetable consumption compared to the control condition. Behavioral measurements also showed a significant increase of resident's interest toward the meal in the primed lunch. However, this effect was no longer observed when the priming session was replicated two weeks later with the same priming odor and the same menu. Although further research is needed to understand why this priming effect cannot be replicated, our experiment is one of the very first to investigate the effect of food odor priming on subsequent food intake in AD patients in a real-life setting.

Impact of Untimely Access to Formal Care on Costs and Quality of Life in Community Dwelling People with Dementia. - Janssen, Niels; Handels, Ron L; Sköldunger, Anders; Woods, Bob; Jelley, Hannah; Edwards, Rhiannon Tudor; Orrell, Martin; Selbæk, Geir; Røsvik, Janne; Gonçalves-Pereira, Manuel; Marques, Maria J; Zanetti, Orazio; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Access to formal care is not always timely and a better understanding on the impact of untimely access is needed. OBJECTIVE: To examine, from a societal perspective, the impact of untimely access to formal care in terms of total costs and quality of life over one year in community dwelling people with dementia. METHODS: Within the Actifcare study, needs, resource use, and quality of life were observed for one year in a cohort of 451 community dwelling people with dementia in 8 European countries. Untimely access to care was operationalized as having at least one unmet need for care identified by the Camberwell Assessment of Need for the Elderly (CANE) instrument. Two regression models were built for both total costs and quality of life measured by the EQ-5D-5L, one using sum of unmet needs and one using a predefined selection of need items. RESULTS: Unmet needs were not associated with higher total costs but they were associated with a lower quality of life of people with dementia. Of all CANE items, only an unmet need for "company" was significantly related to lower total costs. CONCLUSION: Total costs did not seem to differ between participants with unmet and met needs. Only few associations between specific unmet needs and costs and quality of life were found. Furthermore, quality of life of people with dementia decreases when multiple unmet needs are experienced, indicating that assessing and meeting needs is important to improve quality of life.

Improvement of Main Cognitive Functions in Patients with Alzheimer's Disease after Treatment with Coconut Oil Enriched Mediterranean Diet: A Pilot Study. - de la Rubia Ortí, Jose Enrique; García-Pardo, María Pilar; Drehmer, Eraci; Sancho Cantus, David; Julián Rochina, Mariano; Aguilar, Maria Asunción; Hu Yang, Iván (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder (mainly in women), and new therapies are needed. In this way, ketone bodies are a direct source of cellular energy and can be obtained from coconut oil, postulating that coconut oil could be a new non-pharmacological alternative in AD patients. OBJECTIVE: The aim of this study is to detect changes in the main cognitive functions of patients with AD after following a coconut oil enriched Mediterranean diet, and to determine whether there are differences in function of stage or sex. METHODS: A prospective, longitudinal, qualitative, analytic, experimental study was carried out in 44 patients with AD, who were randomly divided into two homogenous groups of 22 patients each: an experimental group of patients who followed a coconut oil enriched Mediterranean diet for 21 days and a control group. In order to determine the cognitive changes after the intervention, we carried out the 7 Minute Screen, which analyses temporal orientation, visuospatial and visuoconstructive abilities, and semantic and episodic memory. RESULTS: After intervention with coconut oil, improvements in episodic, temporal orientation, and semantic memory were observed, and it seems that the positive effect is more evident in women with mild-moderate state, although other improvements in males and severe state were also shown. CONCLUSIONS: The isocaloric coconut oil enriched Mediterranean diet seems to improve cognitive functions in patients with AD, with differences according to patient sex and degree of severity of the disease, although more studies in this line are needed.

In Vitro Potency and Preclinical Pharmacokinetic Comparison of All-D-Enantiomeric Peptides Developed for the Treatment of Alzheimer's Disease. - Schartmann, Elena; Schemmert, Sarah; Niemietz, Nicole; Honold, Dominik; Ziehm, Tamar; Tusche, Markus; Elfgen, Anne; Gering, Ian; Brener, Oleksandr; Shah, Nadim Joni; Langen, Karl-Josef; Kutzsche, Janine; et al. (J Alzheimers Dis, 2018)
Diffusible amyloid-β (Aβ) oligomers are currently presumed to be the most cytotoxic Aβ assembly and held responsible to trigger the pathogenesis of Alzheimer's disease (AD). Thus, Aβ oligomers are a prominent target in AD drug development. Previously, we reported on our solely D-enantiomeric peptide D3 and its derivatives as AD drug candidates. Here, we compare one of the most promising D3 derivatives, ANK6, with its tandem version (tANK6), and its head-to-tail cyclized isoform (cANK6r). In vitro tests investigating the D-peptides' potencies to inhibit Aβ aggregation, eliminate Aβ oligomers, and reduce Aβ-induced cytotoxicity revealed that all three D-peptides efficiently target Aβ. Subsequent preclinical pharmacokinetic studies of the three all-D-peptides in wildtype mice showed promising blood-brain barrier permeability with cANK6r yielding the highest levels in brain. The peptides' potencies to lower Aβ toxicity and their remarkable brain/plasma ratios make them promising AD drug candidates.

Increased Albumin Oxidation in Cerebrospinal Fluid and Plasma from Alzheimer's Disease Patients. - Costa, Montserrat; Horrillo, Raquel; Ortiz, Ana María; Pérez, Alba; Mestre, Anna; Ruiz, Agustin; Boada, Merce; Grancha, Salvador (J Alzheimers Dis, 2018)
BACKGROUND: Oxidative stress in the brain and peripheral systems is considered a major player in Alzheimer's disease (AD). Albumin is the main transporter and the main extracellular antioxidant in the human body. OBJECTIVE: Here we explore for the first time the oxidation status of cerebrospinal fluid (CSF) and plasma albumin in AD in comparison to healthy subjects. METHODS: Plasma and CSF samples were obtained from mild-moderate AD patients and control healthy age-matched donors. Albumin redox state forms (reduced: HMA; reversibly oxidized: HNA1; irreversibly oxidized: HNA2) were determined by HPLC. Albumin post-translational modifications (PTM) analysis was performed by mass spectrometry. RESULTS: HPLC showed less HMA in AD plasma than in controls (54.1% versus 65.2% ; p < 0.0001), mainly at expense of HNA1 (42.8% versus 32.5% ; p < 0.0001). In AD CSF, HMA was drastically decreased compared to controls (9.6% versus 77.4% ; p < 0.0001), while HNA2 was increased (52.8% versus 7.4% ; p < 0.0001). In AD patients but not in healthy controls, CSF albumin was much more irreversibly oxidized than in plasma (close to 20-fold increase in HNA2). PTM analysis showed that AD CSF albumin samples behave as a differentiated cluster, thus confirming the albumin oxidative pattern observed by HPLC. CONCLUSION: CSF albumin oxidation in AD patients was dramatically increased comparing to healthy controls, while in plasma this increase was smaller. CSF albumin in AD patients was much more oxidized than in plasma, but this effect was not observed in healthy controls. These results suggest that albumin oxidation, especially in CSF, and its role in AD deserves further investigation.

Increased Foxo3a Nuclear Translocation and Activity is an Early Neuronal Response to βγ-Secretase-Mediated Processing of the Amyloid-β Protein Precursor: Utility of an AβPP-GAL4 Reporter Assay. - Law, Bernard M; Guest, Amy L; Pullen, Matthew W J; Perkinton, Michael S; Williams, Robert J (J Alzheimers Dis, 2018)
Sequential cleavage of the amyloid-β protein precursor (AβPP) by BACE1 (β-secretase) followed by theγ-secretase complex, is strongly implicated in Alzheimer's disease (AD) but the initial cellular responses to these cleavage events are not fully defined. β-secretase-mediated AβPP processing yields an extracellular domain (sAβPPβ) and a C-terminal fragment of AβPP of 99 amino acids (C99). Subsequent cleavage by γ-secretase produces amyloid-β (Aβ) and an AβPP intracellular domain (AICD). A cellular screen based on the generation of AICD from an AβPP-Gal4 fusion protein was adapted by introducing familial AD (FAD) mutations into the AβPP sequence and linking the assay to Gal4-UAS driven luciferase and GFP expression, to identify responses immediately downstream of AβPP processing in neurons with a focus on the transcription factor Foxo3a which has been implicated in neurodegeneration. The K670N/M671L, E682K, E693G, and V717I FAD mutations and the A673T protective mutation, were introduced into the AβPP sequence by site directed mutagenesis. When expressed in mouse cortical neurons, AβPP-Gal4-UAS driven luciferase and GFP expression was substantially reduced by γ-secretase inhibitors, lowered by β-secretase inhibitors, and enhanced by α-secretase inhibitors suggesting that AICD is a product of the βγ-secretase pathway. AβPP-Gal4-UAS driven GFP expression was exploited to identify individual neurons undergoing amyloidogenic AβPP processing, revealing increased nuclear localization of Foxo3a and enhanced Foxo3a-mediated transcription downstream of AICD production. Foxo3a translocation was not driven by AICD directly but correlated with reduced Akt phosphorylation. Collectively this suggests that βγ-secretase-mediated AβPP processing couples to Foxo3a which could be an early neuronal signaling response in AD.
Keywords: Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Disease Models, Animal; Forkhead Box Protein O3; Mice; Mutagenesis, Site-Directed; Mutation; Neurons; Phosphorylation; Protein Transport; Signal Transduction

Increasing Diagnostic Accuracy of Mild Cognitive Impairment due to Alzheimer's Disease by User-Independent, Web-Based Whole-Brain Volumetry. - Hedderich, Dennis M; Spiro, Judith E; Goldhardt, Oliver; Kaesmacher, Johannes; Wiestler, Benedikt; Yakushev, Igor; Zimmer, Claus; Boeckh-Behrens, Tobias; Grimmer, Timo (J Alzheimers Dis, 2018)
BACKGROUND: Volumetric quantification of structural MRI has been shown to increase the diagnostic accuracy of patients with mild cognitive impairment (MCI); however, its implementation in clinical routine is usually technically difficult and time-consuming. OBJECTIVE: The purpose of this study was to investigate whether volumetric information obtained from the free and easy-to-use online tool volBrain can improve correct identification of MCI patients with Alzheimer's disease (AD) compared to visual reading. METHODS: The study cohort consisted of 27 patients with MCI due to AD (AD positive) as determined by biomarker information and 26 cognitively normal controls (CN). Three blinded readers, 2 radiologists and 1 clinical dementia expert, assessed the patients' MRI regarding brain atrophy and probability of underlying AD two times, without and with supporting volumetric information from volBrain. To assess diagnostic accuracy of volBrain measures alone, a simple sum score based on basic volumetric measures was developed and tested. RESULTS: Correct patient classification by readers 1, 2, and 3 without a volumetric report was 73.6%, 77.4%, and 83.0%. With a volumetric report, correct classification increased for the radiological readers to 77.4% and 81.1%, respectively and decreased to 77.4% for reader 3. Usage of the volumetric report alone yielded the highest diagnostic accuracy of 84.9%. Diagnostic confidence increased significantly for radiological readers. CONCLUSION: Volumetric information from volBrain increases the radiologist's diagnostic performance and confidence in identifying MCI patients with AD. We propose that such tools may be implemented in the routine diagnostic work-up of patients with suspected AD.

INDEL Length and Haplotypes in the β-Synuclein Gene: A Key to Differentiate Dementia with Lewy Bodies? - Gámez-Valero, Ana; Canet-Pons, Julia; Urbizu, Aintzane; Anillo, Ana; Santos, Cristina; Ariza, Aurelio; Beyer, Katrin (J Alzheimers Dis, 2018)
Lewy body diseases (LBD) include Parkinson's disease (PD) and dementia with Lewy bodies (DLB) and together with Alzheimer's disease (AD) they show an important neuropathological and clinical overlap. The human alpha- and beta-synuclein genes (SNCA and SNCB) are key factors for the development of Lewy body diseases. Here, we aimed to analyze the genotype distribution of potentially functional SNPs in SNCA and SNCB, perform haplotype analysis for SNCB, and to identify functional insertion and deletion (INDEL) variations within the regulatory region of SNCB which might be responsible for the drastically diminished beta-synuclein levels reported for pure DLB. Thus, we genotyped brain samples from AD, DLB, PD, and healthy controls for two SNCA and four SNCB SNPs. We also analyzed INDEL variations upstream of SNCB, determined SNCB expression levels, and correlated INDEL lengths with expression levels. Applying Fisher's exact, chi-square, ANOVA tests, and the ΔΔCt method, we found disease-specific genotype distribution of SNCA and SNCB SNPs. Additionally, we identified three INDEL variations upstream of SNCB and showed that the INDEL allele lengths were associated with SNCB expression levels. INDEL alleles associated with low SNCB expression were accumulated in pure DLB. Finally, one major and four minor DLB specific SNCB haplotypes were identified with Haploview and Arlequin. In summary, our study showed that different SNCA and SNCB genotypes are associated with the development of either PD or DLB, and that the frequencies of genotypes associated with low SNCB expression are elevated in DLB.

Induction of Amyloid-β42 Production by Fipronil and Other Pyrazole Insecticides. - Cam, Morgane; Durieu, Emilie; Bodin, Marion; Manousopoulou, Antigoni; Koslowski, Svenja; Vasylieva, Natalia; Barnych, Bogdan; Hammock, Bruce D; Bohl, Bettina; Koch, Philipp; Omori, Chiori; Yamamoto, Kazuo; et al. (J Alzheimers Dis, 2018)
Generation of amyloid-β peptides (Aβs) by proteolytic cleavage of the amyloid-β protein precursor (AβPP), especially increased production of Aβ42/Aβ43 over Aβ40, and their aggregation as oligomers and plaques, represent a characteristic feature of Alzheimer's disease (AD). In familial AD (FAD), altered Aβ production originates from specific mutations of AβPP or presenilins 1/2 (PS1/PS2), the catalytic subunits of γ-secretase. In sporadic AD, the origin of altered production of Aβs remains unknown. We hypothesize that the 'human chemical exposome' contains products able to favor the production of Aβ42/Aβ43 over Aβ40 and shorter Aβs. To detect such products, we screened a library of 3500 + compounds in a cell-based assay for enhanced Aβ42/Aβ43 production. Nine pyrazole insecticides were found to induce a β- and γ-secretase-dependent, 3-10-fold increase in the production of extracellular Aβ42 in various cell lines and neurons differentiated from induced pluripotent stem cells derived from healthy and FAD patients. Immunoprecipitation/mass spectrometry analyses showed increased production of Aβs cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and shorter. Strongly supporting a direct effect on γ-secretase activity, pyrazoles shifted the cleavage pattern of another γ-secretase substrate, alcadeinα, and shifted the cleavage of AβPP by highly purified γ-secretase toward Aβ42/Aβ43. Focusing on fipronil, we showed that some of its metabolites, in particular the persistent fipronil sulfone, also favor the production of Aβ42/Aβ43 in both cell-based and cell-free systems. Fipronil administered orally to mice and rats is known to be metabolized rapidly, mostly to fipronil sulfone, which stably accumulates in adipose tissue and brain. In conclusion, several widely used pyrazole insecticides enhance the production of toxic, aggregation prone Aβ42/Aβ43 peptides, suggesting the possible existence of environmental "Alzheimerogens" which may contribute to the initiation and propagation of the amyloidogenic process in sporadic AD.

Influence of Butyrylcholinesterase in Progression of Mild Cognitive Impairment to Alzheimer's Disease. - Gabriel, António José; Almeida, Maria Rosário; Ribeiro, Maria Helena; Carneiro, Diogo; Valério, Daniela; Pinheiro, Ana Cristina; Pascoal, Rui; Santana, Isabel; Baldeiras, Ines (J Alzheimers Dis, 2018)
BACKGROUND: Several demographic and genetic prognostic factors of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) have been recognized so far. The most frequent polymorphism of butyrylcholinesterase (BuChE), the K-variant, has been proposed as a risk factor for AD, but data regarding its influence on early disease progression is still limited. OBJECTIVE: To investigate the influence of the BuChE-K variant in MCI progression to AD. METHODS: 96 MCI patients were included in the study and were genotyped for BuChE-K variant and Apolipoprotein E (ApoE). Cerebrospinal fluid (CSF) BuChE activity, as well as the levels of AD biomarkers amyloid-β 42 (Aβ42), total and hyperphosphorylated tau (t-tau and p-tau) were also determined. RESULTS: No significant differences were found in either BuChE-K variant or BuChE activity between MCI patients that progressed to AD (MCI-AD) and patients that remained stable during clinical follow-up (MCI-St). As expected, baseline CSF levels of Aβ42 were significantly lower and t-Tau, p-Tau, and ApoE ɛ4 allele frequency were significantly higher in MCI-AD patients. An association between the ApoE ɛ4 allele and the BuChE-K variant in MCI-AD, but not in MCI-St patients, was found with patients carrying both alleles presenting the highest incidence of progression and the lowest estimated time of progression to AD. CONCLUSION: Although BuChE-K alone does not seem to play a major role in progression to AD in MCI patients, a synergistic effect with the ApoE ɛ4 allele was found, highlighting the importance of assessing these combined genotypes for evaluating risk progression in MCI patients.
Keywords: Aged; Alzheimer Disease; Amyloid beta-Peptides; Apolipoproteins E; Biomarkers; Butyrylcholinesterase; Cognitive Dysfunction; Disease Progression; Female; Genetic Predisposition to Disease; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Risk Factors; tau Proteins

The In-Hospital Length of Stay after Hip Fracture in Octogenarians: Do Delirium and Dementia Shape a New Care Process? - Monacelli, Fiammetta; Pizzonia, Monica; Signori, Alessio; Nencioni, Alessio; Giannotti, Chiara; Minaglia, Cecilia; Granello di Casaleto, Tommaso; Podestà, Silvia; Santolini, Federico; Odetti, Patrizio (J Alzheimers Dis, 2018)
BACKGROUND: Hip fracture is a major health problem and a patient's biological age, comorbidity, and cognitive vulnerability have an impact on its related outcomes. Length of stay (LOS) for these highly vulnerable patients is rather long and the possible causes have not been clearly identified yet. OBJECTIVE: We aimed to assess the main clinical factors associated with protracted LOS, focusing on delirium with or without dementia in older age hip fractured patients. METHODS: 218 subjects (mean age 86.70±6.18 years), admitted to the Orthogeriatric Unit of the Ospedale Policlinico San Martino (Italy), were recruited. All patients received physical and comprehensive geriatric assessment. Days to surgery, days from surgery to rehabilitation, and LOS were recorded. In-hospital and three months' mortality were reported. RESULTS: Prevalent delirium at hospital admission was of 3.1%. 35% of patients developed incident delirium. 56.4% were affected by dementia of Alzheimer-type. In addition, 52% of patients developed delirium superimposed to dementia. Mean LOS was 13.5±4.99 days. Namely, delirium, time to surgery, and complication rate disproportionally affected LOS. The analysis with 3 months mortality, based on cognitive vulnerability profiles, showed how delirium mainly affect short-term mortality in patients with dementia. CONCLUSION: Our exploratory study originally pointed out the high incidence of delirium superimposed to dementia in orthogeriatric wards and how delirium turns to be a moderator of LOS. The results meet the need for additional research by virtue of a deeper understanding of the impact of delirium and dementia on orthogeriatric clinical management and outcomes.

Innovative Biomarkers for Alzheimer's Disease: Focus on the Hidden Disease Biomarkers. - Ghidoni, Roberta; Squitti, Rosanna; Siotto, Mariacristina; Benussi, Luisa (J Alzheimers Dis, 2018)
The criteria for the clinical diagnosis of AD include the analysis of biomarkers of the underlying brain disease pathology; a set of cerebrospinal fluid (CSF) tests, amyloid-β1-42 (Aβ42), total-tau (t-tau), and phosphorylated tau (p-tau), are available and their performance in a clinical setting has been assessed in several studies. Thus, in dementia research, great advances have been made in the discovery of putative biomarkers; however, disappointingly, few of them have been translated into clinically applicable assays. To find biomarkers able to reliably detect AD pathology already at prodromal stages and in blood is even more important. Recent technical breakthroughs have provided ultrasensitive methods that allow the detection of brain-specific proteins in blood. In the present review, we will focus on the usefulness of ultrasensitive technologies for biomarker discovery and trace elements detection; moreover, we will review studies on circulating nano-compartments, a promising novel source of material for molecular diagnostics.

Interactions between Atrial Fibrillation, Cardiovascular Risk Factors, and ApoE Genotype in Promoting Cognitive Decline in Patients with Alzheimer's Disease: A Prospective Cohort Study. - Falsetti, Lorenzo; Viticchi, Giovanna; Buratti, Laura; Grigioni, Francesco; Capucci, Alessandro; Silvestrini, Mauro (J Alzheimers Dis, 2018)
BACKGROUND: An association between non-valvular atrial fibrillation (NVAF) and cognitive impairment has been hypothesized. OBJECTIVE: We sought to evaluate whether and how permanent NVAF (pNVAF) is associated with progression of cognitive impairment in patients with Alzheimer's disease (AD) in the presence of vascular or genetic risk factors. METHODS: 310 consecutive patients affected by mild-moderate AD were included and followed for a 24-month period. At the end of the follow-up, based on the results of the neuropsychological evaluation patients were classified as stable or deteriorated to severe AD. Clinical history, therapy, time in therapeutic range for anticoagulation, Framingham cardiovascular risk profile (FCRP), CHA2DS2-VASc score, Mini-Mental State Examination (MMSE), ApoE genotype, brain CT-scan, carotid ultrasound, and ECG were collected. Binary logistic and path analysis were adopted to assess relationships between pNVAF, ApoE, and cognitive outcome. RESULTS: Despite anticoagulant therapy, pNVAF was associated with lower entry MMSE, higher mean intima-media thickness (mIMT) and higher FCRP. Among patients carrying ApoE ɛ4 allele and affected by pNVAF, the lowest MMSE (14.90±7.62) and the highest mIMT (1.16±0.17 mm) and FCRP (26.24±3.96) values were detected. In this group, the risk of cognitive deterioration reached the highest probability. pNVAF was associated with an increased cognitive deterioration in subjects with high FCRP, CHA2DS2-VASc, or mIMT. CONCLUSIONS: pNVAF seems to identify AD patients with a significant atherosclerotic burden and reduced cognitive performances. The interaction between pNVAF and ApoE ɛ4 genotype, especially with aggregated risk factors and an advanced stage of vascular damage is associated with higher risk of fast cognitive deterioration.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Apolipoprotein E4; Atherosclerosis; Atrial Fibrillation; Carotid Intima-Media Thickness; Cognitive Dysfunction; Disease Progression; Female; Humans; Logistic Models; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Prospective Studies; Risk Factors; Tomography, X-Ray Computed

Intracranial Transplantation of Pancreatic Islets Attenuates Cognitive and Peripheral Metabolic Dysfunctions in a Rat Model of Sporadic Alzheimer's Disease. - Bloch, Konstantin; Gil-Ad, Irit; Vanichkin, Alexey; Hornfeld, Shay Henry; Taler, Michal; Dar, Shira; Azarov, Dmitry; Vardi, Pnina; Weizman, Abraham (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) is often associated with brain insulin resistance and peripheral metabolic dysfunctions. Recently, we developed a model of sporadic AD associated with obesity-related peripheral metabolic abnormalities in Lewis rats using intracerebroventricular administration of streptozotocin (icv-STZ). OBJECTIVE: We aimed to assess the effect of intracranially grafted pancreatic islets on cognitive and peripheral metabolic dysfunctions in the icv-STZ Lewis rats. METHODS: AD-like dementia associated with obesity was induced in inbred Lewis rats using a single icv-STZ. Two months after icv-STZ, syngeneic islets (100 islets per recipient) were implanted in the cranial subarachnoid cavity of icv-STZ rats. Morris water maze and marble burying tests were used for studying cognitive and behavioral functions. Central and peripheral metabolic alterations were assessed by histological and biochemical assays. RESULTS: The icv-STZ induced increases in food intake, body weight, and blood levels of insulin and leptin without alteration of glucose homeostasis. Grafted islets reduced body weight gain, food consumption, peripheral insulin resistance, and hyperleptinemia. Biochemical and histological analysis of the brain revealed viable grafted islets expressing insulin and glucagon. The grafted islets did not affect expression of brain insulin receptors and peripheral glucose homeostasis. Two months after islet transplantation, cognitive and behavioral functioning in transplanted rats were significantly better than the sham-operated icv-STZ rats. No significant differences in the locomotor activity between transplanted and non-transplanted icv-STZ rats were found. CONCLUSIONS: Intracranial islet transplantation attenuates cognitive decline and peripheral metabolic dysfunctions providing a novel therapeutic approach for sporadic AD associated with peripheral metabolic dysfunctions.

Involvement of the Cingulate Cortex in Anosognosia: A Multimodal Neuroimaging Study in Alzheimer's Disease Patients. - Guerrier, Laura; Le Men, Johanne; Gane, Anaıs; Planton, Mélanie; Salabert, Anne-Sophie; Payoux, Pierre; Dumas, Hervé; Bonneville, Fabrice; Péran, Patrice; Pariente, Jérémie (J Alzheimers Dis, 2018)
BACKGROUND: Anosognosia is a frequent symptom of Alzheimer's disease (AD), but its neural substrates remain in question. OBJECTIVE: In this study, we combined neuroimaging with a neuropsychological evaluation to assess neural substrates of anosognosia. METHODS: We prospectively recruited 30 patients with probable early-stage AD and matched healthy controls. Participants underwent MRI, FDG-PET, and a neuropsychological evaluation that includes an assessment of anosognosia. In the AD group, correlations between the anosognosia score, neuroimaging modalities, and neuropsychological performance were performed. RESULTS: Atrophy and hypometabolism were correlated with the anosognosia score in the left dorsal anterior cingulate cortex. The anosognosia score was also correlated with atrophy of the cerebellar vermis, the left postcentral gyrus, and the right fusiform gyrus. No relation was found between anosognosia and the neuropsychological assessment. DISCUSSION: Structural and metabolic alteration in the dorsal anterior cingulate cortex seems to be associated with a diminution of awareness in patients with early-stage AD.

Kainic Acid Impairs the Memory Behavior of APP23 Mice by Increasing Brain Amyloid Load through a Tumor Necrosis Factor-α-Dependent Mechanism. - Ruan, Yang; Guo, Shi-Jie; Wang, Xu; Dong, Dong; Shen, Dong-Hui; Zhu, Jie; Zheng, Xiang-Yu (J Alzheimers Dis, 2018)
Kainic acid (KA) was recently identified as an epileptogenic and neuroexcitotoxic agent that is responsible for inducing learning and memory deficits in various neurodegenerative diseases, such as Alzheimer's disease (AD). However, the mechanism by which KA acts upon AD remains unclear. To this end, we presently investigated the roles of KA in processing amyloid-β protein precursor (AβPP) and amyloid-β protein (Aβ) loads during the course of AD development and progression. Specifically, KA treatment clearly caused the upregulation of tumor necrosis factor α (TNF-α) via activation of the PI3-K/AKT, ERK1/2, and p65 pathways in glial cells. TNF-α secreted from glial cells was then found to be responsible for stimulating the expression of BACE-1 and PS1/2, which resulted in the production and deposition of Aβ in neurons. Finally, the accumulation and aggregation of Aβ lead to the cognitive decline of APP23 mice. These results indicate that KA accelerates the progression of AD by inducing the crosstalk between glial cells and neurons.

Leisure-Time Physical Activity and the Risk of Incident Dementia: The Mayo Clinic Study of Aging. - Krell-Roesch, Janina; Feder, Nathanael T; Roberts, Rosebud O; Mielke, Michelle M; Christianson, Teresa J; Knopman, David S; Petersen, Ronald C; Geda, Yonas E (J Alzheimers Dis, 2018)
We conducted a prospective cohort study derived from the population-based Mayo Clinic Study of Aging. We investigated if leisure-time physical activity among individuals with mild cognitive impairment (MCI) was associated with a decreased risk of developing dementia. 280 persons aged≥70 years (median 81 years, 165 males) with MCI and available data from neurologic evaluation, neuropsychological testing, and questionnaire-based physical activity assessment, were followed for a median of 3 years to the outcomes of incident dementia or censoring variables. We conducted Cox proportional hazards regression analyses with age as a time scale and adjusted for sex, education, medical comorbidity, depression, and APOE ɛ4 status. Moderate intensity midlife physical activity among MCI participants was significantly associated with a decreased risk of incident dementia (HR = 0.64; 95% CI, 0.41-0.98). There was a non-significant trend for a decreased risk of dementia for light and vigorous intensity midlife physical activity, as well as light and moderate intensity late-life physical activity. In conclusion, we observed that physical activity may be associated with a reduced risk of dementia among individuals with MCI. Furthermore, intensity and timing of physical activity may be important factors when investigating this association.

Lentivirus-Mediated HDAC3 Inhibition Attenuates Oxidative Stress in APPswe/PS1dE9 Mice. - Yu, Linjie; Liu, Yi; Jin, Yuexinzi; Cao, Xiang; Chen, Jian; Jin, Jiali; Gu, Yue; Bao, Xinyu; Ren, Zhuoying; Xu, Yun; Zhu, Xiaolei (J Alzheimers Dis, 2018)
Amyloid-β (Aβ) induces a burst of oxidative stress and plays a critical role in the pathogenesis of Alzheimer's disease (AD). Our previous results have shown that histone deacetylase 3 (HDAC3) inhibition ameliorates spatial memory deficits and decreases the Aβ burden in the brains of 9-month-old APPswe/PS1dE9 (APP/PS1) mice. In this study, we investigated the role of HDAC3 inhibition in oxidative stress in vivo and in vitro models of AD. HDAC3 was detected mainly in the neurons, and HDAC3 inhibition significantly decreased reactive oxygen species generation and improved primary cortical neuron viability. In addition, HDAC3 inhibition attenuated spatial memory dysfunction in 6-month-old APP/PS1 mice, and decreased the apoptotic rate in the hippocampi as demonstrated by TUNEL staining. HDAC3 inhibition also reduced markers of lipid peroxidation, protein oxidation, and DNA/RNA oxidation in the hippocampi of APP/PS1 mice. Moreover, HDAC3 inhibition inactivated the c-Abl/MST1/YAP signaling pathway in the hippocampi of APP/PS1 mice. In conclusion, our data show that HDAC3 inhibition can attenuate spatial memory deficits and inhibit oxidative stress in APP/PS1 mice; these results indicate a potential strategy for AD treatment.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Hippocampus; Histone Deacetylases; Lentivirus; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Oxidative Stress; Plaque, Amyloid; Primary Cell Culture; Reactive Oxygen Species; Spatial Memory; tau Proteins

The Level of Plasma Amyloid-β40 Is Correlated with Peripheral Transport Proteins in Cognitively Normal Adults: A Population-Based Cross-Sectional Study. - Gao, Ling; Jiang, Yu; Wei, Shan; Shang, Suhang; Li, Pei; Chen, Chen; Dang, Liangjun; Wang, Jin; Huo, Kang; Deng, Meiying; Wang, Jingyi; Zhang, Rong; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Transport proteins, soluble low-density lipoprotein receptor-related protein-1 (sLRP1), and soluble receptor of advanced glycation end products (sRAGE), play an important role in the clearance of plasma amyloid-β (Aβ). However, their relationship is not clear. OBJECTIVE: The aim was to explore the relationship between plasma levels of sLRP1, sRAGE, and Aβ in a cross-sectional study. METHODS: A total of 1,185 cognitively normal participants (age above 40) from a village in the suburbs of Xi'an, China were enrolled from October 8, 2014 to March 30, 2015. Plasma Aβ40, Aβ42, sLRP1, and sRAGE were tested using a commercial ELISA. Apolipoprotein E (APOE) genotyping was conducted using PCR and sequencing. The relationship between plasma levels of sLRP1, sRAGE, and Aβ was analyzed using Pearson's correlation analysis and multiple linear regression. RESULTS: In the total population, Log sLRP1 and Log sRAGE were positively correlated with plasma Aβ40 (r= 0.103, p < 0.001; r= 0.064, p = 0.027, respectively), but neither were associated with plasma Aβ42. After multivariable adjustment in the regression model, Log sLRP1 and Log sRAGE were still positively related with plasma Aβ40 (β= 2.969, p < 0.001; β= 1.936, p = 0.017, respectively) but not Aβ42. Furthermore, the positive correlations between transport proteins and plasma Aβ40 remained significant only in APOEɛ4 non-carriers after Pearson's analysis and multiple regression analysis after stratification by gene status. CONCLUSION: The concentrations of plasma sLRP1 and sRAGE had a significant impact on the level of plasma Aβ40 in cognitively normal adults, especially in APOEɛ4 non-carriers. However, the mechanism by which the transport proteins are involved in peripheral Aβ clearance and the relationship between transporters and amyloid burden in the brain needs further validation.

A Link between Subjective Perceptions of Memory and Physical Function: Implications for Subjective Cognitive Decline. - Cosentino, Stephanie; Devanand, Davangere; Gurland, Barry (J Alzheimers Dis, 2018)
Subjective impairment in memory is a frequently defining feature of subjective cognitive decline (SCD), a state hypothesized to precede objectively apparent cognitive symptoms of Alzheimer's disease (AD) and to hold promise as a non-invasive, inexpensive, preclinical indicator of AD. However, a full model of the factors that contribute to subjective memory (SM), and therefore to SCD, has yet to be articulated. While SM impairment is widely known to be associated with negative affect, the extent to which SM functioning may also reflect other factors, particularly subjective beliefs or perceptions about one's health, is not known. To examine the extent to which SM is associated with subjective perceptions of health more broadly, the current study investigated the link between SM and subjective physical functioning (independent of depressive affect, and objective cognitive and physical function) in an ethnically diverse sample of 471 older adults enrolled in the population-based Northern Manhattan Aging Project. 199 (42%) participants endorsed no difficulty on a 5-point SM index while 272 (58%) endorsed some degree of difficulty. As hypothesized, SM correlated with both depression and subjective physical function, but not with age, education, global cognition, or objective physical function. When objective and subjective physical function were entered in two separate, adjusted linear regressions predicting SM, only subjective physical function and depressive affect independently predicted SM. Subjective perceptions of memory appear to reflect individuals' broader health perceptions in part. Articulating the various correlates of SM will improve identification of SCD specific to preclinical AD.
Keywords: Aged; Aged, 80 and over; Cognitive Dysfunction; Executive Function; Female; Humans; Linear Models; Male; Memory; Neuropsychological Tests; New York City; Perception

Longitudinal Neuroimaging Analysis in Mild-Moderate Alzheimer's Disease Patients Treated with Plasma Exchange with 5% Human Albumin. - Cuberas-Borrós, Gemma; Roca, Isabel; Boada, Merce; Tárraga, Lluís; Hernandez, Isabel; Buendia, Mar; Rubio, Lourdes; Torres, Gustavo; Bittini, Ángel; Guzmán-de-Villoria, Juan A; Pujadas, Francesc; Torres, Mireia; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Recently, modifications of Aβ1-42 levels in CSF and plasma associated with improvement in memory and language functions have been observed in patients with mild-moderate Alzheimer's disease (AD) treated with plasma exchange (PE) with albumin replacement. OBJECTIVE: To detect structural and functional brain changes in PE-treated AD patients as part of a Phase II clinical trial. METHODS: Patients received between 3 and 18 PE with albumin (Albutein® 5%, Grifols) or sham-PE (controls) for 21 weeks (divided in one intensive and two maintenance periods) followed by 6-month follow-up. Brain perfusion assessed by SPECT scans using an automated software (NeuroGam®) and brain structural changes assessed by MRI were performed at weeks 0 (baseline), 21, and 44 (with additional SPECT at weeks 9 and 33). Statistical parametric mapping (voxel-based analysis, SPM) and Z-scores calculations were applied to investigate changes to baseline. RESULTS: 42 patients were recruited (39 evaluable; 37 analyzed: 18 PE-treated; 19 controls). There was a trend toward decreasing hippocampi and total intracranial volume for both patient groups during the study (p < 0.05). After six months, PE-treated patients had less cerebral perfusion loss than controls in frontal, temporal, and parietal areas, and perfusion stabilization in Brodmann area BA38-R during the PE-treatment period (p < 0.05). SPM analysis showed stabilization or absence of progression of perfusion loss in PE-treated patients until week 21, not observed in controls. CONCLUSIONS: Mild-moderate AD patients showed decreased brain volume and impairment of brain perfusion as expected for the progression of the disease. PE-treatment with albumin replacement favored the stabilization of perfusion.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Neuroimaging; Plasma Exchange; Serum Albumin, Human; Time Factors; Tomography, Emission-Computed, Single-Photon; Treatment Outcome

A Longitudinal Study of Total and Phosphorylated α-Synuclein with Other Biomarkers in Cerebrospinal Fluid of Alzheimer's Disease and Mild Cognitive Impairment. - Wang, Hua; Stewart, Tessandra; Toledo, Jon B; Ginghina, Carmen; Tang, Lu; Atik, Anzari; Aro, Patrick; Shaw, Leslie M; Trojanowski, John Q; Galasko, Douglas R; Edland, Steven; Jensen, Poul H; et al. (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) features a dynamic sequence of amyloid deposition, neurodegeneration, and cognitive impairment. A significant fraction of AD brains also displays Lewy body pathology, suggesting that addition of classically Parkinson's disease-related proteins to the AD biomarker panel may be of value. To determine whether addition of cerebrospinal fluid (CSF) total α-synuclein and its form phosphorylated at S129 (pS129) to the AD biomarker panel [Amyloid-β1-42 (Aβ42), tau, and phosphorylated tau (p-tau181)] improves its performance, we examined CSF samples collected longitudinally up to 7 years as part of the Alzheimer's Disease Neuroimaging Initiative. From 87 AD, 177 mild cognitive impairment (MCI), and 104 age-matched healthy controls, 792 baseline and longitudinal CSF samples were tested for total α-synuclein, pS129, Aβ42, tau, and p-tau181. pS129, but not total α-synuclein, was weakly associated with diagnosis at baseline when t-tau/Aβ42 was included in the statistical model (β= 0.0026, p = 0.041, 95% CI [(0.0001)-(0.005)]). CSF α-synuclein predicted Alzheimer's Disease Assessment Scale-Cognitive (β= -0.59, p = 0.0015, 95% CI [(-0.96)-(-0.23)]), memory (β= 0.4, p = 0.00025, 95% CI [(0.16)-(0.59)]), and executive (0.62,<0.0001, 95% CI [(0.31)-(0.93)]) function composite scores, and progression from MCI to AD (β= 0.019, p = 0.0011, 95% CI [(0.002)-(0.20)]). pS129 was associated with executive function (β= -2.55, p = 0.0085, 95% CI [(-4.45)-(-0.66)]). Lower values in the mismatch between α-synuclein and p-tau181 predicted faster cognitive decline (β= 0.64, p = 0.0012, 95% CI [(0.48)-(0.84)]). Longitudinal biomarker changes did not differ between groups, and may not reflect AD progression. The α-synuclein-p-tau181-Mismatch could better predict longitudinal cognitive changes than classical AD markers alone, and its pathological correlates should be investigated further.
Keywords: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Biomarkers; Cognitive Dysfunction; Cross-Sectional Studies; Disease Progression; Executive Function; Female; Humans; Linear Models; Longitudinal Studies; Male; Memory Disorders; Multivariate Analysis; Neuropsychological Tests; Phosphorylation; tau Proteins

Long-Term Severe Mental Disorders Preceding Behavioral Variant Frontotemporal Dementia: Frequency and Clinical Correlates in an Outpatient Sample. - Gambogi, Leandro Boson; Guimarães, Henrique Cerqueira; de Souza, Leonardo Cruz; Caramelli, Paulo (J Alzheimers Dis, 2018)
BACKGROUND: The behavioral variant frontotemporal dementia (bvFTD) shares some clinical features with severe mental disorders, such as bipolar affective disorder (BAD), schizophrenia (SCZ), and schizoaffective disorder (SZA), and at least for a small subgroup of patients, these conditions may share similar pathological genetic mutations. OBJECTIVES: To investigate the frequency of a past medical history satisfying diagnostic criteria for BAD, SCZ, and SZA in a bvFTD outpatient sample, and to compare the clinical profile of patients with and without a positive history. METHODS: Cross-sectional study in which participants were consecutively selected after receiving a diagnosis of probable bvFTD and had a caregiver interviewed with SCID-I. The sample was categorized into two groups: with (bvFTD+) or without (bvFTD-) prior medical history satisfying diagnostic criteria for BAD/SCZ/SZA. Subjects went through cognitive, functional, and neuropsychiatric evaluations. RESULTS: Overall, 46 bvFTD patients were included; bvFTD+ patients accounted for 36.9% of the sample. The main nosology fulfilling criteria was BAD (76.5%). The groups differed in Neuropsychiatric Inventory scores (p = 0.01), use of antipsychotics (p = 0.01), family history of psychosis (p = 0.01), presence of primitive reflexes (p = 0.04), Frontal Assessment Battery performance (p = 0.01), Ekman's facial emotion recognition test (p = 0.03), frequency of apathy (p = 0.03), and stereotyped behavior (p = 0.01). All these parameters were more frequent/worse in the bvFTD+ group. CONCLUSIONS: A prior medical history compatible with BAD/SCZ/SZA was found in more than 1/3 of this sample of bvFTD patients and was associated with subtle distinctive clinical features.

Low Accuracy of Brief Cognitive Tests in Tracking Longitudinal Cognitive Decline in an Asian Elderly Cohort. - Phua, April Ka Sin; Hiu, Shaun Kuan Wei; Goh, Win King; Ikram, Mohammad Kamran; Venketasubramanian, Narayanaswamy; Tan, Boon Yeow; Chen, Christopher Li-Hsian; Xu, Xin (J Alzheimers Dis, 2018)
BACKGROUND: Researchers have questioned the utility of brief cognitive tests such as the Mini-Mental Status Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) in serial administration and suggested that brief cognitive tests may not accurately track changes in Global Cognition. OBJECTIVE: To examine the accuracy of longitudinal changes on brief cognitive tests in reflecting progression in Global Cognition measured using comprehensive neuropsychological assessments. METHODS: Two hundred and seven participants were assessed with the MMSE, MoCA, and a validated comprehensive neuropsychological battery. Global z-scores on the battery were derived and used to assess overall and significant (≥0.5 standard deviation) decline on Global Cognition. Different patterns of decline on MMSE/MoCA were classified. Accuracy was examined using receiver operating characteristic curve, and sensitivity, specificity, positive (PPV) and negative (NPV) predictive values were reported. RESULTS: The overall ability of MMSE/MoCA change scores to discriminate participants who did and did not decline on Global Cognition was fair-to-moderate (AUC [95% CI] = 0.71 [0.64-0.78] & 0.73 [0.66-0.80] for overall decline; 0.78 [0.70-0.85] & 0.80 [0.73-0.86] for significant decline, respectively). Changes in MMSE/MoCA had low accuracy in identifying significant Global Cognitive Decline (PPV = 0.41 & 0.46, respectively) but high accuracy in ruling out significant decline and identifying cognitively stable participants (NPV = 0.89 & 0.88, respectively). CONCLUSION: There is limited utility in brief cognitive tests for tracking cognitive decline. Instead, they should be used for identifying participants who remain cognitively stable on follow up. These results accentuate the importance of acknowledging the limitations of brief cognitive tests when assessing cognitive change.

Low Cerebrospinal Fluid Aβ42 and Aβ40 are Related to White Matter Lesions in Cognitively Normal Elderly. - Skoog, Ingmar; Kern, Silke; Zetterberg, Henrik; Östling, Svante; Börjesson-Hanson, Anne; Guo, Xinxin; Blennow, Kaj (J Alzheimers Dis, 2018)
BACKGROUND: Low cerebrospinal fluid (CSF) levels of Aβ42 may be the earliest manifestation of Alzheimer's disease (AD). Knowledge on how CSF Aβ interacts with different brain pathologies early in the disease process is limited. We examined how CSF Aβ markers relate to brain atrophy and white matter lesions (WMLs) in octogenarians with and without dementia to explore the earliest pathogenetic pathways of AD in the oldest old. OBJECTIVE: To study CSF amyloid biomarkers in relation to brain atrophy and WMLs in 85-year-olds with and without dementia. METHODS: 53 octogenarians took part in neuropsychiatric examinations and underwent both a lumbar puncture and a brain CT scan. CSF levels of Aβ42 and Aβ40 were examined in relation to cerebral atrophy and WMLs. Dementia was diagnosed. RESULTS: In 85-year-olds without dementia, lower levels of both CSF Aβ42 and CSF Aβ40 were associated with WMLs. CSF Aβ42 also correlated with measures of central atrophy, but not with cortical atrophy. In participants with dementia, lower CSF levels of Aβ42 were related to frontal, temporal, and parietal cortical atrophy but not to WMLs. CONCLUSIONS: Our findings may suggest that there is an interrelationship between Aβ and subcortical WMLs in older persons without dementia. After onset of dementia, low CSF Aβ42, probably representing amyloid deposition in plaques, is associated with cortical atrophy. WMLs may be an earlier manifestation of Aβ deposition than cortical degeneration.

Mechanism of Tau Hyperphosphorylation Involving Lysosomal Enzyme Asparagine Endopeptidase in a Mouse Model of Brain Ischemia. - Basurto-Islas, Gustavo; Gu, Jin-Hua; Tung, Yunn Chyn; Liu, Fei; Iqbal, Khalid (J Alzheimers Dis, 2018)
Dementias including Alzheimer's disease (AD) are multifactorial disorders that involve several different etiopathogenic mechanisms. Cerebral ischemia has been suspected in the altered regulation of protein kinases and phosphatases that leads to hyperphosphorylation of tau and further neurofibrillary pathology, a key hallmark of AD and related neurodegenerative diseases. However, the deregulation of these enzymes and their relationship with ischemia and AD remain unclear. Previously, we reported a mechanism by which the lysosomal enzyme asparagine endopeptidase (AEP) is associated with brain acidosis and AD. In this study, we subjected mice to middle cerebral artery occlusion and found that compared with wild type mice, the ischemia-induced brain injury and motor deficit in AEP-knockout mice are reduced, probably because ischemia activates AEP. AEP cleaves inhibitor 2 of protein phosphatase 2A (I2PP2A), which translocates from the neuronal nucleus to the cytoplasm and produces hyperphosphorylation of tau through inhibition of PP2A. These findings suggest a possible mechanism of tau pathology associated with ischemia.

Mediterranean Diet, Its Components, and Amyloid Imaging Biomarkers. - Vassilaki, Maria; Aakre, Jeremiah A; Syrjanen, Jeremy A; Mielke, Michelle M; Geda, Yonas E; Kremers, Walter K; Machulda, Mary M; Alhurani, Rabe E; Staubo, Sara C; Knopman, David S; Petersen, Ronald C; Lowe, Val J; et al. (J Alzheimers Dis, 2018)
BACKGROUND: There is accumulating evidence suggesting that diet may play a role in preventing or delaying cognitive decline and dementia, but the underlying biological mechanisms are not well understood. OBJECTIVES: To examine the cross-sectional associations of the Mediterranean diet (MeDi) and its components with 11C-PiB-PET scan measures of amyloid-β (Aβ) deposition. METHODS: The study consisted of 278 Mayo Clinic Study of Aging participants 70+ years old, who were cognitively unimpaired (CU) at the time of completion of the Food Frequency Questionnaire (FFQ) and when they underwent PET imaging. Adherence to the MeDi was assessed by computing the MeDi score for each participant. All scans were performed after the FFQ completion; median [IQR] time between FFQ and Aβ PET was 3.5 (1.4) years. Z-scores were created for component, macro- and micronutrients measured. Linear and logistic regression models were adjusted for age, sex, education, apolipoprotein E (APOE) ɛ4 allele carrier status, time interval between the FFQ completion and PET scan, and total energy intake. RESULTS: Participants' median age at FFQ was 77.7 years (55.8% men; 26.6% with an APOE ɛ4 allele). Higher MeDi score (linear regression slope (beta):-0.035, p = 0.012; per standard deviation increase), vegetable intake (beta:-0.043, p = 0.002), intake of vitamin A (beta:-0.041, p = 0.003) or β-carotene (beta: -0.039, p = 0.005) from food sources and moderate alcohol consumption (beta: -0.074, p = 0.03) were associated with lower 11C-PiB standardized uptake value ratio. CONCLUSION: Findings are consistent with previous studies suggesting that higher adherence to a MeDi pattern and higher vegetable consumption are associated with better neuroimaging biomarker profile. Prospective studies are needed to validate current findings.

Memantine for the Treatment of Dementia: A Review on its Current and Future Applications. - Folch, Jaume; Busquets, Oriol; Ettcheto, Miren; Sánchez-López, Elena; Castro-Torres, Ruben Dario; Verdaguer, Ester; Garcia, Maria Luisa; Olloquequi, Jordi; Casadesus, Gemma; Beas-Zarate, Carlos; Pelegri, Carme; Vilaplana, Jordi; et al. (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence in the brain of extracellular amyloid-β protein (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. The N-Methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptor, are essential for processes like learning and memory. An excessive activation of NMDARs has been associated with neuronal loss. The discovery of extrasynaptic NMDARs provided a rational and physiological explanation between physiological and excitotoxic actions of glutamate. Memantine (MEM), an antagonist of extrasynaptic NMDAR, is currently used for the treatment of AD jointly with acetylcholinesterase inhibitors. It has been demonstrated that MEM preferentially prevents the excessive continuous extrasynaptic NMDAR disease activation and therefore prevents neuronal cell death induced by excitotoxicity without disrupting physiological synaptic activity. The problem is that MEM has shown no clear positive effects in clinical applications while, in preclinical stages, had very promising results. The data in preclinical studies suggests that MEM has a positive impact on improving AD brain neuropathology, as well as in preventing Aβ production, aggregation, or downstream neurotoxic consequences, in part through the blockade of extrasynaptic NMDAR. Thus, the focus of this review is primarily to discuss the efficacy of MEM in preclinical models of AD, consider possible combinations of this drug with others, and then evaluate possible reasons for its lack of efficacy in clinical trials. Finally, applications in other pathologies are also considered.

Meta-Analysis of Personality Traits in Alzheimer's Disease: A Comparison with Healthy Subjects. - D'Iorio, Alfonsina; Garramone, Federica; Piscopo, Fausta; Baiano, Chiara; Raimo, Simona; Santangelo, Gabriella (J Alzheimers Dis, 2018)
BACKGROUND: The role of specific personality traits as factor risks of Alzheimer's disease (AD) has been consistently found, whereas personality traits specifically related to AD (after the diagnosis) have not been outlined yet. OBJECTIVE: A meta-analysis of published studies was performed to determine whether AD patients have a distinctive personality trait profile compared to healthy subjects (HC), similar to or different from a premorbid personality profile consistently reported in previous studies. METHODS: A systematic literature search was performed using PsycInfo (PROQUEST), PubMed, and Scopus. The meta-analysis pooled results from primary studies using Hedges' g unbiased approach. RESULTS: The meta-analysis included 10 primary studies and revealed that, when the personality was evaluated by informant-rated measures, AD patients had significantly higher levels of Neuroticism, lower levels of Openness, Agreeableness, Conscientiousness, and Extraversion than HCs. When the personality was evaluated by self-rated measures, the results obtained from informants were confirmed for Neuroticism, Openness, and Extraversion but not for Agreeableness and Conscientiousness where AD patients and HCs achieved similar scores. CONCLUSIONS: The meta-analysis revealed that high Neuroticism and low Openness and Extraversion are distinctive personality traits significantly associated with a diagnosis of AD when evaluated both self-rated and informant-rated measures. This personality trait profile is similar to premorbid one, which contributes to development of AD over time. Therefore, our findings indirectly support the idea of specific premorbid personality traits as harbingers of AD.
Keywords: Alzheimer Disease; Case-Control Studies; Humans; Personality; Personality Inventory

Metabolic Syndrome and Amyloid Accumulation in the Aging Brain. - Gomez, Gabriela; Beason-Held, Lori L; Bilgel, Murat; An, Yang; Wong, Dean; Studenski, Stephanie; Ferrucci, Luigi; Resnick, Susan M (J Alzheimers Dis, 2018)
BACKGROUND: Recent studies show links between metabolic syndrome and Alzheimer's disease (AD) neuropathology. Understanding the link between vascular-related health conditions and dementia will help target at risk populations and inform clinical strategies for early detection and prevention of AD. OBJECTIVE: To determine whether metabolic syndrome is associated with global cerebral amyloid-β (Aβ) positivity and longitudinal Aβ accumulation. METHODS: Prospective study of 165 participants who underwent (11)C-Pittsburgh compound B (PiB) PET neuroimaging to measure Aβ, from June 2005 to May 2016. Metabolic syndrome was defined using the revised Third Adults Treatment Panel of the National Cholesterol Education Program criteria. Participants were classified as PiB+/- . Linear mixed effects models assessed the relationships between baseline metabolic syndrome and PiB status and regional Aβ change over time. RESULTS: A total of 165 cognitively normal participants of the Baltimore Longitudinal Study of Aging (BLSA) Neuroimaging substudy, aged 55-92 years (mean baseline age = 76.4 years, 85 participants were male), received an average of 2.5 PET-PiB scans over an average interval of 2.6 (3.08 SD) years between first and last visits. Metabolic syndrome was not associated with baseline PiB positivity or concurrent regional Aβ. Metabolic syndrome was associated with increased rates of Aβ accumulation in superior parietal and precuneus regions over time in the PiB+ group. Elevated fasting glucose and blood pressure showed individual associations with accelerated Aβ accumulation. CONCLUSION: Metabolic syndrome was associated with accelerated Aβ accumulation in PiB+ individuals and may be an important factor in the progression of AD pathology.

Microglia CREB-Phosphorylation Mediates Amyloid-β-Induced Neuronal Toxicity. - Gao, Yuan; Liu, En-Jie; Wang, Wei-Jin; Wang, Ya-Li; Li, Xiao-Guang; Wang, Xin; Li, Shi-Hong; Zhang, Shu-Juan; Li, Meng-Zhu; Zhou, Qiu-Zhi; Long, Xiao-Bing; Zhang, Hua-Qiu; et al. (J Alzheimers Dis, 2018)
Extracellular accumulation of amyloid-β (Aβ) forming senile plaques is one of the hallmark pathologies in Alzheimer's disease (AD), while the mechanisms underlying the neuronal toxic effect of Aβ are not fully understood. Here, we found that intracerebroventricular infusion of the aged Aβ42 in mice only induces memory deficit at 24 h but not at 7 days. Interestingly, a remarkably increased CREB (cAMP response element-binding protein) Ser133-phosphorylation (pS133-CREB) with microglial activation was detected at 24 h but not at 7 days after Aβ infusion. Aβ treatment for 24 h increased pS133-CREB level in microglia of the hippocampal non-granular cell layers with remarkably decreased pS133-CREB immunoreactivity in neurons of the hippocampal granular cell layers, including CA1, CA3, and DG subsets. Inhibition of microglia activation by minocycline or CREB phosphorylation by H89, an inhibitor of protein kinase A (PKA), abolished Aβ-induced microglia CREB hyperphosphorylation with restoration of neuronal function and attenuation of inflammatory response, i.e., reduced levels of interleukin-6 (IL6) and pCREB binding of matrix metalloproteinase-9 (MMP9) DNA. Finally, treatment of the primary hippocampal neurons with Aβ-potentiated microglia media decreased neuronal GluN1 and GluA2 levels, while simultaneous inhibition of PKA restored the levels. These novel findings reveal that intracerebroventricular infusion of Aβ only induces transient memory deficit in mice and the molecular mechanisms involve a stimulated microglial CREB phosphorylation.

Minor Hallucinations in Alzheimer's Disease. - Ruiz, Maria; Arias, Alfonso; Sánchez-Llanos, Ernesto; Gil, Maria Pilar; López-Ortega, Ricard; Dakterzada, Faridé; Purroy, Francisco; Piñol-Ripoll, Gerard (J Alzheimers Dis, 2018)
BACKGROUND: Hallucinations may have a broad spectrum and include so-called minor hallucinations (MHs). MHs include passage hallucinations (PHs), visual illusions, and presence hallucinations (PrHs). OBJECTIVE: To determine the prevalence and characteristics of MHs in Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) patients, and to describe their potential relationship with cognition, behavioral symptoms, and use of psychoactive drugs. METHODS: We have recruited prospectively and consecutively 268 subjects (90 AD mild-moderate drug-naïve patients, 78 aMCI, and 100 controls). All patients responded to a semi-structured questionnaire in order to rate psychotic phenomena. Clinical, neuropsychological, and demographic data of patients with and without MH were compared with those of age, sex, and education-matched controls. RESULTS: The prevalence of MHs was 21.1% (19) in AD, 12.8% (10) in aMCI, and 3% (3) in controls (p < 0.01). The most frequent MH was PrH (9.3%), followed by PH (4.9%) and illusion (0.7%). Eight (27.8%) patients had more than one MH. After adjusting for age and gender, there was a negative correlation between the presence of MHs and MMSE score (r = -0.261; p < 0.01) and a positive correlation between MHs and Neuropsychiatric Inventory score (r = 0.237; p < 0.01). We did not observe a significant relationship between presence of MHs and the consumption of psychoactive drugs (p > 0.05). CONCLUSION: We have shown that the presence of MHs in patients with newly diagnosed, untreated AD and aMCI is more than controls. MHs were correlated with other behavioral symptoms and a worse cognitive performance. We suggest the specific interrogation for MHs as a clinical feature for this population.

miRNA 933 Expression by Endothelial Cells is Increased by 27-Hydroxycholesterol and is More Prevalent in Plasma from Dementia Patients. - Dias, Irundika H K; Brown, Caroline L; Shabir, Kiran; Polidori, M Cristina; Griffiths, Helen R (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) etiology is complex; gene and environmental risk factors may interact to predispose to disease. From single nucleotide polymorphism analyses and genome-wide association studies, a number of candidate risk genes for the onset of AD have been identified and cluster around lipid metabolism and inflammation. We hypothesized that endothelial cells which line the blood-brain barrier are likely to be critical mediators of systemic metabolism within the brain. Therefore, we have studied the effect of 27 hydroxycholesterol (27-OHC) on microvascular endothelial cell (HMVEC) redox state, inflammatory cytokine secretion, and microRNA (miR) expression. Using a transwell method, we have studied directional secretion profiles for the proinflammatory cytokines TNFα and IL-6 and confirmed that 27-OHC induces discrete and directional inflammatory molecular signatures from HMVEC. The lipids caused depletion of cellular glutathione and cytokine secretion is HMVEC-redox state-dependent. Discovery miR expression change in HMVEC with and without 27-OHC treatment was undertaken. We selected three genes for further analysis by qPCR; miR-144 and 146 expression, which are anti-inflammatory and redox regulating modulators, were not affected significantly by 27-OHC. However, increased expression of a putative neurotrophic regulatory factor miR933 in HMVEC with 27-OHC was confirmed by qPCR. In plasma from patients with dementia, all three miR were found at significantly elevated levels compared to healthy older adults. These data highlight that 27-OHC has an important regulatory effect on endothelial microvascular cells to increase expression of a miR (-933) and secretion of inflammatory cytokines that are elevated in plasma from dementia patients.

The Montreal Cognitive Assessment: Normative Data from a German-Speaking Cohort and Comparison with International Normative Samples. - Thomann, Alessandra E; Goettel, Nicolai; Monsch, Raphael J; Berres, Manfred; Jahn, Thomas; Steiner, Luzius A; Monsch, Andreas U (J Alzheimers Dis, 2018)
BACKGROUND: The Montreal Cognitive Assessment (MoCA) is used to evaluate multiple cognitive domains in elderly individuals. However, it is influenced by demographic characteristics that have yet to be adequately considered. OBJECTIVE: The aim of our study was to investigate the effects of age, education, and sex on the MoCA total score and to provide demographically adjusted normative values for a German-speaking population. METHODS: Subjects were recruited from a registry of healthy volunteers. Cognitive health was defined using the Mini-Mental State Examination (score ≥27/30 points) and the Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery (total score ≥85.9 points). Participants were assessed with the German version of the MoCA. Normative values were developed based on regression analysis. Covariates were chosen using the Predicted Residual Sums of Squares approach. RESULTS: The final sample consisted of 283 participants (155 women, 128 men; mean (SD) age = 73.8 (5.2) years; education = 13.6 (2.9) years). Thirty-one percent of participants scored below the original cut-off (<26/30 points). The MoCA total score was best predicted by a regression model with age, education, and sex as covariates. Older age, lower education, and male sex were associated with a lower MoCA total score (p < 0.001). CONCLUSION: We developed a formula to provide demographically adjusted standard scores for the MoCA in a German-speaking population. A comparison with other MoCA normative studies revealed considerable differences with respect to selection of volunteers and methods used to establish normative data.

MRI-Based Screening of Preclinical Alzheimer's Disease for Prevention Clinical Trials. - Casamitjana, Adrià; Petrone, Paula; Tucholka, Alan; Falcon, Carles; Skouras, Stavros; Molinuevo, José Luis; Vilaplana, Verónica; Gispert, Juan Domingo (J Alzheimers Dis, 2018)
The identification of healthy individuals harboring amyloid pathology represents one important challenge for secondary prevention clinical trials in Alzheimer's disease (AD). Consequently, noninvasive and cost-efficient techniques to detect preclinical AD constitute an unmet need of critical importance. In this manuscript, we apply machine learning to structural MRI (T1 and DTI) of 96 cognitively normal subjects to identify amyloid-positive ones. Models were trained on public ADNI data and validated on an independent local cohort. Used for subject classification in a simulated clinical trial setting, the proposed method is able to save 60% of unnecessary CSF/PET tests and to reduce 47% of the cost of recruitment. This recruitment strategy capitalizes on available MR scans to reduce the overall amount of invasive PET/CSF tests in prevention trials, demonstrating a potential value as a tool for preclinical AD screening. This protocol could foster the development of secondary prevention strategies for AD.

A Multi-Center Study on Human Brain Glutathione Conformation using Magnetic Resonance Spectroscopy. - Shukla, Deepika; Mandal, Pravat K; Ersland, Lars; Grüner, Eli Renate; Tripathi, Manjari; Raghunathan, Partha; Sharma, Ankita; Chaithya, G R; Punjabi, Khushboo; Splaine, Christopher (J Alzheimers Dis, 2018)
Molecular dynamics simulation and in vitro nuclear magnetic resonance (NMR) studies on glutathione (GSH) indicated existence of closed and extended conformations. The present work in a multi-center research setting reports in-depth analysis of GSH conformers in vivo using a common magnetic resonance spectroscopy (MRS) protocol and signal processing scheme. MEGA-PRESS pulse sequence was applied on healthy subjects using 3T Philips MRI scanner (India) and 3T GE MRI scanner (Norway) using the same experimental parameters (echo time, repetition time, and selective 180° refocusing ON-pulse at 4.40 ppm and 4.56 ppm). All MRS data were processed at one site National Brain Research Center (NBRC) using in-house MRS processing toolbox (KALPANA) for consistency. We have found that both the closed and extended GSH conformations are present in human brain and the relative proportion of individual conformer peak depends on the specific selection of refocusing ON-pulse position in MEGA-PRESS pulse sequence. It is important to emphasize that in vivo experiments with different refocusing and inversion pulse positions, echo time, and voxel size, clearly evidence the presence of both the GSH conformations. The GSH conformer peak positions for the closed GSH (Cys-Hβ) peak at ∼2.80 ppm and extended GSH (Cys-Hβ) peak at ∼2.95 ppm remain consistent irrespective of the selective refocusing OFF-pulse positions. This is the first in vivo study where both extended and closed GSH conformers are detected using the MEGA-PRESS sequence employing the parameters derived from the high resolution in vitro NMR studies on GSH.

Multisensory Stimulation and Individualized Music Sessions on Older Adults with Severe Dementia: Effects on Mood, Behavior, and Biomedical Parameters. - Maseda, Ana; Cibeira, Nuria; Lorenzo-López, Laura; González-Abraldes, Isabel; Buján, Ana; de Labra, Carmen; Millán-Calenti, José Carlos (J Alzheimers Dis, 2018)
BACKGROUND: Multisensory stimulation and individualized music have shown to be good in handling the psychological and behavioral symptoms in people with severe dementia. OBJECTIVE: Explore the effects of two nonpharmacological interventions, multisensory stimulation environment (MSSE) in a Snoezelen room and individualized music sessions, on mood, behavior, and biomedical parameters of institutionalized elderly patients with severe dementia. METHODS: Randomized trial of 21 patients aged ≥65 years randomly assigned to two groups (MSSE and individualized music). Interventions administered in two-weekly sessions lasted 30 minutes for a period of 12 weeks. Main outcomes were recorded before, during, and at the end of the intervention. RESULTS: Both groups had immediate positive effects on mood and behavior. Participants were more happy/more content (p < 0.001), talked more spontaneously (p = 0.009), related to people better (p = 0.002), were more attentive to/focused on their environment (p < 0.001), enjoyed themselves (p = 0.003), were less bored/inactive (p = 0.004), and more relaxed/content (p = 0.003). The MSSE group performed a better visual follow-up of the stimuli (p = 0.044), and the music group were more relaxed and happy (p = 0.003). A decrease in heart rate (p = 0.013) and an increase in oxygen saturation (p = 0.011) were observed from before to after interventions in both groups, with no significant differences between them. CONCLUSIONS: Both interventions seem to be effective at managing mood and behavioral disturbances in the short term and at improving physiological rates, highlighting the efficacy of nonpharmacological treatments in patients with severe dementia.

Multivariate Approach for Alzheimer's Disease Detection Using Stationary Wavelet Entropy and Predator-Prey Particle Swarm Optimization. - Zhang, Yudong; Wang, Shuihua; Sui, Yuxiu; Yang, Ming; Liu, Bin; Cheng, Hong; Sun, Junding; Jia, Wenjuan; Phillips, Preetha; Górriz, Juan Manuel (J Alzheimers Dis, 2018)
BACKGROUND: The number of patients with Alzheimer's disease is increasing rapidly every year. Scholars often use computer vision and machine learning methods to develop an automatic diagnosis system. OBJECTIVE: In this study, we developed a novel machine learning system that can make diagnoses automatically from brain magnetic resonance images. METHODS: First, the brain imaging was processed, including skull stripping and spatial normalization. Second, one axial slice was selected from the volumetric image, and stationary wavelet entropy (SWE) was done to extract the texture features. Third, a single-hidden-layer neural network was used as the classifier. Finally, a predator-prey particle swarm optimization was proposed to train the weights and biases of the classifier. RESULTS: Our method used 4-level decomposition and yielded 13 SWE features. The classification yielded an overall accuracy of 92.73±1.03%, a sensitivity of 92.69±1.29%, and a specificity of 92.78±1.51%. The area under the curve is 0.95±0.02. Additionally, this method only cost 0.88 s to identify a subject in online stage, after its volumetric image is preprocessed. CONCLUSION: In terms of classification performance, our method performs better than 10 state-of-the-art approaches and the performance of human observers. Therefore, this proposed method is effective in the detection of Alzheimer's disease.

Music and Dementia: Individual Differences in Response to Personalized Playlists. - Garrido, Sandra; Stevens, Catherine J; Chang, Esther; Dunne, Laura; Perz, Janette (J Alzheimers Dis, 2018)
Personalized music playlists are increasingly being used in health-care contexts to address the psychological and behavioral symptoms in people with dementia. However, there is little understanding of how people with different mental health histories and symptoms respond differently to music. A factorial experiment was conducted to investigate the influence of depression, anxiety, apathy, and cognitive decline on affective response to music. Ninety-nine people with dementia listened to three music playlists based on personal preferences. Activation of facial action units was measured, and behavioural responses continuously observed. Results demonstrated that people with high levels of depression and with symptoms of Alzheimer's type dementia demonstrated increased levels of sadness when listening to music. People with low depression but high levels of apathy demonstrated the highest behavioral evidence of pleasure during music listening, although behavioral evidence declined with severity of cognitive impairment. It is concluded that as well as accounting for personal preferences, music interventions for people with dementia need to take mental health history and symptoms into account.

Mutation Screening of the CHCHD2 Gene for Alzheimer's Disease and Frontotemporal Dementia in Chinese Mainland Population. - Che, Xiang-Qian; Zhao, Qian-Hua; Huang, Yue; Li, Xia; Ren, Ru-Jing; Chen, Sheng-Di; Guo, Qi-Hao; Wang, Gang (J Alzheimers Dis, 2018)
As an important multifunctional protein involved in regulation of mitochondrial metabolism, CHCHD2 was identified as a causative gene for Parkinson's disease (PD), yet the relationship between CHCHD2 and neurodegenerative dementia is not well understood. We directly sequenced the entire coding region of CHCHD2 gene in 150 AD patients, 84 FTD patients, and 417 controls. Four rare putative pathogenic variants of CHCHD2, including rs142444896 (c.5C>T, p.P2L), rs752705344 (c.15C>G, p.S5R), rs145190179 (c.94G>A, p.A32T), and rs182992574 (c.255T>A, p.S85R) were identified from a cohort composed of 150 AD and 84 FTD patients. These results suggest that CH CHD2 gene play an important role in other neurodegenerative disorders from our dementia study in China.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Asian Continental Ancestry Group; Case-Control Studies; China; Female; Frontotemporal Dementia; Genetic Association Studies; Humans; Male; Middle Aged; Mitochondrial Proteins; Mutation; Transcription Factors

A Natural Benzofuran from the Patagonic Aleurodiscus vitellinus Fungus has Potent Neuroprotective Properties on a Cellular Model of Amyloid-β Peptide Toxicity. - González-Ramírez, Mariela; Gavilán, Javiera; Silva-Grecchi, Tiare; Cajas-Madriaga, Daniel; Triviño, Sergio; Becerra, José; Saez-Orellana, Francisco; Pérez, Claudia; Fuentealba, Jorge (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is characterized by amyloid plaques that form due to an increase in amyloid-β peptide (Aβ) aggregation. One strategy in the search of new treatments for AD focuses on compounds that decrease Aβ accumulation. Compounds containing a benzofuran ring have been described to play an important role in decreasing Aβ-induced toxicity; however, only synthetic benzofurans have been tested thus far. The aim of the present study was to examine the in vitro neuroprotective properties of fomannoxin (Fx), a natural benzofuran isolated from cultures of the Andean-Patagonian fungi Aleurodiscus vitellinus, and evaluate its effect on Aβ peptide. We tested the effect of Fx at a wide concentration range (10-11-10-4 M) in PC-12 cells, and found the compound did not alter cellular viability. Fx also showed a concentration-dependent effect on the Aβ-induced toxicity in PC12 cells, showing viability above 100% at 10-6 M. We then measured the effect of Fx (10-7-10-5 M) on the frequency of cytosolic Ca2+ transients in rat hippocampal neurons at both acute and chronic (24 h) times. Acute incubation with Fx increased the frequency of cytosolic Ca2+ transients to values around 200%, whereas chronic incubation with Fx increased the frequency of Ca2+ transients. Finally, the Aβ-induced decrease in intracellular Ca2+ transients was prevented when Fx (10-6 M) was co-incubated with Aβ (5×10-6 M). The results suggest a potent neuroprotective effect of this naturally occurring benzofuran against Aβ peptide toxicity that could be mediated by an interference with it binding to plasma membrane, and lead Fx as new chemical entity to develop pharmacological tools against Aβ peptide neurotoxicity.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Basidiomycota; Benzofurans; Cell Survival; Hippocampus; Neurons; Neuroprotective Agents; PC12 Cells; Plaque, Amyloid; Rats

Naturalistic Driving Study Investigating Self-Regulation Behavior in Early Alzheimer's Disease: A Pilot Study. - Paire-Ficout, Laurence; Lafont, Sylviane; Conte, Fanny; Coquillat, Amandine; Fabrigoule, Colette; Ankri, Joël; Blanc, Frédéric; Gabel, Cécilia; Novella, Jean-Luc; Morrone, Isabella; Mahmoudi, Rachid (J Alzheimers Dis, 2018)
BACKGROUND: Because cognitive processes decline in the earliest stages of Alzheimer's disease (AD), the driving abilities are often affected. The naturalistic driving approach is relevant to study the driving habits and behaviors in normal or critical situations in a familiar environment of participants. OBJECTIVE: This pilot study analyzed in-car video recordings of naturalistic driving in patients with early-stage AD and in healthy controls, with a special focus on tactical self-regulation behavior. METHODS: Twenty patients with early-stage AD (Diagnosis and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria), and 21 healthy older adults were included in the study. Data collection equipment was installed in their personal vehicles. Two expert psychologists assessed driving performance using a specially designed Naturalistic Driving Assessment Scale (NaDAS), paying particular attention to tactical self-regulation behavior, and they recorded all critical safety events. RESULTS: Poorer driving performance was observed among AD drivers: their tactical self-regulation behavior was of lower quality. AD patients had also twice as many critical events as healthy drivers and three times more "unaware" critical events. CONCLUSION: This pilot study used a naturalistic approach to accurately show that AD drivers have poorer tactical self-regulation behavior than healthy older drivers. Future deployment of assistance systems in vehicles should specifically target tactical self-regulation components.

Negative 11C-PIB PET Predicts Lack of Alzheimer's Disease Pathology in Postmortem Examination. - Scheinin, Noora M; Gardberg, Maria; Röyttä, Matias; Rinne, Juha O (J Alzheimers Dis, 2018)
Our aim was to assess whether in vivo11C-PIB negative memory-impaired subjects may nonetheless exhibit brain Alzheimer's disease (AD) pathology. We re-evaluated the PET images and systematically characterized the postmortem neuropathology of six individuals who had undergone clinically indicated amyloid PET. The single case with negligible amyloid-β (Aβ) pathology had Lewy body disease, where concomitant AD changes are often seen. Further, the subject's plaques were predominantly diffuse. The predictive value of a negative 11C-PIB scan appears to be good, even in memory-impaired populations. Our results suggest that considerable neuritic Aβ plaque pathology in the absence of specific/cortical 11C-PIB binding upon PET is unlikely.

Negative Prospective Memory in Alzheimer's Disease: "Do Not Perform That Action". - El Haj, Mohamad; Coello, Yann; Kapogiannis, Dimitrios; Gallouj, Karim; Antoine, Pascal (J Alzheimers Dis, 2018)
Relatively to "standard" prospective memory, i.e., remembering to perform a future action, little is known about negative prospective memory, i.e., remembering not to perform a future action. This study investigated the latter ability in Alzheimer's disease (AD). AD participants and healthy older adults were asked to click on the keyboard or not to click on it when a cue word was encountered. Results showed more omissions (i.e., forgetting to click the keyboard when the instruction was to do so) in AD participants than in healthy older adults, suggesting a prospective memory deficit. Interestingly, more commissions (i.e., clicking the keyboard when the instruction was not to do so) were also observed in AD participants than in healthy older adults. Similar levels of commissions and omissions were observed in AD participants and in healthy older adults. Also, commissions and omissions were correlated with performance on an inhibition assessment task. Our findings reveal that AD is characterized by not only difficulty in the retrieval of recent information, but also difficulty to inhibit no-longer appropriate stimulus-response associations previously learned, suggesting a specific deficit of negative prospective memory in AD.
Keywords: Aged; Alzheimer Disease; Case-Control Studies; Female; Humans; Inhibition (Psychology); Male; Memory Disorders; Memory, Episodic; Mental Recall; Neuropsychological Tests

Neuroepigenetics and Alzheimer's Disease: An Update. - Zusso, Morena; Barbierato, Massimo; Facci, Laura; Skaper, Stephen D; Giusti, Pietro (J Alzheimers Dis, 2018)
Epigenetics is the study of changes in gene expression which may be triggered by both genetic and environmental factors, and independent from changes to the underlying DNA sequence-a change in phenotype without a change in genotype-which in turn affects how cells read genes. Epigenetic changes represent a regular and natural occurrence but can be influenced also by factors such as age, environment, and disease state. Epigenetic modifications can manifest themselves not only as the manner in which cells terminally differentiate, but can have also deleterious effects, resulting in diseases such as cancer. At least three systems including DNA methylation, histone modification, and non-coding RNA (ncRNA)-associated gene silencing are thought to initiate and sustain epigenetic change. For example, in Alzheimer's disease (AD), both genetic and non-genetic factors contribute to disease etiopathology. While over 250 gene mutations have been related to familial AD, less than 5% of AD cases are explained by known disease genes. More than likely, non-genetic factors, probably triggered by environmental factors, are causative factors of late-onset AD. AD is associated with dysregulation of DNA methylation, histone modifications, and ncRNAs. Among the classes of ncRNA, microRNAs (miRNAs) have a well-established regulatory relevance. MicroRNAs are highly expressed in CNS neurons, where they play a major role in neuron differentiation, synaptogenesis, and plasticity. MicroRNAs impact higher cognitive functions, as their functional impairment is involved in the etiology of neurological diseases, including AD. Alterations in the miRNA network contribute to AD disease processes, e.g., in the regulation of amyloid peptides, tau, lipid metabolism, and neuroinflammation. MicroRNAs, both as biomarkers for AD and therapeutic targets, are in the early stages of exploration. In addition, emerging data suggest that altered transcription of long ncRNAs, endogenous, ncRNAs longer than 200 nucleotides, may be involved in an elevated risk for AD.

NeuroEPO Preserves Neurons from Glutamate-Induced Excitotoxicity. - Garzón, Fernando; Coimbra, Débora; Parcerisas, Antoni; Rodriguez, Yamila; García, Julio Cesar; Soriano, Eduardo; Rama, Ramón (J Alzheimers Dis, 2018)
Many experimental studies show that erythropoietin (EPO) has a neuroprotective action in the brain. EPO in acute and chronic neurological disorders, particularly in stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, has neuroprotective effects. We previously reported the neuroprotective effect of NeuroEPO, a low sialic form of EPO, against oxidative stress induced by glutamate excitotoxicity. In this paper, we analyze the effect of NeuroEPO against apoptosis induced by glutamate excitotoxicity in primary neuronal cultures obtained from the forebrains of Wistar rat embryos after 17 days of gestation. Excitotoxicity was induced after nine days of in vitro culture by treatment with a culture medium containing 100μM glutamate for 15 min. To withdraw glutamate, a new medium containing 100 ng NeuroEPO/mL was added. Apoptosis was analyzed after 24 h. Images obtained by phase contrast microscopy show that neurons treated with glutamate exhibit cell body shrinkage, loss of dendrites that do not make contact with neighboring cells, and that NeuroEPO was able to preserve the morphological characteristics of the control. Immunocytochemistry images show that the culture is essentially pure in neurons; that glutamate causes cell mortality, and that this is partially avoided when the culture medium is supplemented with NeuroEPO. Activation of intrinsic apoptotic pathways was analyzed. The decreases in Bcl-2/Bax ratio, increase in the release of cytochrome c, and in the expression and activity of caspase-3 observed in cells treated with glutamate, were restored by NeuroEPO. The results from this study show that NeuroEPO protects cortical neurons from glutamate-induced apoptosis via upregulation of Bcl-2 and inhibit glutamate-induced activation of caspase-3.

Neuropathologic Correlates of Psychiatric Symptoms in Alzheimer's Disease. - Ehrenberg, Alexander J; Suemoto, Claudia K; França Resende, Elisa de Paula; Petersen, Cathrine; Leite, Renata Elaine Paraizo; Rodriguez, Roberta Diehl; Ferretti-Rebustini, Renata Eloah de Lucena; You, Michelle; Oh, Jun; Nitrini, Ricardo; Pasqualucci, Carlos Augusto; Jacob-Filho, Wilson; et al. (J Alzheimers Dis, 2018)
Clarifying the relationships between neuropsychiatric symptoms and Alzheimer's disease (AD)-related pathology may open avenues for effective treatments. Here, we investigate the odds of developing neuropsychiatric symptoms across increasing burdens of neurofibrillary tangle and amyloid-β pathology. Participants who passed away between 2004 and 2014 underwent comprehensive neuropathologic evaluation at the Biobank for Aging Studies from the Faculty of Medicine at the University of São Paulo. Postmortem interviews with reliable informants were used to collect information regarding neuropsychiatric and cognitive status. Of 1,092 cases collected, those with any non-Alzheimer pathology were excluded, bringing the cohort to 455 cases. Braak staging was used to evaluate neurofibrillary tangle burden, and the CERAD neuropathology score was used to evaluate amyloid-β burden. The 12-item neuropsychiatric inventory was used to evaluate neuropsychiatric symptoms and CDR-SOB score was used to evaluate dementia status. In Braak I/II, significantly increased odds were detected for agitation, anxiety, appetite changes, depression, and sleep disturbances, compared to controls. Increased odds of agitation continue into Braak III/IV. Braak V/VI is associated with higher odds for delusions. No increased odds for neuropsychiatric symptoms were found to correlate with amyloid-β pathology. Increased odds of neuropsychiatric symptoms are associated with early neurofibrillary tangle pathology, suggesting that subcortical neurofibrillary tangle accumulation with minimal cortical pathology is sufficient to impact quality of life and that neuropsychiatric symptoms are a manifestation of AD biological processes.

Neuroprotective Effects of Amylin Analogues on Alzheimer's Disease Pathogenesis and Cognition. - Grizzanti, John; Corrigan, Rachel; Casadesus, Gemma (J Alzheimers Dis, 2018)
Type II diabetes (T2D) has been identified as a major risk factor for the development of Alzheimer's disease (AD). Interestingly, both AD and T2D have similar characteristics including amyloid peptide aggregation, decreased metabolism, and increased oxidative stress and inflammation. Despite their prevalence, therapies for these diseases are limited. To date, most therapies for AD have targeted amyloid-β or tau. Unfortunately, most of these clinical trials have been largely unsuccessful, creating a crucial need for novel therapies. A number of studies have shown that metabolic hormone therapies are effective at ameliorating high blood glucose levels in diabetics as well as improving cognitive function in AD and mild cognitive impairment patients. Pramlintide, a synthetic analogue of the pancreatic hormone amylin, has been developed and used for years now as a treatment for both type I diabetes and T2D due to the loss of β-islet cells responsible for producing amylin. Importantly, recent data demonstrates its potential therapeutic role for AD as well. This review aims at addressing parallels between T2D and AD at a pathological and functional level, focusing on amylin signaling as a key, overlapping mediator in both diseases. The potential therapeutic use of this hormone to treat AD will also be explored from a mechanistic viewpoint.

Neuropsychological Predictors of Long-Term (10 Years) Mild Cognitive Impairment Stability. - Alves, Luísa; Cardoso, Sandra; Maroco, João; de Mendonça, Alexandre; Guerreiro, Manuela; Silva, Dina (J Alzheimers Dis, 2018)
BACKGROUND: Although the diagnosis of mild cognitive impairment (MCI) corresponds to a condition likely to progress to dementia, essentially Alzheimer's disease, longitudinal studies have shown that some patients may not convert to dementia and maintain the diagnosis of MCI even after many years. OBJECTIVES: To determine whether patients that maintain the diagnosis of MCI in the long term (10 years) are really stable or just declining slowly, and to identify clinical and neuropsychological characteristics associated with long-term stability. METHODS: The Cognitive Complaints Cohort (CCC) was searched for MCI cases who maintained that diagnosis for at least 10 years. For each long-term-stable MCI patient, two MCI patients that converted to dementia during follow-up, matched for age and education, were selected from the same database. The baseline and last neuropsychological evaluations for long-term-stable MCI and converter MCI were compared. Baseline neuropsychological predictors of long-term stability were searched for. RESULTS: Long-term-stable MCI (n = 22) and converter MCI (n = 44) patients did not differ in terms of gender distribution, education, age at first assessment and time between symptom onset and first evaluation. Time of follow-up was on average 11 years for long-term-stable MCI and 3 years for converter MCI. The baseline and follow-up neuropsychological tests were not significantly different in long-term-stable MCI patients, whereas a general decline was observed in converter MCI patients. Higher scores on one memory test, the Word Delayed Total Recall, and on the non-verbal abstraction test, Raven's Progressive Matrices, at the baseline predicted long-term (10 years) clinical stability. CONCLUSIONS: Some patients with MCI remain clinically and neuropsychologically stable for a decade. Better performances at baseline in memory and non-verbal abstraction tests predict long-term stability.

Non-Ashkenazi Jewish Origin is Associated with Early Onset Alzheimer's Disease. - Keret, Ophir; Shochat, Tzippy; Steiner, Israel; Glik, Amir (J Alzheimers Dis, 2018)
Early-onset Alzheimer's disease (EOAD) accounts for 1-5% of Alzheimer's disease cases and is associated with specific ethnicities. It has been our impression that non-Ashkenazi Jews have a higher rate of EOAD and we therefore explored this hypothesis. We performed a retrospective case control study of EOAD cases referred to our cognitive neurology clinic between January 1999 and December 2016. Patients (n = 129) were compared to age- and geographically-matched controls generated from the Second Israeli National Health Survey (n = 1,811). Data on country of origin, education, dementia family history, depression, and vascular risk factors were compared between the groups. The association of non-Ashkenazi Jewish heritage and country of origin with EOAD was calculated using a logistic multivariate regression model. The EOAD group's mean age was 59.6±4.1 years, with a female predominance (64.3%). The EOAD group had a higher percentage of individuals of non-Ashkenazi Jewish origin (64.3% versus 51.4%, p = 0.003) and of Yemenite descent in particular (16.28% versus 6.24%, p < 0.001). On multiple logistic regression analysis, Yemenite Jewish origin was an independently associated with EOAD (OR 2.54, 95% CI 1.4-4.8). There were no significant differences in parameters between non-Ashkenazi and Ashkenazi Jews. Only 4.6% of EOAD cases had a positive EOAD family history. In conclusion, EOAD is over-represented among non-Ashkenazi Jews. Yemenite origin is independently associated with EOAD and the majority of patients with EOAD have no family history of Alzheimer's disease. Further evaluation with genetic studies is warranted.

Non-Genetic Risk Factors for Degenerative and Vascular Young Onset Dementia: Results from the INSPIRED and KGOW Studies. - Cations, Monica; Draper, Brian; Low, Lee-Fay; Radford, Kylie; Trollor, Julian; Brodaty, Henry; Sachdev, Perminder; Gonski, Peter; Broe, Gerald Anthony; Withall, Adrienne (J Alzheimers Dis, 2018)
BACKGROUND: Several brain reserve, vascular risk, and other modifiable factors have been associated with late-onset dementia, but their association with young onset dementia (YOD) has not been adequately explored. OBJECTIVE: To examine the association of cognitive reserve enhancing factors, cardiovascular risk factors (including smoking), depression, alcohol use, and traumatic brain injury (TBI) with non-autosomal dominant degenerative and/or vascular YOD. METHODS: Data for this matched case-control study were taken from two larger studies conducted in NSW, Australia. One comprised all people with YOD within a geographical region, while the other exclusively included Aboriginal and Torres Strait Islander participants. Dementia diagnosis was confirmed by clinical consensus, and risk exposure was retrospectively self- and/or informant-reported. RESULTS: Participants were 96 people with YOD (58.4% with probable Alzheimer's disease) and 175 age-group, sex, and sample matched control participants. Poor educational attainment, low participation in cognitive leisure activity, stroke, transient ischemic attack, and self-reported very heavy alcohol use were related to the risk of primary degenerative and/or vascular YOD. The effect of hypertension and depression varied depending on when they occurred relative to dementia onset. Current smoking was significantly associated with risk in univariate analyses but did not retain significance in multivariate modelling. There was no association with hypercholesterolemia, diabetes, or TBI of any kind. Some compensation for low educational attainment was possible via a complex occupation later in life. CONCLUSION: Non-genetic factors have a role in YOD, though the relative importance of each factor may be different to late onset dementia. The timing and severity of exposure, as well as the potential for compensation with later protective exposures, are important considerations for potential prevention strategies.

Non-Phosphorylated Tau in Cerebrospinal Fluid is a Marker of Alzheimer's Disease Continuum in Young Urbanites Exposed to Air Pollution. - Calderón-Garcidueñas, Lilian; Mukherjee, Partha S; Waniek, Katharina; Holzer, Max; Chao, Chih-Kai; Thompson, Charles; Ruiz-Ramos, Rubén; Calderón-Garcidueñas, Ana; Franco-Lira, Maricela; Reynoso-Robles, Rafael; González-Maciel, Angelica; Lachmann, Ingolf (J Alzheimers Dis, 2018)
Long-term exposure to fine particulate matter (PM2.5) and ozone (O3) above USEPA standards is associated with Alzheimer's disease (AD) risk. Metropolitan Mexico City (MMC) children exhibit subcortical pretangles in infancy and cortical tau pre-tangles, NFTs, and amyloid phases 1-2 by the 2nd decade. Given their AD continuum, we measured in 507 normal cerebrospinal fluid (CSF) samples (MMC 354, controls 153, 12.82±6.73 y), a high affinity monoclonal non-phosphorylated tau antibody (non-P-Tau), as a potential biomarker of AD and axonal damage. In 81 samples, we also measured total tau (T-Tau), tau phosphorylated at threonine 181 (P-Tau), amyloid-β1-42, BDNF, and vitamin D. We documented by electron microscopy myelinated axonal size and the pathology associated with combustion-derived nanoparticles (CDNPs) in anterior cingulate cortex white matter in 6 young residents (16.25±3.34 y). Non-P-Tau showed a strong increase with age significantly faster among MMC versus controls (p = 0.0055). Aβ1 - 42 and BDNF concentrations were lower in MMC children (p = 0.002 and 0.03, respectively). Anterior cingulate cortex showed a significant decrease (p = <0.0001) in the average axonal size and CDNPs were associated with organelle pathology. Significant age increases in non-P-Tau support tau changes early in a population with axonal pathology and evolving AD hallmarks in the first two decades of life. Non-P-Tau is an early biomarker of axonal damage and potentially valuable to monitor progressive longitudinal changes along with AD multianalyte classical CSF markers. Neuroprotection of young urbanites with PM2.5 and CDNPs exposures ought to be a public health priority to halt the development of AD in the first two decades of life.

A Novel Antibody Targeting Tau Phosphorylated at Serine 235 Detects Neurofibrillary Tangles. - Brici, David; Götz, Jürgen; Nisbet, Rebecca M (J Alzheimers Dis, 2018)
Alzheimer's disease is characterized by two main pathological hallmarks in the human brain: the extracellular deposition of amyloid-β as plaques and the intracellular accumulation of the hyperphosphorylated protein tau as neurofibrillary tangles (NFTs). Phosphorylated tau (p-tau) specific-antibodies and silver staining have been used to reveal three morphological stages of NFT formation: pre-NFTs, intraneuronal NFTs (iNFTs), and extraneuronal NFTs (eNFTs). Here we characterize a novel monoclonal antibody, RN235, which is specific for tau phosphorylated at serine 235, and detects iNFTs and eNFTs in brain tissue, suggesting that phosphorylation at this site is indicative of late stage changes in tau.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Animals; Antibodies, Monoclonal; Antibody Specificity; Brain; Disease Models, Animal; Humans; Mice; Neurofibrillary Tangles; Phosphorylation; Plaque, Amyloid; tau Proteins

The Novel DA-CH3 Dual Incretin Restores Endoplasmic Reticulum Stress and Autophagy Impairments to Attenuate Alzheimer-Like Pathology and Cognitive Decrements in the APPSWE/PS1ΔE9 Mouse Model. - Panagaki, Theodora; Gengler, Simon; Holscher, Christian (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) afflicts more than 46.8 million people worldwide, with a newly diagnosed case every 3 seconds and no remission in the disease progression. The discovery of disease-modifying drugs is now on the summit of the neuropharmacological research priorities. The long-lasting derivatives of the insulinotropic incretin hormones-glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)-have repeatedly been shown to cross the blood-brain barrier and counteract an array of deleterious effects across a range of experimental models of neuronal degeneration. Clinical trials for the efficacy of GLP-1 agonists in Alzheimer's and Parkinson's diseases have revealed beneficial effects of these anti-diabetic agents in halting neuronal degeneration progression. Herein, we examine whether the chronic treatment with the novel dual GLP-1/GIP receptor agonist DA-CH3 can restore the cognitive decline and AD-like cerebral pathology of the APPSWE/PS1ΔE9 mouse model at the age of 10 months old. We report that once-a-daily, eight-week intraperitoneal administration of 25 nmol/kg of the novel DA-CH3 dual-incretin analog rescues the spatial acquisition and memory impairments of this murine model that corresponds to the attenuation of the excessive plaque deposition, gliosis and synaptic damage in the APPSWE/PS1ΔE9 brain. The amelioration of the AD-related pathology reflects the resolution of the endoplasmic-reticulum stress and derailed autophagy that both lay downstream of the rectified Akt signaling. Collectively, our findings endorse the beneficial effects of the incretin-based therapeutic approaches for the neurotrophic support of the AD brain and for the first time associate the incretin-induced neuroprotection with the proteostasis machinery in vivo.

Novel GRN Mutations in Alzheimer's Disease and Frontotemporal Lobar Degeneration. - Piaceri, Irene; Imperiale, Daniele; Ghidoni, Enrico; Atzori, Cristiana; Bagnoli, Silvia; Ferrari, Camilla; Ungari, Silvana; Ambrogio, Luca; Sorbi, Sandro; Nacmias, Benedetta (J Alzheimers Dis, 2018)
BACKGROUND: During the twentieth century, frontotemporal dementia (FTD) was often misdiagnosed, confused with Alzheimer's disease or psychiatric disorders, jeopardizing care and research. OBJECTIVE: To analyze the FTD genes in the DNA samples of patients belonging to families clinically classified as probable Alzheimer's disease (FAD) in the early 1990s and not carrying mutation in the three main genes linked to FAD (Presenilin 1, Presenilin 2, and Amyloid precursor protein). METHODS: The genetic screening was performed on 63 probands diagnosed as FAD before the early 2000s. RESULTS: Four patients out of the 63 studied (4/63, 6.3%) resulted as carrying four different GRN genetic variations: p.T272SfsX10, p.R110X, p.C149LfsX10, and p.W304C. The first two mutations (p.T272SfsX10, p.R110X) are the most frequent ones in Italy in FTD patients; the latter two (p.C149LfsX10 and p.W304C) are not described in the scientific literature. CONCLUSION: Our data suggest that it can be important to re-examine FAD patients diagnosed when the FTD spectrum was not well recognized and the causative FTD genes had not yet been identified. Moreover, we propose initially analyzing genes associated with the first form of suspected dementia and, if the results are negative, studying genes implicated in the other form of dementia.

Novel Lipidized Analog of Prolactin-Releasing Peptide Improves Memory Impairment and Attenuates Hyperphosphorylation of Tau Protein in a Mouse Model of Tauopathy. - Popelová, Andrea; Pražienková, Veronika; Neprašová, Barbora; Kasperová, Barbora Judita; Hrubá, Lucie; Holubová, Martina; Zemenová, Jana; Blum, David; Železná, Blanka; Galas, Marie-Christine; Kuneš, Jaroslav; Maletínská, Lenka (J Alzheimers Dis, 2018)
Obesity and type 2 diabetes mellitus (T2DM) were characterized as risk factors for Alzheimer's disease (AD) development. Subsequently, T2DM drugs, such as liraglutide, were proven to be neuroprotective compounds attenuating levels of amyloid deposits, and tau hyperphosphorylation, both hallmarks of AD. The central anorexigenic effects of liraglutide inspired us to examine the potential neuroprotective effects of palm11-PrRP31, a strong anorexigenic analog with glucose-lowering properties, in THY-Tau22 mice overexpressing mutated human tau, a model of AD-like tau pathology. Seven-month-old THY-Tau22 mice were subcutaneously infused with palm11-PrRP31 for 2 months. Spatial memory was tested before and after the treatment, using a Y-maze. At the end of the treatment, mice were sacrificed by decapitation and hippocampi were dissected and analyzed by immunoblotting with specific antibodies. Treatment with palm11-PrRP31 resulted in significantly improved spatial memory. In the hippocampi of palm11-PrRP31-treated THY-Tau22 mice, tau protein phosphorylation was attenuated at Thr231, Ser396, and Ser404, the epitopes linked to AD progression. The mechanism of this attenuation remains unclear, since the activation of those kinases most implicated in tau hyperphosphorylation, such as GSK-3β, JNK, or MAPK/ERK1/2, remained unchanged by palm11-PrRP31 treatment. Furthermore, we observed a significant increase in the amount of postsynaptic density protein PSD95, and a non-significant increase of synaptophysin, both markers of increased synaptic plasticity, which could also result in improved spatial memory of THY-Tau22 mice treated with palm11-PrRP31. Palm11-PrRP31 seems to be a potential tool for the attenuation of neurodegenerative disorders in the brain. However, the exact mechanism of its action must be elucidated.

Nutritional Intervention as a Preventive Approach for Cognitive-Related Outcomes in Cognitively Healthy Older Adults: A Systematic Review. - Solfrizzi, Vincenzo; Agosti, Pasquale; Lozupone, Madia; Custodero, Carlo; Schilardi, Andrea; Valiani, Vincenzo; Sardone, Rodolfo; Dibello, Vittorio; Di Lena, Luca; Lamanna, Angela; Stallone, Roberta; Bellomo, Antonello; et al. (J Alzheimers Dis, 2018)
The link diet-cognitive function/dementia has been largely investigated in observational studies; however, there was a lack of evidence from randomized clinical trials (RCTs) on the prevention of late-life cognitive disorders though dietary intervention in cognitively healthy older adults. In the present article, we systematically reviewed RCTs published in the last four years (2014-2017) exploring nutritional intervention efficacy in preventing the onset of late-life cognitive disorders and dementia in cognitively healthy subjects aged 60 years and older using different levels of investigation (i.e., dietary pattern changes/medical food/nutraceutical supplementation/multidomain approach and dietary macro- and micronutrient approaches) as well as possible underlying mechanisms of nutritional prevention. From the 35 included RCTs, there was moderate evidence that intervention through dietary pattern changes, medical food/nutraceutical supplementation, and multidomain approach improved specific cognitive domains or cognitive-related blood biomarkers. There was high evidence that protein supplementation improved specific cognitive domains or functional status in prefrail older adults without effect.

Olfactory Function is Associated with Cognitive Performance: Results of the Heinz Nixdorf Recall Study. - Tebrügge, Sarah; Winkler, Angela; Gerards, Diana; Weimar, Christian; Moebus, Susanne; Jöckel, Karl-Heinz; Erbel, Raimund; Jokisch, Martha (J Alzheimers Dis, 2018)
BACKGROUND: There is strong evidence for an association of olfactory dysfunction and neurodegenerative diseases. Studies on the association of olfaction and cognition in the general population are rare. OBJECTIVE: To evaluate gender- and age-specific associations of olfactory function and cognitive performance in a well characterized population-based study sample. METHODS: At the third examination of the Heinz Nixdorf Recall study (n = 3,087), 2,640 participants (48% men; 68.2±7.2 years) underwent Sniffin' Sticks Screening Test measuring olfactory function on a scale of 0-12 points. Olfactory function was rated as anosmic, hyposmic, or normosmic (≤6, 7-10 or ≥11 points, respectively). All participants performed eight validated cognitive subtests. Age- (55-64 years, 65-74 years, 75-86 years) and gender-stratified multivariate analysis of covariance was used to evaluate group differences in cognitive performance. RESULTS: Women showed better olfactory function than men (p < 0.001). For middle-aged participants, olfactory groups differed in almost all cognitive subtests. The analyses revealed no gender effects, although associations were slightly greater for women than for men. Anosmics showed the worst cognitive performance and normosmics showed the best cognitive performance. In the young- and old-aged groups, a quantitative association was found for anosmics in all subtests and for normosmics and hyposmics in almost all subtests. CONCLUSION: This is the first study reporting on age-specific associations of olfactory function and cognitive performance in the general population. The association found in middle-aged participants (65-74 years) may serve as a marker to improve identification of persons at high risk for cognitive decline and dementia.

Overactive BRCA1 Affects Presenilin 1 in Induced Pluripotent Stem Cell-Derived Neurons in Alzheimer's Disease. - Wezyk, Michalina; Szybinska, Aleksandra; Wojsiat, Joanna; Szczerba, Marcelina; Day, Kelly; Ronnholm, Harriet; Kele, Malin; Berdynski, Mariusz; Peplonska, Beata; Fichna, Jakub Piotr; Ilkowski, Jan; Styczyńska, Maria; et al. (J Alzheimers Dis, 2018)
The BRCA1 protein, one of the major players responsible for DNA damage response has recently been linked to Alzheimer's disease (AD). Using primary fibroblasts and neurons reprogrammed from induced pluripotent stem cells (iPSC) derived from familial AD (FAD) patients, we studied the role of the BRCA1 protein underlying molecular neurodegeneration. By whole-transcriptome approach, we have found wide range of disturbances in cell cycle and DNA damage response in FAD fibroblasts. This was manifested by significantly increased content of BRCA1 phosphorylated on Ser1524 and abnormal ubiquitination and subcellular distribution of presenilin 1 (PS1). Accordingly, the iPSC-derived FAD neurons showed increased content of BRCA1(Ser1524) colocalized with degraded PS1, accompanied by an enhanced immunostaining pattern of amyloid-β. Finally, overactivation of BRCA1 was followed by an increased content of Cdc25C phosphorylated on Ser216, likely triggering cell cycle re-entry in FAD neurons. This study suggests that overactivated BRCA1 could both influence PS1 turnover leading to amyloid-β pathology and promote cell cycle re-entry-driven cell death of postmitotic neurons in AD.

Oxidative Stress in Elderly with Different Cognitive Status: My Mind Project. - Fattoretti, Patrizia; Malavolta, Marco; Fabbietti, Paolo; Papa, Roberta; Giacconi, Robertina; Costarelli, Laura; Galeazzi, Roberta; Paoloni, Cristina; Postacchini, Demetrio; Lattanzio, Fabrizia; Giuli, Cinzia (J Alzheimers Dis, 2018)
BACKGROUND: Biomarkers of oxidative stress have been associated with cognitive status in humans and have been proposed to guide prognosis/treatment in Alzheimer's disease (AD) and mild cognitive impairment (MCI). OBJECTIVE: The aim of this study was to compare oxidative stress status in the plasma of mild-moderate AD, MCI, and healthy elderly with normal cognition (HE) undergoing a non-pharmacological intervention including multi-modal cognitive training ("My Mind Project"). METHODS: A prospective randomized trial involving 321 elderly people enrolled in Marche Region, Italy. Each subject was randomly assigned to an experimental (cognitive training) or to a control group. Cognitive performances and biomarkers have been analyzed before intervention (baseline), immediately after termination (follow-up 1), after 6 months (follow-up 2), and after 2 years (follow-up 3). The biological antioxidant potential (BAP) to Diacron reactive oxygen metabolites (d-ROM) ratio has been used as an indicator of oxidative stress status and as outcome variable. RESULTS: We have found no differences in the oxidative status among AD, MCI, and HE. Neither did we find a significant effect of the intervention within experimental groups. Gender was the sole factor with a strong significant effect on BAP/d-ROM. CONCLUSIONS: Based on these results, the utility of biomarkers of oxidative stress to guide prognosis/treatment in AD or MCI seems to be limited by lack of specificity, large interindividual variability, and gender bias.

Patterns of Regional Cerebral Blood Flow as a Function of Age Throughout the Lifespan. - Amen, Daniel G; Egan, Sachit; Meysami, Somayeh; Raji, Cyrus A; George, Noble (J Alzheimers Dis, 2018)
BACKGROUND: Understanding the influence of aging on the brain remains a challenge in determining its role as a risk factor for Alzheimer's disease. OBJECTIVE: To identify patterns of aging in a large neuroimaging cohort. METHODS: A large psychiatric cohort of 31,227 individuals received brain SPECT at rest and during a concentration task for a total of 62,454 scans. ANOVA was done to identify the mean age trends over the course of the age range in this group, 0- 105 years. A regression model in which brain SPECT regions of interest was used to predict chronological age (CA) was then utilized to derive brain estimated age (BEA). The difference between CA and BEA was calculated to determine increased brain aging in common disorders in our sample such as depression, dementia, substance use, and anxiety. RESULTS: Throughout the lifespan, variations in perfusion were observed in childhood, adolescence, and late life. Increased brain aging was seen in alcohol use, cannabis use, anxiety, bipolar, schizophrenia, attention-deficit/hyperactivity disorder, and in men. CONCLUSION: Brain SPECT can predict chronological age and this feature varies as a function of common psychiatric disorders.

PCSK9 Concentrations in Cerebrospinal Fluid Are Not Specifically Increased in Alzheimer's Disease. - Courtemanche, Hélène; Bigot, Edith; Pichelin, Matthieu; Guyomarch, Béatrice; Boutoleau-Bretonnière, Claire; Le May, Cédric; Derkinderen, Pascal; Cariou, Bertrand (J Alzheimers Dis, 2018)
The role of PCSK9 in Alzheimer's disease (AD) is controversial. We compared cerebrospinal fluid (CSF) PCSK9 concentrations in 36 AD and 31 non-AD patients. CSF PCSK9 levels did not differ between AD and non-AD groups (2.80 versus 2.62 ng/mL). However, PCSK9 CSF levels were increased in AD and non-AD patients with other neurodegenerative process (non-AD ND, n = 20) compared to patients without neurodegenerative disorders (non-ND, n = 11): 2.80 versus 2.30 (p < 0.005) and 2.83 versus 2.30 ng/mL (p = NS), respectively. CSF PCSK9 were positively correlated with AD biomarkers (Aβ1-42, T-tau, and P-tau). PCSK9 concentrations in CSF are increased in neurodegenerative disorders rather than specifically in AD.

Personality Modulates the Efficacy of Art Intervention on Chronic Pain in a Population of Patients with Alzheimer's Disease. - Rouch, Isabelle; Pongan, Elodie; Leveque, Yohana; Tillmann, Barbara; Trombert, Béatrice; Getenet, Jean Claude; Auguste, Nicolas; Krolak-Salmon, Pierre; Laurent, Bernard; Dorey, Jean-Michel (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) mainly occurs in elderly individuals. Comorbidities and chronic pain are frequent in this population. Previous studies revealed that personality modulates both chronic pain (CP) andADoccurrence and evolution. Moreover, as pain treatments can induce side-effects, non-drugs treatments, such as art interventions, are interesting alternative therapies for decreasing CP in these patients. OBJECTIVE: Our aim was to assess the potential role of personality traits on art intervention efficacy for reducing CP in a population of patients with mild AD. METHODS: Design: multicenter randomized controlled trial. Fifty mild AD patients underwent a 12-week art intervention including singing and painting groups. Personality was assessed with the Big Five Inventory before the sessions. CP was measured with Numeric Rating Scale (NRS) [Usual pain (NRS-U) and most Intense pain (NRS-I)], Simple Visual Scale [Usual pain (SVS-U) and most Intense pain (SVS-I)] and Brief Pain Inventory (BPI) before and after the sessions. The influence of personality traits on CP evolution before and after art intervention was assessed with multiple linear regression models. RESULTS: A positive association was observed between neuroticism and the evolution of three CP measures including NRS-U (B = 0.34, p = 0.01), SVS-U (B = 0.20, p = 0.04), and BPI-U (B = 0.46, p = 0.02) evolution. No significant relationship was observed between neuroticism and NRS-I, SVS-I and BPI-R evolution. CONCLUSIONS: Our findings suggest that neuroticism can decrease the efficacy of group art intervention on pain in patients with mild AD. Individual therapies could be more appropriate for these patients. These results emphasize the interest of taking into account patients' personality before proposing them to participate to a group therapy.

Perspectives on Communicating Biomarker-Based Assessments of Alzheimer's Disease to Cognitively Healthy Individuals. - Milne, Richard; Bunnik, Eline; Diaz, Ana; Richard, Edo; Badger, Shirlene; Gove, Dianne; Georges, Jean; Fauria, Karine; Molinuevo, Jose-Luis; Wells, Katie; Ritchie, Craig; Brayne, Carol (J Alzheimers Dis, 2018)
In clinical trials which target pathophysiological mechanisms associated with Alzheimer's disease, research participants who are recruited based on biomarker test results should be informed about their increased risk of developing Alzheimer's dementia. This paper presents the results of a qualitative focus group study of attitudes and concerns toward learning information about biomarker-based risk status among healthy research participants in the United Kingdom and Spain and people with dementia and their supporters/caregivers from countries represented in the European Working Group of People with Dementia of Alzheimer Europe. The study identified expectations related to learning risk status and preferences related to the content, quality, and follow-up of the disclosure process. The latter emphasize distinctions between risk and diagnoses, the importance of clear information about risk, and suggestions for risk reduction, as well as expectations for follow up and support. The implications of these preferences for practice are discussed. Providing details of research participants' experience and views may serve as a guide for the development of processes for the responsible disclosure of Alzheimer's disease biomarkers.
Keywords: Adult; Aged; Alzheimer Disease; Biomarkers; Caregivers; Disclosure; Female; Focus Groups; Humans; Male; Middle Aged; Qualitative Research; Risk Factors; Spain; United Kingdom

PICALM Gene Methylation in Blood of Alzheimer's Disease Patients Is Associated with Cognitive Decline. - Mercorio, Roberta; Pergoli, Laura; Galimberti, Daniela; Favero, Chiara; Carugno, Michele; Dalla Valle, Elisabetta; Barretta, Francesco; Cortini, Francesca; Scarpini, Elio; Valentina, Valentina Bollati; Pesatori, Angela Cecilia (J Alzheimers Dis, 2018)
Epigenetic mechanisms might be involved in Alzheimer's disease (AD). Genetic polymorphisms in several genes, including APOE (Apolipoprotein E), PSEN1 (Presenilin 1), CR1 (Complement receptor 1), and PICALM (Phosphatidylinositol binding clathrin assembly protein), have been associated to an increased AD risk. However, data regarding methylation of these specific genes are lacking. We evaluated DNA methylation measured by quantitative bisulfite-PCR pyrosequencing in 43 AD patients and 38 healthy subjects (HS). In a multivariate age- and gender-adjusted model, PICALM methylation was decreased in AD compared to HS (mean = 3.54 and 4.63, respectively, p = 0.007). In AD, PICALM methylation level was also positively associated to Mini-Mental Scale Examination (MMSE) score (percent change 3.48%, p = 0.008). Moreover, a negative association between PICALM methylation and age was observed only in HS (percent change - 2.29%, p = 0.002). In conclusion, our data suggest a possible role of PICALM methylation in AD, particularly related to cognitive function. Given the small study sample and the associative nature of our study, further prospective investigations are required to assess the dynamics of DNA methylation in the early stages of AD development.

Pink1 Regulates Tyrosine Hydroxylase Expression and Dopamine Synthesis. - Lu, Lingling; Jia, Huanzhen; Gao, Ge; Duan, Chunli; Ren, Jing; Li, Yi; Yang, Hui (J Alzheimers Dis, 2018)
PTEN induced putative kinase 1 (PINK1), also known as PARK6, is causally linked to familial Parkinsonism, and heterozygous loss of PINK1 is a risk factor for sporadic Parkinson's disease. However, little is known about its physiological function. Its deficiency was shown to decrease dopamine without significant loss of dopaminergic neurons. We investigated the mechanistic basis for this observation in the present study using dopaminergic MN9D cells. We found that PINK1 knockdown resulted in dopamine content to decrease with suppressed tyrosine hydroxylase expression in cells. Conversely, PINK1 overexpression increased tyrosine hydroxylase protein level. We also found that PINK1 deficiency blocked the nuclear translocation and activity of nuclear receptor-related 1, a transcription factor regulating tyrosine hydroxylase gene expression. These data suggest that PINK1 regulates tyrosine hydroxylase gene expression and dopamine content by modulating the transcriptional activity of nuclear receptor-related 1. Taken together, our results reveal a novel function of PINK1 in dopamine homeostasis.

Platelets: Peripheral Biomarkers of Dementia? - Akingbade, Oluwatomi E S; Gibson, Claire; Kalaria, Raj N; Mukaetova-Ladinska, Elizabeta B (J Alzheimers Dis, 2018)
Dementia continues to be the most burdening neurocognitive disorder, having a negative impact on the lives of millions. The search for biomarkers to improve the clinical diagnosis of dementia is ongoing, with the focus on effective use of readily accessible peripheral markers. In this review, we concentrate on platelets as biomarkers of dementia and analyze their potential as easily-accessible clinical biomarkers for various subtypes of dementia. Current platelet protein biomarkers that have been investigated for their clinical utility in the diagnosis of dementia, in particular Alzheimer's disease, include amyloid-β protein precursor (AβPP), the AβPP secretases (BACE1 and ADAM10), α-synuclein, tau protein, serotonin, cholesterol, phospholipases, clusterin, IgG, surface receptors, MAO-B, and coated platelets. Few of them, i.e., platelet tau, AβPP (particularly with regards to coated platelets) and secreted ADAM10 and BACE1 show the most promise to be taken forward into clinical setting to diagnose dementia. Aside from protein biomarkers, changes in factors such as mean platelet volume have the potential to play a very specific role in both the dementia diagnosis and prognosis. This review raises a number of research questions for consideration before application of the above biomarkers to routine clinical setting. It is without doubt that there is a need for more clarification on the effects of dementia on platelet morphology and protein content before these changes can be clinically applied as dementia biomarkers and explored further in differentiating distinct dementia subtypes.

Polypharmacy and Potentially Inappropriate Medication in People with Dementia: A Nationwide Study. - Kristensen, Rachel Underlien; Nørgaard, Ane; Jensen-Dahm, Christina; Gasse, Christiane; Wimberley, Theresa; Waldemar, Gunhild (J Alzheimers Dis, 2018)
BACKGROUND: Polypharmacy (use of ≥5 different medications) and potentially inappropriate medication (PIM) are well-known risk factors for numerous negative health outcomes. However, the use of polypharmacy and PIM in people with dementia is not well-described. OBJECTIVE: To examine the prevalence of polypharmacy and PIM in older people with and without dementia in a nationwide population. METHODS: Cross-sectional study of the Danish population aged ≥65 in 2014 (n = 1,032,120) based on register data, including information on diagnoses and dispensed prescriptions. Polypharmacy and PIM use among people with (n = 35,476) and without dementia (n = 994,231) were compared, stratified by living situation and adjusted for age, sex, and comorbidity. The red-yellow-green list from the Danish Institute for Rational Pharmacotherapy and the German PRISCUS list were used to define PIM. RESULTS: People with dementia were more frequently exposed to polypharmacy (dementia: 62.6% versus no-dementia: 35.1%, p < 0.001) and likewise PIM (red-yellow-green: 45.0% versus 29.7%, p < 0.001; PRISCUS: 24.4% versus 13.2%, p < 0.001). After adjustments for age, sex, and comorbidity, the likelihood of polypharmacy and PIM was higher for community-dwelling people with dementia than without dementia (odds ratio (OR); [95% confidence interval (CI)] polypharmacy: 1.50 [1.45-1.55]; red-yellow-green: 1.27 [1.23-1.31]; PRISCUS: 1.25 [1.20-1.30]). In contrast, dementia slightly decreased the odds of polypharmacy and PIM in nursing home residents. CONCLUSION: Use of polypharmacy and PIM were widespread in the older population and more so in people with dementia. This could have negative implications for patient-safety and demonstrates the need for interventions to improve drug therapy in people with dementia.

The Positive Effects of Viewing Gardens for Persons with Dementia. - Goto, Seiko; Shen, Xuting; Sun, Minkai; Hamano, Yutaka; Herrup, Karl (J Alzheimers Dis, 2018)
Dementia is highly prevalent among the worldwide elderly population. Only a small number of the currently marketed drugs are effective in controlling its symptoms, and none has any effect on its progression. Further, as the condition advances, even these pharmaceuticals lose their efficiency, and new research into interventions that might improve the life quality of patients at the end stage of dementia and their families is increasingly rare. In our previous studies, we explored the benefits of exposure to nature, in the form of a Japanese garden, for persons with advanced dementia. In the current work, we extended our observations to two new locations and a new set of subjects with a different ethnic composition with the goal of identifying interventions that might improve their quality of life. We found that, even in these new settings, garden observation not only relieved physiological stress, it improved qualitative measures such as verbalization and memory retrieval. We present data that viewing the garden is a holistic experience rather a solely visual stimulus. Our new data further support the conclusion that garden observation is worth including in the care planning schedule of advanced dementia patients. Its low cost and easy availability make it an economical adjunct to current pharmacological methods that has the potential to improve the quality of life of people with dementia.

Postmortem T2*- Weighted MRI Imaging of Cortical Iron Reflects Severity of Alzheimer's Disease. - Bulk, Marjolein; Kenkhuis, Boyd; Graaf, Linda M van der; Goeman, Jelle J; Natté, Remco; Weerd, Louise van der (J Alzheimers Dis, 2018)
The value of iron-based MRI changes for the diagnosis and staging of Alzheimer's disease (AD) depends on an association between cortical iron accumulation and AD pathology. Therefore, this study determined the cortical distribution pattern of MRI contrast changes in cortical regions selected based on the known distribution pattern of tau pathology and investigated whether MRI contrast changes reflect the underlying AD pathology in the different lobes. T2*-weighted MRI was performed on postmortem cortical tissue of controls, late-onset AD (LOAD), and early-onset AD (EOAD) followed by histology and correlation analyses. Combining ex vivo high-resolution MRI and histopathology revealed that: 1) LOAD and EOAD have a different distribution pattern of AD pathological hallmarks and MRI contrast changes over the cortex, with EOAD showing more severe MRI changes; 2) per lobe, severity of AD pathological hallmarks correlates with iron accumulation, and hence with MRI. Therefore, iron-sensitive MRI sequences allow detection of the cortical distribution pattern of AD pathology ex vivo.

Potential Novel Approaches to Understand the Pathogenesis and Treat Alzheimer's Disease. - Drummond, Eleanor; Goñi, Fernando; Liu, Shan; Prelli, Frances; Scholtzova, Henrieta; Wisniewski, Thomas (J Alzheimers Dis, 2018)
There is growing genetic and proteomic data highlighting the complexity of Alzheimer's disease (AD) pathogenesis. Greater use of unbiased "omics" approaches is being increasingly recognized as essential for the future development of effective AD research, that need to better reflect the multiple distinct pathway abnormalities that can drive AD pathology. The track record of success in AD clinical trials thus far has been very poor. In part, this high failure rate has been related to the premature translation of highly successful results in animal models that mirror only limited aspects of AD pathology to humans. We highlight our recent efforts to increase use of human tissue to gain a better understanding of the AD pathogenesis subtype variety and to develop several distinct therapeutic approaches tailored to address this diversity. These therapeutic approaches include the blocking of the Aβ/apoE interaction, stimulation of innate immunity, and the simultaneous blocking of Aβ/tau oligomer toxicity. We believe that future successful therapeutic approaches will need to be combined to better reflect the complexity of the abnormal pathways triggered in AD pathogenesis.

Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer's Disease: Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial. - Wilcock, Gordon K; Gauthier, Serge; Frisoni, Giovanni B; Jia, Jianping; Hardlund, Jiri H; Moebius, Hans J; Bentham, Peter; Kook, Karin A; Schelter, Bjoern O; Wischik, Damon J; Davis, Charles S; Staff, Roger T; et al. (J Alzheimers Dis, 2018)
BACKGROUND: LMTM is being developed as a treatment for AD based on inhibition of tau aggregation. OBJECTIVES: To examine the efficacy of LMTM as monotherapy in non-randomized cohort analyses as modified primary outcomes in an 18-month Phase III trial in mild AD. METHODS: Mild AD patients (n = 800) were randomly assigned to 100 mg twice a day or 4 mg twice a day. Prior to unblinding, the Statistical Analysis Plan was revised to compare the 100 mg twice a day as monotherapy subgroup (n = 79) versus 4 mg twice a day as randomized (n = 396), and 4 mg twice a day as monotherapy (n = 76) versus 4 mg twice a day as add-on therapy (n = 297), with strong control of family-wise type I error. RESULTS: The revised analyses were statistically significant at the required threshold of p < 0.025 in both comparisons for change in ADAS-cog, ADCS-ADL, MRI atrophy, and glucose uptake. The brain atrophy rate was initially typical of mild AD in both add-on and monotherapy groups, but after 9 months of treatment, the rate in monotherapy patients declined significantly to that reported for normal elderly controls. Differences in severity or diagnosis at baseline between monotherapy and add-on patients did not account for significant differences in favor of monotherapy. CONCLUSIONS: The results are consistent with earlier studies in supporting the hypothesis that LMTM might be effective as monotherapy and that 4 mg twice a day may serve as well as higher doses. A further suitably randomized trial is required to test this hypothesis.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Antipsychotic Agents; Cohort Studies; Double-Blind Method; Female; Humans; International Cooperation; Male; Mental Status and Dementia Tests; Methylene Blue; Middle Aged; Treatment Outcome

A Precision Medicine Model for Targeted NSAID Therapy in Alzheimer's Disease. - O'Bryant, Sid E; Zhang, Fan; Johnson, Leigh A; Hall, James; Edwards, Melissa; Grammas, Paula; Oh, Esther; Lyketsos, Constantine G; Rissman, Robert A (J Alzheimers Dis, 2018)
BACKGROUND: To date, the therapeutic paradigm for Alzheimer's disease (AD) has focused on a single intervention for all patients. However, a large literature in oncology supports the therapeutic benefits of a precision medicine approach to therapy. Here we test a precision-medicine approach to AD therapy. OBJECTIVE: To determine if a baseline, blood-based proteomic companion diagnostic predicts response to NSAID therapy. METHODS: Proteomic assays of plasma from a multicenter, randomized, double-blind, placebo-controlled, parallel group trial, with 1-year exposure to rofecoxib (25 mg once daily), naproxen (220 mg twice-daily) or placebo. RESULTS: 474 participants with mild-to-moderate AD were screened with 351 enrolled into the trial. Using support vector machine (SVM) analyses, 89% of the subjects randomized to either NSAID treatment arms were correctly classified using a general NSAID companion diagnostic. Drug-specific companion diagnostics yielded 98% theragnostic accuracy in the rofecoxib arm and 97% accuracy in the naproxen arm. CONCLUSION: Inflammatory-based companion diagnostics have significant potential to identify select patients with AD who have a high likelihood of responding to NSAID therapy. This work provides empirical support for a precision medicine model approach to treating AD.

Predicting and Tracking Short Term Disease Progression in Amnestic Mild Cognitive Impairment Patients with Prodromal Alzheimer's Disease: Structural Brain Biomarkers. - Marizzoni, Moira; Ferrari, Clarissa; Jovicich, Jorge; Albani, Diego; Babiloni, Claudio; Cavaliere, Libera; Didic, Mira; Forloni, Gianluigi; Galluzzi, Samantha; Hoffmann, Karl-Titus; Molinuevo, José Luis; Nobili, Flavio; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Early Alzheimer's disease (AD) detection using cerebrospinal fluid (CSF) biomarkers has been recommended as enrichment strategy for trials involving mild cognitive impairment (MCI) patients. OBJECTIVE: To model a prodromal AD trial for identifying MRI structural biomarkers to improve subject selection and to be used as surrogate outcomes of disease progression. METHODS: APOE ɛ4 specific CSF Aβ42/P-tau cut-offs were used to identify MCI with prodromal AD (Aβ42/P-tau positive) in the WP5-PharmaCog (E-ADNI) cohort. Linear mixed models were performed 1) with baseline structural biomarker, time, and biomarker×time interaction as factors to predict longitudinal changes in ADAS-cog13, 2) with Aβ42/P-tau status, time, and Aβ42/P-tau status×time interaction as factors to explain the longitudinal changes in MRI measures, and 3) to compute sample size estimation for a trial implemented with the selected biomarkers. RESULTS: Only baseline lateral ventricle volume was able to identify a subgroup of prodromal AD patients who declined faster (interaction, p = 0.003). Lateral ventricle volume and medial temporal lobe measures were the biomarkers most sensitive to disease progression (interaction, p≤0.042). Enrichment through ventricular volume reduced the sample size that a clinical trial would require from 13 to 76%, depending on structural outcome variable. The biomarker needing the lowest sample size was the hippocampal subfield GC-ML-DG (granule cells of molecular layer of the dentate gyrus) (n = 82 per arm to demonstrate a 20% atrophy reduction). CONCLUSION: MRI structural biomarkers can enrich prodromal AD with fast progressors and significantly decrease group size in clinical trials of disease modifying drugs.

Predictors of Age of Diagnosis and Survival of Alzheimer's Disease in Down Syndrome. - Sinai, Amanda; Mokrysz, Claire; Bernal, Jane; Bohnen, Ingrid; Bonell, Simon; Courtenay, Ken; Dodd, Karen; Gazizova, Dina; Hassiotis, Angela; Hillier, Richard; McBrien, Judith; McCarthy, Jane; et al. (J Alzheimers Dis, 2018)
BACKGROUND: People with Down syndrome (DS) are an ultra-high risk population for Alzheimer's disease (AD). Understanding the factors associated with age of onset and survival in this population could highlight factors associated with modulation of the amyloid cascade. OBJECTIVE: This study aimed to establish the typical age at diagnosis and survival associated with AD in DS and the risk factors associated with these. METHODS: Data was obtained from the Aging with Down Syndrome and Intellectual Disabilities (ADSID) research database, consisting of data extracted from clinical records of patients seen by Community Intellectual Disability Services (CIDS) in England. Survival times when considering different risk factors were calculated. RESULTS: The mean age of diagnosis was 55.80 years, SD 6.29. Median survival time after diagnosis was 3.78 years, and median age at death was approximately 60 years. Survival time was associated with age of diagnosis, severity of intellectual disability, living status, anti-dementia medication status, and history of epilepsy. Age at diagnosis and treatment status remained predictive of survival time following adjustment. CONCLUSION: This study provides the best estimate of survival in dementia within the DS population to date, and is in keeping with previous estimates from smaller studies in the DS population. This study provides important estimates and insights into possible predictors of survival and age of diagnosis of AD in adults with DS, which will inform selection of participants for treatment trials in the future.
Keywords: Age of Onset; Alzheimer Disease; Down Syndrome; England; Female; Humans; Male; Middle Aged; Risk Factors; Survival Analysis

Prevalence and Determinants of Agonistic Autoantibodies Against α1-Adrenergic Receptors in Patients Screened Positive for Dementia: Results from the Population-Based DelpHi-Study. - Thyrian, Jochen René; Hertel, Johannes; Schulze, Lara N; Dörr, Marcus; Prüss, Harald; Hempel, Petra; Bimmler, Marion; Kunze, Rudolf; Grabe, Hans Jörgen; Teipel, Stefan; Hoffmann, Wolfgang (J Alzheimers Dis, 2018)
BACKGROUND: There is a need to assess promising biomarkers for diagnosis and treatment response in real-life settings. Despite the important role of vascular risk factors, cardiovascular biomarkers have played a minor role in dementia research. Agonistic autoantibodies (agAAB) directed against G-protein-coupled receptors (GPCR) are discussed as modulators of pathology and clinical manifestation. OBJECTIVE: 1) Describe prevalence of agAAB directed against GPCR, especially agABB against α1-adrenergic receptors (α1-AR-agAAB) and agABB directed against β2-adrenergic receptors (β2-AR-agAAB) and 2) identify factors associated with agAAB in people with dementia during routine care. METHODS: Blood samples and data from 95 subjects who screened positive for dementia from a primary care cohort, analyzed using an enzyme-linked immunosorbent assay (ELISA) for detecting agAAB. Sociodemographic and clinical data were assessed, and medical records checked. RESULTS: In 40 (42%) samples, agAAB was detected, with n = 29 (31%) representing α1-AR-agAAB and n = 21 (22%) β2-AR-agAAB. There was no association between the presence of any antibody and a formal diagnosis of dementia. However, patients with coronary heart disease were more likely (OR = 4.23) to have α1-AR-agAAB than those without coronary heart disease. There were no associations between agAAB and age, sex, education, or cognitive impairment. DISCUSSION: For the first time, we show that autoantibodies have a significant prevalence in people with dementia in a routine care setting. Previous findings were restricted to highly selective samples. We replicated the association between α1-AR-agAAB in patients with coronary heart diseases but were not able to find other factors associated with the presence of agAAB.

Prevalence of Potentially Inappropriate Medication Use in Older Inpatients with and without Cognitive Impairment: A Systematic Review. - Redston, Mitchell R; Hilmer, Sarah N; McLachlan, Andrew J; Clough, Alexander J; Gnjidic, Danijela (J Alzheimers Dis, 2018)
BACKGROUND: Older people with cognitive impairment, including dementia and delirium, are high users of acute care services internationally. Potentially inappropriate medication (PIM) use may be associated with adverse outcomes, including hospital re-admission, functional disability, and mortality. OBJECTIVE: This systematic review aimed to quantify and compare the prevalence of PIMs in older inpatients with and without cognitive impairment. METHODS: A systematic search of observational studies was performed independently assessed by two reviewers in Embase, Medline, PsycINFO, International Pharmaceutical Abstracts, Scopus, and Informit. Articles published in English during the period January 2007-June 2017 that reported PIM prevalence in hospital inpatients ≥ 65 years were included. PIMs were defined as the presence of polypharmacy (multiple medication use) and using implicit or explicit tools, such as the Beers criteria, and 'Screening Tool of Older Person's Prescriptions' (STOPP). RESULTS: 47 articles were included. In studies measuring polypharmacy (n = 15), the prevalence of PIMs ranged from 53.2% to 89.8% and 30.4% to 97.1% for inpatients with and without cognitive impairment, respectively, and 24.0% to 80.0% when cognitive status was unreported. In studies employing explicit and implicit tools (n = 35), the prevalence of PIMs when cognitive impairment was reported ranged from 20.6% to 80.5% using the Beers criteria, and 39.3% to 88.5% using STOPP. When cognitive status was unreported, the prevalence of PIMs ranged from 7.0% to 79.2% using the Beers criteria, and 20.0% to 63.4% using STOPP. CONCLUSION: Our findings suggest a high prevalence of PIMs in older inpatients with and without cognitive impairment. Future studies should investigate the impact of PIM use on patient-centered outcomes, such as functional status and quality of life, to inform enhanced acute care services.
Keywords: Aged; Cognitive Dysfunction; Dementia; Humans; Inpatients; Polypharmacy; Potentially Inappropriate Medication List; Prevalence; Quality of Life

Profiling of Specific Gene Expression Pathways in Peripheral Cells from Prodromal Alzheimer's Disease Patients. - Serpente, Maria; Fenoglio, Chiara; Cioffi, Sara Maria Giulia; Oldoni, Emanuela; Arcaro, Marina; Arighi, Andrea; Fumagalli, Giorgio Giulio; Ghezzi, Laura; Scarpini, Elio; Galimberti, Daniela (J Alzheimers Dis, 2018)
Herein, we performed a gene expression profiling in a cohort of 10 mild cognitive impairment (MCI), subdivided, according to the analysis of cerebrospinal fluid biomarkers, in prodromal Alzheimer's disease (AD) and non-AD MCI, as compared with 27 AD patients and 24 controls, in order to detect early gene expression alterations. We observed a significant upregulation of insulin (INS) and INS Receptor (INSR) expression levels in AD both prodromal and fully symptomatic, as compared with controls, but not in MCI subjects. Our results suggest an early dysregulation of INS and INSR in AD pathogenesis and pave the way to a possible utility of these transcripts as peripheral biomarkers.
Keywords: Aged; Alzheimer Disease; Antigens, CD; Biomarkers; Case-Control Studies; Cognitive Dysfunction; Female; Gene Expression Profiling; Humans; Insulin; Male; Middle Aged; Receptor, Insulin

The Progression of Dementia and Cognitive Decline in a Dutch 2-Year Cohort Study of People with Young-Onset Dementia. - Gerritsen, Adrie A J; Bakker, Christian; Verhey, Frans R J; Bor, Hans; Pijnenburg, Yolande A L; de Vugt, Marjolein E; Koopmans, Raymond T C M (J Alzheimers Dis, 2018)
BACKGROUND: The progression of dementia in people with young-onset dementia (YOD) is relatively unknown. OBJECTIVE: To investigate the progression of dementia and cognitive decline in the three most common subtypes in YOD and to explore which factors are associated with this course. METHODS: The course of dementia was examined in 198 people with YOD. The primary outcomes were cognitive function, as assessed by the Mini-Mental State Examination (MMSE) and dementia severity, as assessed by the Global Deterioration Scale (GDS). Mixed-model analyses were used to explore factors associated with the course of dementia of the diagnostic sub-types. RESULTS: The mean overall two-year progression of dementia severity was 0.9 GDS points, this was a statistically significant change (p = 0.012) and was not significant different for the three dementia subtypes. The mean overall two-year decline in cognitive function was 1.6 points on the MMSE. The differences in cognitive decline were statistically significant (p = 0.046) among the three diagnosis groups, AD participants showed the greatest decline, of 2.3 points. In addition to lower education (p = 0.010), higher scores on the Neuropsychiatric Inventory (NPI) sub-syndromes psychosis (p < 0.001) and hyperactivity (p = 0.002) were associated with higher rates of cognitive decline. In contrast, higher scores on the NPI affect cluster were associated with lower levels of cognitive decline (p < 0.001). CONCLUSION: Different YOD subtypes show different rates of decline in cognitive functioning, and this decline seems less progressive compared to those observed in studies in late-onset AD. Further research is needed to evaluate whether managing neuropsychiatric symptoms can positively influence the decline of cognitive function.

Protective Effects of Indian Spice Curcumin Against Amyloid-β in Alzheimer's Disease. - Reddy, P Hemachandra; Manczak, Maria; Yin, XiangLing; Grady, Mary Catherine; Mitchell, Andrew; Tonk, Sahil; Kuruva, Chandra Sekhar; Bhatti, Jasvinder Singh; Kandimalla, Ramesh; Vijayan, Murali; Kumar, Subodh; Wang, Rui; et al. (J Alzheimers Dis, 2018)
The purpose of our article is to assess the current understanding of Indian spice, curcumin, against amyloid-β (Aβ)-induced toxicity in Alzheimer's disease (AD) pathogenesis. Natural products, such as ginger, curcumin, and gingko biloba have been used as diets and dietary supplements to treat human diseases, including cancer, cardiovascular, respiratory, infectious, diabetes, obesity, metabolic syndromes, and neurological disorders. Products derived from plants are known to have protective effects, including anti-inflammatory, antioxidant, anti-arthritis, pro-healing, and boosting memory cognitive functions. In the last decade, several groups have designed and synthesized curcumin and its derivatives and extensively tested using cell and mouse models of AD. Recent research on Aβ and curcumin has revealed that curcumin prevents Aβ aggregation and crosses the blood-brain barrier, reach brain cells, and protect neurons from various toxic insults of aging and Aβ in humans. Recent research has also reported that curcumin ameliorates cognitive decline and improves synaptic functions in mouse models of AD. Further, recent groups have initiated studies on elderly individuals and patients with AD and the outcome of these studies is currently being assessed. This article highlights the beneficial effects of curcumin on AD. This article also critically assesses the current limitations of curcumin's bioavailability and urgent need for new formulations to increase its brain levels to treat patients with AD.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Curcumin; Disease Models, Animal; Humans; Mice; Neuroprotective Agents; Randomized Controlled Trials as Topic; Spices

Proteomic Profiling of Mouse Brains Exposed to Blast-Induced Mild Traumatic Brain Injury Reveals Changes in Axonal Proteins and Phosphorylated Tau. - Chen, Mei; Song, Hailong; Cui, Jiankun; Johnson, Catherine E; Hubler, Graham K; DePalma, Ralph G; Gu, Zezong; Xia, Weiming (J Alzheimers Dis, 2018)
Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by two pathological hallmarks: Tau-containing neurofibrillary tangles and amyloid-β protein (Aβ)-containing neuritic plaques. The goal of this study is to understand mild traumatic brain injury (mTBI)-related brain proteomic changes and tau-related biochemical adaptations that may contribute to AD-like neurodegeneration. We found that both phosphorylated tau (p-tau) and the ratio of p-tau/tau were significantly increased in brains of mice collected at 3 and 24 h after exposure to 82-kPa low-intensity open-field blast. Neurological deficits were observed in animals at 24 h and 7 days after the blast using Simple Neuroassessment of Asymmetric imPairment (SNAP) test, and axon/dendrite degeneration was revealed at 7 days by silver staining. Liquid chromatography-mass spectrometry (LC-MS/MS) was used to analyze brain tissue labeled with isobaric mass tags for relative protein quantification. The results from the proteomics and bioinformatic analysis illustrated the alterations of axonal and synaptic proteins in related pathways, including but not being limited to substantia nigra development, cortical cytoskeleton organization, and synaptic vesicle exocytosis, suggesting a potential axonal damage caused by blast-induced mTBI. Among altered proteins found in brains suffering blast, microtubule-associated protein 1B, stathmin, neurofilaments, actin binding proteins, myelin basic protein, calcium/calmodulin-dependent protein kinase, and synaptotagmin I were representative ones involved in altered pathways elicited by mTBI. Therefore, TBI induces elevated phospho-tau, a pathological feature found in brains of AD, and altered a number of neurophysiological processes, supporting the notion that blast-induced mTBI as a risk factor contributes to AD pathogenesis. LC/MS-based profiling has presented candidate target/pathways that could be explored for future therapeutic development.

Pyk2 is a Novel Tau Tyrosine Kinase that is Regulated by the Tyrosine Kinase Fyn. - Li, Chuanzhou; Götz, Jürgen (J Alzheimers Dis, 2018)
The protein tyrosine kinase Pyk2 is encoded by PTK2B, a novel Alzheimer's disease (AD) susceptibility variant, with the PTK2B risk allele being associated with increased mRNA levels, suggestive of increased Pyk2 levels. However, the role of Pyk2, a member of the focal adhesion kinase (FAK) family, in AD pathology and its regulation are largely unknown. To address this, we generated mice with neuronal expression of human Pyk2. Because we had previously reported an association of Pyk2 and hyperphosphorylated tau (a hallmark feature of AD) in human tau transgenic pR5 mice, we also generated Pyk2/tau double-transgenic mice, which exhibit increased tyrosine phosphorylation and accumulation of tau. We further demonstrated that Pyk2 colocalizes, interacts with, and phosphorylates tau in vivo and in vitro. Importantly, although Pyk2 interacts with the established tyrosine-directed tau kinase Fyn, we identified an increased Pyk2 activity in mice which constitutively overexpress Fyn (FynCA), and a decreased activity in mice lacking Fyn (FynKO). Together, our study reveals a novel role for Pyk2 as a direct tyrosine kinase of tau that is active downstream of Fyn. Our analysis may enhance the understanding of how the PTK2B risk allele contributes to tauopathy.

Quality of Life, Care Resource Use, and Costs of Dementia in 8 European Countries in a Cross-Sectional Cohort of the Actifcare Study. - Handels, Ron L H; Sköldunger, Anders; Bieber, Anja; Edwards, Rhiannon Tudor; Gonçalves-Pereira, Manuel; Hopper, Louise; Irving, Kate; Jelley, Hannah; Kerpershoek, Liselot; Marques, Maria J; Meyer, Gabriele; Michelet, Mona; et al. (J Alzheimers Dis, 2018)
BACKGROUND: With 10.5 million people with dementia in Europe and $301 billion associated costs, governments face challenges organizing access to care. OBJECTIVE: To examine the costs related to formal and informal care use and quality of life for people with dementia in eight European countries, and explore the association with unmet needs. METHODS: Cross-sectional data from 451 persons with dementia and their informal caregivers of the Actifcare cohort study were obtained. Formal and informal care use was multiplied by country specific unit prices of services. Needs were measured using the CANE and health-related quality of life (HRQOL) of the person with dementia (both self- and proxy-rated) and informal caregiver's quality of life using EQ-5D-5L, ICECAP-O, DEMQOL-U, and CarerQol utility scores. The association between costs and country, European region, and unmet needs was assessed using multi-level linear regression. RESULTS: Self-rated EQ-5D-5L utility score was higher than proxy-rated (0.84 and 0.71, respectively). Informal caregivers' utility score was 0.84. Across eight countries annual mean costs of formal and informal care were approximately € 17,000. Unmet needs were not associated with annual costs of care, nor with proxy-rated HRQOL, but were associated with self-rated HRQOL. CONCLUSION: We found varying relationships between unmet needs and quality of life, and no association between unmet needs and care costs, although the results were sensitive to various factors. Future research should further investigate the relation between unmet needs, quality of life and costs to generate a better understanding of the effects of (un)timely access to care.

Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer's Disease Cerebrospinal Fluid Biomarkers. - Ramos de Matos, Mafalda; Ferreira, Catarina; Herukka, Sanna-Kaisa; Soininen, Hilkka; Janeiro, André; Santana, Isabel; Baldeiras, Ines; Almeida, Maria Rosário; Lleo, Alberto; Dols-Icardo, Oriol; Alcolea, Daniel; Benussi, Luisa; et al. (J Alzheimers Dis, 2018)
Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the Alzheimer's disease (AD) field, and are now being applied in clinical practice. CSF amyloid-beta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect disease pathology, and may be used as quantitative traits for genetic analyses, fostering the identification of new genetic factors and the proposal of novel biological pathways of the disease. In patients, the concentration of CSF Aβ1-42 is decreased due to the accumulation of Aβ1-42 in amyloid plaques in the brain, while t-tau and p-tau levels are increased, indicating the extent of neuronal damage. To better understand the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the association between 36 selected single nucleotide polymorphisms (SNPs) and AD biomarkers Aβ1-42, t-tau, and p-tau in CSF in a cohort of 672 samples (571 AD patients and 101 controls) collected within 10 European consortium centers.Our results highlighted five genes, APOE, LOC100129500, PVRL2, SNAR-I, and TOMM40, previously described as main players in the regulation of CSF biomarkers levels, further reinforcing a role for these in AD pathogenesis. Three new AD susceptibility loci, INPP5D, CD2AP, and CASS4, showed specific association with CSF tau biomarkers. The identification of genes that specifically influence tau biomarkers point out to mechanisms, independent of amyloid processing, but in turn related to tau biology that may open new venues to be explored for AD treatment.

Quantitative PET and Histology of Brain Biopsy Reveal Lack of Selective Pittsburgh Compound-B Binding to Intracerebral Amyloidoma. - Groot, Colin; Tolboom, Nelleke; Ikonomovic, Milos D; Lammertsma, Adriaan A; Boon, Baayla D C; Barkhof, Frederik; Scheltens, Philip; Klunk, William E; Rozemuller, Annemieke J M; Ossenkoppele, Rik; van Berckel, Bart N M (J Alzheimers Dis, 2018)
This single case study examines selective Pittsburgh compound-B (PiB) binding to an intracerebral light-chain amyloidoma using a 90-minute dynamic [11C]PiB-PET scan and brain biopsy tissue. Parametric non-displaceable binding potential (BPND) images showed low specific binding in the amyloidoma (BPND = 0.23), while relative tracer delivery was adequate (R1 = 0.44). Histology of the tissue revealed strong coloring with Congo-red, thioflavin-S, and X-34, indicating presence of amyloid. However, immunological staining with 6F/3D revealed absence of amyloid-β and histofluorescence of 6-CN-PiB, a highly fluorescent derivative of PiB, was at background levels. Our results suggest that PiB does not detect the atypical amyloid pathology associated with an intracerebral light-chain amyloidoma. These findings are of interest to clinicians and researchers applying [11C]PiB-PET to detect atypical forms of amyloid pathology.

Quantitative Susceptibility Mapping of Amyloid-β Aggregates in Alzheimer's Disease with 7T MR. - Tiepolt, Solveig; Schäfer, Andreas; Rullmann, Michael; Roggenhofer, Elisabeth; Gertz, Hermann-Josef; Schroeter, Matthias L; Patt, Marianne; Bazin, Pierre-Louis; Jochimsen, Thies H; Turner, Robert; Sabri, Osama; Barthel, Henryk (J Alzheimers Dis, 2018)
BACKGROUND: PET imaging is an established technique to detect cerebral amyloid-β (Aβ) plaques in vivo. Some preclinical and postmortem data report an accumulation of redox-active iron near Aβ plaques. Quantitative susceptibility mapping (QSM) at high-field MRI enables iron deposits to be depicted with high spatial resolution. OBJECTIVE: Aim of this study was to examine whether iron and Aβ plaque accumulation is related and thus, whether 7T MRI might be an additive diagnostic tool to Aβ PET imaging. METHODS: Postmortem human Alzheimer's disease (AD) and healthy control (HC) frontal gray matter (GM) was imaged with 7T MRI which resulted in T1 maps and QSM. Aβ plaque load was determined by histopathology. In vivo, 10 Aβ PET-positive AD patients (74.1±6.0a) and 10 Aβ PET-negative HCs (67.1±4.4a) underwent 7T MR examination and QSM maps were analyzed. Severity of cognitive deficits was determined by MMSE. RESULTS: Postmortem, the susceptibility of Aβ plaque-containing GM were higher than those of Aβ plaque-free GM (0.011±0.002 versus - 0.008±0.003 ppm, p < 0.001). In vivo, only the bilateral globus pallidus showed significantly higher susceptibility in AD patients compared to HCs (right: 0.277±0.018 versus - 0.009±0.009 ppm; left: 0.293±0.014 versus - 0.007±0.012 ppm, p < 0.0001). The pallidal QSM values were negatively correlated with those of the MMSE (r = - 0.69, p = 0.001). CONCLUSION: The postmortem study revealed significant susceptibility differences between the Aβ plaque-containing and Aβ plaque-free GM, whereas in vivo only the QSM values of the globus pallidus differed significantly between AD and HC group. The pallidal QSM values correlated with the severity of cognitive deficits. These findings encourage efforts to optimize the 7T-QSM methodology.

Rab10 Phosphorylation is a Prominent Pathological Feature in Alzheimer's Disease. - Yan, Tingxiang; Wang, Luwen; Gao, Ju; Siedlak, Sandra L; Huntley, Mikayla L; Termsarasab, Pichet; Perry, George; Chen, Shu G; Wang, Xinglong (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized by neurofibrillary tangles (NFTs), senile plaques (SPs), and a progressive loss of neuronal cells in selective brain regions. Rab10, a small Rab GTPase involved in vesicular trafficking, has recently been identified as a novel protein associated with AD. Interestingly, Rab10 is a key substrate of leucine-rich repeat kinase 2 (LRRK2), a serine/threonine protein kinase genetically associated with the second most common neurodegenerative disease Parkinson's disease. However, the phosphorylation state of Rab10 has not yet been investigated in AD. Here, using a specific antibody recognizing LRRK2-mediated Rab10 phosphorylation at the amino acid residue threonine 73 (pRab10-T73), we performed immunocytochemical analysis of pRab10-T73 in hippocampal tissues of patients with AD. pRab10-T73 was prominent in NFTs in neurons within the hippocampus in all cases of AD examined, whereas immunoreactivity was very faint in control cases. Other characteristic AD pathological structures including granulovacuolar degeneration, dystrophic neurites and neuropil threads also contained pRab10-T73. The pRab10-T73 immunoreactivity was diminished greatly following dephosphorylation with alkaline phosphatase. pRab10-T73 was further found to be highly co-localized with hyperphosphorylated tau (pTau) in AD, and demonstrated similar pathological patterns as pTau in Down syndrome and progressive supranuclear palsy. Although pRab10-T73 immunoreactivity could be noted in dystrophic neurites surrounding SPs, SPs were largely negative for pRab10-T73. These findings indicate that Rab10 phosphorylation could be responsible for aberrations in the vesicle trafficking observed in AD leading to neurodegeneration.

Rationale and Design of the Mechanistic Potential of Antihypertensives in Preclinical Alzheimer's (HEART) Trial. - Wharton, Whitney; Goldstein, Felicia C; Tansey, Malú G; Brown, Alexandra L; Tharwani, Sonum D; Verble, Danielle D; Cintron, Amarallys; Kehoe, Patrick G (J Alzheimers Dis, 2018)
Research indicates that certain antihypertensive medications alter Alzheimer's disease (AD) biomarkers in Caucasians. The renin angiotensin system (RAS) regulates blood pressure (BP) in the body and the brain and may directly influence AD biomarkers, including amyloid-β (Aβ) neuropathology, cerebral blood flow (CBF), and inflammatory markers. This hypothesis is supported by studies, including ours, showing that antihypertensives targeting the RAS reduce the risk and slow the progression of AD in Caucasians. While mounting evidence supports a protective role of RAS medications in Caucasians, this mechanism has not been explored in African Americans. To assess the mechanism by which RAS medications modify the brain RAS, cerebrospinal fluid (CSF) Aβ, CBF, and inflammatory markers in African Americans, we are conducting an eight month, Phase Ib randomized, placebo controlled trial, enrolling 60 middle-aged (45-70 years), non-demented individuals, at risk for AD by virtue of a parental history. Participants include normotensive and treated hypertensives that have never been exposed to a RAS medication. Participants are randomized (1 : 1:1) by gender and BP medication use (yes/no) to one of three groups: placebo, or 20 mg, or 40 mg telmisartan (Micardis), to determine the dose required to penetrate the CNS. Our overarching hypothesis is that, compared to placebo, both doses of telmisartan will penetrate the CNS and produce salutary, dose dependent effects on the brain RAS as well as CSF Aβ, CBF, and CSF inflammatory markers in African Americans, over eight months. This manuscript describes the trial rationale and design.
Keywords: African Americans; Aged; Alzheimer Disease; Amyloid beta-Peptides; Antihypertensive Agents; Biomarkers; Blood Pressure; Brain; Clinical Trials, Phase I as Topic; Female; Georgia; Humans; Linear Models; Male; Middle Aged; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Telmisartan

The Rationale Behind the New Alzheimer's Disease Conceptualization: Lessons Learned During the Last Decades. - Molinuevo, José Luis; Minguillon, Carolina; Rami, Lorena; Gispert, Juan Domingo (J Alzheimers Dis, 2018)
In the last decades, progress in neuroimaging techniques and cerebrospinal fluid assays has enabled the characterization of several Alzheimer's disease (AD) biomarkers. This knowledge has shifted the conceptualization of AD from a clinical-pathological construct, where its diagnosis required the presence of dementia with distinct pathologic features, toward a clinical-biological one that recognizes AD as a pathological continuum with a clinical picture that ranges from normal cognition to a dementia stage. Specifically, AD is now divided into three stages: preclinical (abnormal biomarkers and no or only subtle cognitive impairment), mild cognitive impairment or prodromal AD (abnormal pathophysiological biomarkers and episodic memory impairment), and dementia (abnormal biomarkers and clear cognitive and functional impairment). The possibility of assessing AD pathophysiology in vivo before the onset of clinical symptoms in the preclinical stage provides the unprecedented opportunity to intervene at earlier stages of the continuum in secondary prevention trials. Currently, large cohort studies of cognitively healthy participants are undergoing with the main aim of disentangling the natural history of AD to identify individuals with an increased risk of developing AD in the near future to be recruited in these clinical trials. In this paper, we review how the concept of AD has changed over the years as well as discuss the implications of this conceptual change.

Rbfox3/NeuN Regulates Alternative Splicing of Tau Exon 10. - Gu, Jianlan; Chen, Feng; Chu, Dandan; Lu, Ying; Iqbal, Khalid; Gong, Cheng-Xin; Liu, Fei (J Alzheimers Dis, 2018)
Alternative splicing of tau exon 10 generates tau isoforms with three or four microtubule-binding repeats, 3R-tau or 4R-tau, which are under developmental regulation. Dysregulation of tau exon 10 splicing is sufficient to cause neurodegenerative disorders. The RNA-binding Fox3 (Rbfox3), identified as NeuN, regulates RNA processing. However, whether Rbfox3/NeuN regulates tau exon 10 splicing is unknown. In the present study, we found that the developmental expression of 4R-tau coincided with the expression of Rbfox3 in rat brains. Rbfox3 enhanced tau exon 10 inclusion. Tau intron 10 contains UGCAUG, the conservative binding sequence of Rbfox3. Intron 10 of tau pre-mRNA was co-immunoprecipitated by Rbfox3/NeuN. Deletion mutants of the RNA recognition motif (RRM) or three RNA-binding sites of the RRM in Rbfox3/NeuN failed to enhance tau exon 10 inclusion. Rbfox3, specifically expressed in the fetal brain, did not affect tau exon 10 splicing. The level of Rbfox3/NeuN was reduced and was associated with the ratio of 4R-tau/3R-tau in the excitotoxic mouse brains induced by kainic acid. These findings suggest that Rbfox3/NeuN regulates the alternative splicing of tau exon 10 and that decreased Rbfox3/NeuN may lower the ratio of 4R-tau/3R-tau.

Regional Distribution, Asymmetry, and Clinical Correlates of Tau Uptake on [18F]AV-1451 PET in Atypical Alzheimer's Disease. - Tetzloff, Katerina A; Graff-Radford, Jonathan; Martin, Peter R; Tosakulwong, Nirubol; Machulda, Mary M; Duffy, Joseph R; Clark, Heather M; Senjem, Matthew L; Schwarz, Christopher G; Spychalla, Anthony J; Drubach, Daniel A; Jack, Clifford R; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Despite common pathology, Alzheimer's disease (AD) can have multiple clinical presentations which pathological studies suggest result from differences in the regional distribution of tau pathology. Positron emission tomography (PET) ligands are now available that can detect tau proteins in vivo and hence can be used to investigate the biological mechanisms underlying atypical AD. OBJECTIVE: To assess regional patterns of tau uptake on PET imaging in two atypical AD variants, posterior cortical atrophy (PCA) and logopenic progressive aphasia (lvPPA). METHODS: Eighteen PCA and 19 lvPPA subjects that showed amyloid-β deposition on PET underwent tau-PET imaging with [18F]AV-1451. Group comparisons of tau uptake in PCA and lvPPA were performed using voxel-level and regional-level analyses. We also assessed the degree of lobar tau asymmetry and correlated regional tau uptake to age and performance on clinical evaluations. RESULTS: Both syndromes showed diffuse tau uptake throughout all cortical regions, although PCA showed greater uptake in occipital regions compared to lvPPA, and lvPPA showed greater uptake in left frontal and temporal regions compared to PCA. While lvPPA showed predominant left-asymmetric tau deposition, PCA was more bilateral. Younger subjects showed greater tau uptake bilaterally in frontal and parietal lobes than older subjects, and sentence repetition, Boston naming test, simultanagnosia, and visuoperceptual function showed specific regional tau correlates. CONCLUSION: Tau deposition is closely related to clinical presentation in atypical AD with age playing a role in determining the degree of cortical tau deposition.

REM Sleep Behavior Disorder and Alzheimer's Disease: Definitely No Relationship? - Galbiati, Andrea; Carli, Giulia; Hensley, Michael; Ferini-Strambi, Luigi (J Alzheimers Dis, 2018)
Rapid eye movement (REM) sleep behavior disorder (RBD) is a REM sleep parasomnia characterized by the loss of the typical muscular atonia present during healthy REM sleep. RBD can occur in the absence of other neurological conditions or in association with a neurodegenerative disorder. It is now well established that RBD is a strong predictor of neurodegeneration, in particular synucleinopathies, such as Parkinson's disease, Lewy body dementia (LBD), or multiple system atrophy. However, some longitudinal studies report that a minority of patients develop either overlapping form of dementia or Alzheimer disease's (AD). Although AD is reported as a possible development in patients with RBD, it is in a limited number of cases and there are concerns about the accuracy of the diagnostic criteria. Neuropsychological impairments identified in cross-sectional studies of RBD patients describe a profile similar to that observed in dementia related to synucleinopathies. However, only deficits in executive function predict the development of neurodegeneration. Longitudinal studies reported the development of AD in RBD patients in about 7% of cases with variability ranging from 3% and 11%. Since the majority of longitudinal investigations do not report AD as a possible development for RBD patients the proportion may be overestimated. The study of the relationship between RBD and AD may be confounded by two factors that lead to misdiagnosis: the use of clinical criteria alone and the overlap between the clinical features and neuropathology of AD and LBD. Future studies to investigate this association must use updated diagnostic criteria incorporating ancillary investigations.

Rethinking the Reserve with a Translational Approach: Novel Ideas on the Construct and the Interventions. - Serra, Laura; Gelfo, Francesca; Petrosini, Laura; Di Domenico, Carlotta; Bozzali, Marco; Caltagirone, Carlo (J Alzheimers Dis, 2018)
The concept of brain, cognitive, and neural reserves has been introduced to account for the apparent discrepancies between neurological damage and clinical manifestations. However, these ideas are yet theoretical suggestions that are not completely assimilated in the clinical routine. The mechanisms of the reserves have been extensively studied in neurodegenerative pathologies, in particular in Alzheimer's disease. Both human and animal studies addressed this topic by following two parallel pathways. The specific aim of the present review is to attempt to combine the suggestions derived from the two different research fields to deepen the knowledge about reserves. In fact, the achievement of a comprehensive theoretical framework on reserve mechanisms is an essential step to propose well-timed interventions tailored to the clinical characteristics of patients. The present review highlights the importance of addressing three main aspects: the definition of reserve proxy measures, the interaction between reserve level and therapeutic interventions, and the specific time-window of reserve efficacy.

Revolution of Alzheimer Precision Neurology. Passageway of Systems Biology and Neurophysiology. - Hampel, Harald; Toschi, Nicola; Babiloni, Claudio; Baldacci, Filippo; Black, Keith L; Bokde, Arun L W; Bun, René S; Cacciola, Francesco; Cavedo, Enrica; Chiesa, Patrizia A; Colliot, Olivier; Coman, Cristina-Maria; et al. (J Alzheimers Dis, 2018)
The Precision Neurology development process implements systems theory with system biology and neurophysiology in a parallel, bidirectional research path: a combined hypothesis-driven investigation of systems dysfunction within distinct molecular, cellular, and large-scale neural network systems in both animal models as well as through tests for the usefulness of these candidate dynamic systems biomarkers in different diseases and subgroups at different stages of pathophysiological progression. This translational research path is paralleled by an "omics"-based, hypothesis-free, exploratory research pathway, which will collect multimodal data from progressing asymptomatic, preclinical, and clinical neurodegenerative disease (ND) populations, within the wide continuous biological and clinical spectrum of ND, applying high-throughput and high-content technologies combined with powerful computational and statistical modeling tools, aimed at identifying novel dysfunctional systems and predictive marker signatures associated with ND. The goals are to identify common biological denominators or differentiating classifiers across the continuum of ND during detectable stages of pathophysiological progression, characterize systems-based intermediate endophenotypes, validate multi-modal novel diagnostic systems biomarkers, and advance clinical intervention trial designs by utilizing systems-based intermediate endophenotypes and candidate surrogate markers. Achieving these goals is key to the ultimate development of early and effective individualized treatment of ND, such as Alzheimer's disease. The Alzheimer Precision Medicine Initiative (APMI) and cohort program (APMI-CP), as well as the Paris based core of the Sorbonne University Clinical Research Group "Alzheimer Precision Medicine" (GRC-APM) were recently launched to facilitate the passageway from conventional clinical diagnostic and drug development toward breakthrough innovation based on the investigation of the comprehensive biological nature of aging individuals. The APMI movement is gaining momentum to systematically apply both systems neurophysiology and systems biology in exploratory translational neuroscience research on ND.
Keywords: Alzheimer Disease; Animals; Brain; Humans; Neurology; Neurophysiology; Precision Medicine; Systems Biology; Translational Medical Research

Risk of Conversion to Dementia in a Mild Behavioral Impairment Group Compared to a Psychiatric Group and to a Mild Cognitive Impairment Group. - Taragano, Fernando E; Allegri, Ricardo F; Heisecke, Silvina L; Martelli, María I; Feldman, Mónica L; Sánchez, Viviana; García, Virginia A; Tufro, Graciela; Castro, Diego M; Leguizamón, Patricio Perez; Guelar, Verónica; Ruotolo, Eva; et al. (J Alzheimers Dis, 2018)
BACKGROUND: There is insufficient available information on behavioral changes in the absence of cognitive impairment as factors increasing the risk of conversion to dementia. OBJECTIVE: To observe and analyze patients with mild behavioral impairment (MBI), mild cognitive impairment (MCI), and a psychiatry group (PG) to compare the risk of progression to dementia. METHODS: From 677 initially assessed ≥60-year-old patients, a series of 348 patients was studied for a five-year period until censoring or conversion to dementia: 96 with MBI, 87 with MCI, and 165 with general psychiatry disorders, including 4 subgroups: Anxiety, Depression, Psychosis and Others. All patients were assessed with clinical, psychiatric, neurological, neuropsychological, and neuroimaging studies. RESULTS: From 348 patients, 126 evolved to dementia (36.2%). Conversion was significantly higher in MBI (71.5%), followed by the MCI-MBI overlap (59.6%) and MCI (37.8%) groups, compared to PG (13.9%) (Log-rank p < 0.001). MCI patients mostly converted to Alzheimer's dementia, while MBI converted to frontotemporal dementia and Lewy body dementia. Patients in PG converted to Lewy body dementia and frontotemporal dementia. CONCLUSION: Conversion to dementia is significantly higher in patients with neuropsychiatric symptoms. The MBI concept generates a new milestone in the refining of diagnosis of neurodegenerative diseases and the possibility of creating neuropsychiatric profiles. Its earlier identification will allow new possibilities for therapeutic intervention.

Role of Amyloid-β and Tau Proteins in Alzheimer's Disease: Confuting the Amyloid Cascade. - Gulisano, Walter; Maugeri, Daniele; Baltrons, Marian A; Fà, Mauro; Amato, Arianna; Palmeri, Agostino; D'Adamio, Luciano; Grassi, Claudio; Devanand, D P; Honig, Lawrence S; Puzzo, Daniela; Arancio, Ottavio (J Alzheimers Dis, 2018)
The "Amyloid Cascade Hypothesis" has dominated the Alzheimer's disease (AD) field in the last 25 years. It posits that the increase of amyloid-β (Aβ) is the key event in AD that triggers tau pathology followed by neuronal death and eventually, the disease. However, therapeutic approaches aimed at decreasing Aβ levels have so far failed, and tau-based clinical trials have not yet produced positive findings. This begs the question of whether the hypothesis is correct. Here we have examined literature on the role of Aβ and tau in synaptic dysfunction, memory loss, and seeding and spreading of AD, highlighting important parallelisms between the two proteins in all of these phenomena. We discuss novel findings showing binding of both Aβ and tau oligomers to amyloid-β protein precursor (AβPP), and the requirement for the presence of this protein for both Aβ and tau to enter neurons and induce abnormal synaptic function and memory. Most importantly, we propose a novel view of AD pathogenesis in which extracellular oligomers of Aβ and tau act in parallel and upstream of AβPP. Such a view will call for a reconsideration of therapeutic approaches directed against Aβ and tau, paving the way to an increased interest toward AβPP, both for understanding the pathogenesis of the disease and elaborating new therapeutic strategies.

Role of Genetics and Epigenetics in the Pathogenesis of Alzheimer's Disease and Frontotemporal Dementia. - Fenoglio, Chiara; Scarpini, Elio; Serpente, Maria; Galimberti, Daniela (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) and frontotemporal dementia (FTD) represent the first cause of dementia in senile and pre-senile population, respectively. A percentage of cases have a genetic cause, inherited with an autosomal dominant pattern of transmission. The majority of cases, however, derive from complex interactions between a number of genetic and environmental factors. Gene variants may act as risk or protective factors. Their combination with a variety of environmental exposures may result in increased susceptibility to these diseases or may influence their course. The scenario is even more complicated considering the effect of epigenetics, which encompasses mechanisms able to alter the expression of genes without altering the DNA sequence. In this review, an overview of the current genetic and epigenetic progresses in AD and FTD will be provided, with particular focus on 1) causative genes, 2) genetic risk factors and disease modifiers, and 3) epigenetics, including methylation, non-coding RNAs and chromatin remodeling.
Keywords: Alzheimer Disease; Animals; Epigenesis, Genetic; Frontotemporal Dementia; Genetic Predisposition to Disease; Humans

A Selection of Important Genes and Their Correlated Behavior in Alzheimer's Disease. - Cruz-Rivera, Yazeli E; Perez-Morales, Jaileene; Santiago, Yaritza M; Gonzalez, Valerie M; Morales, Luisa; Cabrera-Rios, Mauricio; Isaza, Clara E (J Alzheimers Dis, 2018)
In 2017, approximately 5 million Americans were living with Alzheimer's disease (AD), and it is estimated that by 2050 this number could increase to 16 million. In this study, we apply mathematical optimization to approach microarray analysis to detect differentially expressed genes and determine the most correlated structure among their expression changes. The analysis of GSE4757 microarray dataset, which compares expression between AD neurons without neurofibrillary tangles (controls) and with neurofibrillary tangles (cases), was casted as a multiple criteria optimization (MCO) problem. Through the analysis it was possible to determine a series of Pareto efficient frontiers to find the most differentially expressed genes, which are here proposed as potential AD biomarkers. The Traveling Sales Problem (TSP) model was used to find the cyclical path of maximal correlation between the expression changes among the genes deemed important from the previous stage. This leads to a structure capable of guiding biological exploration with enhanced precision and repeatability. Ten genes were selected (FTL, GFAP, HNRNPA3, COX1, ND2, ND3, ND4, NUCKS1, RPL41, and RPS10) and their most correlated cyclic structure was found in our analyses. The biological functions of their products were found to be linked to inflammation and neurodegenerative diseases and some of them had not been reported for AD before. The TSP path connects genes coding for mitochondrial electron transfer proteins. Some of these proteins are closely related to other electron transport proteins already reported as important for AD.

Self- and Informant-Reported Memory Complaints: Frequency and Severity in Cognitively Intact Individuals and those with Mild Cognitive Impairment and Neurodegenerative Dementias. - Rahman-Filipiak, Annalise M; Giordani, Bruno; Heidebrink, Judith; Bhaumik, Arijit; Hampstead, Benjamin M (J Alzheimers Dis, 2018)
BACKGROUND: Subjective memory complaints (SMCs) are incorporated into the diagnosis of mild cognitive impairment (MCI) and neurodegenerative dementias; however, the relative frequency of SMCs in cognitively intact older adults and those with different types of dementia is poorly understood. Similarly, the concordance between self- versus informant-reported SMCs has not been compared across different diagnostic groups. OBJECTIVE: This study aimed to evaluate the frequency of self-reported (Objective 1) and informant-reported (Objective 2) SMCs in cognitively intact adults or those diagnosed with MCI or a neurodegenerative dementia. Agreement between participant and informant complaints was also evaluated (Objective 3). METHODS: Baseline evaluation data were drawn from 488 participants (Mage = 70.49 years; Medu = 15.62 years) diagnosed as cognitively intact, non-amnestic MCI, amnestic single domain MCI, amnestic multi-domain MCI, possible/probable Alzheimer's disease, dementia with Lewy bodies, or frontotemporal dementia. Participants and their informants completed the Memory Assessment Clinic Questionnaire. RESULTS: One-way ANCOVAs controlling for age, education, and depression revealed no group differences in severity of self-reported SMCs. In contrast, informant memory ratings followed the expected clinical pattern, with comparable and most impaired ratings given to participants with any dementia diagnosis, followed by those with any MCI diagnosis, followed by cognitively intact participants. There was inconsistent agreement between self- and informant-reported SMC ratings in any of the impaired groups. CONCLUSIONS: Given greater diagnostic specificity and internal consistency of informant report, clinicians should weigh this information more heavily than self-report in the diagnostic process.

Serotonin Selective Reuptake Inhibitor Treatment Improves Cognition and Grey Matter Atrophy but not Amyloid Burden During Two-Year Follow-Up in Mild Cognitive Impairment and Alzheimer's Disease Patients with Depressive Symptoms. - Brendel, Matthias; Sauerbeck, Julia; Greven, Sonja; Kotz, Sebastian; Scheiwein, Franziska; Blautzik, Janusch; Delker, Andreas; Pogarell, Oliver; Ishii, Kazunari; Bartenstein, Peter; Rominger, Axel (J Alzheimers Dis, 2018)
Late-life depression, even when of subsyndromal severity, has shown strong associations with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Preclinical studies have suggested that serotonin selective reuptake inhibitors (SSRIs) can attenuate amyloidogenesis. Therefore, we aimed to investigate the effect of SSRI medication on amyloidosis and grey matter volume in subsyndromal depressed subjects with MCI and AD during an interval of two years. 256 cognitively affected subjects (225 MCI/ 31 AD) undergoing [18F]-AV45-PET and MRI at baseline and 2-year follow-up were selected from the ADNI database. Subjects with a positive depression item (DEP(+); n = 73) in the Neuropsychiatric Inventory Questionnaire were subdivided to those receiving SSRI medication (SSRI(+); n = 24) and those without SSRI treatment (SSRI(-); n = 49). Longitudinal cognition (Δ-ADAS), amyloid deposition rate (standardized uptake value, using white matter as reference region (SUVRWM), and changes in grey matter volume were compared using common covariates. Analyses were performed separately in all subjects and in the subgroup of amyloid-positive subjects. Cognitive performance in DEP(+)/SSRI(+) subjects (Δ-ADAS: -5.0%) showed less deterioration with 2-year follow-up when compared to DEP(+)/SSRI(-) subjects (Δ-ADAS: +18.6%, p < 0.05), independent of amyloid SUVRWM at baseline. With SSRI treatment, the progression of grey matter atrophy was reduced (-0.9% versus -2.7%, p < 0.05), notably in fronto-temporal cortex. A slight trend towards lower amyloid deposition rate was observed in DEP(+)/SSRI(+) subjects versus DEP(+)/SSRI(-). Despite the lack of effect to amyloid PET, SSRI medication distinctly rescued the declining cognitive performance in cognitively affected patients with depressive symptoms, and likewise attenuated grey matter atrophy.

Serum Copper is not Altered in Frontotemporal Lobar Degeneration. - Squitti, Rosanna; Fostinelli, Silvia; Siotto, Mariacristina; Ferrari, Clarissa; Binetti, Giuliano; Benussi, Luisa; Rongioletti, Mauro; Ghidoni, Roberta (J Alzheimers Dis, 2018)
Meta-analyses show copper dyshomeostasis in Alzheimer's disease. However, a study evaluating copper changes in other neurodegenerative forms of dementia has not yet been performed. In this study, we assessed copper, ceruloplasmin, copper not bound to ceruloplasmin, and copper to ceruloplasmin ratio in 85 patients affected by frontotemporal lobar degeneration (FTLD) and 55 healthy controls. Data were analyzed through multivariate ANOVA models taking into account age and sex as covariates and the stratification for FTLD variants, after calculating power analysis to ensure the reliability of the conclusions drawn. The study revealed no difference between the groups.

Serum C-Peptide, Visfatin, Resistin, and Ghrelin are Altered in Sporadic and GRN-Associated Frontotemporal Lobar Degeneration. - Zanardini, Roberta; Benussi, Luisa; Fostinelli, Silvia; Saraceno, Claudia; Ciani, Miriam; Borroni, Barbara; Padovani, Alessandro; Binetti, Giuliano; Ghidoni, Roberta (J Alzheimers Dis, 2018)
Frontotemporal lobar degeneration (FTLD) is a group of complex neurodegenerative disease characterized by progressive deterioration of the frontal and anterior temporal lobes of the brain resulting in different heterogeneous conditions, mainly characterized by personality changes, behavioral disturbances, such as binge eating, and deficits in language and executive functions. Null mutations in progranulin gene (GRN) are one of the most frequent genetic determinants in familial frontotemporal dementia. Recently, progranulin was recognized as an adipokine involved in diet-induced obesity and insulin resistance revealing its metabolic function. Increasing evidence suggests that neurodegenerative dementias are associated with a higher prevalence of metabolic changes than in the general population. According to these findings, the aim of this study is to investigate putative alterations in markers linked to metabolic functions (i.e., C-peptide, ghrelin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, glucagon, insulin, resistin, and three adipokines as visfatin, leptin, and plasminogen activator inhibitor-1 total) in sporadic and GRN-related FTLD. We found that 1) C-peptide is increased in sporadic and GRN-mutated FTLD patients; in addition, we demonstrated an anticipation of the disease in patients with the highest C-peptide concentrations; 2) visfatin is slightly reduced in the whole FTLD group; 3) resistin, an adipokine involved in inflammatory-related diseases, is specifically increased in FTLD due to GRN null mutations; 4) ghrelin concentration is specifically increased in pre-symptomatic subjects and FTLD patients with GRN mutations. These findings support the hypothesis that alterations in metabolic pattern are involved in FTLD progression highlighting novel putative targets for the development of preventive and personalized therapies.
Keywords: Aged; Biomarkers; C-Peptide; Female; Frontotemporal Lobar Degeneration; Ghrelin; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mutation; Nicotinamide Phosphoribosyltransferase; Progranulins; Resistin

Serum Non-Ceruloplasmin Non-Albumin Copper Elevation in Mild Cognitive Impairment and Dementia due to Alzheimer's Disease: A Case Control Study. - Rozzini, Luca; Lanfranchi, Francesco; Pilotto, Andrea; Catalani, Simona; Gilberti, Maria Enrica; Paganelli, Matteo; Apostoli, Pietro; Padovani, Alessandro (J Alzheimers Dis, 2018)
Several studies showed high serum copper levels in Alzheimer's disease (AD). The present study applied a newly developed method to detect serum copper free from proteins (free-Cu). Forty-four patients affected by dementia due to AD, thirty-six patients affected by mild cognitive impairment (MCI) due to AD, and twenty-eight healthy controls underwent clinical, cognitive, and MRI assessment. The new method showed higher free-Cu concentrations in MCI and dementia due to AD compared to controls (p < 0.0001). No correlation between copper levels, cognitive or MRI measures were found.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Case-Control Studies; Cognitive Dysfunction; Copper; Female; Humans; Magnetic Resonance Imaging; Male; Psychiatric Status Rating Scales

Severe Agitation in Dementia: An Explorative Secondary Data Analysis on the Prevalence and Associated Factors in Nursing Home Residents. - Palm, Rebecca; Sorg, Christian G G; Ströbel, Armin; Gerritsen, Debby L; Holle, Bernhard (J Alzheimers Dis, 2018)
BACKGROUND: The phenomena of severe agitation is not well understood and often not adequately treated. OBJECTIVE: This article determines the prevalence and associated factors of severe agitation in nursing home residents with dementia. METHODS: Secondary data analysis within an observational study in German nursing homes with n = 1,967 participants. We assessed severity of agitation with the Neuropsychiatric Inventory Questionnaire (NPI-Q) and defined the construct of agitation as a composite score of the NPI-Q items agitation/aggression, disinhibition, and irritability/lability; the dependent variable of severe agitation was considered as being present in residents who scored 'severe' in at least one of these symptoms. A binary logistic regression model was calculated to estimate associations. RESULTS: The prevalence of severe agitation was 6.3% (n = 124). The strongest associations were found for elation/euphoria (OR 7.6, CI 3.1-18.5), delusions (OR 7.3, CI 4.0-13.2), apathy/indifference (OR 2.8, CI 1.7-4.7), anxiety (OR 2.2, CI 1.2-3.8), nighttime behaviors (OR 2.4, CI 1.4-4.2), motor disturbances (OR 2.4, CI 1.4-4.1), and male sex (OR 2.4. CI 1.3-4.2). CONCLUSION: Severe agitation in nursing home residents with dementia is a relevant clinical issue as approximately 70% of residents have a dementia. Residents with elation/euphoria and delusions may have a stronger risk of showing severe agitation. We consider delusions as a possible cause of agitation and therefore a prelude to agitation. Although it might be possible that elation/euphoria follows from agitation, we hypothesize that the residents first experience elation/ euphoria and exhibit agitation afterwards.

Sex Influences the Accuracy of Subjective Memory Complaint Reporting in Older Adults. - Sundermann, Erin E; Edmonds, Emily C; Delano-Wood, Lisa; Galasko, Douglas R; Salmon, David P; Rubin, Leah H; Bondi, Mark W (J Alzheimers Dis, 2018)
Subjective memory complaints (SMC) are required when diagnosing amnestic mild cognitive impairment (aMCI), although their relationship with objective memory performance and Alzheimer's disease (AD) pathology remains unclear. We investigated whether the sex of the patient/participant moderates these associations. Participants were 940 normal control (NC) and aMCI participants from the Alzheimer's Disease Neuroimaging Initiative. SMC were assessed via the memory scale of the Everyday Cognition questionnaire. Discrepancy scores were calculated between self- and informant-reports and categorized into "overestimates," "comparable estimates", and "underestimates" of SMC. We conducted linear and logistic regressions to examine the interaction of sex with self- and informant-reported SMC and discrepancy group on the Rey Auditory Verbal Learning Test (RAVLT) Immediate and Delayed Recall and on PET measures of amyloid-β (Aβ) positivity. Diagnosis-stratified analyses were also conducted. Overall, there were sex by self- and informant-reported SMC interactions for Immediate and Delayed Recall. Despite a higher proportion of "overestimates" in women, greater self- and informant-reported SMC showed a stronger relationship to poorer RAVLT scores in women versus men. Diagnosis-stratified analyses revealed that results were driven by aMCI participants. Conversely, overall, greater self- and informant-reported SMC related to greater odds of Aβ positivity regardless of sex. In diagnosis-stratified analyses, only informant-reported SMC related to Aβ positivity in aMCI. Relative to "comparable estimates," "underestimates" of SMC were associated with poorer RAVLT scores across sexes in the overall sample and in aMCI. The predictive utility of self-report SMC may be limited to women in aMCI. Sex differences should be considered when evaluating SMC.
Keywords: Aged; Cognitive Dysfunction; Female; Humans; Logistic Models; Male; Memory Disorders; Mental Recall; Neuropsychological Tests; Self Report; Sex Factors

Simultaneous Aerobic Exercise and Memory Training Program in Older Adults with Subjective Memory Impairments. - McEwen, Sarah C; Siddarth, Prabha; Abedelsater, Berna; Kim, Yena; Mui, Wenli; Wu, Pauline; Emerson, Natacha D; Lee, Jacob; Greenberg, Shayna; Shelton, Tiffany; Kaiser, Scott; Small, Gary W; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Several modifiable lifestyle factors have been shown to have potential beneficial effects in slowing cognitive decline. Two such factors that may affect cognitive performance and slow the progression of memory loss into dementia in older adults are cognitive training and physical activity. There are currently no effective treatments for dementia; therefore, preventative strategies to delay or prevent the onset of dementia are of critical importance. OBJECTIVE: The aim of this study was to determine the relative effectiveness of simultaneous performance of memory training and aerobic exercise to a sequential performance intervention on memory functioning in older adults. METHODS: 55 older adults (aged 60- 75) with subjective memory impairments (non-demented and non-MCI) completed the intervention that consisted of 90-minute small group classes held twice weekly. Participants were randomized to either 4-weeks of supervised strategy-based memory training done simultaneously while stationary cycling (SIM) or sequentially after the stationary cycling (SEQ). Standardized neurocognitive measures of memory, executive functioning, speed of processing, attention, and cognitive flexibility were assessed at baseline and post-intervention. RESULTS: The SIM group, but not the SEQ group, had a significant improvement on composite memory following the intervention (t(51) = 2.7, p = 0.01, effect size (ES) = 0.42) and transfer to non-trained reasoning abilities (t(51) = 6.0, ES = 0.49) and complex attention (t(51) = 3.1, p = 0.003, ES = 0.70). Conversely, the SEQ group, but not the SIM, showed significant improvement in executive functioning (t(51) = 5.0, p = 0.0001, ES = 0.96). CONCLUSION: These findings indicate that a 4-week simultaneous memory training and aerobic exercise program is sufficient to improve memory, attention, and reasoning abilities in older adults.
Keywords: Aged; Attention; California; Cognition; Executive Function; Exercise; Female; Humans; Learning; Male; Memory; Memory Disorders; Middle Aged; Treatment Outcome

Social Dysfunction in Older Age and Relationships with Cognition, Depression, and Apathy: The GreatAGE Study. - Lozupone, Madia; Panza, Francesco; Piccininni, Marco; Copetti, Massimiliano; Sardone, Rodolfo; Imbimbo, Bruno P; Stella, Eleonora; D'Urso, Francesca; Barulli, Maria Rosaria; Battista, Petronilla; Grasso, Alessandra; Tortelli, Rosanna; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Most studies focused on only one measure of social dysfunction in older age, without proper validation and distinction across different dimensions including subjectivity, structural, and functional aspects. OBJECTIVE: We sought to validate the Social Dysfunction Rating Scale (SDRS) and its factorial structure, also determining the association of SDRS with cognitive functions, global psychopathology, and social deprivation. METHODS: The SDRS was administered to 484 Italian community-dwelling elderly, recruited in the GreatAGE study, a population-based study on aging conducted in Castellana Grotte, Bari, Southern Italy. We determined objective and subjective psychometric properties of SDRS against the gold standard evaluation of social dysfunction according to the Semi-structured Clinical Diagnostic Interview for DSM-IV-TR Axis I Disorders (SCID-I) criterion. RESULTS: The SDRS showed a moderate accuracy with an optimal cut-off of 26 maximized with higher sensitivity (0.74,95% CI:0.63-0.84) than specificity (0.57,95% CI:0.50-0.64). A five-factor structure was carried out and five dimensions of SDRS were identified (loneliness; social isolation; feeling of contribution/uselessness; lack of leisure activities; anxiety for the health). Education and global cognitive functions were inversely correlated to SDRS, while a direct association with global psychopathology, depression, and apathy was found. The prevalence of higher SDRS scores was major in subjects with current psychiatric disorders versus other subjects.∥Conclusion: The SDRS could be a valid instrument to capture both size and quality of social dysfunction, both in subjects with psychiatric disorders and in normal subjects. Several categories of social dysfunction differed only in the degree of health deprivation, not in social or material deprivation.

SORL1 Variants in Familial Alzheimer's Disease. - Gómez-Tortosa, Estrella; Ruggiero, María; Sainz, Ma José; Villarejo-Galende, Alberto; Prieto-Jurczynska, Cristina; Venegas Pérez, Begoña; Ordás, Carlos; Agüero, Pablo; Guerrero-López, Rosa; Pérez-Pérez, Julián (J Alzheimers Dis, 2018)
The SORL1 gene encodes a protein involved in the amyloidogenic process, and its variants have been associated with Alzheimer's disease (AD) physiopathology. We screened for SORL1 variants in 124 familial (44 early- and 80 late-onset) dementia of Alzheimer type (DAT) cases. Nine potentially pathogenic changes (three not previously reported and six rare variants) were found in nine probands (7%). After screening the control population and siblings (presence in at least 1/200 controls and/or absence of segregation pattern), a causal relationship with the disease was considered unlikely in six variants and uncertain in one. The change Trp848Ter and a splice-site variant remained likely correlated with the disease. SORL1 mutations are present in 7% of our familial DAT cohort, though in most cases cannot be considered the direct cause of the disease.
Keywords: Aged; Alzheimer Disease; Case-Control Studies; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; LDL-Receptor Related Proteins; Male; Membrane Transport Proteins; Middle Aged; Mutation; Polymorphism, Single Nucleotide; Siblings; Spain

Stabilized Low-n Amyloid-β Oligomers Induce Robust Novel Object Recognition Deficits Associated with Inflammatory, Synaptic, and GABAergic Dysfunction in the Rat. - Watremez, William; Jackson, Joshua; Almari, Bushra; McLean, Samantha L; Grayson, Ben; Neill, Joanna C; Fischer, Nicolas; Allouche, Ahmad; Koziel, Violette; Pillot, Thierry; Harte, Michael K (J Alzheimers Dis, 2018)
BACKGROUND: With current treatments for Alzheimer's disease (AD) only providing temporary symptomatic benefits, disease modifying drugs are urgently required. This approach relies on improved understanding of the early pathophysiology of AD. A new hypothesis has emerged, in which early memory loss is considered a synapse failure caused by soluble amyloid-β oligomers (Aβo). These small soluble Aβo, which precede the formation of larger fibrillar assemblies, may be the main cause of early AD pathologies. OBJECTIVE: The aim of the current study was to investigate the effect of acute administration of stabilized low-n amyloid-β1-42 oligomers (Aβo1-42) on cognitive, inflammatory, synaptic, and neuronal markers in the rat. METHODS: Female and male Lister Hooded rats received acute intracerebroventricular (ICV) administration of either vehicle or 5 nmol of Aβo1-42 (10μL). Cognition was assessed in the novel object recognition (NOR) paradigm at different time points. Levels of inflammatory (IL-1β, IL-6, TNF-α), synaptic (PSD-95, SNAP-25), and neuronal (n-acetylaspartate, parvalbumin-positive cells) markers were investigated in different brain regions (prefrontal and frontal cortex, striatum, dorsal and ventral hippocampus). RESULTS: Acute ICV administration of Aβo1-42 induced robust and enduring NOR deficits. These deficits were reversed by acute administration of donepezil and rolipram but not risperidone. Postmortem analysis revealed an increase in inflammatory markers, a decrease in synaptic markers and parvalbumin containing interneurons in the frontal cortex, with no evidence of widespread neuronal loss. CONCLUSION: Taken together the results suggest that acute administration of soluble low-n Aβo may be a useful model to study the early mechanisms involved in AD and provide us with a platform for testing novel therapeutic approaches that target the early underlying synaptic pathology.

Statins and Brain Health: Alzheimer's Disease and Cerebrovascular Disease Biomarkers in Older Adults. - Ramanan, Vijay K; Przybelski, Scott A; Graff-Radford, Jonathan; Castillo, Anna M; Lowe, Val J; Mielke, Michelle M; Roberts, Rosebud O; Reid, Robert I; Knopman, David S; Jack, Clifford R; Petersen, Ronald C; Vemuri, Prashanthi (J Alzheimers Dis, 2018)
BACKGROUND: Statins have been proposed to reduce the risk of Alzheimer's disease (AD). OBJECTIVE: Assess whether long-term statin use was associated with neuroimaging biomarkers of aging and dementia. METHODS: Methods: We analyzed neuroimaging biomarkers in 1,160 individuals aged 65+ from the Mayo Clinic Study of Aging, a population-based prospective longitudinal study of cognitive aging. RESULTS: Statin-treated (5+ years of therapy) individuals had greater burden of mid-and late-life cardiovascular disease (p < 0.001) than statin-untreated (≤3 months) individuals. Lower fractional anisotropy in the genu of the corpus callosum, an early marker of cerebrovascular disease, was associated with long-term statin exposure (p < 0.035). No significant associations were identified between long-term statin exposure and cerebral amyloid or tau burden, AD pattern neurodegeneration, or white matter hyperintensity burden. CONCLUSIONS: Long-term statin therapy was not associated with differences in AD biomarkers. Individuals with long-term statin exposure had worse white matter integrity in the genu of the corpus callosum, consistent with the coexistence of higher cerebrovascular risk factor burden in this group.

Stimulation of SIRT1 Attenuates the Level of Oxidative Stress in the Brains of APP/PS1 Double Transgenic Mice and in Primary Neurons Exposed to Oligomers of the Amyloid-β Peptide. - Dong, Yang-Ting; Cao, Kun; Tan, Long-Chun; Wang, Xiao-Ling; Qi, Xiao-Lan; Xiao, Yan; Guan, Zhi-Zhong (J Alzheimers Dis, 2018)
In the study, we examined whether the silent information regulator 1 (SIRT1) can attenuate oxidative stress in the brains of mice carrying the APP/PS1 double mutation and/or in primary neonatal rat neurons exposed to oligomers of amyloid-β peptide (AβOs). Starting at 4 or 8 months of age, the transgenic mice were treated with resveratrol (RSV, a stimulator of SIRT1) or suramin (an inhibitor) (each 20 mg/kg BW/day) for two months. The primary neurons were exposed to AβOs (0.5 μM) for 48 h and thereafter RSV (20 μM) or suramin (300 mg/ml) for 24 h. Cell viability was assessed by the CCK-8 assay; SIRT1 protein and mRNA determined by western blotting and real-time PCR, respectively; senile plaques examined immunohistochemically; ROS monitored by flow cytometry; and the contents of OH-, H2O2, O2·-, and MDA, and the activities of SOD and GSH-Px measured by standard biochemical procedures. In comparison to wild-type mice or untreated primary neurons, the expression of SIRT1 was significantly lower in the brains of APP/PS1 mice or neurons exposed to AβOs. In these same systems, increased numbers of senile plaques and a high level of oxidative stress were apparent. Interestingly, these two latter changes were attenuated by treatment with RSV, but enhanced by suramin. These findings indicate that SIRT1 may be neuroprotective.

Structural Connectivity Alterations Along the Alzheimer's Disease Continuum: Reproducibility Across Two Independent Samples and Correlation with Cerebrospinal Fluid Amyloid-β and Tau. - Tucholka, Alan; Grau-Rivera, Oriol; Falcon, Carles; Rami, Lorena; Sánchez-Valle, Raquel; Lladó, Albert; Gispert, Juan Domingo; Molinuevo, José Luis (J Alzheimers Dis, 2018)
BACKGROUND: Gray matter changes associated with the progression of Alzheimer's disease (AD) have been thoroughly studied. However, alterations in white matter tracts have received less attention, particularly during early or preclinical stages of the disease. OBJECTIVE: To identify the structural connectivity changes across the AD continuum. METHODS: We performed probabilistic tractography in a total of 183 subjects on two independent samples that include control (n = 68) and preclinical AD individuals (n = 28), patients diagnosed with mild cognitive impairment (MCI) due to AD (n = 44), and AD patients (n = 43). We compared the connectivity between groups, and with CSF Aβ42 and tau biomarkers. RESULTS: We observed disconnections in preclinical individuals, mainly located in the temporal lobe. This pattern of disconnection spread to the parietal and frontal lobes at the MCI stage and involved almost all the brain in AD. These findings were not driven by gray matter atrophy. DISCUSSION: Using tractography, we were able to identify white matter changes between subsequent disease stages and, notably, also in preclinical AD. Therefore, this method may be useful for detecting early and specific brain structural changes during preclinical AD stage.
Keywords: Aged; Alzheimer Disease; Amyloid beta-Peptides; Atrophy; Biomarkers; Case-Control Studies; Cognitive Dysfunction; Cohort Studies; Disease Progression; Female; Gray Matter; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Reproducibility of Results; Spain; tau Proteins; White Matter

Subjective Cognitive Decline and APOE ɛ4: A Systematic Review. - Ali, Jordan I; Smart, Colette M; Gawryluk, Jodie R (J Alzheimers Dis, 2018)
Individuals with subjective cognitive decline (SCD) report self-perceived declines in cognitive function but perform within normal limits on standardized tests. However, for some, these self-perceived changes may herald eventual decline to Alzheimer's disease (AD). In light of this, the relationship between SCD and APOE ɛ4, a known genetic risk factor for AD, has garnered interest; however, no systematic review of this literature exists. The current review (n = 36 articles) examined the prevalence of APOE ɛ4 in SCD samples relative to healthy and objectively impaired samples, and summarized APOE ɛ4-related risk of conversion from SCD to AD. Univariate ANOVA indicated that APOE ɛ4 frequency was comparable between healthy control and SCD samples, yet significantly higher in objectively impaired samples (i.e., MCI, AD) relative to either of these groups. Narrative review provided mixed evidence linking coincident APOE ɛ4-positive genotype and SCD to structural neuropathology. Though there was little evidence to suggest that APOE ɛ4 predisposes individuals to developing SCD, both APOE ɛ4 and SCD were found to confer individual and multiplicative risk of conversion to objective cognitive impairment. Combined, it is likely that a relationship between APOE ɛ4, SCD, and AD exists, though its exact nature remains undetermined. A clearer understanding of these relationships is hindered by a lack of standardization in SCD classification and a dearth of longitudinal outcome research. Wide-scale adoption of genetic screening for dementia risk in persons with SCD is considered premature at this time. Ethical considerations and clinical implications of genetic testing for dementia risk are discussed.

Subjective Cognitive Decline, Objective Cognition, and Depression in Older Hispanics Screened for Memory Impairment. - Zlatar, Zvinka Z; Muniz, Martha C; Espinoza, Sarah G; Gratianne, Roberto; Gollan, Tamar H; Galasko, Douglas; Salmon, David P (J Alzheimers Dis, 2018)
Subjective cognitive decline (SCD) is common in older adults and may be an early marker of future cognitive decline. Research suggest that SCD is more closely related to concurrent symptoms of depression than to objective cognitive performance in non-Hispanic Whites, but it is unknown whether the associations of SCD, cognition, and depression manifest differently in Hispanic older adults. We examined if SCD is associated with objective cognitive performance or with depression symptoms in 145 Hispanic individuals ages 60 or older referred by community health clinics for screening of cognitive complaints. All participants lived near the U.S.-Mexico border, spoke Spanish only, or were Spanish-English bilingual. Memory-only and global cognitive composites were created from scores on Spanish versions of several neuropsychological tests. The Geriatric Depression Scale (GDS) and a five-item SCD questionnaire developed by our group were also completed. Multiple regression analyses showed no significant associations between SCD and memory or global cognitive composite scores after adjusting for age, sex, education, and GDS score. In contrast, there was a significant association between GDS and SCD after adjusting for age, sex, education, global and memory composite scores. Findings suggest that SCD does not accurately reflect current cognitive status in older Hispanics who present to their primary care physician with cognitive complaints. Clinicians should interpret SCD in this population within the context of information about symptoms of depression. Longitudinal research is needed in older Hispanics to better characterize SCD in this population and to determine if it can predict future cognitive decline.

Targeted Assessment of Enlargement of the Perivascular Space in Alzheimer's Disease and Vascular Dementia Subtypes Implicates Astroglial Involvement Specific to Alzheimer's Disease. - Boespflug, Erin L; Simon, Matthew J; Leonard, Emmalyn; Grafe, Marjorie; Woltjer, Randall; Silbert, Lisa C; Kaye, Jeffrey A; Iliff, Jeffrey J (J Alzheimers Dis, 2018)
Waste clearance from the brain parenchyma occurs along perivascular pathways. Enlargement of the perivascular space (ePVS) is associated with pathologic features of Alzheimer's disease (AD), although the mechanisms and implications of this dilation are unclear. Fluid exchange along the cerebral vasculature is dependent on the perivascular astrocytic water channel aquaporin-4 (AQP4) and loss of perivascular AQP4 localization is found in AD. We directly measured ePVS in postmortem samples of pathologically characterized tissue from participants who were cognitively intact or had AD or mixed dementia (vascular lesions with AD). We found that both AD and mixed dementia groups had significantly increased ePVS compared to cognitively intact subjects. In addition, we found increased global AQP4 expression of the AD group over both control and mixed dementia groups and a qualitative reduction in perivascular localization of AQP4 in the AD group. Among these cases, increasing ePVS burden was associated with the presence of tau and amyloid-β pathology. These findings are consistent with the existing evidence of ePVS in AD and provide novel information regarding differences in AD and vascular dementia and the potential role of astroglial pathology in ePVS.

Targeting Alzheimer's Disease at the Right Time and the Right Place: Validation of a Personalized Approach to Diagnosis and Treatment. - Gauthier, Serge; Ng, Kok Pin; Pascoal, Tharick A; Zhang, Hua; Rosa-Neto, Pedro (J Alzheimers Dis, 2018)
Cautious optimism is appropriate for a near future (five years) time frame for a number of drugs acting on the different pathophysiological components of Alzheimer's disease (amyloid deposition, tau hyperphosphorylation, neuroinflammation, vascular changes, to name the most important known so far). Since the relative weight of these components will be different between individuals and will even change over time for each individual, a 'one drug fit for all' approach is no longer defensible. Precision medicine using biomarkers in the diagnosis and treatment of Alzheimer's disease is the new strategy.

Tau and Amyloid Positron Emission Tomography Imaging Predict Driving Performance Among Older Adults with and without Preclinical Alzheimer's Disease. - Roe, Catherine M; Babulal, Ganesh M; Mishra, Shruti; Gordon, Brian A; Stout, Sarah H; Ott, Brian R; Carr, David B; Ances, Beau M; Morris, John C; Benzinger, Tammie L S (J Alzheimers Dis, 2018)
Abnormal levels of Alzheimer's disease (AD) biomarkers, measured by positron emission tomography imaging using amyloid-based radiotracers and cerebrospinal fluid, are associated with impaired driving performance in older adults. We examined whether preclinical AD staging, defined using amyloid imaging and tau imaging using the radiotracer T807 (AKA flortaucipir or AV-1451), was associated with receiving a marginal/fail rating on a standardized road test (n = 42). Participants at Stage 2 (positive amyloid and tau scans) of preclinical AD were more likely to receive a marginal/fail rating compared to participants at Stage 0 or 1. Stage 2 preclinical AD may manifest in worse driving performance.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Automobile Driving; Biomarkers; Carbolines; Female; Humans; Logistic Models; Male; Neuroimaging; Positron-Emission Tomography; tau Proteins

Is There a Characteristic Clinical Profile for Patients with Dementia and Sundown Syndrome? - Angulo Sevilla, David; Carreras Rodríguez, María Teresa; Heredia Rodríguez, Patricia; Fernández Sánchez, Marisa; Vivancos Mora, José Aurelio; Gago-Veiga, Ana Beatriz (J Alzheimers Dis, 2018)
BACKGROUND: Sundown syndrome (SS) is the onset or worsening of behavioral symptoms in the evening in patients with dementia. OBJECTIVE: To identify the differential clinical profile of patients with dementia who present SS. METHODS: A cross-sectional, case-control observational study was conducted by retrospectively reviewing the medical records of patients with dementia in a specialized Memory Unit. We compared the characteristics of patients with and without SS, including sociodemographic variables, etiology, and severity of the dementia, behavioral symptoms, sleep disorders (considering insomnia and hypersomnia), other diseases and treatments employed. We identified the factors related to SS and conducted a logistic regression analysis to establish a predictive nomogram. RESULTS: Of the 216 study patients with dementia, 41 (19%) had SS. There was a predominance of women (2.4:1), advanced age (p = 0.0001), dependence (p < 0.0001), institutionalization (p < 0.0001), caregiver burden (p < 0.0001), anxiety (p < 0.0001), delirium (p < 0.0001), hallucinations (p < 0.0001), wandering (p < 0.0001), Lewy body dementia (p = 0.05), higher Global Deterioration Scale score (GDS; p < 0.0001), and sleep disorders (p < 0.0001). The multivariate analysis revealed that age (p = 0.048), GDS score (p = 0.01), and the presence of insomnia or hypersomnia (p < 0.0001) independently defined the presence of SS. We established a predictive nomogram for developing SS in patients with dementia, with a predictive capacity of 80.1%. CONCLUSION: In our study, age, a higher score on the GDS, and the presence of insomnia or hypersomnia are differential clinical characteristics of patients with SS. We defined a nomogram that helps predicting the occurrence of SS in patients with dementia.

A Three-Factor Structure of Cognitive Functioning Among Unimpaired Carriers and Non-Carriers of Autosomal-Dominant Alzheimer's Disease. - Guzmán-Vélez, Edmarie; Jaimes, Sehily; Aguirre-Acevedo, Daniel C; Norton, Daniel J; Papp, Kathryn V; Amariglio, Rebecca; Rentz, Dorene; Baena, Ana; Henao, Eliana; Tirado, Victoria; Munoz, Claudia; Giraldo, Margarita; et al. (J Alzheimers Dis, 2018)
BACKGROUND: There is a need to find cognitive markers that can help identify individuals at risk for Alzheimer's disease (AD), and that can be used to reliably measure cognitive decline. OBJECTIVE: We tested whether a theoretically driven three-factor structure would characterize cognitive functioning in individuals who are genetically-determined to develop AD due to a mutation in Presenilin-1 (PSEN1) gene. We also examined whether these factors could distinguish cognitively unimpaired PSEN1 mutation carriers from age-matched non-carrier family members. METHODS: 1,395 cognitively unimpaired members of a Colombian kindred with the PSEN1 E280A mutation were included in the study. A confirmatory factor analysis examined the fit of the three-factor model comprising episodic memory (MMSE memory recall, CERAD-COL Word list recall, and Constructional praxis recall), executive function (Phonemic fluency and WCST perseverative errors), and psychomotor processing speed (TMT-A and WAIS-III Digit Symbol). RESULTS: The three-factor model provided an excellent fit for all participants (p = 0.24; RMSEA = 0.01). Further, the episodic memory (p = 0.0004, d = 0.25) and executive functioning (p = 0.001, d = 0.18) factors distinguished cognitively unimpaired carriers from non-carriers. The episodic memory factor provided the earliest indication of preclinical cognitive decline at 35 years of age, nine years before individuals' estimated age of clinical onset. CONCLUSIONS: The three theoretically derived cognitive factors provide a reliable measure of cognition and may be useful for the early detection of AD, as well as for measuring disease progression. However, longitudinal studies are needed to confirm that these factors can be used to track the progression of cognitive decline in preclinical AD.

Translational Research in Alzheimer's and Prion Diseases. - Di Fede, Giuseppe; Giaccone, Giorgio; Salmona, Mario; Tagliavini, Fabrizio (J Alzheimers Dis, 2018)
Translational neuroscience integrates the knowledge derived by basic neuroscience with the development of new diagnostic and therapeutic tools that may be applied to clinical practice in neurological diseases. This information can be used to improve clinical trial designs and outcomes that will accelerate drug development, and to discover novel biomarkers which can be efficiently employed to early recognize neurological disorders and provide information regarding the effects of drugs on the underlying disease biology. Alzheimer's disease (AD) and prion disease are two classes of neurodegenerative disorders characterized by incomplete knowledge of the molecular mechanisms underlying their occurrence and the lack of valid biomarkers and effective treatments. For these reasons, the design of therapies that prevent or delay the onset, slow the progression, or improve the symptoms associated to these disorders is urgently needed. During the last few decades, translational research provided a framework for advancing development of new diagnostic devices and promising disease-modifying therapies for patients with prion encephalopathies and AD. In this review, we provide present evidence of how supportive can be the translational approach to the study of dementias and show some results of our preclinical studies which have been translated to the clinical application following the 'bed-to-bench-and-back' research model.

Treatment of Atrial Fibrillation in Patients with Dementia: A Cohort Study from the Swedish Dementia Registry. - Subic, Ana; Cermakova, Pavla; Religa, Dorota; Han, Shuang; von Euler, Mia; Kåreholt, Ingemar; Johnell, Kristina; Fastbom, Johan; Bognandi, Liselia; Winblad, Bengt; Kramberger, Milica G; Eriksdotter, Maria; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Patients with dementia might have higher risk for hemorrhagic complications with anticoagulant therapy prescribed for atrial fibrillation (AF). OBJECTIVE: This study assesses the risks and benefits of warfarin, antiplatelets, and no treatment in patients with dementia and AF. METHODS: Of 49,792 patients registered in the Swedish Dementia Registry 2007-2014, 8,096 (16%) had a previous diagnosis of AF. Cox proportional hazards models were used to calculate the risk for ischemic stroke (IS), nontraumatic intracranial hemorrhage, any-cause hemorrhage, and death. RESULTS: Out of the 8,096 dementia patients with AF, 2,143 (26%) received warfarin treatment, 2,975 (37%) antiplatelet treatment, and 2,978 (37%) had no antithrombotic treatment at the time of dementia diagnosis. Patients on warfarin had fewer IS than those without treatment (5.2% versus 8.7%; p < 0.001) with no differences compared to antiplatelets. In adjusted analyses, warfarin was associated with a lower risk for IS (HR 0.76, CI 0.59-0.98), while antiplatelets were associated with increased risk (HR 1.25, CI 1.01-1.54) compared to no treatment. For any-cause hemorrhage, there was a higher risk with warfarin (HR 1.28, CI 1.03-1.59) compared to antiplatelets. Warfarin and antiplatelets were associated with a lower risk for death compared to no treatment. CONCLUSIONS: Warfarin treatment in Swedish patients with dementia is associated with lower risk of IS and mortality, and a small increase in any-cause hemorrhage. This study supports the use of warfarin in appropriate cases in patients with dementia. The low percentage of patients on warfarin treatment indicates that further gains in stroke prevention are possible.
Keywords: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dementia; Female; Hemorrhage; Humans; Longitudinal Studies; Male; Registries; Risk Factors; Stroke; Survival Analysis; Sweden; Warfarin

TRPC1 Null Exacerbates Memory Deficit and Apoptosis Induced by Amyloid-β. - Li, Mengzhu; Liu, Enjie; Zhou, Qiuzhi; Li, Shihong; Wang, Xin; Liu, Yanchao; Wang, Lin; Sun, Dongsheng; Ye, Jinwang; Gao, Yuan; Yang, Xifei; Liu, Jianjun; et al. (J Alzheimers Dis, 2018)
The transient receptor potential cation (TRPC) channels are widely expressed in nervous system but their functions remain largely unclear. Here, we found that TRPC1 deletion did not affect learning and memory in physiological conditions, while it aggravated learning and memory deficits induced by amyloid-β (Aβ), the major component of the senile plaques observed in the brains of Alzheimer's disease (AD). Further studies demonstrated that TRPC1 deletion did not affect cell apoptosis in physiological condition, but it exacerbated the Aβ-induced cell death in mouse hippocampus. Moreover, the level of TRPC1 was decreased in AD cell and mouse models, and upregulation of TRPC1 decreased Aβ levels with attenuation of apoptosis in the cells stably overexpressing amyloid-β protein precursor (AβPP). Finally, the transmembrane domain of TRPC1 could bind to AβPP and thus decreased Aβ production. These findings indicate that loss of TRPC1 exacerbates Aβ-induced memory deficit and cell apoptosis, though it does not impair cognitive function or induce cell death in physiological conditions.

Ubisol-Q10 (a Nanomicellar Water-Soluble Formulation of CoQ10) Treatment Inhibits Alzheimer-Type Behavioral and Pathological Symptoms in a Double Transgenic Mouse (TgAPEswe, PSEN1dE9) Model of Alzheimer's Disease. - Muthukumaran, Krithika; Kanwar, Annie; Vegh, Caleb; Marginean, Alexandra; Elliott, Austin; Guilbeault, Nicholas; Badour, Alexander; Sikorska, Marianna; Cohen, Jerome; Pandey, Siyaram (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is one of the most common neurodegenerative pathologies for which there are no effective therapies to halt disease progression. Given the increase in the incidence of this disorder, there is an urgent need for pharmacological intervention. Unfortunately, recent clinical trials produced disappointing results. Molecular mechanisms of AD are converging on the notion that mitochondrial dysfunction, oxidative stress, and accumulation of dysfunctional proteins are involved in AD pathology. Previously, we have shown that a water-soluble formulation of Coenzyme Q10 (Ubisol-Q10), an integral part of the electron transport chain, stabilizes mitochondria and prevents neuronal cell death caused by neurotoxins or oxidative stress both in vitro and in vivo. In this study, we evaluated the neuroprotective effects of Ubisol-Q10 treatment in double transgenic AD mice. In the present study, we report that providing Ubisol-Q10 in drinking water (at a dose of ∼6 mg/kg/day) reduced circulating amyloid-β (Aβ) peptide, improved long term memory, preserved working spatial memory, and drastically inhibited Aβ plaque formation in 18-month-old transgenic mice compared to an untreated transgenic group. Thus Ubisol-Q10 supplementation has the potential to inhibit the progression of neurodegeneration, leading to a better quality of life for humans suffering with AD.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Male; Maze Learning; Memory; Memory Disorders; Mice; Mice, Transgenic; Microglia; Mutation; Nerve Tissue Proteins; Peptide Fragments; Presenilin-1; Ubiquinone; Vitamins

Understanding Epigenetics in the Neurodegeneration of Alzheimer's Disease: SAMP8 Mouse Model. - Griñán-Ferré, Christian; Corpas, Rubén; Puigoriol-Illamola, Dolors; Palomera-Ávalos, Verónica; Sanfeliu, Coral; Pallas, Merce (J Alzheimers Dis, 2018)
Epigenetics is emerging as the missing link among genetic inheritance, environmental influences, and body and brain health status. In the brain, specific changes in nucleic acids or their associated proteins in neurons and glial cells might imprint differential patterns of gene activation that will favor either cognitive enhancement or cognitive loss for more than one generation. Furthermore, derangement of age-related epigenetic signaling is appearing as a significant risk factor for illnesses of aging, including neurodegeneration and Alzheimer's disease (AD). In addition, better knowledge of epigenetic mechanisms might provide hints and clues in the triggering and progression of AD. Intense research in experimental models suggests that molecular interventions for modulating epigenetic mechanisms might have therapeutic applications to promote cognitive maintenance through an advanced age. The SAMP8 mouse is a senescence model with AD traits in which the study of epigenetic alterations may unveil epigenetic therapies against the AD.

The Unexpected Role of Aβ1-42 Monomers in the Pathogenesis of Alzheimer's Disease. - Tamagno, Elena; Guglielmotto, Michela; Monteleone, Debora; Manassero, Giusi; Vasciaveo, Valeria; Tabaton, Massimo (J Alzheimers Dis, 2018)
Amyloid-β (Aβ) has been proposed as a biomarker and a drug target for the therapy of Alzheimer's disease (AD). The neurotoxic entity and relevance of each conformational form of Aβ to AD pathology is still under debate; Aβ oligomers are considered the major killer form of the peptide whereas monomers have been proposed to be involved in physiological process. Here we reviewed some different effects mediated by monomers and oligomers on mechanisms involved in AD pathogenesis such as autophagy and tau aggregation. Data reported in this review demonstrate that Aβ monomers could have a major role in sustaining the pathogenesis of AD and that AD therapy should be focused not only in the removal of oligomers but also of monomers.

Usefulness of Dual-Point Amyloid PET Scans in Appropriate Use Criteria: A Multicenter Study. - Segovia, Fermín; Gómez-Río, Manuel; Sánchez-Vañó, Raquel; Górriz, Juan Manuel; Ramírez, Javier; Triviño-Ibáñez, Eva; Carnero-Pardo, Cristóbal; Martínez-Lozano, María Dolores; Sopena-Novales, Pablo (J Alzheimers Dis, 2018)
BACKGROUND: Biomarkers of neurodegeneration play a major role in the diagnosis of Alzheimer's disease (AD). Information on both amyloid-β accumulation, e.g., from amyloid positron emission tomography (PET), and downstream neuronal injury, e.g., from 18F-fluorodeoxyglucose (FDG) PET, would ideally be obtained in a single procedure. OBJECTIVE: On the basis that the parallelism between brain perfusion and glucose metabolism is well documented, the objective of this work is to evaluate whether brain perfusion estimated in a dual-point protocol of 18F-florbetaben (FBB) PET can be a surrogate of FDG PET in appropriate use criteria (AUC) for amyloid PET. METHODS: This study included 47 patients fulfilling international AUC for amyloid PET. FDG PET, early FBB (pFBB) PET (0-10 min post injection), and standard FBB (sFBB) PET (90-110 min post injection) scans were acquired. Results of clinical subjective reports and of quantitative region of interest (ROI)-based analyses were compared between procedures using statistical techniques such as Pearson's correlation coefficients and t-tests. RESULTS: pFBB and FDG visual reports on the 47 patients showed good agreement (k  >  0.74); ROI quantitative analysis indicated that both data modalities are highly correlated; and the t-test analysis does not reject the null hypothesis that data from pFBB and FDG examinations comes from independent random samples from normal distributions with equal means and variances. CONCLUSIONS: A good agreement was found between pFBB and FDG data as obtained by subjective visual and quantitative analyses. Dual-point FBB PET scans could offer complementary information (similar to that from FDG PET and FBB PET) in a single procedure, considering pFBB as a surrogate of FDG.

Utility of Amyloid PET Scans in the Evaluation of Patients Presenting with Diverse Cognitive Complaints. - Shea, Yat-Fung; Barker, Warren; Greig-Gusto, Maria T; Loewenstein, David A; DeKosky, Steven T; Duara, Ranjan (J Alzheimers Dis, 2018)
BACKGROUND: The impact of amyloid positron emission tomography (Aβ-PET) in a "real-world" memory disorders clinic remains poorly studied. OBJECTIVE: We studied the impact of Aβ-PET in diagnosis and management in the memory clinic and factors making the most impact in diagnosis and management. METHODS: We studied 102 patients who had presented at a memory disorders clinic (the Wien Center for Alzheimer's Disease and Memory Disorders, Miami Beach, FL) and had a diagnostic work-up for cognitive complaints, including Aβ-PET scans. RESULTS: Following Aβ-PET, changes were made in diagnosis (37.3%), in specific treatments for Alzheimer's disease (26.5%) and in psychiatric treatments (25.5%). The agreement between diagnosis pre-Aβ-PET versus post-Aβ-PET diagnosis was only fair, with a Cohen's kappa of 0.23 (95% CI 0-0.42). Patients with MRI findings suggestive of AD (medial temporal and/or parietal atrophy) were more frequently amyloid positive than amyloid negative (66.2% versus 33.8%, p = 0.04). Among patients with atypical clinical features for AD, but with MRI findings suggestive of AD, an amyloid negative PET scan had a greater impact than an amyloid positive PET scan on diagnosis (84.2% versus 17.1%, p < 0.001), management (84.2% versus 40%, p < 0.01) and discussion of results and advice on lifestyle (73.7% versus 22.9%, p < 0.001). CONCLUSIONS: We conclude that MRI features suggestive of AD predict a positive amyloid PET scan. However, among those with MRI features suggestive of AD but with atypical clinical features of AD, the clinical impact on diagnosis and management is greater for an amyloid negative than an amyloid positive Aβ-PET scans.

Utility of an Alzheimer's Disease Risk-Weighted Polygenic Risk Score for Predicting Rates of Cognitive Decline in Preclinical Alzheimer's Disease: A Prospective Longitudinal Study. - Porter, Tenielle; Burnham, Samantha C; Milicic, Lidija; Savage, Greg; Maruff, Paul; Lim, Yen Ying; Li, Qiao-Xin; Ames, David; Masters, Colin L; Rainey-Smith, Stephanie; Rowe, Christopher C; Salvado, Olivier; et al. (J Alzheimers Dis, 2018)
BACKGROUND: With the exception of APOE, genetic variants associated with increased Alzheimer's disease (AD) risk are characterized by small effect sizes. Polygenic risk scores (PRS) have shown utility in predicting AD risk; however, their utility for predicting decline in cognition at preclinical stages of AD is poorly understood. OBJECTIVE: To validate associations of a 22-variant AD-risk-weighted PRS with AD risk and related biomarkers and to assess its utility to predict cognitive decline. METHODS: The PRS was evaluated with respect to brain amyloid-β (Aβ) burden, cerebrospinal fluid (CSF) Aβ42, total-tau, and phospho-tau, and decline in cognition in 643 (570 cognitively normal (CN), 73 AD) PET-imaged participants from the longitudinal Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. Cognition was assessed using three composite measures; global cognition, verbal episodic memory, and a Pre-Alzheimer's Cognitive Composite (PACC). RESULTS: PRS, both with and without APOE, were positively correlated with brain Aβ burden, CSF total-tau, and phospho-tau in CN older adults. Further, in CN biomarker positive (Aβhigh) participants, significant associations were observed with baseline and longitudinal cognition. However, this association was not observed after the removal of APOE. Partitioning the PRS into quartiles revealed that the PRS associations with cognitive decline in Aβhigh CN older adults is due to a saturating effect of APOE genotype. CONCLUSIONS: An AD-risk-weighted PRS is associated with cognitive decline in CN older adults. However, this association is absent when APOE genotype is excluded from the PRS, suggesting that associations with cognitive decline in this model of polygenic risk are driven by APOE genotype alone. Further research is needed to define appropriate PRSs with greater utility for predicting preclinical AD cognitive decline.

Visual Processing of Emotional Faces is Preserved in Mild Cognitive Impairment. - McCade, Donna L; Guastella, Adam J; Chen, Nigel T M; Lewis, Simon J G; Naismith, Sharon L (J Alzheimers Dis, 2018)
BACKGROUND: Research suggests that deficits in emotion recognition are evident in individuals with amnestic mild cognitive impairment (aMCI), a group 'at risk' of developing dementia. The mechanisms underlying this deficit, however, are unclear. OBJECTIVE: In this study, we sought to determine whether there are alterations in the way in which individuals with MCI visually explore emotional facial stimuli. METHODS: Eighteen healthy older controls (mean age = 64.6 years) and 32 individuals with MCI were recruited including 18 with the non-amnestic multiple domain (naMCI-md) subtype (mean age = 63.8 years) and 14 with the amnestic multiple domain (aMCI-md) subtype (mean age = 67.9 years). All participants were given a novel eye-tracking paradigm to investigate eye gaze while viewing images of emotional faces on a computer screen. RESULTS: Analyses of eye gaze revealed no significant difference in the percentage of time that groups spent fixating on facial and peripheral facial regions when viewing emotional faces. All participants showed a relative preference for the eye region of faces relative to all other regions. Individuals with aMCI-md were found to be less accurate than controls and naMCI-md on emotion recognition measures. For naMCI-md individuals, significant relationships were found between efficiencies in visual scanning and increased fixation time on the eye region. CONCLUSIONS: Visual processing strategies adopted by aMCI-md individuals when exploring emotional faces do not significantly differ from those of healthy controls or naMCI-md individuals. This suggests that impaired facial emotion recognition in aMCI-md is not likely accounted for by visual processing differences, but rather may reflect an eroded ability to extract meaningful cues from the eye region.

Visualization of Focal Thinning of the Ganglion Cell-Inner Plexiform Layer in Patients with Mild Cognitive Impairment and Alzheimer's Disease. - Shao, Yi; Jiang, Hong; Wei, Yantao; Shi, Yingying; Shi, Ce; Wright, Clinton B; Sun, Xiaoyan; Vanner, Elizabeth A; Rodriguez, Anny D; Lam, Byron L; Rundek, Tatjana; Baumel, Barry S; et al. (J Alzheimers Dis, 2018)
BACKGROUND: A detailed analysis of the tomographic thickness of intraretinal layers may provide more information on neurodegeneration in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). OBJECTIVE: The goal was to analyze tomographic thickness patterns of intraretinal layers in patients with AD andMCI. METHOD: Forty-nine patients (25 AD and 24 MCI) and 21 cognitively normal (CN) controls were imaged using ultra-high-resolution optical coherence tomography to obtain volumetric data centered on the fovea. The segmented intraretinal layers were retinal nerve fiber layer (RNFL), ganglion cell- inner plexiform layer (GCIPL), inner nuclear layer (INL), outer nuclear layer (ONL), outer plexiform layer (OPL), and retinal photoreceptor (PR), in addition to the total retinal thickness(TRT). RESULTS: The thickness differences were negative (thinning) mainly in TRT, RNFL, and GCIPL in both AD and MCI groups in comparison to CN, while the thickness differences were positive (thickening) mainly in ONL and PR in AD. GCIPL of AD and MCI was thinner in superior, nasal superior, and temporal superior quadrants, compared to CN (p < 0.05). GCIPL of the inner superior, inner nasal superior, inner temporal superior, and outer nasal superior sectors was significantly thinner in AD than CN (p < 0.05). GCIPL of the outer superior, inner temporal superior, outer nasal, and temporal superior sectors was significantly thinner in MCI than CN (p < 0.05). CONCLUSION: Focal thinning of the GCIPL was visualized and quantified by detailed partitions in AD and MCI, which provides specific information about neurodegeneration in MCI and AD.

White Matter Hyperintensities and Cognition in Mild Cognitive Impairment and Alzheimer's Disease: A Domain-Specific Meta-Analysis. - van den Berg, Esther; Geerlings, Mirjam I; Biessels, Geert Jan; Nederkoorn, Paul J; Kloppenborg, Raoul P (J Alzheimers Dis, 2018)
BACKGROUND: White matter hyperintensities (WMHs) are related to cognitive dysfunction in the general population. The clinical relevance of WMHs in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) is, however, unclear. OBJECTIVE: This meta-analysis aimed to quantify the association of WMHs and specific cognitive domains in patients with MCI or AD. METHODS: PubMed (January 1990-January 2017) was searched for studies that used MRI to quantify WMHs, and measured cognitive functioning (≥1 predefined cognitive domain with ≥1 test) in a well-defined population of persons diagnosed with MCI or AD. Fischer's Z was used as the common metric for effect size. Modifying effects of demographics, MMSE, and WMH location were examined. RESULTS: Twelve cross-sectional studies on AD (total n = 1,370, median age 75 years) and 10 studies on MCI (9 cross-sectional, 1 longitudinal; total n = 2,286, median age 73 years) were included. The association between WMHs and overall cognition was significantly stronger for MCI (-0.25, -0.36 to -0.14) than for AD (-0.11, -0.14 to -0.08; QM = 10.7, p < 0.05). For both groups, largest effect sizes were found in attention and executive functions (-0.26, -0.36 to -0.15) and processing speed (-0.21, -0.35 to -0.12). No significant modifying effects of age and gender were found. CONCLUSION: WMHs have a medium-sized association with different cognitive functions in patients with MCI and a small, but statistically significant, association with cognition in AD. These result underscore the role of co-occurring vascular brain damage in MCI and AD.

White Matter Hyperintensity Predicts the Risk of Incident Cognitive Decline in Community Dwelling Elderly. - Ding, Ding; Xiong, Yunyun; Zhao, Qianhua; Guo, Qihao; Chu, Shuguang; Chu, Winnie W C; Luo, Jianfeng; Liang, Xiaoniu; Zheng, Li; Hong, Zhen; Wong, Lawrence K S; Mok, Vincent C T (J Alzheimers Dis, 2018)
BACKGROUND: Unlike western countries, data on white matter hyperintensity (WMH) in community dwelling elderly in Asian population is very limited. OBJECTIVE: To examine the relation between baseline WMH burden and the risk of incident cognitive decline in a community-based cohort with Chinese-dwelling elderly. METHODS: We prospectively evaluated the incident cognitive decline for 226 participants in the Shanghai Aging Study. Baseline WMH severity was visually rated by the age-related white matter changes (ARWMC) scale based on MRI. Cox proportional hazards regression model was used to estimate the relative risk (RR) of total ARWMC scale, global ARWMC score, presence of lacune and microbleed, for incident cognitive decline by adjusting potential confounders. RESULTS: Forty subjects were identified with incident cognitive decline (new onset 34 mild cognitive impairment and 6 dementia) during a median duration of 6 years follow-up. The incidence of cognitive decline was 3.0 (95% confidence interval [CI] 2.2-4.1) per 100 person-years. Increasing total ARWMC scale [RR1.21 (95% CI 1.06-1.39), p = 0.004)], confluent WMH [RR3.16 (95% CI 1.50-6.64), p = 0.002), and presence of lacunes [RR 2.73 (95% CI 1.21-6.15)] at baseline were independent predictors of incident cognitive decline. CONCLUSION: Our study demonstrated that confluent WMH may increase the risk of incident cognitive decline by 3 folds in community dwelling subjects. Small vessel disease may cause heavy burden of cognitive impairment in the elderly in China.
Keywords: Aged; China; Cognitive Dysfunction; Female; Humans; Independent Living; Kaplan-Meier Estimate; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Proportional Hazards Models; Prospective Studies; Risk Factors; White Matter

Word and Picture Version of the Free and Cued Selective Reminding Test (FCSRT): Is There Any Difference? - Arighi, Andrea; Carandini, Tiziana; Mercurio, Matteo; Carpani, Giovanni; Pietroboni, Anna Margherita; Fumagalli, Giorgio; Ghezzi, Laura; Basilico, Paola; Calvi, Alberto; Scarioni, Marta; De Riz, Milena; Fenoglio, Chiara; et al. (J Alzheimers Dis, 2018)
The Free and Cued Selective Reminding Test (FCSRT) is the most commonly used neuropsychological test to evaluate episodic memory. Two variants of FCSRT exist, using the recall of words (FCSRT-w) or pictures (FCSRT-p). Fourteen patients with mild cognitive impairment underwent neuropsychological evaluation and brain magnetic resonance. We found differences in FCSRT-w and FCSRT-p variants scores. FCSRT-p was correlated with atrophy in areas involved in visual stimuli processing while FCSRT-w was correlated to hippocampal atrophy. Our study suggests that FCSRT-w and FCSRT-p scores are not equivalent, but a larger cohort of patients is needed to validate these results.
Keywords: Aged; Aged, 80 and over; Association Learning; Cognitive Dysfunction; Cues; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Mental Recall; Middle Aged; Neuropsychological Tests; Photic Stimulation; Vocabulary

A 24-Week Multi-Modality Exercise Program Improves Executive Control in Older Adults with a Self-Reported Cognitive Complaint: Evidence from the Antisaccade Task. - Heath, Matthew; Shellington, Erin; Titheridge, Sam; Gill, Dawn P; Petrella, Robert J (J Alzheimers Dis, 2017)
Exercise programs involving aerobic and resistance training (i.e., multiple-modality) have shown promise in improving cognition and executive control in older adults at risk, or experiencing, cognitive decline. It is, however, unclear whether cognitive training within a multiple-modality program elicits an additive benefit to executive/cognitive processes. This is an important question to resolve in order to identify optimal training programs that delay, or ameliorate, executive deficits in persons at risk for further cognitive decline. In the present study, individuals with a self-reported cognitive complaint (SCC) participated in a 24-week multiple-modality (i.e., the M2 group) exercise intervention program. In addition, a separate group of individuals with a SCC completed the same aerobic and resistance training as the M2 group but also completed a cognitive-based stepping task (i.e., multiple-modality, mind-motor intervention: M4 group). Notably, pre- and post-intervention executive control was examined via the antisaccade task (i.e., eye movement mirror-symmetrical to a target). Antisaccades are an ideal tool for the study of individuals with subtle executive deficits because of its hands- and language-free nature and because the task's neural mechanisms are linked to neuropathology in cognitive decline (i.e., prefrontal cortex). Results showed that M2 and M4 group antisaccade reaction times reliably decreased from pre- to post-intervention and the magnitude of the decrease was consistent across groups. Thus, multi-modality exercise training improved executive performance in persons with a SCC independent of mind-motor training. Accordingly, we propose that multiple-modality training provides a sufficient intervention to improve executive control in persons with a SCC.

A 9-microRNA Signature in Serum Serves as a Noninvasive Biomarker in Early Diagnosis of Alzheimer's Disease. - Guo, Rui; Fan, Gang; Zhang, Jian; Wu, Chunxiao; Du, Yifeng; Ye, Hui; Li, Zhang; Wang, Lili; Zhang, Zhihui; Zhang, Lu; Zhao, Yueran; Lu, Zhiming (J Alzheimers Dis, 2017)
Alzheimer's disease (AD) is the most common type of age-related neurodegenerative disorder; nevertheless, nowadays there are no reliable biomarkers or non-invasive techniques available for its early detection. Recent studies have indicated that the circulating level profiles of microRNAs (miRNAs) have the potential to be used as valuable biomarkers for diagnosis, staging, and progress monitoring of various diseases. Here we report a novel 9-miRNA signature (hsa-miR-26a-5p, hsa-miR-181c-3p, hsa-miR-126-5p, hsa-miR-22-3p, hsa-miR-148b-5p, hsa-miR-106b-3p, hsa-miR-6119-5p, hsa-miR-1246, and hsa-miR-660-5p) that can be utilized as biomarker for detecting AD. We respectively profiled the serum miRNAs from 19 AD patients and 9 healthy control (HC) participants using the Next-Generation Sequencing (NGS). The NGS results were validated by quantitative real-time polymerase chain reaction (qRT-PCR) on a larger cohort of 121 AD and 86 HC cases. All the patients were divided into three groups (mild, moderate, and severe AD) based on the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR). Our research indicates that abnormal expression of distinct serum miRNAs occurs at different stages of AD. The difference of the area under the receiver operator characteristics curve (AUC) between the AD and the HC is between 70% and 85%. Among the 9 miRNAs, hsa-miR-22-3p has the best sensitivity (81.8%) and specificity (70.9%). The miRNA-panel is more valuable for AD diagnosis. The data suggest that the differentially expressed serum miRNAs could be used as biomarkers to improve the diagnosis of AD, particularly at the early stage, and to classify its clinical stages.

Abnormalities of Cortical Neural Synchronization Mechanisms in Subjects with Mild Cognitive Impairment due to Alzheimer's and Parkinson's Diseases: An EEG Study. - Babiloni, Claudio; Del Percio, Claudio; Lizio, Roberta; Noce, Giuseppe; Cordone, Susanna; Lopez, Susanna; Soricelli, Andrea; Ferri, Raffaele; Pascarelli, Maria Teresa; Nobili, Flavio; Arnaldi, Dario; Famá, Francesco; et al. (J Alzheimers Dis, 2017)
The aim of this retrospective and exploratory study was that the cortical sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms might reveal different abnormalities in cortical neural synchronization in groups of patients with mild cognitive impairment due to Alzheimer's disease (ADMCI) and Parkinson's disease (PDMCI) as compared to healthy subjects. Clinical and rsEEG data of 75 ADMCI, 75 PDMCI, and 75 cognitively normal elderly (Nold) subjects were available in an international archive. Age, gender, and education were carefully matched in the three groups. The Mini-Mental State Evaluation (MMSE) was matched between the ADMCI and PDMCI groups. Individual alpha frequency peak (IAF) was used to determine the delta, theta, alpha1, alpha2, and alpha3 frequency band ranges. Fixed beta1, beta2, and gamma bands were also considered. eLORETA estimated the rsEEG cortical sources. Receiver operating characteristic curve (ROC) classified these sources across individuals. Results showed that compared to the Nold group, the posterior alpha2 and alpha3 source activities were more abnormal in the ADMCI than the PDMCI group, while the parietal delta source activities were more abnormal in the PDMCI than the ADMCI group. The parietal delta and alpha sources correlated with MMSE score and correctly classified the Nold and diseased individuals (area under the ROC = 0.77-0.79). In conclusion, the PDMCI and ADMCI patients showed different features of cortical neural synchronization at delta and alpha frequencies underpinning brain arousal and vigilance in the quiet wakefulness. Future prospective cross-validation studies will have to test these rsEEG markers for clinical applications and drug discovery.

Acidity and Acid-Sensing Ion Channels in the Normal and Alzheimer's Disease Brain. - Gonzales, Eric B; Sumien, Nathalie (J Alzheimers Dis, 2017)
Alzheimer's disease prevalence has reached epidemic proportion with very few treatment options, which are associated with a multitude of side effects. A potential avenue of research for new therapies are protons, and their associated receptor: acid-sensing ion channels (ASIC). Protons are often overlooked neurotransmitters, and proton-gated currents have been identified in the brain. Furthermore, ASICs have been determined to be crucial for proper brain function. While there is more work to be done, this review is intended to highlight protons as neurotransmitters and their role along with the role of ASICs within physiological functioning of the brain. We will also cover the pathophysiological associations between ASICs and modulators of ASICs. Finally, this review will sum up how the studies of protons, ASICs and their modulators may generate new therapeutic molecules for Alzheimer's disease and other neurodegenerative diseases.

Activation of Macrophages and Microglia by Interferon-γ and Lipopolysaccharide Increases Methylglyoxal Production: A New Mechanism in the Development of Vascular Complications and Cognitive Decline in Type 2 Diabetes Mellitus? - Dhananjayan, Karthik; Gunawardena, Dhanushka; Hearn, Nerissa; Sonntag, Tanja; Moran, Chris; Gyengesi, Erika; Srikanth, Velandai; Münch, Gerald (J Alzheimers Dis, 2017)
Methylglyoxal (MGO), a dicarbonyl compound derived from glucose, is elevated in diabetes mellitus and contributes to vascular complications by crosslinking collagen and increasing arterial stiffness. It is known that MGO contributes to inflammation as it forms advanced glycation end products (AGEs), which activate macrophages via the receptor RAGE. The aim of study was to investigate whether inflammatory activation can increase MGO levels, thereby completing a vicious cycle. In order to validate this, macrophage (RAW264.7, J774A.1) and microglial (N11) cells were stimulated with IFN-γ and LPS (5 + 5 and 10 + 10 IFN-γ U/ml or μg/ml LPS), and extracellular MGO concentration was determined after derivatization with 5,6-Diamino-2,4-dihydroxypyrimidine sulfate by HPLC. MGO levels in activated macrophage cells (RAW264.7) peaked at 48 h, increasing 2.86-fold (3.14±0.4 μM) at 5 U/ml IFN-γ+5 μg/ml LPS, and 4.74-fold (5.46±0.30 μM) at 10 U/ml IFN-γ+10 μg/ml LPS compared to the non-activated controls (1.15±0.02 μM). The other two cell lines, J774A.1 macrophages and N11 microglia, showed a similar response. We suggest that inflammation increases MGO production, possibly exacerbating arterial stiffness, cardiovascular complications, and diabetes-related cognitive decline.

Adherence to Clinical Practice Guidelines during Dementia Work-Up in a Real-World Setting: A Study from the Registry of Dementias of Girona. - Turró-Garriga, Oriol; Calvó-Perxas, Laia; Vilalta-Franch, Joan; Hernández-Ferrándiz, Marta; Flaqué, Margarita; Linares, Marta; Cullell, Marta; Gich, Jordi; Casas, Isabel; Perkal, Héctor; Garre-Olmo, Josep (J Alzheimers Dis, 2017)
BACKGROUND: There are several position statements and clinical practice guidelines (CPG) for diagnosing dementia. OBJECTIVE: Our aims were to evaluate the adherence to CPG among specialists in the 7 memory clinics included in the Registry of Dementias of Girona (ReDeGi), and to compare the results between 2007-2011 and 2012-2015. We also determined the time and number of visits required to achieve a diagnosis, the supplementary tests ordered, and the drugs prescribed according to dementia subtypes. METHODS: Medical charts of a stratified random sample of 475 ReDeGi cases were reviewed. Basic dementia work-up was evaluated using as a reference evidence-based CPG. An Index of Adherence (AI) was calculated using the following items in the medical chart: cognitive symptomatology; functional disability evaluation; physical examination; neurological examination; psychiatric examination; brief cognitive examination; activities of daily living performance examination; blood test; structural neuroimaging (CT-scan or MRI). RESULTS: The mean AI to CPG among specialists was of 8.2 points, and it improved from 7.9 points in 2007-2011 to 8.5 points in 2012-2015 (Cohen's d = 0.46). A lower adherence was detected in the most severe cases. A dementia diagnosis required 3.5 visits, regardless of the subtype of dementia, although milder cases required more time, more visits, and more supplementary tests than severe cases. CONCLUSION: The adherence to CPG in the catchment area of the ReDeGi is high, and an epidemiological surveillance system such as the ReDeGi may help in improving it. Dementia guidelines should establish procedures adapted to clinical practice, with simplified recommendations for most severe cases.

Adult-Onset Epilepsy in Presymptomatic Alzheimer's Disease: A Retrospective Study. - DiFrancesco, Jacopo C; Tremolizzo, Lucio; Polonia, Valeria; Giussani, Giorgia; Bianchi, Elisa; Franchi, Carlotta; Nobili, Alessandro; Appollonio, Ildebrando; Beghi, Ettore; Ferrarese, Carlo (J Alzheimers Dis, 2017)
BACKGROUND: The prevalence of epilepsy with onset in adulthood increases with age, mainly due to the accumulation of brain damage. However, a significant proportion of patients experience seizures of unknown cause. Alzheimer's disease (AD) is associated with an increased risk of seizures. Seizure activity is interpreted as a secondary event related to hyperexcitability caused by amyloid-β aggregation. OBJECTIVE: Since neurodegenerative processes begin several years before clinical symptoms, epilepsy could be more frequent in the presymptomatic stages of dementia. METHODS: We retrospectively reviewed the prevalence of epilepsy of unknown origin with adult onset before cognitive decline in a large cohort of AD patients (EPS-AD) recruited based on clinical and neuropsychological data. Data of patients with epilepsy followed by AD were compared with two control groups: patients with AD without seizures (no EPS-AD) and a large reference population (RP). RESULTS: In AD patients, the prevalence of epilepsy of unknown origin, with onset in the adulthood before cognitive decline is 17.1 times higher compared with the RP (95% CI: 10.3-28.3). In EPS-AD, seizures begin on average 4.6 years (median 2.0) before the onset of cognitive symptoms and cognitive decline starts 3.6 years earlier compared with noEPS-AD. CONCLUSIONS: Neurodegenerative processes of dementia could play a key role in the pathogenesis of epilepsy in a subgroup of individuals intended to develop cognitive decline. Adult-onset epilepsy of undefined cause could thus represent a risk factor for the ongoing neurodegenerative damage, even preceding by years the onset of clinical symptoms of dementia.

Aerosol Delivery of Curcumin Reduced Amyloid-β Deposition and Improved Cognitive Performance in a Transgenic Model of Alzheimer's Disease. - McClure, Richard; Ong, Henry; Janve, Vaibhab; Barton, Shawn; Zhu, Meiying; Li, Bo; Dawes, Mary; Jerome, W Gray; Anderson, Adam; Massion, Pierre; Gore, John C; Pham, Wellington (J Alzheimers Dis, 2017)
We report a novel approach for the delivery of curcumin to the brain via inhalation of the aerosol for the potential treatment of Alzheimer's disease. The percentage of plaque fraction in the subiculum and hippocampus reduced significantly when young 5XFAD mice were treated with inhalable curcumin over an extended period of time compared to age-matched nontreated counterparts. Further, treated animals demonstrated remarkably improved overall cognitive function, no registered systemic or pulmonary toxicity associated with inhalable curcumin observed during the course of this work.

Alterations of Clock Gene RNA Expression in Brain Regions of a Triple Transgenic Model of Alzheimer's Disease. - Bellanti, Francesco; Iannelli, Giuseppina; Blonda, Maria; Tamborra, Rosanna; Villani, Rosanna; Romano, Adele; Calcagnini, Silvio; Mazzoccoli, Gianluigi; Vinciguerra, Manlio; Gaetani, Silvana; Giudetti, Anna Maria; Vendemiale, Gianluigi; et al. (J Alzheimers Dis, 2017)
A disruption to circadian rhythmicity and the sleep/wake cycle constitutes a major feature of Alzheimer's disease (AD). The maintenance of circadian rhythmicity is regulated by endogenous clock genes and a number of external Zeitgebers, including light. This study investigated the light induced changes in the expression of clock genes in a triple transgenic model of AD (3×Tg-AD) and their wild type littermates (Non-Tg). Changes in gene expression were evaluated in four brain areas¾suprachiasmatic nucleus (SCN), hippocampus, frontal cortex and brainstem¾of 6- and 18-month-old Non-Tg and 3×Tg-AD mice after 12 h exposure to light or darkness. Light exposure exerted significant effects on clock gene expression in the SCN, the site of the major circadian pacemaker. These patterns of expression were disrupted in 3×Tg-AD and in 18-month-old compared with 6-month-old Non-Tg mice. In other brain areas, age rather than genotype affected gene expression; the effect of genotype was observed on hippocampal Sirt1 expression, while it modified the expression of genes regulating the negative feedback loop as well as Rorα, Csnk1ɛ and Sirt1 in the brainstem. In conclusion, during the early development of AD, there is a disruption to the normal expression of genes regulating circadian function after exposure to light, particularly in the SCN but also in extra-hypothalamic brain areas supporting circadian regulation, suggesting a severe impairment of functioning of the clock gene pathway. Even though this study did not demonstrate a direct association between these alterations in clock gene expression among brain areas with the cognitive impairments and chrono-disruption that characterize the early onset of AD, our novel results encourage further investigation aimed at testing this hypothesis.

Altered Gut Microbiome Composition and Tryptic Activity of the 5xFAD Alzheimer's Mouse Model. - Brandscheid, Carolin; Schuck, Florian; Reinhardt, Sven; Schäfer, Karl-Herbert; Pietrzik, Claus U; Grimm, Marcus; Hartmann, Tobias; Schwiertz, Andreas; Endres, Kristina (J Alzheimers Dis, 2017)
The regulation of physiological gut functions such as peristalsis or secretion of digestive enzymes by the central nervous system via the Nervus vagus is well known. Recent investigations highlight that pathological conditions of neurological or psychiatric disorders might directly interfere with the autonomous neuronal network of the gut - the enteric nervous system, or even derive from there. By using a murine Alzheimer's disease model, we investigated a potential influence of disease-associated changes on gastrointestinal properties. 5xFAD mice at three different ages were compared to wild type littermates in regard to metabolic parameters and enzymes of the gut by fluorimetric enzyme assay and western blotting. Overexpression of human amyloid-β protein precursor (AβPP) within the gut was assessed by qPCR and IHC; fecal microbiome analysis was conducted by 16SrRNA quantitation of selected phyla and species. While general composition of fecal samples, locomotion, and food consumption of male 5xFAD animals were not changed, we observed a reduced body weight occurring at early pathological stages. Human AβPP was not only expressed within the brain of these mice but also in gut tissue. Analysis of fecal proteins revealed a reduced trypsin amount in the 5xFAD model mice as compared to the wild type. In addition, we observed changes in fecal microbiota composition along with age. We therefore suggest that the presence of the mutated transgenes (AβPP and PS1), which are per se the basis for the genetic form of Alzheimer's disease in humans, directly interferes with gut function as shown here for the disease model mice.

Alzheimer's Disease Biomarkers and Future Decline in Cognitive Normal Older Adults. - Dumurgier, Julien; Hanseeuw, Bernard J; Hatling, Frances B; Judge, Kelly A; Schultz, Aaron P; Chhatwal, Jasmeer P; Blacker, Deborah; Sperling, Reisa A; Johnson, Keith A; Hyman, Bradley T; Gómez-Isla, Teresa (J Alzheimers Dis, 2017)
BACKGROUND: Identifying older adults at risk of cognitive decline represents a challenge as Alzheimer's disease (AD) modifying therapies move toward preclinical stages. OBJECTIVE: To investigate the relationship between AD biomarkers and subsequent change in cognition in a cohort of cognitively intact older adults. METHODS: 84 cognitively normal subjects (mean age 72.0 years, 59% women) were recruited through the Massachusetts Alzheimer's Disease Research Center and the Harvard Aging Brain Study and followed over 3 years. Measurements of amyloid-β 1-42 (Aβ42), total Tau (t-Tau), and Tau phosphorylated at threonine 181 (p-Tau181) in the cerebrospinal fluid (CSF) at study entry were available in all cases. Baseline brain MRI, FDG-PET, and PiB-PET data were available in the majority of participants. Relationship between baseline AD biomarkers and longitudinal change in cognition was assessed using Cox proportional hazard regression and linear mixed models. RESULTS: 14% participants increased their global Clinical Dementia Rating (CDR) score from 0 to 0.5 during follow-up. A CDR score increase was associated with higher baseline CSF t-Tau and p-Tau181, higher global cortical PiB retention, and lower hippocampal volume. The combination of high CSF t-Tau and low Aβ42 or low hippocampal volume was more strongly related to cognitive outcome than each single biomarker. Higher CSF t-Tau was the only biomarker associated with subsequent decline in MMSE score. CONCLUSIONS: Baseline CSF t-Tau and p-Tau181, in vivo amyloid load, and hippocampal volume were all independently associated with future decline in cognition. The discriminatory ability of these biomarkers to predict risk of cognitive decline, however, was only modest.

Amylin Treatment Reduces Neuroinflammation and Ameliorates Abnormal Patterns of Gene Expression in the Cerebral Cortex of an Alzheimer's Disease Mouse Model. - Wang, Erming; Zhu, Haihao; Wang, Xiaofan; Gower, Adam; Wallack, Max; Blusztajn, Jan Krzysztof; Kowall, Neil; Qiu, Wei Qiao (J Alzheimers Dis, 2017)
Our recent study has demonstrated that peripheral amylin treatment reduces the amyloid pathology in the brain of Alzheimer's disease (AD) mouse models, and improves their learning and memory. We hypothesized that the beneficial effects of amylin for AD was beyond reducing the amyloids in the brain, and have now directly tested the actions of amylin on other aspects of AD pathogenesis, especially neuroinflammation. A 10-week course of peripheral amylin treatment significantly reduced levels of cerebral inflammation markers, Cd68 and Iba1, in amyloid precursor protein (APP) transgenic mice. Mechanistic studies indicated the protective effect of amylin required interaction with its cognate receptor because silencing the amylin receptor expression blocked the amylin effect on Cd68 in microglia. Using weighted gene co-expression network analysis, we discovered that amylin treatment influenced two gene modules linked with amyloid pathology: 1) a module related to proinflammation and transport/vesicle process that included a hub gene of Cd68, and 2) a module related to mitochondria function that included a hub gene of Atp5b. Amylin treatment restored the expression of most genes in the APP cortex toward levels observed in the wild-type (WT) cortex in these two modules including Cd68 and Atp5b. Using a human dataset, we found that the expression levels of Cd68 and Atp5b were significantly correlated with the neurofibrillary tangle burden in the AD brain and with their cognition. These data suggest that amylin acts on the pathological cascade in animal models of AD, and further supports the therapeutic potential of amylin-type peptides for AD.

Amyloid Burden in Obstructive Sleep Apnea. - Yun, Chang-Ho; Lee, Ho-Young; Lee, Seung Ku; Kim, Hyun; Seo, Hyung Suk; Bang, Seong Ae; Kim, Sang Eun; Greve, Douglas N; Au, Rhoda; Shin, Chol; Thomas, Robert J (J Alzheimers Dis, 2017)
To test the hypothesis that excessive amyloid deposition is a biological link between obstructive sleep apnea (OSA) and Alzheimer's disease, we determined whether OSA increases cerebral amyloid burden, relative to controls, using Pittsburgh Compound B (PiB) PET imaging. The subjects were adult participants (age 50-65 years) from the Korean Genome and Epidemiology Study. Polysomnography, brain MRI including 3D images, and a detailed neuro-cognitive function test battery were done in 2011-2012. Nineteen OSA subjects (Apnea-Hypopnea Index [AHI] ≥15/h, 21.2±5.1/h; age 58.5±4.1 years; 9 male) and 19 controls (AHI 1.8±1.3/h; age 58.5±4.2 years; 9 male) underwent 60-min dynamic 11C-PiB PET. All subjects were right-handed with normal cognitive function and brain MRI. Controls were matched by age, gender, education, and APOE genotype. A voxel-wise comparison of PiB-PET images between the two groups was performed after spatial and count normalization with cerebellar gray matter as a reference. Covariates included the status of sleep duration, hypertension, diabetes, body mass index, exercise, depressive mood, smoking, and alcohol drinking. Cortical thickness on 3D MRI was also measured and compared between the two groups. The OSA group showed a higher PiB deposition in the right posterior cingulate gyrus and right temporal cortex (corrected p < 0.05). There was no area of higher uptake in the control compared with OSA. Regional differences in cortical thickness were not significant. The study suggests that OSA accelerates amyloid deposition and may contribute to the development or progression of Alzheimer's disease.

Amyloid Plaques Show Binding Capacity of Exogenous Injected Amyloid-β. - Gureviciene, Irina; Gurevicius, Kestutis; Mugantseva, Ekaterina; Kislin, Mikhail; Khiroug, Leonard; Tanila, Heikki (J Alzheimers Dis, 2017)
Amyloid plaques, although inducing damage to the immediately surrounding neuropil, have been proposed to provide a relatively innocuous way to deposit toxic soluble amyloid-β (Aβ) species. Here we address this hypothesis by exploring spread and absorption of fluorescent Aβ to pre-existing amyloid plaques after local application in wild-type mice versus APP/PS1 transgenic mice with amyloid plaques. Local intracortical or intracerebroventricular injection of fluorescently-labeled Aβ in APP/PS1 mice with a high plaque density resulted in preferential accumulation of the peptide in amyloid plaques in both conventional postmortem histology and in live imaging using two-photon microscopy. These findings support the contention that amyloid plaques may act as buffers to protect neurons from the toxic effects of momentary high concentrations of soluble Aβ oligomers.

Anomalous White Matter Structure and the Effect of Age in Down Syndrome Patients. - Fenoll, Raquel; Pujol, Jesus; Esteba-Castillo, Susanna; de Sola, Susana; Ribas-Vidal, Núria; García-Alba, Javier; Sánchez-Benavides, Gonzalo; Martínez-Vilavella, Gerard; Deus, Joan; Dierssen, Mara; Novell-Alsina, Ramón; de la Torre, Rafael (J Alzheimers Dis, 2017)
BACKGROUND: Neural tissue alterations in Down syndrome are fully expressed at relatively late developmental stages. In addition, there is an early presence of neurodegenerative changes in the late life stages. OBJECTIVE: The aims of this study were both to characterize white matter abnormalities in the brain of adult Down syndrome patients using diffusion tensor imaging (DTI) and to investigate whether degenerative alterations in white matter structure are detectable before dementia is clinically evident. METHODS: Forty-five adult non-demented Down syndrome patients showing a wide age range (18-52 years) and a matched 45-subject control group were assessed. DTI fractional anisotropy (FA) brain maps were generated and selected cognitive tests were administered. RESULTS: Compared with healthy controls, non-demented Down syndrome patients showed lower DTI FA in white matter involving the major pathways, but with more severe alterations in the frontal-subcortical circuits. White matter FA decreased with age at a similar rate in both DS and control groups. CONCLUSIONS: Our results contribute to characterizing the expression of white matter structural alterations in adult Down syndrome. However, an accelerated aging effect was not demonstrated, which may suggest that the FA measurements used are not sufficiently sensitive or, alternatively, age-related white matter neurodegeneration is not obvious prior to overt clinical dementia.

Antibodies to Signaling Molecules and Receptors in Alzheimer's Disease are Associated with Psychomotor Slowing, Depression, and Poor Visuospatial Function. - Giil, Lasse M; Vedeler, Christian A; Kristoffersen, Einar K; Nordrehaug, Jan Erik; Heidecke, Harald; Dechend, Ralf; Schulze-Forster, Kai; Muller, Dominik N; von Goetze, Victoria S; Cabral-Marques, Otavio; Riemekasten, Gabriela; Vogelsang, Petra; et al. (J Alzheimers Dis, 2017)
BACKGROUND: Alzheimer's disease (AD) is associated with several antibodies as well as signaling molecules and receptors. These may be detrimental in the presence of a disrupted blood-brain barrier (BBB). OBJECTIVE: To investigate whether the levels of antibodies toward 33 signaling molecules involved in neurotransmitter, vascular, and immune functions were associated with AD and, within the AD group; cognitive function and mood. METHODS: Antibodies in sera from patients with mild AD [(n = 91) defined as a Mini-Mental State Examination ≥ 20 or a Clinical Dementia Rating Scale≤1] and healthy controls (n = 102) were measured with enzyme-linked immunosorbent assays. Levels in AD and controls were compared by Mann-Whitney test. In the AD group, associations between antibodies and psychometric test scores were analyzed by robust regression. The false discovery threshold was set to 0.05. RESULTS: Antibodies to serotonin receptors [5-HT2AR (effect size (r) = 0.21, p = 0.004), 5-HT2CR (r = 0.25, p = 0.0005) and 5-HT7R (r = 0.21, p = 0.003)], vascular endothelial growth factor receptor 1 [VEGFR1 (r = 0.29, p < 0.001)] and immune-receptors (Stabilin-1 (r = 0.23, p = 0.001) and C5aR1 (r = 0.21, p = 0.004) were higher in AD. Psychomotor speed was associated with D1R-abs (β 0.49, p < 0.001), depression with ETAR-abs (β 0.31, p < 0.001), and visuospatial function with 5-HT1AR-abs (β 0.27, p = 0.004) despite similar antibody levels compared to controls. CONCLUSIONS: Antibody levels to VEGFR1, serotonergic receptors, and receptors in the immune system were increased in AD. Antibodies at similar levels as in controls were associated cognitive dysfunction and depression in AD.

APP Mutations in Cerebral Amyloid Angiopathy with or without Cortical Calcifications: Report of Three Families and a Literature Review. - Sellal, François; Wallon, David; Martinez-Almoyna, Laurent; Marelli, Cecilia; Dhar, Abhinav; Oesterlé, Héléne; Rovelet-Lecrux, Anne; Rousseau, Stéphane; Kourkoulis, Christina E; Rosand, Jon; DiPucchio, Zora Y; Frosch, Matthew; et al. (J Alzheimers Dis, 2017)
BACKGROUND: Specific APP mutations cause cerebral amyloid angiopathy (CAA) with or without Alzheimer's disease (AD). OBJECTIVE: We aimed at reporting APP mutations associated with CAA, describe the clinical, cerebrospinal fluid AD biomarkers, and neuroimaging features, and compare them with the data from the literature. METHODS: We performed a retrospective study in two French genetics laboratories by gathering all clinical and neuroimaging data from patients referred for a genetic diagnosis of CAA with an age of onset before 66 years and fulfilling the other Boston revised criteria. We studied the segregation of mutations in families and performed a comprehensive literature review of all cases reported with the same APP mutation. RESULTS: We screened APP in 61 unrelated French patients. Three mutations, located in the Aβ coding region, were detected in five patients from three families: p.Ala692Gly (Flemish), p.Glu693Lys (Italian), and p.Asp694Asn (Iowa). Patients exhibited CAA and progressive cognitive impairment associated with cortical calcifications in the Iowa and Italian mutation carriers, but not the patient carrying the Flemish mutation. CONCLUSIONS: This is the first evidence of cortical calcification in patients with an APP mutation other than the Iowa mutation. We discuss the radiological, cerebrospinal fluid, and clinical phenotype of patients carrying these mutations in the literature.

Association of Central Arterial Stiffness and Pressure Pulsatility with Mild Cognitive Impairment and Dementia: The Atherosclerosis Risk in Communities Study-Neurocognitive Study (ARIC-NCS). - Meyer, Michelle L; Palta, Priya; Tanaka, Hirofumi; Deal, Jennifer A; Wright, Jacqueline; Knopman, David S; Griswold, Michael E; Mosley, Thomas H; Heiss, Gerardo (J Alzheimers Dis, 2017)
BACKGROUND: The association of central arterial stiffness and pressure pulsatility with mild cognitive impairment (MCI) and dementia is not well characterized in the population-based setting. OBJECTIVE: The aim of this study was to quantify the cross-sectional association of arterial stiffness and pressure pulsatility with MCI and dementia among 4,461 older white and black adults from the population-based Atherosclerosis Risk in Communities Study-Neurocognitive Study. METHODS: We used race-stratified multinomial logistic regression to evaluate associations of percentile cut points of carotid-femoral pulse wave velocity, central systolic blood pressure, central pulse pressure, and pulse pressure amplification with MCI and dementia versus no cognitive impairment. RESULTS: Among whites, those with carotid-femoral pulse wave velocity or central systolic blood pressure ≥75th percentile had a higher prevalence of MCI compared to participants <75th percentile (conditional odds ratio (OR); 95% confidence interval (CI): 1.27 (1.02, 1.56) and 1.28 (1.04, 1.57), respectively) and those with central pulse pressure ≥75th percentile had a higher prevalence of MCI (OR 1.27 (95% CI: 1.03, 1.58)) and dementia (OR 1.76 (95% CI: 1.06, 2.92) compared to participants <75th percentile. Also among whites, those with pulse pressure amplification ≤25th percentile had a higher prevalence of dementia compared to participants >25th percentile (OR 1.65; (95% CI: 1.01, 2.70). Weaker associations were seen among black participants. CONCLUSION: Higher arterial stiffness and pulsatility were associated with MCI and dementia in white participants. Longitudinal characterization of the observed associations is warranted to assess whether arterial stiffness and pressure pulsatility predict MCI and dementia among older adults.

Attitudes toward Potential Participant Registries. - Grill, Joshua D; Holbrook, Andrew; Pierce, Aimee; Hoang, Dan; Gillen, Daniel L (J Alzheimers Dis, 2017)
Difficult participant recruitment is a consistent barrier to successful medical research. Potential participant registries represent an increasingly common intervention to overcome this barrier. A variety of models for registries exist, but few data are available to instruct their design and implementation. To provide such data, we surveyed 110 cognitively normal research participants enrolled in a longitudinal study of aging and dementia. Seventy-four (67%) individuals participated in the study. Most (78%, CI: 0.67, 0.87) participants were likely to enroll in a registry. Willingness to participate was reduced for registries that required enrollment through the Internet using a password (26%, CI: 0.16, 0.36) or through email (38%, CI: 0.27, 0.49). Respondents acknowledged their expectations that researchers share information about their health and risk for disease and their concerns that their data could be shared with for-profit companies. We found no difference in respondent preferences for registries that shared contact information with researchers, compared to honest broker models that take extra precautions to protect registrant confidentiality (28% versus 30%; p = 0.46). Compared to those preferring a shared information model, respondents who preferred the honest broker model or who lacked model preference voiced increased concerns about sharing registrant data, especially with for-profit organizations. These results suggest that the design of potential participant registries may impact the population enrolled, and hence the population that will eventually be enrolled in clinical studies. Investigators operating registries may need to offer particular assurances about data security to maximize registry enrollment but also must carefully manage participant expectations.

AZD3293: Pharmacokinetic and Pharmacodynamic Effects in Healthy Subjects and Patients with Alzheimer's Disease. - Cebers, Gvido; Alexander, Robert C; Haeberlein, Samantha Budd; Han, David; Goldwater, Ronald; Ereshefsky, Larry; Olsson, Tina; Ye, Naidong; Rosen, Laura; Russell, Muir; Maltby, Justine; Eketjäll, Susanna; et al. (J Alzheimers Dis, 2017)
AZD3293 (LY3314814) is a promising new potentially disease-modifying BACE1 (β-secretase) inhibitor in Phase III clinical development for the treatment of Alzheimer's disease. Reported here are the first two Phase I studies: (1) a single ascending dose study evaluating doses of 1-750 mg with a food-effect component (n = 72), and (2) a 2-week multiple ascending dose study evaluating doses of 15 or 50 mg once daily (QD) or 70 mg once weekly (QW) in elderly subjects (Part 1, n = 31), and 15, 50, or 150 mg QD in patients with mild to moderate Alzheimer's disease (Part 2, n = 16). AZD3293 was generally well tolerated up to the highest doses given. No notable food effects were observed. PK following multiple doses (Part 2) were tmax of 1 to 3 h and mean t1/2 of 16 to 21 h across the 15 to 150 mg dose range. For single doses of ≥5 mg, a ≥70% reduction was observed in mean plasma Aβ40 and Aβ42 concentrations, with prolonged suppression for up to 3 weeks at the highest dose level studied. Following multiple doses, robust reductions in plasma (≥64% at 15 mg and ≥78% at ≥50 mg) and cerebrospinal fluid (≥51% at 15 mg and ≥76% at ≥50 mg) Aβ peptides were seen, including prolonged suppression even with a QW dosing regimen. AZD3293 is the only BACE1 inhibitor for which prolonged suppression of plasma Aβ with a QW dosing schedule has been reported. Two Phase III studies of AZD3293 (AMARANTH, NCT02245737; and DAYBREAK-ALZ, NCT02783573) are now ongoing.

Baseline Predictors of Antipsychotic Treatment Continuation and Response at Week 8 in Patients with Alzheimer's Disease with Psychosis or Aggressive Symptoms: An Analysis of the CATIE-AD Study. - Nagata, Tomoyuki; Nakajima, Shinichiro; Shinagawa, Shunichiro; Plitman, Eric; Nakayama, Kazuhiko; Graff-Guerrero, Ariel; Mimura, Masaru (J Alzheimers Dis, 2017)
BACKGROUND/OBJECTIVE: The aim of the present study was to investigate predictors of atypical antipsychotic (AAP) treatment continuation and response by week 8 in patients with Alzheimer's disease (AD) who have psychotic/aggressive symptoms using the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) dataset. METHODS: Clinical data was utilized from 421 AD outpatients with psychotic/aggressive symptoms who needed interventional treatment. Logistic regression analyses were performed to examine which baseline sociodemographic and clinical characteristics contributed to treatment 'continuation' and 'response', the latter of which was evaluated by the Clinical Global Impression of Change (CGI-C), Neuropsychiatric Inventory (NPI), and Brief Psychiatric Scale (BPRS). RESULTS: The treatment continuation rate was 48.7%, and CGI-C, NPI, and BPRS response rate by the last observation carried forward method were 42.7%, 48.6%, and 37.5%, respectively. No significant predictor was identified for treatment continuation in the Caucasian patients (n = 331), while better treatment response was predicted by a lower Mini-Mental State Examination score, treatment with risperidone (versus olanzapine and quetiapine), history of diabetes mellitus, healthier physical status, and more severe initial psychotic symptoms. CONCLUSIONS: Comparatively high intolerability from AAPs in the short term was confirmed. We found that baseline clinical predictors to treatment response in Caucasian AD patients with psychotic/aggressive symptoms include treatment with risperidone (versus quetiapine and olanzapine), diabetes mellitus, global physical status, cognitive impairment, and psychotic symptoms. Going forward, these findings may help to determine treatment strategies or care plans.

BDNF Responses in Healthy Older Persons to 35 Minutes of Physical Exercise, Cognitive Training, and Mindfulness: Associations with Working Memory Function. - Håkansson, Krister; Ledreux, Aurélie; Daffner, Kirk; Terjestam, Yvonne; Bergman, Patrick; Carlsson, Roger; Kivipelto, Miia; Winblad, Bengt; Granholm, Ann-Charlotte; Mohammed, Abdul Kadir H (J Alzheimers Dis, 2017)
Brain-derived neurotrophic factor (BDNF) has a central role in brain plasticity by mediating changes in cortical thickness and synaptic density in response to physical activity and environmental enrichment. Previous studies suggest that physical exercise can augment BDNF levels, both in serum and the brain, but no other study has examined how different types of activities compare with physical exercise in their ability to affect BDNF levels. By using a balanced cross over experimental design, we exposed nineteen healthy older adults to 35-minute sessions of physical exercise, cognitive training, and mindfulness practice, and compared the resulting changes in mature BDNF levels between the three activities. We show that a single bout of physical exercise has significantly larger impact on serum BDNF levels than either cognitive training or mindfulness practice in the same persons. This is the first study on immediate BDNF effects of physical activity in older healthy humans and also the first study to demonstrate an association between serum BDNF responsivity to acute physical exercise and working memory function. We conclude that the BDNF increase we found after physical exercise more probably has a peripheral than a central origin, but that the association between post-intervention BDNF levels and cognitive function could have implications for BDNF responsivity in serum as a potential marker of cognitive health.

Biomarkers for Early Diagnosis of Alzheimer's Disease in the Oldest Old: Yes or No? - Paolacci, Lucia; Giannandrea, David; Mecocci, Patrizia; Parnetti, Lucilla (J Alzheimers Dis, 2017)
In recent years, many efforts have been spent to identify sensitive biomarkers able to improve the accuracy of Alzheimer's disease (AD) diagnosis. Two different workgroups (NIA-AA and IWG) included cerebrospinal fluid (CSF) and neuroimaging findings in their sets of criteria in order to improve diagnostic accuracy as well as early diagnosis. The number of subjects with cognitive impairment increases with aging but the oldest old (≥85 years of age), the fastest growing age group, is still the most unknown from a biological point of view. For this reason, the aim of our narrative mini-review is to evaluate the pertinence of the new criteria for AD diagnosis in the oldest old. Moreover, since different subgroups of oldest old have been described in scientific literature (escapers, delayers, survivors), we want to outline the clinical profile of the oldest old who could really benefit from the use of biomarkers for early diagnosis. Reviewing the literature on biomarkers included in the diagnostic criteria, we did not find a high degree of evidence for their use in the oldest old, although CSF biomarkers seem to be still the most useful for excluding AD diagnosis in the "fit" subgroup of oldest old subjects, due to the high negative predictive value maintained in this age group.

Blood Pressure and Hispanic/Latino Cognitive Function: Hispanic Community Health Study/Study of Latinos Results. - Tarraf, Wassim; Rodríguez, Carlos J; Daviglus, Martha L; Lamar, Melissa; Schneiderman, Neil; Gallo, Linda; Talavera, Gregory A; Kaplan, Robert C; Fornage, Myriam; Conceicao, Alan; González, Hector M (J Alzheimers Dis, 2017)
BACKGROUND: Hispanics/Latinos are at increased risk for cardiovascular disease and cognitive decline and dementias. High blood pressure (BP) has been implicated in both stroke and dementias. Associations between BP and cognition among diverse Latinos are still unpublished. OBJECTIVE: We examined associations between cognition and four BP based measures among diverse Hispanics/Latinos. We hypothesized that higher BP, particularly systolic pressure, and increased arterial stiffness (i.e., pulse pressure), would be associated with lower cognitive function. METHODS: We used baseline (2008-2011) Hispanic Community Health Study/Study of Latinos (HCHS/SOL; n = 9,019; ages 45-74 years) data to examine cognition in relation to BP measures. RESULTS: In age, sex, and education adjusted models, systolic, pulse, and mean arterial pressure were consistently negatively associated with executive function, psychomotor speed and sustained attention, verbal episodic learning and memory, speech fluency, and mental status measures. These associations were attenuated but remained statistically significant in fully adjusted models. CONCLUSION: Among middle-aged and older diverse Hispanics/Latinos, we found modest but consistent associations between indicators of arterial stiffness, and compromised blood flow and lower cognitive function. Clinical management and public health interventions to raise awareness and enhance BP management beginning in midlife could reduce disparities and improve population health by reducing cognitive decline burdens.

Brain Regions Involved in Arousal and Reward Processing are Associated with Apathy in Alzheimer's Disease and Frontotemporal Dementia. - Huey, Edward D; Lee, Seonjoo; Cheran, Gayathri; Grafman, Jordan; Devanand, Davangere P (J Alzheimers Dis, 2017)
BACKGROUND: Apathy is a common and problematic symptom of several neurodegenerative illnesses, but its neuroanatomical bases are not understood. OBJECTIVE: To determine the regions associated with apathy in subjects with mild Alzheimer's disease (AD) using a method that accounts for the significant co-linearity of regional atrophy and neuropsychiatric symptoms. METHODS: We identified 57 subjects with mild AD (CDR = 1) and neuropsychiatric symptoms in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We performed a multivariate multiple regression with LASSO regularization on all symptom subscales of the Neuropsychiatric Inventory and the whole-brain ROI volumes calculated from their baseline MRIs with FreeSurfer. We compared our results to those from a previous study using the same method in patients with frontotemporal dementia (FTD) and corticobasal syndrome (CBS). RESULTS: Of neuropsychiatric symptoms, apathy showed the most robust neuroanatomical associations in the AD subjects. Atrophy of the following regions were independently associated with apathy: the ventromedial prefrontal cortex; ventrolateral prefrontal cortex; posterior cingulate cortex and adjacent lateral cortex; and the bank of the superior temporal sulcus. These results replicate previous studies using FTD and CBS patients, mostly agree with the previous literature on apathy in AD, and correspond to the Medial and Orbital Prefrontal Cortex networks identified in non-human primates. CONCLUSION: The current study, previous studies from our laboratory, and the previous literature suggest that impairment of the same brain networks involved in arousal, threat response, and reward processing are associated with apathy in AD and FTD.

Can Musical or Painting Interventions Improve Chronic Pain, Mood, Quality of Life, and Cognition in Patients with Mild Alzheimer's Disease? Evidence from a Randomized Controlled Trial. - Pongan, Elodie; Tillmann, Barbara; Leveque, Yohana; Trombert, Béatrice; Getenet, Jean Claude; Auguste, Nicolas; Dauphinot, Virginie; El Haouari, Hanane; Navez, Malou; Dorey, Jean-Michel; Krolak-Salmon, Pierre; Laurent, Bernard; et al. (J Alzheimers Dis, 2017)
BACKGROUND: Among non-pharmacological therapies, musical intervention is often used for patients with Alzheimer's disease (AD) and patients presenting chronic pain. However, their efficacy is still under debate. OBJECTIVE: Our aim was to determine the efficacy of choral singing versus painting sessions on chronic pain, mood, quality of life, and cognition in AD patients. METHODS: In this multicenter randomized controlled trial, 59 mild AD patients were randomized to a 12-week singing (SG; n = 31) or painting group (PG; n = 28). Chronic pain, anxiety, depression, and quality of life were assessed before, after, and 1 month after the sessions. Cognitive abilities were assessed before and after interventions. The evolution of these different measures was assessed with mixed linear models. The primary data analysis was by intention-to-treat, and completed by a 'per protocol' approach. RESULTS: Both singing and painting interventions led to significant pain reduction (Time effect: F = 4.71; p = 0.01), reduced anxiety (Time effect: F = 10.74; p < 0.0001), improved Quality of Life (Time effect: F = 6.79; p = 0.002), improved digit span (F = 12.93; p = 0.001), and inhibitory processes (Time effect: F = 4.93; p = 0.03). Depression was reduced over time in PG only (Time x Group effect: F = 4.53; p = 0.01). Verbal Memory performance remained stable over time in SG, but decreased in PG (Time x group effect: F = 9.29; p = 0.004). CONCLUSION: Findings suggest that singing and painting interventions may reduce pain and improve mood, quality of life, and cognition in patients with mild AD, with differential effects of painting for depression and singing for memory performance.

CD44 Splice Variants as Potential Players in Alzheimer's Disease Pathology. - Pinner, Elhanan; Gruper, Yaron; Ben Zimra, Micha; Kristt, Don; Laudon, Moshe; Naor, David; Zisapel, Nava (J Alzheimers Dis, 2017)
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive deficits, deposition of amyloid-β (Aβ) plaques, intracellular neurofibrillary tangles, and neuronal cell death. Neuroinflammation is commonly believed to participate in AD pathogenesis. CD44 is an inflammation-related gene encoding a widely-distributed family of alternatively spliced cell surface glycoproteins that have been implicated in inflammation, metastases, and inflammation-linked neuronal injuries. Here we investigated the expression patterns of CD44S (which does not contain any alternative exon) and CD44 splice variants in postmortem hippocampal samples from AD patients and matched non-AD controls. The expression of CD44S and CD44 splice variants CD44V3, CD44V6, and CD44V10 was significantly higher in AD patients compared to non-AD controls. Immunohistochemistry of human hippocampal sections revealed that CD44S differentially localized to neuritic plaques and astrocytes, whereas CD44V3, CD44V6, and CD44V10 expression was mostly neuronal. Consistent with these findings, we found that the expression of CD44V6 and CD44V10 was induced by Aβ peptide in neuroblastoma cells and primary neurons. Furthermore, in loss of function studies we found that both CD44V10-specific siRNA and CD44V10 antibody protected neuronal cells from Aβ-induced toxicity, suggesting a causal relationship between CD44V10 and neuronal cell death. These data indicate that certain CD44 splice variants contribute to AD pathology and that CD44V10 inhibition may serve as a new neuroprotective treatment strategy for this disease.

Central Olfactory Dysfunction in Alzheimer's Disease and Mild Cognitive Impairment: A Functional MRI Study. - Vasavada, Megha M; Martinez, Brittany; Wang, Jianli; Eslinger, Paul J; Gill, David J; Sun, Xiaoyu; Karunanayaka, Prasanna; Yang, Qing X (J Alzheimers Dis, 2017)
BACKGROUND: Olfactory deficits are present in early Alzheimer's disease (AD) and mild cognitively impaired (MCI) patients. However, whether these deficits are due to dysfunction of the central or peripheral olfactory nervous system remains uncertain. This question is fundamentally important for developing imaging biomarkers for AD using olfactory testing. OBJECTIVE: This study sought to use olfactory functional magnetic resonance imaging (fMRI) to further demonstrate the involvement of the central olfactory system in olfactory deficits in MCI and AD. METHODS: We investigated the central olfactory system in 27 cognitively normal controls (CN), 21 MCI, and 15 AD subjects using olfactory fMRI with an odor-visual association paradigm during which a visual cue was paired with lavender odorant (odor condition) or odorless air (no-odor condition). RESULTS: The CN subjects had significantly greater activated volume in the primary olfactory cortex during both the odor and no-odor conditions compared to either the MCI or AD groups (p < 0.05). No significant differences were observed between the odor and no-odor conditions within each group. No-odor condition activation in AD and MCI correlated with the cognitive and olfactory assessments. CONCLUSION: The no-odor condition, allowing investigation of activation patterns when the peripheral olfactory system was not directly involved, elicited the same functional response as the odor condition for each of the three groups. Thus, the olfactory activation deficits present in AD and MCI patients are most likely caused by degeneration of the central olfactory nervous system.

Central Review of Amyloid-Related Imaging Abnormalities in Two Phase III Clinical Trials of Bapineuzumab in Mild-To-Moderate Alzheimer's Disease Patients. - Ketter, Nzeera; Brashear, H Robert; Bogert, Jennifer; Di, Jianing; Miaux, Yves; Gass, Achim; Purcell, Derk D; Barkhof, Frederik; Arrighi, H Michael (J Alzheimers Dis, 2017)
BACKGROUND: Amyloid-related imaging abnormalities (ARIA) consist of ARIA-E (with effusion or edema) and ARIA-H (hemosiderin deposits [HDs]). OBJECTIVES: To address accurate ascertainment of ARIA identification, a final magnetic resonance imaging (MRI) reading was performed on patients with mild-to-moderate Alzheimer's disease randomized to bapineuzumab IV or placebo during two Phase III trials (APOE ɛ4 allele carriers or noncarriers). METHODS: Final MRI central review consisted of a systematic sequential locked, adjudicated read in 1,331 APOE ɛ4 noncarriers and 1,121 carriers by independent neuroradiologists. Assessment of ARIA-E, ARIA-H, intracerebral hemorrhages, and age-related white matter changes is described. RESULTS: In the Final Read, treatment-emergent ARIA-E were identified in 242 patients including 76 additional cases not noted previously in real time. Overall, incidence proportion of ARIA-E was higher in carriers (active 21.2%; placebo 1.1%) than in noncarriers (pooled active 11.3%; placebo 0.6%), and was more often identified in homozygote APOE ɛ4 carriers than heterozygotes (34.5% versus 16.9%). Incidence rate of ARIA-E increased with increased dose in noncarriers. Frequency of ARIA-E first episodes was highest after the first and second bapineuzumab infusion and declined after repeated infusions. Incidence of total HDs <10 mm (cerebral microhemorrhages) was higher in active groups versus placebo. CONCLUSION: ARIA was detected more often on MRI scans when every scan was reviewed by trained neuroradiologists and results adjudicated. There was increased incidence of ARIA-E in bapineuzumab-treated carriers who had a microhemorrhage at baseline. ARIA-E was a risk factor for incident ARIA-H and late onset ARIA-E was milder radiologically. Age-related white matter changes did not progress during the study.

The Cerebrospinal Fluid Aβ1-42/Aβ1-40 Ratio Improves Concordance with Amyloid-PET for Diagnosing Alzheimer's Disease in a Clinical Setting. - Niemantsverdriet, Ellis; Ottoy, Julie; Somers, Charisse; De Roeck, Ellen; Struyfs, Hanne; Soetewey, Femke; Verhaeghe, Jeroen; Van den Bossche, Tobi; Van Mossevelde, Sara; Goeman, Johan; De Deyn, Peter Paul; Mariën, Peter; et al. (J Alzheimers Dis, 2017)
BACKGROUND: Evidence suggests that the concordance between amyloid-PET and cerebrospinal fluid (CSF) amyloid-β (Aβ) increases when the CSF Aβ1-42/Aβ1-40 ratio is used as compared to CSF Aβ1-42 levels alone. OBJECTIVE: In order to test this hypothesis, we set up a prospective longitudinal study comparing the concordance between different amyloid biomarkers for Alzheimer's disease (AD) in a clinical setting. METHODS: Seventy-eight subjects (AD dementia (n = 17), mild cognitive impairment (MCI, n = 48), and cognitively healthy controls (n = 13)) underwent a [18F]Florbetapir ([18F]AV45) PET scan, [18F]FDG PET scan, MRI scan, and an extensive neuropsychological examination. In a large subset (n = 67), a lumbar puncture was performed and AD biomarkers were analyzed (Aβ1-42, Aβ1-40, T-tau, P-tau181). RESULTS: We detected an increased concordance in the visual and quantitative (standardized uptake value ratio (SUVR) and total volume of distribution (VT)) [18F]AV45 PET measures when the CSF Aβ1-42/Aβ1-40 was applied compared to Aβ1-42 alone. CSF biomarkers were stronger associated to [18F]AV45 PET for SUVR values when considering the total brain white matter as reference region instead of cerebellar grey matterConclusions:The concordance between CSF Aβ and [18F]AV45 PET increases when the CSF Aβ1-42/Aβ1-40 ratio is applied. This finding is of most importance for the biomarker-based diagnosis of AD as well as for selection of subjects for clinical trials with potential disease-modifying therapies for AD.

Cerebrospinal Fluid Aβ42/Aβ40 as a Means to Limiting Tube- and Storage-Dependent Pre-Analytical Variability in Clinical Setting. - Gervaise-Henry, Christelle; Watfa, Gasshan; Albuisson, Eliane; Kolodziej, Allan; Dousset, Brigitte; Olivier, Jean-Luc; Jonveaux, Thérèse Rivasseau; Malaplate-Armand, Catherine (J Alzheimers Dis, 2017)
BACKGROUND: Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers have recently been included in the criteria for AD diagnosis. Unfortunately, their wider use in routine and interpretation require more standardization, particularly for the pre-analytical steps. In particular, amyloid-β (Aβ)42 peptide measurement is strongly influenced by the type of collection tube and by repeated freeze/thaw cycles. OBJECTIVE: The objectives of this study were to compare, in clinical setting, the impact of collection tubes and the repetition of freeze/thaw cycles on Aβ42 and Aβ40 concentrations and consequently determine if the Aβ42/Aβ40 ratio could resolve the diagnosis difficulties related to these pre-analytical parameters. METHODS: CSF from 35 patients was collected in different polypropylene (PP) and stored at - 80°C after sampling. For CSF collected in the reference tube, three successive freeze-thaw cycles were done. Aβ42 and Aβ40 concentrations were determined in each condition in order to calculate the Aβ42/Aβ40 ratio. RESULTS: Our results showed that CSF Aβ42 and Aβ40 values were significantly different according to the type of collection tube and the number of freeze/thaw cycles. Although the calculation of the Aβ42/Aβ40 ratio eliminated the effect of PP tube-dependent variation, this was not the case for freeze-thaw cycle-associated variation. CONCLUSION: The use of Aβ42/Aβ40 ratio rather than Aβ42 alone could contribute toward pre-analytical standardization, thus allowing the general use of CSF AD biomarkers in routine practice.