Pages 553-569
Review
Danton H. O’Day, Kristeen Eshak, Michael A. Myre (Handling Associate Editor: Urszula Wodja)
Calmodulin Binding Proteins and Alzheimer’s Disease
Abstract: The small, calcium-sensor protein calmodulin is ubiquitously expressed and central to cell function in all cell types. Here the literature linking calmodulin to Alzheimer’s disease is reviewed. Several experimentally-verified calmodulin-binding proteins are involved in the formation of amyloid-β plaques including amyloid-β protein precursor, β-secretase, presenilin-1, and ADAM10. Many others possess potential calmodulin-binding domains that remain to be verified. Three calmodulin binding proteins are associated with the formation of neurofibrillary tangles: two kinases (CaMKII, CDK5) and one protein phosphatase (PP2B or calcineurin). Many of the genes recently identified by genome wide association studies and other studies encode proteins that contain putative calmodulin-binding domains but only a couple (e.g., APOE, BIN1) have been experimentally confirmed as calmodulin binding proteins. At least two receptors involved in calcium metabolism and linked to Alzheimer’s disease (mAchR; NMDAR) have also been identified as calmodulin-binding proteins. In addition to this, many proteins that are involved in other cellular events intimately associated with Alzheimer’s disease including calcium channel function, cholesterol metabolism, neuroinflammation, endocytosis, cell cycle events, and apoptosis have been tentatively or experimentally verified as calmodulin binding proteins. The use of calmodulin as a potential biomarker and as a therapeutic target is discussed.
Pages 571-580
Review
Chiara Villa, Luigi Ferini-Strambi, Romina Combi (Handling Associate Editor: Beatrice Arosio)
The Synergistic Relationship between Alzheimer’s Disease and Sleep Disorders: An Update
Abstract: Sleep disorders are frequently reported in Alzheimer’s disease (AD), with a significant impact on patients and caregivers and a major risk factor for early institutionalization. Although changes in sleep organization are a hallmark of the normal aging processes, sleep macro- and micro-architectural alterations are more evident in patients affected by AD. Degeneration of neural pathways regulating sleep-wake patterns and sleep architecture may contribute to sleep alterations. In return, several recent studies suggested that common sleep disorders may precede clinical symptoms of dementia and represent risk factors for cognitive decline, through impairment of sleep-dependent memory consolidation processes. Thus, a close relationship between sleep disorders and AD has been largely hypothesized. Here, sleep alterations in AD and its pre-dementia stage, mild cognitive impairment, and their complex interactions are reviewed.
Pages 581-591
Review
Narayan R. Bhat
Vasculoprotection as a Convergent, Multi-Targeted Mechanism of Anti-AD Therapeutics and Interventions
Abstract: Using a variety of animal models of Alzheimer’s disease (AD), there have been a number of recent studies reporting varying degrees of success with anti-AD therapeutics. The efficacies are often discussed in terms of the modulatory effects of the compounds tested on identified or assumed targets among the known (or proposed) pathogenic and neuroprotective mechanisms, largely within the context of the dominant amyloid cascade hypothesis. However, it is clear that several of the relatively more efficacious treatments tend to be multifunctional and target multiple pathological processes associated with AD including most commonly, oxidative and metabolic stress and neuroinflammation. Increasing evidence suggests that vascular and neurodegenerative pathologies often co-exist and that neurovascular dysfunction plays a critical role in the development or progression of AD. In this review, we will discuss the significance of vasculoprotection or neurovascular unit integrity as a common, multi-targeted mechanism underlying the reported efficacy of a majority of anti-AD therapeutics—amyloid-targeted or otherwise—while providing a strong support for future neurovascular-based treatment strategies and interventions.
Pages 593-604
Hypothesis
George J. Brewer
Divalent Copper as a Major Triggering Agent in Alzheimer’s Disease
Abstract:Alzheimer’s disease (AD) is at epidemic proportions in developed countries, with a steady increase in the early 1900s, and then exploding over the last 50 years. This epidemiology points to something causative in the environment of developed countries. This paper will review the considerable evidence that that something could be inorganic copper ingestion. The epidemic parallels closely the spread of copper plumbing, with copper leached from the plumbing into drinking water being a main causal feature, aided by the increasingly common use of supplement pills containing copper. Inorganic copper is divalent copper, or copper-2, while we now know that organic copper, or copper in foods, is primarily monovalent copper, or copper-1. The intestinal transport system, Ctr1, absorbs copper-1 and the copper moves to the liver, where it is put into safe channels. Copper-2 is not absorbed by Ctr1, and some of it bypasses the liver and goes directly into the blood, where it appears to be exquisitely toxic to brain cognition. Thus, while aggregation of amyloid-β has been postulated to be the cause of AD under current dogma, the great increase in prevalence over the last century appears to be due to ingestion of copper-2, which may be causing the aggregation, and/or increasing the oxidant toxicity of the aggregates. An alternative hypothesis proposes that oxidant stress is the primary injuring agent, and under this hypothesis, copper-2 accumulation in the brain may be a causal factor of the oxidant injury. Thus, irrespective of which hypothesis is correct, AD can be classified, at least in part, as a copper-2 toxicity disease. It is relatively easy to avoid copper-2 ingestion, as discussed in this review. If most people begin avoiding copper-2 ingestion, perhaps the epidemic of this serious disease can be aborted.
Pages 605-609
Short Communication
Mareike Müller, Jurgen A. Claassen, H. Bea Kuiperij, Marcel M. Verbeek (Handling Associate Editor: Sebastiaan Engelborghs)
Cerebrospinal Fluid NrCAM is not a Suitable Biomarker to Discriminate between Dementia Disorders: A Pilot Study
Abstract: Neuronal Cell Adhesion Molecule (NrCAM) is a proposed new cerebrospinal fluid (CSF) biomarker in Alzheimer’s disease (AD). In this pilot study, we aimed to validate and extend previous results and measured NrCAM by ELISA in CSF of patients with AD, frontotemporal dementia, dementia with Lewy bodies, and non-demented controls. NrCAM levels were comparable in all groups, but correlated positively with total tau and phosphorylated tau levels. Furthermore, NrCAM had no significant additional diagnostic value when combined with amyloid-β42, total tau, and phosphorylated tau proteins. Therefore, NrCAM is not a suitable CSF biomarker to differentiate between dementia groups.
Pages 611-629
Jia-Hao Sun, Lan Tan, Hui-Fu Wang, Meng-Shan Tan, Lin Tan, Jie-Qiong Li, Wei Xu, Xi-Chen Zhu, Teng Jiang, Jin-Tai Yu (Handling Associate Editor: Benedetta Nacmias)
Genetics of Vascular Dementia: Systematic Review and Meta-Analysis
Abstract: Background: Vascular dementia (VaD) is the second most common type of dementia. So far, little is known about the contribution of genetic polymorphisms to the risk of VaD. Many candidate genetic polymorphisms have been examined in a large numbers of studies. However, due to the conflicting results, the genetics of VaD is still behind the shadow. Objective: We conducted a comprehensive meta-analysis on associations between genetic polymorphisms of any gene and VaD to investigate the genetics of VaD. Method: We sought the published studies of associations between any genetic polymorphism and VaD and critically appraised them. We assessed the effects of genetic models by calculating pooled odds ratios (ORs), investigating the origin of heterogeneity by subgroup analysis, and testing the robustness by random effect model and sensitivity analysis. Results: 69 studies with 4,462 cases and 11,583 controls were included. We identified APOE ɛ2/ɛ3/ɛ4 and additional four genetic polymorphisms including MTHFR C677T, PON1 L55M, TGF-β1 +29C/T, and TNF-α -850C/T associated with VaD. Tested by random effect model and sensitivity analysis, the pooled results show nice robustness. Conclusions: Our comprehensive meta-analysis highlighted the genetic contribution to sporadic VaD. Because of the small amount of data on associations between genetic polymorphisms, except for APOE, and VaD, more studies are needed to test the existing genetic polymorphisms and detect other related genetic variants.
Pages 631-637
Gisela Pusswald, Johann Lehrner, Michael Hagmann, Peter Dal-Bianco, Thomas Benke, Marisa Loitfelder, Josef Marksteiner, Jochen Mosbacher, Gerhard Ransmayr, Guenter Sanin, Reinhold Schmidt; PRODEM Study Group
Gender-Specific Differences in Cognitive Profiles of Patients with Alzheimer’s Disease: Results of the Prospective Dementia Registry Austria (PRODEM-Austria)
Abstract: Background: Alzheimer’s disease (AD) is one of the most common age-related diseases in the western world. Gender differences in neuropsychological functions are seldom evaluated in AD. Objective: Recent investigations suggested that gender may be an important modifying factor in the development and progression of AD. We examined gender-specific differences in the pattern of cognitive dysfunction of patients with mild to moderate AD. Methods: We examined 113 males (mean age 78) and 173 females (mean age 80) of the prospective registry on dementia in Austria (PRODEM). We analyzed differences in the cognitive profile between male and female AD patients on the CERAD-Plus test battery. Results: We found gender-related differences in the neuropsychological domains of verbal learning; the women tended to perform worse than men. Controlling for depression, stage and duration of dementia, and the level of education, there was still a significant effect of gender on verbal episodic memory. Conclusion: There is an interaction between gender and cognitive function, most notable in verbal episodic memory; female patients in the early stage of AD performed worse on verbal episodic memory than men. This indicates that the gender-specificities of neuropsychological functions should be given careful consideration in clinical diagnosis of dementia.
Pages 639-653
Kuven K Moodley*, Daniela Perani*, Ludovico Minati, Pasquale Anthony Della Rosa, Frank Pennycook, John C. Dickson, Anna Barnes, Valeria Elisa Contarino, Sofia Michopoulou, Ludovico D’Incerti, Catriona Good, Federico Fallanca, Emilia Giovanna Vanoli, Peter J. Ell, Dennis Chan *These authors contributed equally to this work.
Simultaneous PET-MRI Studies of the Concordance of Atrophy and Hypometabolism in Syndromic Variants of Alzheimer’s Disease and Frontotemporal Dementia: An Extended Case Series
Abstract: Background. Simultaneous PET-MRI is used to compare patterns of cerebral hypometabolism and atrophy in six different dementia syndromes. Objectives. The primary objective was to conduct an initial exploratory study regarding the concordance of atrophy and hypometabolism in syndromic variants of Alzheimer’s disease (AD) and frontotemporal dementia (FTD). The secondary objective was to determine the effect of image analysis methods on determination of atrophy and hypometabolism. Method. PET and MRI data were acquired simultaneously on 24 subjects with six variants of AD and FTD (n=4 per group). Atrophy was rated visually and also quantified with measures of cortical thickness. Hypometabolism was rated visually and also quantified using atlas- and SPM-based approaches. Concordance was measured using weighted Cohen’s kappa. Results. Atrophy-hypometabolism concordance differed markedly between patient groups; kappa scores ranged from 0.13 (nonfluent/agrammatic variant of primary progressive aphasia, nfvPPA) to 0.49 (posterior cortical variant of AD, PCA). Heterogeneity was also observed within groups; the confidence intervals of kappa scores ranging from 0-0.25 for PCA to 0.29-0.61 for nfvPPA. More widespread MRI and PET changes were identified using quantitative methods than on visual rating. Conclusion. The marked differences in concordance identified in this initial study may reflect differences in the molecular pathologies underlying AD and FTD syndromic variants but also operational differences in the methods used to diagnose these syndromes. The superior ability of quantitative methodologies to detect changes on PET and MRI, if confirmed on larger cohorts, may favor their usage over qualitative visual inspection in future clinical diagnostic practice.
Pages 655-663
Federico Licastro, Elena Raschi, Ilaria Carbone, Elisa Porcellini (Handling Associate Editor: Calogero Caruso)
Variants in Antiviral Genes are Risk Factors for Cognitive Decline and Dementia
Abstract: A gene association study of factors regulating antiviral response such as interferon (IFN)-λ3, also known as IL-28B, mediator complex (Med) 23, and interferon regulatory factor (IRF) 7 with cognitive deterioration and Alzheimer’s disease (AD) was performed. Differences in the TT genotype distribution of IL-28B single nucleotide polymorphism (SNP) between AD patients and controls were found. The GG genotype of Med23 gene appeared to influence the progression of the disease, being more frequent in the APOE ε4 negative elderly that developed AD during the five year follow-up. Leukocyte positivity for Epstein Barr virus (EBV) and human herpes virus (HHV)-6 DNA was analyzed. Med23 GG genotype correlated with the positivity to HHV-6 DNA. EBV and HHV-6 plasma IgG levels were also investigated and EBV IgG levels were increased in AD with the IRF7 GG genotype. A differential genetic background in genes regulating anti-virus responses was associated with an increased risk of cognitive decline and AD. EBV and HHV-6 appeared to be risk factors for AD in genetically susceptible elderly.
Pages 665-676
Junying Zhang*, Xu Kai*, Dongfeng Wei*, Rongjuan Guo, He Li, Yongyan Wang, Zhanjun Zhang (Handling Associate Editor: Dehua Chui) *These authors contributed equally to this work.
The Effects of Bushen Capsule on Episodic Memory in Amnestic Mild Cognitive Impairment Patients: A Pilot Placebo Controlled fMRI Study
Abstract: Background: Observing the effects of a drug on episodic memory and the underlying brain function has extreme significance in evaluating its therapeutic value in treating amnestic mild cognitive impairment (aMCI). Objective: To observe the effects of Bushen capsule (BSC), a Chinese herbal medicine, on episodic memory in aMCI and further explore the underlying mechanism. Methods: 44 aMCI patients from hospitals and local communities in Beijing were randomly divided into the BSC treatment group (22 patients orally treated with BSC) and the placebo group (22 patients treated with placebo). The duration of intervention lasted for 3 months. Before and after the 3 months treatment, neuropsychological tests and fMRI examinations were carried out to assess cognitive ability and brain activation changes, respectively. Results: Compared to the placebo group, the BSC group presented a significant increase in the AVLT(N5) (p=0.003) and Stroop (C-B) time (p=0.002). fMRI results showed a reduction of brain negative activation in the right middle temporal gyrus and a positive activation enhancement in the right putamen among the BSC group after treatment. Meanwhile, the variation in activation values in the right middle temporal gyrus was significantly correlated with the improvement in test values of AVLT(N5), and the variation in deactivation values in the right putamen was significantly correlated with the improvement in test values of Stroop (C-B) time. Conclusions: BSC can improve the behavioral performances of episodic memory in aMCI; this effect may be related to its modulation on the activations of the temporal lobe and the putamen under episodic memory encoding task.
Pages 677-686
Rebekah M. Ahmed*, Cassandra Kaizik*, Muireann Irish, Eneida Mioshi, Nadene Dermody, Matthew C. Kiernan, Olivier Piguet, John R. Hodges (Handling Associate Editor: Marc Sollberger) *These authors contributed equally to this work.
Characterizing Sexual Behavior in Frontotemporal Dementia
Abstract: Background: Frontotemporal dementia (FTD) is characterized by a number of prominent behavioral changes. While FTD has been associated with the presence of aberrant or unusual sexual behaviors in a proportion of patients, few studies have formally investigated changes in sexual function in this disease. Objective: We aimed to systematically quantify changes in sexual behavior, including current symptoms and changes from prior to diagnoses, in behavioral-variant (bvFTD) and semantic dementia (SD), compared to Alzheimer’s disease (AD). Methods: Carers of 49 dementia patients (21 bvFTD, 11 SD, 17 AD) were interviewed using the Sexual Behavior and Intimacy Questionnaire (SIQ), a survey designed to assess changes in sexual function across multiple domains including initiating, level of affection, and aberrant or unusual sexual behavior. Results: BvFTD patients show prominent hyposexual behavior including decreased affection, initiation, and response to advances by partners, and decreased frequency of sexual relations, compared to AD and to SD patients. The greatest changes in sexual behavior compared to pre-diagnoses were found in the bvFTD group with a 90-100% decrease in initiation, response, and frequency of sexual relations. Notably, aberrant or unusual sexual behavior was reported in a minority of bvFTD and SD patients and occurred in patients who also showed hyposexual behavior toward their partner. Conclusion: Overall loss of affection, reduced initiation of sexual activity, and responsiveness is an overwhelming feature of bvFTD. In contrast, aberrant or unusual sexual behavior is observed in the minority of bvFTD patients. The underlying pathophysiology of these changes likely reflects structural and functional changes in frontoinsular and limbic regions including the hypothalamus.
Pages 687-693
Kosuke Matsuzono, Toru Yamashita, Yasuyuki Ohta, Nozomi Hishikawa, Kota Sato, Syoichiro Kono, Kentaro Deguchi, Yumiko Nakano, Koji Abe
Clinical Benefits for Older Alzheimer’s Disease Patients: Okayama Late Dementia Study (OLDS)
Abstract: Background/Objective: There are few reports on the effects of anti-Alzheimer’s disease (AD) drugs on older AD patients, and possible differences based on gender in a real world setting. Methods: “Okayama Late Dementia Study (OLDS)” is a retrospective clinical cohort study focusing on older AD patients (n=373) treated with monotherapy donepezil (n=55), galantamine (n=222), rivastigmine (n=63), or memantine (n=33). The patients were evaluated as an entire group and separated by gender, using seven batteries for dementia assessment at baseline and at 3, 6, and 12 months of drug therapy. Results: All four drugs preserved cognitive and affective functions until 12 months, except for Frontal Assessment Battery (FAB) with memantine (*p<0.05 versus baseline). Donepezil monotherapy significantly improved Hasegawa Dementia Rating Scale-Revised (HDS-R) at 3 months (*p<0.05), and memantine (3 and 6 months, *p<0.05) and rivastigmine (3 months, **p<0.01) improved Abe’s Behavior and Psychological Symptom of Dementia Score (ABS), respectively. Activities of daily living (ADL) became significantly worse with galantamine at 12 months (*p<0.05). Male Mini-Mental State Examination scores became worse at 12 months with donepezil (*p<0.05), as did female Geriatric Depression Scale scores at 6 months (*p<0.05). Male HDS-R and ABS scores were preserved in the galantamine group until 12 months. Female ABS scores with memantine improved at 6 months (*p<0.05), while male ADL scores became worse with rivastigmine at 12 months (*p<0.05). Conclusion: OLDS revealed that anti-AD drugs were effective even for older AD patients, and the clinical benefits of each drug showed a small difference with regard to gender.
Pages 695-702
Dehan Kong*, Kelly S. Giovanello*, Yalin Wang, Weili Lin, Eunjee Lee, Yong Fan, P. Murali Doraiswamy**, Hongtu Zhu** for the Alzheimer’s Disease Neuroimaging Initiative* *These authors contributed equally to this work. **These authors are co-senior authors of this work.
Predicting Alzheimer’s Disease Using Combined Imaging-Whole Genome SNP Data
Abstract: The growing public threat of Alzheimer’s disease (AD) has raised the urgency to discover and validate prognostic biomarkers in order to predicting time to onset of AD. It is anticipated that both whole genome single nucleotide polymorphism (SNP) data and high dimensional whole brain imaging data offer predictive values to identify subjects at risk for progressing to AD. The aim of this paper is to test whether both whole genome SNP data and whole brain imaging data offer predictive values to identify subjects at risk for progressing to AD. In 343 subjects with mild cognitive impairment (MCI) enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI-1), we extracted high dimensional MR imaging (volumetric data on 93 brain regions plus a surface fluid registration based hippocampal subregion and surface data), and whole genome data (504,095 SNPs from GWAS), as well as routine neurocognitive and clinical data at baseline. MCI patients were then followed over 48 months, with 150 participants progressing to AD. Combining information from whole brain MR imaging and whole genome data was substantially superior to the standard model for predicting time to onset of AD in a 48-month national study of subjects at risk. Our findings demonstrate the promise of combined imaging-whole genome prognostic markers in people with mild memory impairment.
Pages 703-717
Hsueh-Sheng Chiang, Raksha A. Mudar, Athula Pudhiyidath, Jeffrey S. Spence, Kyle B. Womack, C. Munro Cullum, Jeremy A. Tanner, Justin Eroh, Michael A. Kraut, John Hart, Jr. (Handling Associate Editor: Kirk Daffner)
Altered Neural Activity during Semantic Object Memory Retrieval in Amnestic Mild Cognitive Impairment as Measured by Event-Related Potentials
Abstract: Deficits in semantic memory in individuals with amnestic mild cognitive impairment (aMCI) have been previously reported, but the underlying neurobiological mechanisms remain to be clarified. We examined event-related potentials (ERPs) associated with semantic memory retrieval in 16 individuals with aMCI as compared to 17 normal controls using the Semantic Object Retrieval Task (EEG SORT). In this task, subjects judged whether pairs of words (object features) elicited retrieval of an object (retrieval trials) or not (non-retrieval trials). Behavioral findings revealed that aMCI subjects had lower accuracy scores and marginally longer reaction time compared to controls. We used a multivariate analytical technique (STAT-PCA) to investigate similarities and differences in ERPs between aMCI and control groups. STAT-PCA revealed a left fronto-temporal component starting at around 750 ms post-stimulus in both groups. However, unlike controls, aMCI subjects showed an increase in the frontal-parietal scalp potential that distinguished retrieval from non-retrieval trials between 950 and 1050 ms post-stimulus, which negatively correlated with the performance on the logical memory subtest of the Wechsler Memory Scale- III. Thus, individuals with aMCI were not only impaired in their behavioral performance on SORT relative to controls, but also displayed alteration in the corresponding ERPs. The altered neural activity in aMCI compared to controls suggests a more sustained and effortful search during object memory retrieval, which may be a potential marker indicating disease processes at the pre-dementia stage.
Pages 719-726
Ki Jung Chang, Soojin Lee, Yunhwan Lee, Kang Soo Lee, Joung Hwan Back, Young Ki Jung, Ki Young Lim, Jai Sung Noh, Hyun Chung Kim, Hyun Woong Roh, Seong Hye Choi, Seong Yoon Kim, Sang Joon Son, Chang Hyung Hong (Handling Associate Editor: Sang Won Seo)
Severity of White Matter Hyperintensities and Length of Hospital Stay in Patients with Cognitive Impairment: a CREDOS (Clinical Research Center for Dementia of South Korea) study
Abstract: Background & Objective: White matter hyperintensities (WMHs) contribute to aggravation of dementia or geriatric syndrome, thereby resulting in functional impairment. However, evidence of direct association between WMHs and medical resource utilization indicated by length of hospital stay (LOS) is scarce in patients with cognitive impairment. This study aimed to examine the relationship between the severity of WMHs and LOS in patients with cognitive impairment. Methods: 4,253 older adults with cognitive impairment were enrolled in this study. We defined LOS as the total sum of days from January 1, 2008 to December 31, 2012. The severity of periventricular (PVWMHs), deep (DWMHs), and overall white matter hyperintensities (Overall WMHs) was evaluated by a visual rating scale. We conducted multinomial logistic regression to demonstrate the relationship between LOS and severity of PVWHMs, DWHMs, and Overall WMHs, respectively. Results: The median LOS was 20 days. Severe PVWMHs had a higher likelihood of longer LOS (Q3: odd ratio/OR = 1.32, 95% confidence interval/CI = 1.06-1.64; Q4: OR = 1.33, 95% CI = 1.07-1.65; Q5: OR = 1.55, 95% CI = 1.26-1.91). As for DWMHs, moderate DWMHs were related to longer LOS (Q4: OR = 1.33, 95% CI = 1.03-1.71; Q5: OR = 1.63, 95% CI = 1.26-2.11). Finally, severity of overall WMHs was independently associated with LOS, which was similar to the results of DWMHs. Conclusion: These findings would advocate for prevention of WMHs to stave off excess medical resource utilization in patients with cognitive impairment.
Pages 727-735
Catherine E. Munro, Nancy J. Donovan, Brendan J. Guercio, Sarah E. Wigman, Aaron P. Schultz, Rebecca E. Amariglio, Dorene M. Rentz, Keith A. Johnson, Reisa A. Sperling, Gad A. Marshall
Neuropsychiatric Symptoms and Functional Connectivity in Mild Cognitive Impairment
Abstract: Background: Neuropsychiatric symptoms (NPS), such as apathy and depression, commonly accompany cognitive and functional decline in early Alzheimer’s disease (AD). Prior studies have shown associations between affective NPS and neurodegeneration of medial frontal and inferior temporal regions in mild cognitive impairment (MCI) and AD dementia. Objective: To investigate the association between functional connectivity in four brain networks and NPS in elderly with MCI. Methods: NPS were assessed using the Neuropsychiatric Inventory in 42 subjects with MCI. Resting-state functional connectivity in four networks (default mode network, fronto-parietal control network (FPCN), dorsal attention network, and ventral attention network) was assessed using seed-based magnetic resonance imaging. Factor analysis was used to identify two factors of NPS: Affective and Hyperactivity. Linear regression models were utilized with the neuropsychiatric factors as the dependent variable and the four networks as the predictors of interest. Covariates included age, gender, premorbid intelligence, processing speed, memory, head movement, and signal-to-noise ratio. These analyses were repeated with the individual items of the affective factor, using the same predictors. Results: There was a significant association between greater Affective factor symptoms and reduced FPCN connectivity (p=0.03). There was no association between the Hyperactivity factor and any of the networks. Secondary analyses revealed an association between greater apathy and reduced FPCN connectivity (p=0.005), but none in other networks. Conclusions: Decreased connectivity in the FPCN may be associated with greater affective symptoms, particularly apathy, early in AD. These findings extend prior studies, using different functional imaging modalities in individuals with greater disease severity.
Pages 737-745
Nicholas J. Milano, Kenneth M. Heilman (Handling Associate Editor: Anjan Chatterjee)
Primary Progressive Speech Abulia
Abstract: Background and Objective: Primary progressive aphasia (PPA) is a neurodegenerative disorder characterized by progressive language impairment. The three variants of PPA include the nonfluent/agrammatic, semantic, and logopenic types. The goal of this report is to describe two patients with a loss of speech initiation that was associated with bilateral medial frontal atrophy. Methods and Results: Two patients with progressive speech deficits were evaluated and their examinations revealed a paucity of spontaneous speech; however their naming, repetition, reading, and writing were all normal. The patients had no evidence of agrammatism or apraxia of speech but did have impaired speech fluency. In addition to impaired production of propositional spontaneous speech, these patients had impaired production of automatic speech (e.g., reciting the Lord’s Prayer) and singing. Structural brain imaging revealed bilateral medial frontal atrophy in both patients. Conclusion: These patients’ language deficits are consistent with a PPA, but they are in the pattern of a dynamic aphasia. Whereas the signs-symptoms of dynamic aphasia have been previously described, to our knowledge these are the first cases associated with predominantly bilateral medial frontal atrophy that impaired both propositional and automatic speech. Thus, this profile may represent a new variant of PPA.
Pages 747-760
Fábio Henrique de Gobbi Porto, Artur Martins Novaes Coutinho, Ana Lucia de Sá Pinto, Bruno Gualano, Fabio Luís de Souza Duran, Silvana Prando, Carla Rachel Ono, Lívia Spíndola, Maira Okada de Oliveira, Patrícia Helena Figuerêdo do Vale, Ricardo Nitrini, Carlos Alberto Buchpiguel, Sonia Maria Dozzi Brucki (Handling Associate Editor: Paulo Caramelli)
Effects of Aerobic Training on Cognition and Brain Glucose Metabolism in Subjects with Mild Cognitive Impairment
Abstract: Background: Aerobic training (AT) is a promising intervention for mild cognitive impairment (MCI). Objective: To evaluate the effects of AT on cognition and regional brain glucose metabolism (rBGM) in MCI patients. Methods: Subjects performed a twice-a-week, moderate intensity, AT program for 24 weeks. Assessment with ADAS-cog, a comprehensive neuropsychological battery, and evaluation of rBGM with positron emission tomography with 18F-fluorodeoxyglucose ([18F]FDG-PET) were performed before and after the intervention. Aerobic capacity was compared using the maximal oxygen consumption VO2max (mL/Kg/min). [18F]FDG-PET data were analyzed on a voxel-by-voxel basis with SPM8 software. Results: Forty subjects were included, with a mean (M) age of 70.3 (5.4) years and an initial Mini-Mental State Exam score of 27.4 (1.7). Comparisons using paired t-tests revealed improvements in the ADAS-cog (M difference: -2.7 (3.7), p < 0.001) and VO2max scores (M difference: 1.8 (2.0) mL/kg/min, p < 0.001). Brain metabolic analysis revealed a bilateral decrease in the rBGM of the dorsal anterior cingulate cortex, pFWE = 0.04. This rBGM decrease was negatively correlated with improvement in a visuospatial function/attentional test (rho = -0.31, p = 0.04). Several other brain areas also showed increases or decreases in rBGM. Of note, there was an increase in the retrosplenial cortex, an important node of the default mode network, that was negatively correlated with the metabolic decrease in the dorsal anterior cingulate cortex (r = -0.51, p = 0.001). Conclusion: AT improved cognition and changed rBGM in areas related to cognition in subjects with MCI.
Pages 761-769
Enzo Tedone, Beatrice Arosio, Federico Colombo, Evelyn Ferri, Delphine Asselineau, Francois Piette, Cristina Gussago, Joel Belmin, Sylvie Pariel, Khadija Benlhassan, Martina Casati, Anne Bornand, Paolo Dionigi Rossi, Paolo Mazzola, Giorgio Annoni, Mohamed Doulazmi, Jean Mariani, Laura Porretti, Dorothy H. Bray, Daniela Mari (Handling Associate Editor: Daniela Galimberti)
Leukocyte Telomere Length in Alzheimer’s Disease Patients with a Different Rate of Progression
Abstract: Background: Age and short leukocyte telomeres have been associated with a higher risk of Alzheimer’s disease (AD). Inflammation is involved in AD and it is suggested that anti-inflammatory interleukin-10 (IL-10) may partly antagonize these processes. Objective: The aim is to correlate telomere length (TL) in peripheral blood mononuclear cells (PBMC) from patients with AD to disease progression rate. Moreover, we evaluated whether TL was associated with IL-10 production by unstimulated or amyloid-β (Aβ)-stimulated PBMC. Methods: We enrolled 31 late onset AD and 20 age-matched healthy elderly (HE). After a two-year follow-up period, patients were retrospectively evaluated as slow-progressing (ADS) (Mini Mental State Examination (MMSE) decline over the two years of follow-up ≤ 3 points) or fast progressing AD (ADF) (MMSE decline ≥ 5 points). TL was measured by flow cytometry and in vitro IL-10 production by enzyme-linked immunosorbent assay. Results: TL (mean±SD) for HE, ADS, and ADF was 2.3±0.1, 2.0±0.1, and 2.5±0.1 Kb, respectively. ADS showed a shorter TL compared to HE (p=0.034) and to ADF (p=0.005). MMSE decline correlated with TL in AD (R2=0.284; p=0.008). We found a significant difference in IL-10 production between unstimulated and Aβ-stimulated PBMC from ADS (40.7±13.7 versus 59.0±27.0; p=0.004) but not from ADF (39.7±14.4 versus 42.2±22.4). HE showed a trend toward significance (47.1±25.4 versus 55.3±27.9; p=0.10). Conclusion: PBMC from ADF may be characterized by an impaired response induced by Aβ and by a reduced proliferative response responsible for the longer telomeres. TL might be a contributing factor in predicting the rate of AD progression.
Pages 771-776
Paola Piscopo, Giuseppe Tosto, Chiara Belli, Giuseppina Talarico, Daniela Galimberti, Marina Gasparini, Marco Canevelli, Anna Poleggi, Alessio Crestini, Diego Albani, Gianluigi Forloni, Ugo Lucca, Pierluigi Quadri, Mauro Tettamanti, Chiara Fenoglio, Elio Scarpini, Giuseppe Bruno, Nicola Vanacore, Annamaria Confaloni (Handling Associate Editor: Emilio Di Maria)
SORL1 Gene is Associated with the Conversion from Mild Cognitive Impairment to Alzheimer’s Disease
Abstract: Several studies have established the sortilin-related receptor gene (SORL1) as a susceptibility locus for Alzheimer’s disease (AD). Single nucleotide polymorphisms of SORL1 reported in literature as being associated with AD were investigated in an Italian case-control data set, and their role as a risk factor of conversion to AD was studied in an independent sample of subjects diagnosed with mild cognitive impairment (MCI) at baseline. rs641120, rs2070045, and rs1010159 were genotyped in 734 subjects diagnosed with AD (n=338) and MCI (n=181) and in healthy controls (n=215). Our results confirmed the association between rs641120 and AD (p=0.01). In the MCI cohort, rs1010159 was associated with conversion to AD (HR=1.56, p=0.002). Taken together, these findings confirm that SORL1 is associated with AD and might be a potential tool for identifying MCI subjects at high risk of conversion to AD.
Pages 777-790
Liang Shen, Hong-Fang Ji
Associations between Homocysteine, Folic Acid, Vitamin B12 and Alzheimer’s Disease: Insights from Meta-Analyses
Abstract: The associations between homocysteine (Hcy), folic acid, and vitamin B12 and Alzheimer’s disease (AD) have gained much interest, while remain controversial. We aim to perform meta-analyses to evaluate comprehensively: i) Hcy, folic acid, and vitamin B12 levels in AD patients in comparison with controls; and ii) the association between Hcy, folic acid, and vitamin B12 levels and risk of AD. A literature search was performed using Medline and Scopus databases. A total of 68 studies were identified and included in the meta-analyses. Stata 12.0 statistical software was used to perform the meta-analyses. First, AD patients may have higher level of Hcy, and lower levels of folate and vitamin B12 in plasma than controls. Further age-subgroup analysis showed no age effect for Hcy levels in plasma between AD patients and matched controls, while the differences in folate and vitamin B12 levels further enlarged with increased age. Second, data suggests that high Hcy and low folate levels may correlate with increased risk of AD occurrence. The comprehensive meta-analyses not only confirmed higher Hcy, lower folic acid, and vitamin B12 levels in AD patients than controls, but also implicated that high Hcy and low folic acid levels may be risk factors of AD. Further studies are encouraged to elucidate mechanisms linking these conditions.
Pages 791-803
Stephanie Oleson, Claire Murphy
Olfactory Dysfunction in ApoE ε4/4 Homozygotes with Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory impairment and the presence of amyloid plaques and neurofibrillary tangles. The associated neuropathology originates in brain areas responsible for olfaction, which makes olfactory tasks potentially useful for assessing AD. The strongest genetic risk factor for AD is the apolipoprotein E (ApoE) ε4 allele that has been associated with increased cognitive and olfactory deficits. While individuals carrying one ε4 allele of the ApoE gene are at increased risk for AD relative to non-carriers, those with two copies of the ε4 allele demonstrate an even higher risk for developing AD. Furthermore, homozygous ApoE ε4/4 individuals diagnosed with AD are known to have heightened amyloid burden and a more rapid rate of cognitive decline relative to heterozygous ε3/4 ApoE carriers. All of these factors suggest there are differences in severity and progression of AD as a function of possessing one versus two ε4 alleles. The current study investigated olfactory functioning in homozygous ε4/4 older adults diagnosed with probable AD. Compared to demographically matched ε3/3 and ε3/4 individuals, ε4/4 individuals showed deficits in odor identification and remote odor memory as measured by odor familiarity ratings. The current findings suggest that these particular domains of olfactory functioning may be more impaired in AD ε4/4 homozygotes compared to ε3/4 heterozygotes and ε3/3 homozygotes. These deficits give insight into how the presence of two ε4 alleles may differentially affect the progression of AD and suggest the usefulness of odor tasks in detecting those at risk for AD.
Pages 805-812
Inez H.G.B. Ramakers, Steven T.H. Honings, Rudolf W. Ponds, Pauline Aalten, Sebastian Köhler, Frans R.J. Verhey, Pieter Jelle Visser (Handling Associate Editor: Philippe Robert)
The Effect of Psychological Distress and Personality Traits on Cognitive Performances and the Risk of Dementia in Patients with Mild Cognitive Impairment
Abstract: Background: The relation between psychological distress, personality traits, and cognitive decline in cognitively impaired patients remains unclear. Objective: To investigate the effect of psychological distress and personality traits on cognitive functioning in subjects with mild cognitive impairment (MCI); and to investigate the predictive accuracy of these factors for the development of dementia. Methods: MCI patients (n=343, age: 60.9±9.9 years, 38% female, and MMSE score: 28.1±1.9) were included from the Maastricht memory clinic. All patients underwent a standardized neuropsychological assessment (including tests for measuring mental speed (Trail Making Test (TMT) part A and Stroop Color Word Test (SCWT) part I), executive functioning (TMT part B and SCWT part III), memory (15-Word Learning Tests), and verbal fluency (1-minute animals)), CT or MRI, and blood assessment. The Dutch Personality Questionnaire (DPQ) and the 90-items Symptom Check List (SCL-90) were used to measure personality traits and psychological distress. Conversion to dementia was assessed two, five, and ten years after baseline. The mean follow-up period was 6.7±3.4 years. Results: The Psychoneuroticism score of the SCL-90 was associated with slower performances on SCWT part I and TMT part A. The subdomain Neuroticism of the DPQ was also associated with slower scores on the TMT part A. At follow-up, 85 (25.9%) subjects had developed dementia. The SCL-90 total score, and the subscales, Anxiety, Somatization, Insufficiency in thought and action, and Sleeping problems were associated with a decreased risk for developing (AD-type) dementia. Conclusion: Psychological distress negatively affected information processing speed, but was not associated with an increased risk of developing dementia in patients with MCI.
