Volume 60, Number 3, IN PRESS

Obituary
Jamie Talan
The Life and Science of Allen Roses’ Lives On

Mini-Forum on Sphingolipids in Alzheimer’s Disease and Related Disorders (Guest Editors: Michelle Mielke and Pilar Martinez)

Editorial
Pilar Martinez Martinez, Michelle Mielke
Sphingolipids in Alzheimer’s Disease and Related Disorders

Review
Michael B. Dinkins, Guanghu Wang, Erhard Bieberich
Sphingolipid-Enriched Extracellular Vesicles and Alzheimer’s Disease: A Decade of Research
Abstract: Extracellular vesicles (EVs), particularly exosomes, have emerged in the last 10 years as a new player in the progression of Alzheimer’s disease (AD) with high potential for being useful as a diagnostic and treatment tool. Exosomes and other EVs are enriched with the sphingolipid ceramide as well as other more complex glycosphingolipids such as gangliosides. At least a subpopulation of exosomes requires neutral sphingomyelinase activity for their biogenesis and secretion. As ceramide is often elevated in AD, exosome secretion may be affected as well. Here, we review the available data showing that exosomes regulate the aggregation and clearance of amyloid-beta (Aβ) and discuss the differences in data from laboratories regarding Aβ binding, induction of aggregation, and glial clearance. We also summarize available data on the role of exosomes in extracellular tau propagation, AD-related exosomal mRNA/miRNA cargo, and the use of exosomes as biomarker and gene therapy vehicles for diagnosis and potential treatment.

Sandra den Hoedt, Carola I.F. Janssen, Guiseppe Astarita, Daniele Piomelli, Frank P.J. Leijten, Simone M. Crivelli, Adrie J. M. Verhoeven, Helga E. de Vries, Jochen Walter, Pilar Martinez-Martinez, Eric J.G. Sijbrands, Amanda J. Kiliaan, Monique T. Mulder
Pleiotropic Effect of Human ApoE4 on Cerebral Ceramide and Saturated Fatty Acid Levels
Abstract: Background: Apolipoprotein E (ApoE) is known for its role in lipid trafficking and the ε4 allele is a risk factor for late onset Alzheimer’s disease (AD). Recently, aberrant ceramide and fatty acid (FA) levels have been implicated in AD. Objective: To determine the specific effects of human ApoE4 (hE4) on cerebral ceramide and FA content during chow or a high fat/high cholesterol (HFHC) diet. Methods: Cerebral ceramide and FA profiles were determined by LC-MSMS in 15-month-old female wild-type (WT), ApoE-knockout (E0), and hE4-knockin mice fed chow or a HFHC diet for 3 months. mRNA levels of genes involved in ceramide and FA metabolism were determined by qPCR. Results: Similar to E0, hE4 mice displayed lower cerebral total ceramide, Cer16:0, and Cer24:1 levels than WT mice on both diets. Akin to WT mice, hE4 mice had lower total and saturated FA levels on chow than E0 mice. The HFHC diet significantly increased total and saturated FA levels in hE4 mice. Chow-fed hE4 mice showed lower mRNA levels of ceramide synthase (CerS) 6, acid sphingomyelinase, and of most ceramide and FA transporters than WT and E0 mice. The HFHC diet downregulated the expression of CerSs in hE4 and WT mice, and of ceramide and FA transporters in WT mice, but not in E0 mice. Conclusion: hE4 reduced cerebral ceramide levels to levels observed in E0 mice independent of diet. The HFHC diet increased cerebral FA levels in hE4 mice. This was associated with alterations in the expression of ceramide and FA transporters specifically in hE4 mice.

Simone M. Crivelli*, Andreas Paulus*, Jozef Markus, Matthias Bauwens, Dusan Berkes, Helga E. De Vries, Monique T. Mulder, Jochen Walter, Felix M. Mottaghy, Mario Losen, Pilar Martinez-Martinez *These authors contributed equally to this work.
Synthesis, Radiosynthesis, and Preliminary in vitro and in vivo Evaluation of the Fluorinated Ceramide Trafficking Inhibitor (HPA-12) for Brain Applications
Abstract: Ceramide levels are increased in blood and brain tissue of Alzheimer’s disease (AD) patients. Since the ceramide transporter protein (CERT) is the only known protein able to mediate non-vesicular transfer of ceramide between organelle membranes, the modulation of CERT function may impact on ceramide accumulation. The competitive CERT inhibitor N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl) dodecanamide (HPA-12) interferes with ceramide trafficking. To understand the role of ceramide/CERT in AD, HPA-12 can be a useful tool to modulate ceramide trafficking. Here we first report the synthesis and in vitro properties of HPA-12 radiolabeled with fluorine-18 and present preliminary in vitro and in vivo positron emission tomography (PET) imaging and biodistribution data. In vitro results demonstrated that the fluorination did not alter the biological properties of HPA-12 since the [fluorine-19]HPA-12, interferes with 5-DMB-ceramide trafficking in HeLa cells. Radiolabeled HPA-12, [fluorine-18]HPA-12, was obtained with a radiochemical yield of 90% and a specific activity of 73 MBq/µmol. PET imaging on wild-type mice showed hepatobiliary clearance and a brain uptake on the order of 0.3 standard uptake value (SUV) one hour post injection. Furthermore, the biodistribution data showed that after removal of the blood by intracardial perfusion, radioactivity was still measurable in the brain demonstrating that the [fluorine-18]HPA-12 crosses the blood brain barrier and is retained in the brain.

Nienke M. de Wit*, Hripsime Snkhchyan*, Sandra den Hoedt, Darcos Wattimena, Rob de Vos, Monique T. Mulder, Jochen Walter, Pilar Martinez-Martinez, Jeroen J. Hoozemans, Annemieke J. Rozemuller, Helga E. de Vries *These authors contributed equally to this work.
Altered Sphingolipid Balance in Capillary Cerebral Amyloid Angiopathy
Abstract: Background: The majority of patients with Alzheimer’s disease (AD) exhibit amyloid-β (Aβ) deposits at the brain vasculature, a process referred to as cerebral amyloid angiopathy (CAA). In over 51% of AD cases, Aβ also accumulates in cortical capillaries, which is termed capillary CAA (capCAA). It has been postulated that the presence of capCAA in AD is a specific subtype of AD, although underlying mechanisms are not yet fully understood. Sphingolipids (SLs) are implicated in neurodegenerative disorders, including AD. However, to date it remains unknown whether alterations in the SL pathway are involved in capCAA pathogenesis and if these differ from AD. Objective: To determine whether AD cases with capCAA have an altered SL profile compared to AD cases without capCAA. Methods: Immunohistochemistry was performed to assess the expression and localization of ceramide, acid sphingomyelinase (ASM), and sphingosine-1-phosphate receptors (S1P1, S1P3). In addition, we determined the concentrations of S1P as well as different chain-lengths of ceramides using HPLC-MS/MS. Results: Immunohistochemical analysis revealed an altered expression of ceramide, ASM, and S1P receptors by reactive astrocytes and microglial cells specifically associated with capCAA. Moreover, a shift in the balance of ceramides with different chain-lengths and S1P content is observed in capCAA. Conclusion: Here we provide evidence of a deregulated SL balance in capCAA. The increased levels of ASM and ceramide in activated glia cells suggest that the SL pathway is involved in the neuroinflammatory response in capCAA pathogenesis. Future research is needed to elucidate the role of S1P in capCAA.

Min Kim*, Alejo Nevado-Holgado*, Luke Whiley, Stuart G. Snowden, Hilkka Soininen, Iwona Kloszewska, Patrizia Mecocci, Magda Tsolaki, Bruno Vellas, Madhav Thambisetty, Richard J. B. Dobson, John F. Powell, Michelle K Lupton, Andy Simmons, Latha Velayudhan, Simon Lovestone, Petroula Proitsi, Cristina Legido-Quigley *These authors contributed equally to this work.
Association between Plasma Ceramides and Phosphatidylcholines and Hippocampal Brain Volume in Late Onset Alzheimer’s Disease
Abstract: Lipids such as ceramides and phosphatidylcholines (PC) have been found altered in the plasma of Alzheimer’s disease (AD) patients in a number of discovery studies. For this reason, the levels of 6 ceramides and 3 PCs, with different fatty acid length and saturation levels, were measured in the plasma from 412 participants (AD n=205, Control n=207) using mass spectrometry coupled with ultra-performance liquid chromatography. After this, associations with AD status, brain atrophy, and age-related effects were studied. In the plasma of AD participants, cross-sectional analysis revealed elevated levels of three ceramides (Cer16:0 p<0.01, Cer18:0 p<0.01, Cer24:1 p<0.05). In addition, two PCs in AD plasma (PC36:5 p<0.05, PC38:6 p<0.05) were found to be depleted compared to the control group, with PC36:5 also associating with hippocampal atrophy (p<0.01). Age-specific analysis further revealed that levels of Cer16:0, Cer18:0, and Cer20:0 were associated with hippocampal atrophy only in younger participants (age<75, p<0.05), while all 3 PCs did so in the older participants (age>75, p<0.05). PC36:5 was associated with AD status in the younger group (p<0.01), while PC38:6 and 40:6 did so in the older group (p<0.05). In this study, elevated ceramides and depleted PCs were found in the plasma from 205 AD volunteers. Our findings also suggest that dysregulation in PC and ceramide metabolism could be occurring in different stages of AD progression.

Michelle M. Mielke, Norman J. Haughey, Dingfen Han, Yang An, Veera Venkata Ratnam Bandaru, Constantine G. Lyketsos, Luigi Ferrucci, Susan M. Resnick
The Association Between Plasma Ceramides and Sphingomyelins and Risk of Alzheimer’s Disease Differs by Sex and APOE in the Baltimore Longitudinal Study of Aging
Abstract: Background: Cellular and animal studies demonstrated relationships between sphingolipid metabolism and Alzheimer’s disease (AD) pathology. High blood ceramide levels have been shown to predict cognitive impairment and AD, but these studies had small sample sizes and did not assess differences in risk by sex or APOE genotype. Objective: To determine whether plasma ceramides and sphingomyelins were associated with risk of AD, and whether the association varied by sex and APOE genotype. Methods: Participants included 626 men and 366 women, aged 55 years and older, enrolled in the Baltimore Longitudinal Study of Aging. Plasma ceramides and sphingomyelins were determined using quantitative analyses performed on a high-performance liquid chromatography coupled electrospray ionization tandem mass spectrometer. Cox proportional hazards models, stratified by sex, were used to examine the relationship of plasma ceramides and sphingomyelins with risk of AD over a mean (SD) follow-up of 15.0 (7.0) years for men and 13.1 (5.9) years for women. Results: Among men, the highest tertile of most ceramides and sphingomyelins were associated with an increased risk of AD. Among women, there were no associations between any of the ceramides and risk of AD. In contrast, women in the highest tertile of most sphingomyelins had a reduced risk of AD, which was most pronounced among APOE ɛ4 carriers. Conclusion: These results provide further evidence for the role of sphingolipid metabolism in AD and highlight the importance of considering sex and APOE genotype in assessing this relationship.

Mahwesh Saleem, Nathan Herrmann, Adam Dinoff, Michelle M. Mielke, Paul I. Oh, Prathiba Shammi, Xingshan Cao, Swarajya Lakshmi Vattem Venkata, Norman J. Haughey, Krista L. Lanctôt
A Lipidomics Approach to Assess the Association between Plasma Sphingolipids and Verbal Memory Performance in Coronary Artery Disease Patients Undertaking Cardiac Rehabilitation: A C18:0 Signature for Cognitive Response to Exercise
Abstract: Background: Early subtle deficits in verbal memory, which may indicate early neural risk, are common in patients with coronary artery disease (CAD). While exercise can improve cognition, cognitive response to exercise is heterogeneous. Sphingolipids have been associated with the development and progression of CAD, and impairments in sphingolipid metabolism may play roles in neurodegeneration and in the neural adaptation response to exercise. Objective: In this study, change in plasma concentrations of sphingolipids was assessed in relation to change in verbal memory performance and in other cognitive domains among CAD subjects undertaking a 6-month cardiac rehabilitation (CR) program. Methods: Patients with CAD (n=120, mean age=64±6 y, 84% male, years of education=16±3) underwent CR with neuropsychological assessments and blood collected at baseline, 3-, and 6-months. Z-scores based on age, gender, and education were combined for verbal memory, visuospatial memory, processing speed, executive function, and global cognition tasks to calculate cognitive domain Z-scores. Plasma sphingolipid concentrations were measured from fasting blood samples using high performance liquid chromatography coupled electrospray ionization tandem mass spectrometry (LC/MS/MS). Mixed models were used to identify sphingolipids significantly associated with performance in verbal memory and other cognitive domains, adjusting for potential confounders. Results: Lower ceramide C18:0 concentrations were significantly associated with improvement in verbal memory performance (b[SE]=-0.51 [0.25], p=0.04), visuospatial memory (b[SE]=-0.44 [0.22], p=0.05), processing speed (b[SE]=-0.89 [0.32], p=0.007), and global cognition (b[SE]=-1.47 [0.59], p=0.01) over 6 months of CR. Conclusions: Plasma ceramide C18:0 concentrations may be a sensitive marker of cognitive response to exercise in patients with CAD.

Regular Section

Review
Anna Stevenson, Dianne Lopez, Paul Khoo, Rajesh N. Kalaria, Elizabeta B. Mukaetova-Ladinska
Exploring Erythrocytes as Blood Biomarkers for Alzheimer’s Disease
Abstract: Peripheral biomarkers for dementia are few and far between. Despite research into blood plasma/serum biomarkers for dementia diagnostics, there is lack of information on erythrocytes and their vast proteomes as potential biomarkers. This review identifies a number of relevant and potentially promising erythrocyte biomarkers for various subtypes of dementia. These include erythrocyte morphology, oxidative stress, and erythrocyte membrane proteins such as the glucose transporter (GLUT-1), amyloid-β, IgG, Hsp90, calpain-1, and band 3 protein. Of those proteins identified, Hsp90, amyloid-β, calpain-1. and band 3 show the most promise as pre-clinical biomarkers. However, the most intriguing aspect of erythrocytes is their changed morphology in dementia. The altered morphology not only could be used as a diagnostic biomarker but may be crucial in early pathogenesis of the disease. Further work must be done to establish the pathological connection between the periphery and central disease processes.

Hypothesis
Costa Vakalopoulos (Handling Associate Editor: Udo Rüb)
Alzheimer’s Disease: The Alternative Serotonergic Hypothesis of Cognitive Decline
Abstract: The pathognomonic feature of Alzheimer’s disease is loss of declarative recall. This has generally been attributed to early involvement of medial temporal lobe structures with neurofibrillary tangles and loss of neurons in the entorhinal cortex. However, there has been a remerging emphasis on the causal role of brainstem monoaminergic nuclei as involvement of the cholinergic basal forebrain loses prominence. The rejection of this alternative theory of cognitive decline is related to inconsistencies in time course and modest effects of treatment using cholinergic agents. The amyloid hypothesis of cortical dysfunction is also losing favor as current trials of plaque dissolution are proving again disappointing. Recent pre-clinical studies on APP/PS1 (familial Alzheimer’s disease) transgenic mouse models using serotonergic receptor modulating agents, demonstrate clear neuroprotective effects. The involvement of midbrain raphe in the earliest stages of dementia requires a reassessment of relevant pathophysiology beyond behavioral and affective dimensions. Indeed, a theory of serotonergic modulation of explicit memory formation by direct enhancement of synaptic strength could change the view of the role of these nuclei in AD and lead to more effective treatments.

Russell Jude Chander, Levinia Lim, Sagarika Handa, Shaun Hiu, Angeline Choong, Xuling Lin, Rajinder Singh, Daniel Oh, Nagaendran Kandiah
Atrial Fibrillation is Independently Associated with Cognitive Impairment after Ischemic Stroke
Abstract: Background: While atrial fibrillation (AF) is an important risk factor for ischemic strokes and mild cognitive impairment (MCI) in Alzheimer’s disease, the association between AF and post-stroke cognitive impairment (PSCI), and the factors mediating this association, is unclear. Objective: To investigate the role of AF in PSCI, especially in relation to other markers of cerebrovascular disease. Methods: 445 subjects with mild ischemic stroke without pre-stroke cognitive decline were assessed 3-6 months post-stroke for cognitive deficits. MRIs were reviewed by trained raters for acute infarct characteristics, global cortical atrophy, white matter hyperintensities, cerebral microbleeds, and intracranial stenosis. Logistic regression analysis was used to identify factors independently associated with PSCI. Subjects were also categorized according to paroxysmal (pAF) or persistent/chronic AF (p/cAF), and presence or absence of AF or large cortical infarcts (LCI) to study cognitive trends. Results: 80 (18.0%) subjects had AF. 76.3% of AF subjects and 42.7% of subjects without AF had PSCI. The odds ratio (OR) of AF in developing PSCI was 2.31 (95% CI: 1.12 – 4.75; p = 0.035), after correcting for other risk factors. pAF subjects and AF subjects with LCIs had higher ORs for PSCI. AF subjects performed worse in neuropsychological tasks associated with global cognition, episodic memory, and executive function. Conclusion: AF is a significant risk factor for PSCI, even after correcting for AF-related infarcts. Other mechanisms, such as hypoperfusion, microhemorrhages, and neuroinflammation, may be at play. All stroke patients with AF, regardless of the type of infarction, should be closely monitored for PSCI.

Yoshitaka Inui, Kengo Ito, Takashi Kato, SEAD-J Study Group
Longer-Term Investigation of the Value of 18F-FDG-PET and Magnetic Resonance Imaging for Predicting the Conversion of Mild Cognitive Impairment to Alzheimer’s Disease: A Multicenter Study
Abstract: Background: The value of fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) and magnetic resonance imaging (MRI) for predicting conversion of mild cognitive impairment (MCI) to Alzheimer’s disease (AD) in longer-term is unclear. Objective: To evaluate longer-term prediction of MCI to AD conversion using 18F-FDG-PET and MRI in a multicenter study. Methods: One-hundred and fourteen patients with MCI were followed for 5 years. They underwent clinical and neuropsychological examinations, 18F-FDG-PET, and MRI at baseline. PET images were visually classified into predefined dementia patterns. PET scores were calculated as a semi quantitative index. For structural MRI, z-scores in medial temporal area were calculated by automated volume-based morphometry (VBM). Results: Overall, 72% patients with amnestic MCI progressed to AD during the 5-year follow-up. The diagnostic accuracy of PET scores over 5 years was 60% with 53% sensitivity and 84% specificity. Visual interpretation of PET images predicted conversion to AD with an overall 82% diagnostic accuracy, 94% sensitivity, and 53% specificity. The accuracy of VBM analysis presented little fluctuation through 5 years and it was highest (73%) at the 5-year follow-up, with 79% sensitivity and 63% specificity. The best performance (87.9% diagnostic accuracy, 89.8% sensitivity, and 82.4% specificity) was with a combination identified using multivariate logistic regression analysis that included PET visual interpretation, educational level, and neuropsychological tests as predictors. Conclusion: 18F-FDG-PET visual assessment showed high performance for predicting conversion to AD from MCI, particularly in combination with neuropsychological tests. PET scores showed high diagnostic specificity. Structural MRI focused on the medial temporal area showed stable predictive value throughout the 5-year course.

Alex Bahar-Fuchs, Shannon Webb, Lauren Bartsch, Linda Clare, George Rebok, Nicolas Cherbuin, Kaarin J. Anstey (Handling Associate Editor: Sharon Naismith)
Tailored and Adaptive Computerized Cognitive Training in Older Adults at Risk for Dementia: A Randomized Controlled Trial
Abstract: Background: Computerized Cognitive Training (CCT) has been shown to improve cognitive function in older adults with mild cognitive impairment (MCI) or mood-related neuropsychiatric symptoms (MrNPS), but many questions remain unresolved. Objective: To evaluate the extent to which CCT benefits older adults with both MCI and MrNPS, and its effects on meta-cognitive and non-cognitive outcomes, as well as establish whether adapting difficulty levels and tailoring to individuals' profile is superior to generic training. Method: Older adults with MCI (n=9), MrNPS (n=11), or both (n=25) were randomized into a home-based individually-tailored and adaptive CCT (n=21) or an active control condition (AC; n=23) in a double-blind design. Interventions lasted 8-12 weeks and outcomes were assessed after the intervention, and at a 3-month follow-up. Results: Participants in both conditions reported greater satisfaction with their everyday memory following intervention and at follow-up. However, participants in the CCT condition showed a greater improvement on composite measures of memory, learning, and global cognition at follow-up. Participants with MrNPS in the CCT condition were also found to have improved mood at 3-month follow-up and reported using fewer memory strategies at the post-intervention and follow-up assessments. There was no evidence that participants with MCI+ were disadvantaged relative to the other diagnostic conditions. Finally, informant-rated caregiver burden declined at follow-up assessment in the CCT condition relative to the AC condition. Conclusions: Home-based CCT with adaptive difficulty and personal tailoring appears superior to more generic CCT in relation to both cognitive and non-cognitive outcomes. Mechanisms of treatment effect and future directions are discussed.

Seongryu Bae, Hiroyuki Shimada, Sangyoon Lee, Hyuma Makizako, Sungchul Lee, Kazuhiro Harada, Takehiko Doi, Kota Tsutsumimoto, Ryo Hotta, Sho Nakakubo, Hyuntae Park, Takao Suzuki
The Relationships Between Components of Metabolic Syndrome and Mild Cognitive Impairment Subtypes: A Cross-Sectional Study of Japanese Older Adults
Abstract: Background: The associations between components of metabolic syndrome (MetS) and mild cognitive impairment (MCI) subtypes remain unclear. Objective: The study aim was to identify the prevalence of MetS for MCI subtypes and to investigate sex differences in the association between MetS and MCI subtypes in older Japanese adults. Methods: The study analyzed data from 3,312 men and women aged 70 years or more. MetS was diagnosed according to International Diabetes Federation criteria. Participants completed cognitive tests and were categorized into normal cognition, amnestic MCI (aMCI), and non-amnestic MCI (naMCI). The associations between MetS and its components and MCI subtypes were analyzed using multiple logistic regression. Results: MetS prevalence was greater in participants with naMCI (men: p = 0.030; women: p = 0.040). Participants with naMCI showed higher odds ratios (OR) of MetS (men: 2.45, 95% confidence intervals (CI): 1.13–5.32; women: OR: 1.94, 95% CI: 1.12–3.39) compared with participants with normal cognition. MetS was not associated with aMCI. Analysis of MetS components showed that raised glucose (OR: 1.62, 95% CI: 1.19–2.22) and reduced high-density lipoprotein cholesterol (OR: 1.97, 95% CI: 1.25–3.12) were associated with naMCI in men. In women, raised blood pressure (OR: 1.42, 95% CI: 1.03–1.94) and raised glucose (OR: 1.32, 95% CI: 1.02–1.71) were associated with naMCI. Conclusion: MetS was associated only with naMCI regardless of sex, which suggests etiologic differences in MCI subtypes. We also found sex differences in the relationship between naMCI risk and MetS and its components.

Roberta Cascella, Elisa Evangelisti, Alessandra Bigi, Matteo Becatti, Claudia Fiorillo, Massimo Stefani, Fabrizio Chiti, Cristina Cecchi (Handling Associate Editor: Benedetta Nacmias)
Soluble Oligomers Require a Ganglioside to Trigger Neuronal Calcium Overload
Abstract: An altered distribution of membrane gangliosides (GM), including GM1, has recently been reported in the brains of Alzheimer’s disease (AD) patients. Moreover, amyloid-positive synaptosomes obtained from AD brains were found to contain high-density GM1 clusters, suggesting a pathological significance of GM1 increase at presynaptic neuritic terminals in AD. Here, we show that membrane GM1 specifically recruits small soluble oligomers of the 42-residue form of amyloid-β peptide (Aβ42), with intracellular flux of Ca2+ ions in primary rat hippocampal neurons and in human neuroblastoma cells. Specific membrane proteins appear to be involved in the early and transient influx of Ca2+ ions induced by Aβ42 oligomers with high solvent-exposed hydrophobicity (A+), but not in the sustained late influx of the same oligomers and in that induced by Aβ42 oligomers with low solvent-exposed hydrophobicity (A-) in GM1-enriched cells. In addition, A+ oligomers accumulate in proximity of membrane NMDA and AMPA receptors, inducing the early and transient Ca2+ influx, although FRET shows that the interaction is not direct. These results suggest that age-dependent clustering of GM1 within neuronal membranes could induce neurodegeneration in elderly people as a consequence of an increased ability of the lipid bilayers to recruit membrane-permeabilizing oligomers. We also show that both lipid and protein components of the plasma membrane can contribute to neuronal dysfunction, thus expanding the molecular targets for therapeutic intervention in AD.

Martin J. Lan, R. Todd Ogden, Dileep Kumar, Yaakov Stern, Ramin V. Parsey, Gregory H. Pelton, Harry Rubin-Falcone, Gnanavalli Pradhaban, Francesca Zanderigo, Jeffrey M. Miller, J. John Mann, D.P. Devanand (Handling Associate Editor: Christopher Rowe)
Utility of Molecular and Structural Brain Imaging to Predict Progression from Mild Cognitive Impairment to Dementia
Abstract: This project compares three neuroimaging biomarkers to predict progression to dementia in subjects with mild cognitive impairment (MCI). Eighty-eight subjects with MCI and 40 healthy controls (HCs) were recruited. Subjects had a 3T magnetic resonance imaging (MRI) scan, and two positron emission tomography (PET) scans, one with Pittsburgh compound B ([11C]PIB) and one with fluorodeoxyglucose ([18F]FDG). MCI subjects were followed for up to 4 y and progression to dementia was assessed on an annual basis. MCI subjects had higher [11C]PIB binding potential (BPND) than HCs in multiple brain regions, and lower hippocampus volumes. [11C]PIB BPND, [18F]FDG standard uptake value ratio (SUVR), and hippocampus volume were associated with time to progression to dementia using a Cox proportional hazards model. [18F]FDG SUVR demonstrated the most statistically significant association with progression, followed by [11C]PIB BPND and then hippocampus volume. [11C]PIB BPND and [18F]FDG SUVR were independently predictive, suggesting that combining these measures is useful to increase accuracy in the prediction of progression to dementia. Hippocampus volume also had independent predictive properties to [11C]PIB BPND, but did not add predictive power when combined with the [18F]FDG SUVR data. This work suggests that PET imaging with both [11C]PIB and [18F]FDG may help to determine which MCI subjects are likely to progress to AD, possibly directing future treatment options.

Yafit Kuttner-Hirshler*, Palamadai N. Venkatasubramanian*, Joan Apolinario, Jacqueline Bonds, Alice M. Wyrwicz, Orly Lazarov *These authors contributed equally to this work.
Brain Biomarkers in Familial Alzheimer’s Disease Mouse Models
Abstract: Alzheimer’s disease (AD) is characterized by progressive loss of memory and cognitive deterioration. It is thought that the onset of the disease takes place several decades before memory deficits are apparent. Reliable biomarkers for the diagnosis or prognostication of the disease are highly desirable. Neural stem cells (NSC) exist in the adult brain throughout life and give rise to neural progenitor cells (NPC), which differentiate into neurons or glia. The level of NPC proliferation and new neuron formation is significantly compromised in mouse models of familial Alzheimer’s disease (FAD). These deficits are readily detected in young adults, at 2-3 months of age, preceding amyloid deposition and cognitive impairments, which may indicate that impaired neurogenesis can be an early biomarker for cognitive deficits in AD. Recent studies suggest that NSC can be detected in live rodents, noninvasively, using proton magnetic resonance spectroscopy (1H-MRS) at 1.28 ppm signal. Here we examined the use of 1H-MRS for determining the extent of neurogenesis in the brains of FAD mice. We observed that the reduction in neurogenesis in the FAD mice as observed by immunohistochemistry, was not manifested by a reduction in the 1.28 ppm signal, suggesting that this marker is either not specific for neurogenesis or not sensitive enough for the detection of alterations in hippocampal neurogenesis in the brains of FAD mice.

Welmoed A. Krudop, Annemieke Dols, Cora J. Kerssens, Piet Eikelenboom, Niels D. Prins, Christiane Möller, Sigfried Schouws, Didi Rhebergen, Eric van Exel, Wiesje M. van der Flier, Sietske Sikkes, Philip Scheltens, Max L. Stek, Yolande A.L. Pijnenburg (Handling Associate Editor: Shunichiro Shinagawa)
The Pitfall of Behavioral Variant Frontotemporal Dementia Mimics Despite Multidisciplinary Application of the FTDC Criteria
Abstract: Background: The behavioral variant of frontotemporal dementia (bvFTD) has a broad differential diagnosis including other neurological and psychiatric disorders. Psychiatric misdiagnoses occur in up to 50% of bvFTD patients. Numbers on misdiagnosis of bvFTD in psychiatric disorders are lacking. Objective: The aim of our study was to investigate the frequency and characteristics of bvFTD misdiagnoses in psychiatric disorders and other neurologic disorders. Methods: Thirty-five patients with a (possible or probable) bvFTD diagnosis made by specialized memory clinic neurologists were included. Change in diagnosis after consulting a psychiatrist at baseline was recorded as well as change in diagnosis after two years of multidisciplinary neuropsychiatric follow-up. Differences in cognitive and behavioral profiles were investigated per diagnostic group after follow-up (bvFTD, psychiatry, other neurologic disorders). Clinical profiles are described in detail. Results: In 17 patients (48.5%), the bvFTD baseline diagnosis changed: Two at baseline after psychiatric consultation, and 15 after two years of multidisciplinary follow-up. Eleven (64.5%) of these 17 patients (31.5% of total) were reclassified with a psychiatric diagnosis. We found no differences for cognitive baseline profiles between patients with bvFTD versus psychiatric diagnoses. Conclusion: In almost half of cases, the initial bvFTD diagnosis was changed after follow-up, most often into a psychiatric disorder. A multidisciplinary neuropsychiatric approach in the diagnostic process of bvFTD results in the identification of treatable disorders. Our findings illustrate a limited specificity of the [18F]FDG-PET-scan and the bvFTD criteria in a neuropsychiatric cohort, especially combined with certain clinical symptoms, like disinhibition, apathy, or loss of empathy.

Saima Hilal, Saloua Akoudad, Cornelia M. van Duijn, Wiro J. Niessen, Marcel M. Verbeek, Hugo Vanderstichele, Erik Stoops, M. Arfan Ikram, Meike W. Vernooij (Handling Associate Editor: Laura Zahodne)
Plasma Amyloid-β Levels, Cerebral Small Vessel Disease, and Cognition: The Rotterdam Study
Abstract: Background: Plasma amyloid-β (Aβ) levels are increasingly studied as a potential, accessible marker of cognitive impairment and dementia. The most common plasma Aβ isoforms, i.e., Aβ1-40 and Aβ1-42 have been linked with risk of Alzheimer’s disease. However, it remains under-explored whether plasma Aβ levels including novel Aβ1-38 relate to vascular brain disease and cognition in a preclinical-phase of dementia. Objective: To examine the association of plasma Aβ levels (i.e., Aβ1-38, Aβ1-40, and Aβ1-42) with markers of cerebral small vessel disease (SVD) and cognition in a large population-based setting. Methods: We analyzed plasma Aβ1 levels in 1201 subjects from two independent cohorts of the Rotterdam Study. Markers of SVD [lacunes, white matter hyperintensity (WMH) volume] were assessed on brain MRI (1.5T). Cognition was assessed by a detailed neuropsychological battery. In each cohort, the association of Aβ levels with SVD and cognition was performed using regression models. Estimates were then pooled across cohorts using inverse variance meta-analysis with fixed effects. Results: Higher levels of plasma Aβ1-38, Aβ1-40, Aβ1-42, and Aβ1-40/ Aβ1-42 ratio were associated with increasing lacunar and microbleeds counts. Moreover, higher levels of Aβ1-40 and Aβ1-40/ Aβ1-42 were significantly associated with larger WMH volumes. With regard to cognition, a higher level of Aβ1-38 Aβ1-40 and Aβ1-40/ Aβ1-42 was related to worse performance on cognitive test specifically in memory domain. Conclusion: Higher plasma levels of Aβ levels are associated with subclinical markers of vascular disease and poorer memory. Plasma Aβ levels thus mark the presence of vascular brain pathology.

Silvan Licher, Renée F.A.G. de Bruijn, Frank J. Wolters, M. Carola Zillikens, M. Arfan Ikram, M. Kamran Ikram (Handling Associate Editor: Corinne Engelman)
Vitamin D and the Risk of Dementia: The Rotterdam Study
Abstract: Background: Vitamin D has gained interest as a potentially modifiable risk factor for dementia because of its putative neuroprotective effects. However, longitudinal studies examining the association between vitamin D and dementia have provided inconsistent results. Objective: To determine the relationship of serum vitamin D with prevalent and incident dementia in the general population. Methods: Within the prospective Rotterdam Study, we measured serum 25-hydroxyvitamin D concentrations between 1997 and 2001 using electrochemiluminescence-immunoassay in 6220 participants 55 years or older. We assessed dementia at baseline and continuously during follow-up until 1 January 2015. We used appropriate regression models to determine the relationship of vitamin D with prevalent and incident dementia, including Alzheimer’s disease (AD). We adjusted models for age, sex, and season of blood collection. Additionally, we adjusted for ethnicity, education, cardiovascular risk factors, serum calcium, kidney function, depression, outdoor-activity and APOE ε4 carriership. Results: At baseline, 127 of 6,220 participants had dementia, of whom 97 had AD. Lower vitamin D concentrations were associated with a non-significantly higher prevalence of dementia (adjusted OR, per SD decrease 1.20, 95% CI 0.95;1.52), but not with AD (adjusted OR: 0.97, 95% CI 0.74;1.29). Among 6,087 non-demented participants with 68,884 person-years of follow-up, 795 participants developed dementia, of whom 641 had AD. Lower vitamin D concentrations were associated with higher risk of dementia (adjusted HR, per SD decrease 1.11, 95% CI 1.02;1.20) and AD (adjusted HR: 1.13, 95% CI 1.03;1.24). Conclusion: Lower serum vitamin D concentrations are associated with a higher incidence of dementia.

Jitendra Subhash Rane, Prasenjit Bhaumik, Dulal Panda
Curcumin Inhibits Tau Aggregation and Disintegrates Preformed Tau Filaments in vitro
Abstract: The pathological aggregation of tau is a common feature of most of the neuronal disorders including frontotemporal dementia, Parkinson’s disease, and Alzheimer’s disease. The inhibition of tau aggregation is considered to be one of the important strategies for treating these neurodegenerative diseases. Curcumin, a natural polyphenolic molecule, has been reported to have neuroprotective ability. In this work, curcumin was found to bind to adult tau and fetal tau with a dissociation constant of 3.3 ± 0.4 and 8 ± 1 µM, respectively. Molecular docking studies indicated a putative binding site of curcumin in the microtubule-binding region of tau. Using several complementary techniques, including dynamic light scattering, thioflavin S fluorescence, 90º light scattering, electron microscopy, and atomic force microscopy, curcumin was found to inhibit the aggregation of tau. The dynamic light scattering analysis and atomic force microscopic images revealed that curcumin inhibits the oligomerization of tau. Curcumin also disintegrated preformed tau oligomers. Using Far-UV circular dichroism, curcumin was found to inhibit the β-sheets formation in tau indicating that curcumin inhibits an initial step of tau aggregation. In addition, curcumin inhibited tau fibril formation. Furthermore, the effect of curcumin on the preformed tau filaments was analyzed by atomic force microscopy, transmission electron microscopy, and 90º light scattering. Curcumin treatment disintegrated preformed tau filaments. The results indicated that curcumin inhibited the oligomerization of tau and could disaggregate tau filaments.

Laura Serra, Giulia Bechi Gabrielli, Elisa Tuzzi, Barbara Spanò, Giovanni Giulietti, Virginia Failoni, Camillo Marra, Carlo Caltagirone, Giacomo Koch, Mara Cercignani, Marco Bozzali (Handling Associate Editor: Daniela Galimberti)
Damage to the Frontal Aslant Tract Accounts for Visuo-Constructive Deficits in Alzheimer’s Disease
Abstract: The frontal aslant tract (FAT) has been described as a bundle connecting the Broca’s area to the supplementary motor area (SMA) and the pre-SMA in both hemispheres. The functional properties of this tract and its role in degenerative dementia, such as Alzheimer’s disease (AD), still need to be fully clarified. The aim of this study was to explore the microstructural integrity of the FAT in patients with AD and its potential relationship with cognitive functioning. Twenty-three patients with AD and 25 healthy subjects (HS) were enrolled. All subjects underwent cognitive and MRI examination. MRI, including diffusion sequences, was used for probabilistic tractography analysis. We reconstructed individual FATs bilaterally and assessed their microstructural integrity using fractional anisotropy (FA), computed as both mean tract value and voxel-wise using SPM-8. Mean FA values were then used to test for correlations with cognitive measures. Mean tract FA and voxel-wise analyses revealed that patients with AD, compared to HS, had decreased FA in the FAT bilaterally. In addition, positive associations were found between FA in the FATs and patients’ performance at tests for constructional praxis and visuospatial logical reasoning. The present results reveal a bilateral damage of FAT in AD patients. The association between FATs’ microscopic abnormalities and constructive abilities fits well with the knowledge of a functional involvement of SMA and pre-SMA in movement sequences when executing constructive praxis tasks. The FAT is an associative bundle critically involved in the network sub-serving constructional praxis in patients with AD.

Babette L.R. Reijs, Inez H.G.B. Ramakers, Lyzel Elias-Sonnenschein, Charlotte E. Teunissen, Marleen Koel-Simmelink, Magda Tsolaki, Lars-Olof Wahlund, Gunhild Waldemar, Lucrezia Hausner, Peter Johannsen, Hugo Vanderstichele, Frans Verhey, D.P. Devanand, Pieter Jelle Visser
Relation of Odor Identification with Alzheimer’s Disease Markers in Cerebrospinal Fluid and Cognition
Abstract: Background: Impaired olfactory function is an early characteristic of Alzheimer’s disease (AD), but it remains unclear if odor identification also relates to early markers of AD in cerebrospinal fluid (CSF). Objective: To investigate the association between odor identification and amyloid-β 1-42 (Aβ42) and total tau (t-tau) concentrations in CSF. In addition, to examine the relation between odor identification and cognitive function at baseline and at follow-up, and whether these associations are moderated by CSF Aβ42 and t-tau and apolipoprotein E (APOE) genotype. Methods: We included 160 individuals (40 with normal cognition, 45 with mild cognitive impairment (MCI), 42 with AD-type dementia, and 26 individuals with non-AD dementia) from the EDAR study. Individuals were recruited from six memory clinics across Europe. Odor identification was tested with the brief University of Pennsylvania Smell Identification Test. CSF Aβ42 and t-tau were assessed with INNO-BIA AlzBio3 Luminex assay. Neuropsychological assessment included tests for verbal memory, verbal fluency, attention, executive function, and visuoconstruction. Follow-up was performed within 3 years after baseline. Results: Lower odor identification scores correlated with increased CSF t-tau concentrations and with lower scores on all cognitive measures at baseline independent of diagnostic group. Lower odor identification scores predicted decline on the MMSE in the total group, and decline on wordlist learning and delayed recall in APOE ε4 carriers and in individuals with abnormal Aβ42. Conclusion: Odor identification impairment may be an indicator of neuronal injury rather than amyloid pathology.

Maria Niures Pimentel dos Santos Matioli*, Claudia Kimie Suemoto*, Roberta Diehl Rodriguez, Daniela Souza Farias, Magnólia Moreira da Silva, Renata Elaine Paraizo Leite, Renata Eloah Lucena Ferretti-Rebustini, José Marcelo Farfel, Carlos Augusto Pasqualucci, Wilson Jacob Filho, Zoe Arvanitakis, Michel Satya Naslavsky, Mayana Zatz, Lea Tenenholz Grinberg, Ricardo Nitrini *These authors contributed equally to this work.
Diabetes is Not Associated with Alzheimer’s Disease Neuropathology
Abstract: Background: Previous evidence linking diabetes to Alzheimer’s disease (AD) neuropathology is mixed and scant data are available from low- and middle-income countries. Objective: To investigate the association between diabetes and AD neuropathology in a large autopsy study of older Brazilian adults. Methods: In this cross-sectional study, diabetes was defined by diagnosis during life or use of antidiabetic medication. A standardized neuropathological examination was performed using immunohistochemistry. The associations of diabetes with Consortium to Establish and Registry for Alzheimer Disease (CERAD) scores for neuritic plaques and Braak-Braak (BB) scores for neurofibrillary tangles were investigated using multivariable ordinal logistic regression. We investigated effect modification of education, race, and APOE on these associations. Results: Among 1,037 subjects (mean age=74.4 ± 11.5 y; mean education=4.0 ± 3.7 y; 48% male, 61% White), diabetes was present in 279 subjects. Diabetes was not associated with BB (OR=1.12, 95% CI=0.81-1.54, p=0.48) or with CERAD (OR=0.97, 95% CI=0.68-1.38, p=0.86) scores on analyses adjusted for sociodemographic and clinical variables. We observed effect modification by the APOE allele ε4 on the association between diabetes mellitus and BB scores. Conclusion: No evidence of an association between diabetes and AD neuropathology was found in a large sample of Brazilians; however, certain subgroups, such as APOE allele ε4 carriers, had higher odds of accumulation of neurofibrillary tangles.

Yaohua Chen, Adeline Rollin Sillaire, Jean Dallongeville, Emilie Skrobala, David Wallon, Bruno Dubois, Didier Hannequin, Florence Pasquier, the Lille YOD study group
Low Prevalence and Clinical Effect of Vascular Risk Factors in Early-Onset Alzheimer’s Disease
Abstract: Background: Determinants of early-onset Alzheimer’s disease (EOAD) are not well known. In late-onset AD, vascular risk factors (VRFs) are associated with earlier clinical manifestation. Objective: The objective of this study was to assess the putative association between VRFs and EOAD. Methods: We studied participants with dementia meeting criteria for EOAD (recruited into the French CoMAJ prospective cohort study from 1 June 2009 to 28 February 2014) and age-, gender-matched controls (ratio 1:3, drawn randomly from the French MONA-LISA population-based survey between 2005 and 2007). Demographic data, VRFs, comorbidities, treatments, and APOE genotypes were compared in multivariable logistic regression analyses. Results: We studied 102 participants with dementia (mean ± standard deviation age: 59.5±3.8; women: 59.8%) and 306 controls. Compared with controls, EOAD participants had spent less time in formal education (9.9±2.9 versus 11.7±3.8 y; p<0.0001), were less likely to be regular alcohol consumers (p<0.0001), had a lower body mass index (-2 kg/m2; p<0.0004), and a lower mean systolic blood pressure (-6.2 mmHg; p=0.0036). The prevalence of APOE ε4 allele was higher in participants with dementia than in controls (50% versus 29.4%; p=0.0002), as was the prevalence of depression (48% versus 32%; p<0.001). Similar results were observed in multivariable analysis. Compared with EOAD participants lacking VRFs, EOAD participants with at least one VRF had a higher prevalence of depression (29.6% versus 53.3%, respectively; p=0.03). Conclusion: The prevalence of VRFs is not elevated in EOAD patients (in contrast to older AD patients). Extensive genetic testing should be considered more frequently in the context of EOAD.

Andrea Saul Costa, Simone Agostini, Franca Rosa Guerini, Roberta Mancuso, Milena Zanzottera, Enrico Ripamonti, Vittorio Racca, Raffaello Nemni, Mario Clerici (Handling Associate Editor: Beatrice Arosio)
Modulation of Immune Responses to Herpes Simplex Virus Type 1 by IFNL3 and IRF7 Polymorphisms: A Study in Alzheimer’s Disease
Abstract: Herpes simplex virus type 1 (HSV-1) has long been suspected to play a role in Alzheimer's disease (AD), the most common form of dementia. IFN-lambda (IFN-λ) is one of the key cytokine in innate antiviral defenses and, in particular, has an appreciable antiviral activity against HSV-1 infection. IFN-λ expression is regulated by the interaction between two different proteins: Mediator Complex 23 (MED23) and Interferon-Responsive Transcription Factor 7 (IRF7); single nucleotide polymorphisms (SNPs) in these genes as well as in IFNL3 were shown to be differently distributed in AD patients. In this study, allelic discrimination analysis for IFNL3 rs12979860, MED23 rs3756784, and IRF7 rs6598008, as well as IFN-λ serum concentration and anti-HSV-1 antibody (Ab) titers were performed in 79 AD patients, 57 mild cognitive impairment (MCI) individuals, and 81 healthy controls (HC) who were HSV-1-seropositive. Results showed that INF-λ serum concentration was increased in AD and MCI carrying the IFNL3 T allele compared to HC (AD versus HC: p = 0.014; MCI versus HC: p = 0.029), with the highest anti-HSV-1 Ab titers seen in AD patients carrying the IFNL3 CC genotype (p = 0.012 versus HC). Notably, anti-HSV-1 Ab titers were higher in AD and MCI individuals carrying the IRF7 AA genotype compared to HC (p = 0.018 for both). MED23 polymorphisms did not show any statistical association either with serum IFN-λ or with anti-HSV-1 Ab. Data herein suggest that the IFNL3 rs12979860 and IRF7 rs6598008 polymorphisms modulate immune responses against HSV-1 via their effect on the IFN-λ pathway. These results help to clarify the possible role of HSV-1 infection in AD pathogenesis.

James M. Noble*, Nicole Schupf*, Jennifer J. Manly, Howard Andrews, Ming-Xin Tang, Richard Mayeux *These authors contributed equally to this work.
Secular Trends in the Incidence of Dementia in a Multi-Ethnic Community
Abstract: Background: Determination of secular trends in cognitive aging is important for prioritization of resources, services, and research in aging populations. Prior studies have identified declining dementia incidence associated with changes in cardiovascular risk factors and increased educational attainment. However, few studies have examined these factors in multi-ethnic cohorts. Objective: To identify secular trends in the incidence rate of dementia in an elderly population. Methods: Participants in this study were drawn from the Washington Heights-Inwood Columbia Aging Project, a multi-ethnic cohort study of northern Manhattan residents aged 65 years and older. Cox proportional hazards models were used to examine differences in the incidence of dementia in cohorts recruited in 1992 and 1999, with age at dementia or age at last follow-up visit as the “time-to-event” variable. Results: Overall, there was a 41% reduction in the hazard ratio for dementia among participants in the 1999 cohort compared with those in the 1992 cohort, adjusting for age, sex, race, and baseline memory complaints (HR=0.59). The reduction in incidence was greatest among non-Hispanic Whites and African-Americans and lowest among Hispanic participants (HRs= 0.60, 0.52 and 0.64, respectively), and was associated with increases in level of educational attainment, especially among African-Americans. Reduction in incidence of dementia was also greater among persons 75 years or older than among younger participants (HR= 0.52 versus HR=0.69). Conclusions: Our results support previous findings that secular trends in dementia incidence are changing, including in aging minority populations.

Joel Huovinen, Seppo Helisalmi, Jussi Paananen, Tiina Laiterä, Maria Kojoukhova, Anna Sutela, Ritva Vanninen, Marjo Laitinen, Tuomas Rauramaa, Anne M. Koivisto, Anne M. Remes, Hilkka Soininen, Mitja Kurki, Annakaisa Haapasalo, Juha E. Jääskeläinen, Mikko Hiltunen, Ville Leinonen
Alzheimer’s Disease-Related Polymorphisms in Shunt-Responsive Idiopathic Normal Pressure Hydrocephalus
Abstract: Background: Idiopathic normal pressure hydrocephalus (iNPH) is a late onset, surgically treated progressive brain disease caused by impaired cerebrospinal fluid dynamics and subsequent ventriculomegaly. Comorbid Alzheimer’s disease (AD) seems to be frequent in iNPH. Objective: We aim to evaluate the role of AD-related polymorphisms in iNPH. Methods: Overall 188 shunt-operated iNPH patients and 688 controls without diagnosed neurodegenerative disease were included into analysis. Twenty-three single-nucleotide polymorphisms (SNPs FRMD4A [rs7081208_A, rs2446581_A, rs17314229_T], CR1, BIN, CD2AP, CLU, MS4A6A, MS4A4E, PICALM, ABCA7, CD33, INPP5D, HLA_DRB5, EPHA1, PTK2B, CELF1, SORL1, FERMT2, SLC24A, DSG2, CASS4, and NME8) adjusted to APOE were analyzed between groups by using binary logistic regression analysis. Neuroradiological characteristics and AD-related changes in the right frontal cortical brain biopsies were available for further analysis. Results: Logistic regression analysis adjusted to age, gender, and other SNPs indicated allelic variation of NME8 between iNPH patients and non-demented controls (p = 0.014). The allelic variation of NME8 was not related to the neuropathological changes in the brain biopsies of iNPH patients. However, periventricular white matter changes (p = 0.017) were more frequent in the iNPH patients with the AA-genotype, an identified risk factor of AD. Conclusions: Our findings increase the evidence that iNPH is characterized by genetic and pathophysiological mechanisms independent from AD. Considering that NME8 plays a role in the ciliary function and displays SNP-related diversity in white matter changes, the mechanisms of NME8 in iNPH and other neurodegenerative processes are worth further study.

Celeste A. de Jager, William Msumburi, Katy Pepper, Marc I. Combrinck
Dementia Prevalence in a Rural Region of South Africa: A Cross-Sectional Community Study
Abstract: Background: Dementia is a growing concern for low- and middle-income countries where longevity is increasing and service provision is poor. Global prevalence estimates vary from 2% to 8.5% for those aged 60 years and older. There have been few dementia studies in sub-Saharan Africa, and prevalence data are lacking for South Africa. Objective: To conduct a large dementia prevalence study in a low income rural population in South Africa. Methods: 1,394 Xhosa-speaking community dwellers, aged ≥60 y (mean age ± sd 71.3 ± 8.3 y), in three clinic catchment areas, were screened at home. Trained community health workers administered the brief Community Screening Instrument for Dementia (CSID) to participants and informants to assess cognitive and functional capacity. Depressive symptoms were assessed with three questions from the EURO-D. Results: The prevalence estimate using published CSID sensitivity/specificity values was 0.8 (95% CI: 0.06–0.09). Using CSID cut-off scores the estimated prevalence was 0.12 (95% CI: 0.10–0.13), with 161 screen-positives. Both methods gave a rate of 0.11 (95% CI: 0.09–0.13) for those over 65 years (n=1051). 68.6% of participants were female and 69.8% had less than 7 years of education. Dementia risk was associated with older age and symptoms of depression, but not with sex. The association with education was not significant when controlled for by age. Conclusions: Dementia prevalence estimates were higher than expected for this low-income rural community. There is a need for increased dementia awareness and feasible support interventions. We also need further studies of regional prevalences, dementia subtypes, and modifiable risk factors in South Africa.

Gianna Palmieri, Ennio Cocca, Marta Gogliettino, Roberta Valentino, Menotti Ruvo, Gloria Cristofano, Antonella Angiolillo, Marco Balestrieri, Mosè Rossi, Alfonso Di Costanzo (Handling Associate Editor: Sharmistha Dey)
Low Erythrocyte Levels of Proteasome and Acyl-Peptide Hydrolase (APEH) Activities in Alzheimer’s Disease: A Sign of Defective Proteostasis?
Abstract: Alzheimer’s disease (AD) is a progressive, multifactorial neurodegenerative disorder that is the main cause of dementia. To date, there are no definitive diagnostic tests that can predict or assess onset and progression of the disease. Blood biomarkers for AD are being sought for many years but their identification remains a challenging task. In this study, we investigated the potential relationship between AD and levels of acyl-peptide hydrolase (APEH) and proteasome in erythrocyte samples of 52 participants (26 AD and 26 cognitively healthy controls). A statistically significant decrease in proteasome and exopeptidase/endopeptidase APEH activities was found in AD samples compared to those of healthy controls. Moreover, in contrast to what was observed for proteasome transcripts, APEH activities reduction in AD patients was unrelated to its gene expression levels, suggesting the occurrence of posttranslational modifications or the expression of endogenous inhibitors might impair enzyme activity. These preliminary data further support a relationship between the APEH-proteasome system and AD molecular players, providing the first evidence of its potential use as a novel blood-based indicator for the routine detection of AD.

Ayano Mise*, Yuta Yoshino*, Kiyohiro Yamazaki, Yuki Ozaki, Tomoko Sao, Taku Yoshida, Takaaki Mori, Yoko Mori, Shinichiro Ochi, Jun-ichi Iga, Shu-ichi Ueno *These authors contributed equally to this work.
TOMM40 and APOE Gene Expression and Cognitive Decline in Japanese Alzheimer’s Disease Subjects
Abstract: Background: TOMM40is located on chromosome 19, is in linkage disequilibrium with apolipoprotein E (APOE), and is reported in several genome-wide association studies to be associated with Alzheimer’s disease (AD). Objective: Assess APOE and TOM40 and mitochondrial genes as blood biomarkers for AD. Methods: We examined TOMM40, PTEN-induced putative kinase 1 (PINK1), Parkin RBR E3 ubiquitin protein ligase (PARK2), and APOE mRNA expression in relation to the methylation rates of CpG sites in the upstream region of TOMM40exon 1 in peripheral leukocytes and TOMM40523 polyT genotypes in 60 AD and age- and sex-matched control subjects. Results: TOMM40 mRNA expression was significantly lower in AD subjects (0.87 ± 0.18 versus 1.0 ± 0.23, p = 0.005), and PINK1 mRNA expression was higher in AD subjects (1.5 ± 0.61 versus 1.0 ± 0.52, p < 0.001). TOMM40 mRNA expression was significantly correlated with the Mini-Mental State Examination total score (r = 0.290, p = 0.027). There was no expressional change in peripheral APOE mRNA in either AD or control subjects (p = 0.32). Methylation rates in the upstream region of TOMM40exon 1 were not different between AD and control subjects (average rate: 1.37 ± 0.99 versus 1.39 ± 1.20, p = 0.885), and TOMM40523 polyT genotypes were also not different between AD and control subjects (p = 0.67). Conclusion: TOMM40 mRNA expression was lower in AD subjects and was correlated with cognitive decline. Significant changes in both TOMM40and PINK1 mRNA may be related to mitochondrial dysfunction.

Babette L.R. Reijs, Inez H.G.B. Ramakers, Sebastian Köhler, Charlotte E. Teunissen, Marleen Koel-Simmelink, Pradeep J. Nathan, Magda Tsolaki, Lars-Olof Wahlund, Gunhild Waldemar, Lucrezia Hausner, Rik Vandenberghe, Peter Johannsen, Andrew Blackwell, Hugo Vanderstichele, Frans Verhey, Pieter Jelle Visser (Handling Associate Editor: Adrian Ivanoie)
Memory Correlates of Alzheimer’s Disease Cerebrospinal Fluid Markers: A Longitudinal Cohort Study
Abstract: Background: Performance on episodic, semantic, and working memory tests is impaired in Alzheimer’s disease (AD)-type dementia, but it is unclear which type of memory test is most strongly associated with early AD biomarkers in cerebrospinal fluid (CSF), and most useful for monitoring disease progression. Objective: To examine the association between amyloid-β 1-42 (Aβ42) and tau in CSF with performance on different memory domains at baseline, and how these CSF markers are related with memory decline. Methods: We included 263 individuals with normal cognition, mild cognitive impairment, AD-type dementia, and non-AD dementia from the European EDAR study. Assessment included CSF Aβ42 and t-tau analyses with INNO-BIA AlzBio3 Luminex assay, the CERAD wordlist learning and delayed recall, animal fluency test, and the CANTAB Paired Associates Learning (PAL) and Spatial Working Memory tasks. Follow-up assessments were performed within 3 years after baseline. Results: At baseline, decreased CSF Aβ42 correlated most strongly with the PAL total errors adjusted and the wordlist delayed recall and increased CSF t-tau with the wordlist delayed recall. Over time, decreased CSF Aβ42 was associated with decline on the wordlist learning, whereas increased CSF t-tau were associated with decline in scores on the wordlist learning, wordlist delayed recall, and animal fluency. Associations were independent of baseline diagnosis. Conclusion: Tests assessing episodic verbal and visuospatial memory are most useful for detection of AD pathology. Tests for episodic verbal memory and semantic memory are most useful for tracking memory decline.

Sandra Garrido, Laura Dunne, Esther Chang, Janette Perz, Catherine J. Stevens, Maggie Haertsch
The Use of Music Playlists for People with Dementia: A Critical Synthesis
Abstract: The use of pre-recorded music to ease behavioral and psychological symptoms associated with dementia is popular in health-care contexts in both formal music therapy settings and in non-therapist led interventions. However, further understanding of how non-therapist led interventions compare to therapist led interventions is needed. This paper reviews 28 studies that used pre-recorded music with people with dementia using a critical interpretive synthesis model. Results revealed that pre-recorded music can be effective in reducing a variety of affective and behavioral symptoms, in particular agitation, even where a trained music therapist is not present. However, the results are not universally positive, suggesting the need for further clarification of protocols for music use and closer investigation of variables that influence individual response to music.

Mohammad Ejaz Ahmed, Shankar Iyer , Ramasamy Thangavel, Duraisamy Kempuraj, Govindhasamy Pushpavathi Selvakumar, Sudhanshu P. Raikwar, Smita Zaheer, Asgar Zaheer (Handling Associate Editor: P. Hemachandra Reddy)
Co-Localization of Glia Maturation Factor with NLRP3 Inflammasome and Autophagosome Markers in Human Alzheimer’s Disease Brain
Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the presence of intracellular neurofibrillary tangles (NFTs) containing hyperphosphorylated tau, and the extracellular deposition of amyloid plaques (APs) with misfolded amyloid-β (Aβ) peptide. Glia maturation factor (GMF), a highly conserved pro-inflammatory protein, isolated and cloned in our laboratory, has been shown to activate glial cells leading to neuroinflammation and neurodegeneration in AD. We hypothesized that inflammatory reactions promoted by NLRP3-Caspase-1inflammasome pathway trigger dysfunction in autophagy and accumulation of Aβ which is amplified and regulated by GMF in AD. In this study, using immunohistochemical techniques we analyzed components of the NLRP3 inflammasome and autophagy- lysosomal markers in relation to Aβ, p-tau and GMF in human postmortem AD and age-matched non-AD brains. Tissue sections were prepared from the temporal cortex of human postmortem brains. Here, we demonstrate an increased expression of the inflammasome components NLRP3 and Caspase-1 and the products of inflammasome activation IL-1β and IL-18 along with GMF in the temporal cortex of AD brains. These inflammasome components and the pro-inflammatory cytokines co-localized with GMF in the vicinity and periphery of the APs and NFTs. Moreover, using double immunofluorescence staining, AD brain displayed an increase in the autophagy SQSTM1/p62 and LC3 positive vesicles and the lysosomal marker LAMP1 that also co-localized with GMF, Aβ and hyperphosphorylated p-tau. Our results indicate that in AD, the neuroinflammation promoted by the NLRP3 inflammasome may be amplified and regulated by GMF, which further impairs clearance of protein aggregates mediated by the auto-phagosomal pathway.

Elizabeth Finger, Jing Zhang, Bradford Dickerson, Yves Bureau, Mario Masellis for the Alzheimer’s Disease Neuroimaging Initiative
Disinhibition in Alzheimer’s Disease is Associated with Reduced Right Frontal Pole Cortical Thickness
Abstract: Neuropsychiatric symptoms in Alzheimer’s disease are among the most disabling and difficult aspects for caregivers and treating health professionals to manage. Despite the high prevalence of these behaviors, little is known about the factors which lead some patients to develop florid behavioral symptoms while others may progress to severe dementia without such phenomenon. We examined whether regional brain volumes as measured by cortical thickness would predict the presence or absence of disinhibition in patients with Alzheimer’s disease. Using data from the ADNI, we identified 758 patients with caregiver ratings on the Neuropsychiatric Inventory and a volumetric MRI scan with cortical thickness measurements completed in FreeSurfer by the UCSF core. Of these, 177 patients were found to have disinhibition. Logistic regression models demonstrated that reduced cortical thickness in the right frontal pole was associated with the presence of disinhibition even when controlling for age, disease severity, total intracranial volume, gender, and APOE genotype. The results are considered in the context of leading models of the functions of frontopolar cortex.

Ilona Dutzi, Michael Schwenk, Marietta Kirchner, Jürgen Bauer, Klaus Hauer
Cognitive Change in Rehabilitation Patients with Dementia: Prevalence and Association with Rehabilitation Success
Abstract: Background: Dementia is a frequent diagnosis in geriatric rehabilitation. Studies in patients with dementia on the development of their cognitive status during rehabilitation and its relation to functional outcomes have been scarce. Objectives: To describe the changes in cognitive status in patients with dementia during inpatient rehabilitation and to determine its association with patient characteristics and rehabilitation outcome. Methods: Cohort study in a geriatric rehabilitation center with data collection at admission and discharge. Outcome measures were change in global and domain-related cognitive functioning and its association with activities of daily living (ADL) and discharge home. Results: 154 patients (mean age 83.7 years) diagnosed with mild to moderate dementia were included. Cognitive performance significantly improved from admission to discharge for all cognitive variables tested (p<0.001 to 0.03). Change in global cognitive functioning, executive functions, and episodic memory were positively associated with ADL recovery. Change in global cognitive functioning predicted ADL improvements (β=0.32; p=0.006). Only 7.8% of patients, characterized by worse ADL and motor abilities as well as higher frailty scores at admission, deteriorated in global cognitive scores. In comparison to patients with stable or improved cognition, these patients showed least improvements in ADL-scores (4.1 versus 12.5) and a trend for higher institutionalization (50% versus 26.5%). Conclusions: The findings highlight the potential of patients with dementia to recover cognitive functioning during rehabilitation. Cognitive change represents an independent rehabilitation outcome and a prognostic factor for successful rehabilitation suggesting that specific interventions are indicated to maintain and enhance cognitive functioning in these highly vulnerable patients.

Stella M. Sánchez*, Carolina Abulafia*, Barbara Duarte-Abritta, M. Soledad Ladrón de Guevara, Mariana N. Castro, Lucas Drucaroff, Gustavo Sevlever, Charles B. Nemeroff, Daniel E. Vigo, David A. Loewenstein, Mirta F. Villarreal, Salvador M. Guinjoan (Handling Associate Editor: Jordi Matias-Guiu) *These authors contributed equally to this work.
Failure to Recover from Proactive Semantic Interference and Abnormal Limbic Connectivity in Asymptomatic, Middle-Aged Offspring of Patients with Late-Onset Alzheimer’s Disease
Abstract: Background: We have obtained previous evidence of limbic dysfunction in middle-aged, asymptomatic offspring of late-onset Alzheimer’s disease (LOAD) patients, and failure to recover from proactive semantic interference has been shown to be a sensitive cognitive test in other groups at risk for LOAD. Objective: To assess the effects of specific proactive semantic interference deficits as they relate to functional magnetic resonance imaging (fMRI) neocortical and limbic functional connectivity in middle aged offspring of individuals with LOAD (O-LOAD) and age-equivalent controls. Methods: We examined 21 O-LOAD and 20 controls without family history of neurodegenerative disorders (CS) on traditional measures of cognitive functioning and the LASSI-L, a novel semantic interference test uniquely sensitive to the failure to recover from proactive interference (frPSI). Cognitive tests then were correlated to fMRI connectivity of seeds located in entorhinal cortex and anterodorsal thalamic nuclei among O-LOAD and CS participants. Results: Relative to CS, O-LOAD participants evidenced lower connectivity between entorhinal cortex and orbitofrontal, anterior cingulate, and anterior temporal cortex. In the offspring of LOAD patients, LASSI-L measures of frPSI were inversely associated with connectivity between anterodorsal thalamus and contralateral posterior cingulate. Intrusions on the task related to frPSI were inversely correlated with a widespread connectivity network involving hippocampal, insular, posterior cingulate, and dorsolateral prefrontal cortices, along with precunei and anterior thalamus in this group. Different patterns of connectivity associated with frPSI were observed among controls. Conclusion: The present results suggest that both semantic interference deficits and connectivity abnormalities might reflect limbic circuit dysfunction as a very early clinical signature of LOAD pathology, as previously demonstrated for other limbic phenotypes, such as sleep and circadian alterations.

Laura Buratti, Giovanna Viticchi, Sara Baldinelli, Lorenzo Falsetti, Simona Luzzi, Alessandra Pulcini, Cristina Petrelli, Leandro Provinciali, Mauro Silvestrini (Handling Associate Editor: Mario Tombini)
Sleep Apnea, Cognitive Profile, and Vascular Changes: An Intriguing Relationship
Abstract: Background: Sleep breathing disorders can affect cognitive performances through complex brain anatomical and functional changes. Objective: Our aim was to evaluate the correlations between cognitive performances and obstructive sleep apnea syndrome (OSAS), as well as the possible influence of vascular factors. Methods: Thirty-four non-demented OSAS patients and 34 controls were submitted to a neuropsychological evaluation and to a vascular screening including the study of cerebrovascular reactivity by means of the breath-holding index (BHI) calculation. After 6 months, polisomnographic, neuropsychologic, and hemodynamics assessment was repeated in patients. Results: At baseline, some cognitive performances involved in executive and memory functions were significantly lower in patients with respect to controls. Significantly lower values in mean BHI were also detected in patients with respect to controls (p<0.0001). At the 6-month evaluation, 18 patients had a reduction in OSAS severity (group 1) and 16 remained stable (group 2). Group 1 patients had a significant improvement in left and mean BHI (p<0.001) and in short-term (p=0.02) and long-term Rey Auditory Verbal Learning Test (p<0.001). No change in cerebrovascular reactivity and cognitive profile was detected in group 2 patients. Conclusions: Patients with OSAS may experience a reduced cognitive efficiency. Improvement of OSAS was associated to favorable hemodynamic changes and increased level of performances in verbal memory tasks so suggesting an involvement of vascular underlying mechanisms in sustaining cognitive dysfunctions in OSAS. Our preliminary data suggest the need for further studies to deepen the knowledge about the relationships between OSAS, cerebral hemodynamic compromise, and cognitive impairment risk.

Book Review
The End of Alzheimer’s: The First Program to Prevent and Reverse Cognitive Decline, by Dale E. Bredensen, M.D., Avery, 2017, 320 p., ISBN-10: 0735216207. Reviewed by Dharma Singh Khalsa