Volume 68, Number 3, 2019

Pages 843-855

Nicole Cortés, Leonardo Guzmán-Martínez, Víctor Andrade, Andrea González, Ricardo B. Maccioni
CDK5: A Unique CDK and Its Multiple Roles in the Nervous System
Abstract: The cyclin-dependent kinase 5 (CDK5) is known as an exceptional component of the CDK family, due to its characteristic regulatory pathways and its atypical roles in comparison to the classical cyclins. Despite its functional uniqueness, CDK5 shares a great part of its structural similarity with other members of the cyclin-dependent kinase family. After its discovery 26 years ago, a progressive set of cellular functions has been associated with this protein kinase, ranging from neuronal migration, axonal guidance, and synaptic plasticity in diverse stages of brain development, including specific and complex cognitive functions. More than 30 substrates for CDK5 have been found in different cellular pathways. Together with its essential physiological roles, a major discovery was the finding twenty years ago that CDK5 participates in neurodegenerative diseases responsible for tau hyperphosphorylations, and, as a consequence, it becomes a neurotoxic factor. This review focuses on the wide roles of CDK5 in the central nervous system, its implications in neurodegeneration, and provides an integrative insight of its involvement in pain modulation, Alzheimer’s disease, and other contexts.

Pages 857-883

Mathilde Groussard, Tyler G. Chan, Renaud Coppalle, Hervé Platel
Preservation of Musical Memory Throughout the Progression of Alzheimer’s Disease? Toward a Reconciliation of Theoretical, Clinical, and Neuroimaging Evidence
Abstract: Through this review of 25 clinical and experimental works on long-term musical memories in Alzheimer’s disease (AD) patients, we attempt to clarify the conceptual understanding of musical memories, identify their evolution across the stages of the pathology, and propose possible explanations concerning the neural and cognitive mechanisms that underpin the preservation and impairment of certain musical memories. After clarifying the different kind of musical memories, we investigated their alterations throughout AD’s progression from mild to severe stages. Both procedural and retrograde semantic memory seem relatively spared in AD, while episodic memory appears to be impaired early. Moreover, partial preservation of music encoding in AD can be revealed through paradigms that are especially designed for AD patients (relying on behavioral cues, using adapted settings, etc.). Although seldomly used, they would definitely help understanding the preserved capacities in every stage of AD. However, more research is needed to better understand this phenomenon and assess its specificity to music or other types of supports. These findings could lead to multiple applications in care settings and research designs, bringing more nuanced understanding of how long-term musical memory degrades throughout the course of AD, and should encourage us to prioritize patients’ preserved cognitive abilities in current AD recreational and care programs.

Pages 885-923

Carr J. Smith, J. Wesson Ashford, Thomas A. Perfetti
Putative Survival Advantages in Young Apolipoprotein ε4 Carriers Are Associated with Increased Neural Stress
Abstract: Inheritance of a single copy of the apolipoprotein E (APOE) ε4 allele increases risk of Alzheimer’s disease (AD) by 3-4-fold, with homozygosity associated with a 12-16-fold increase in risk, relative to ε3 allele homozygosity. There is a decreased risk associated with the APOE ε2 allele. The pathological consequence of APOE genotype has led to intense efforts to understand the mechanistic basis of the interplay between APOE status and loss of synapses. Numerous ε4 allele-related associations have been reported with the potential relevance of these associations to the pathogenesis of AD unknown at this time. In primarily young subjects, we have reviewed a representative body of literature on ε4 allele-associations related to the following: cardiovascular responses; impacts on reproduction and fetal development; co-morbidities; resistance to infectious disease; responses to head injury; biochemical differences possibly related to neural stress; and brain structure-function differences. In addition, the literature on the association between the ε4 allele and cognitive performance has been reviewed comprehensively. The weight-of-the-evidence supports the hypothesis that possession of the ancestral ε4 allele in youth is associated with improved fitness during fetal development, infancy, and youth relative to the more recently appearing ε3 allele, at the expense of decreased fitness in old age, which is substantially improved by the ε3 allele. However, possession of the ε4 allele is also associated with higher levels of synaptic macromolecular turnover, which likely stresses basic cellular neuroplasticity mechanisms. Clinical trials of potential AD therapeutics should consider APOE status as an enrollment criterion.

Pages 925-930
Short Communication

Jens Bohlken, Karel Kostev
Diagnostic Behavior for Mild Cognitive Impairment in General and Neuropsychiatric Practices in Germany
Abstract: Little is known about the diagnostic methods currently used in routine care for patients with mild cognitive impairment (PwMCI). We estimated the frequency of diagnostic procedures in incident PwMCI compared to incident patients with dementia (PwD) in 2016-2017. The study is based on the Disease Analyzer database. After matching by age and sex, 4,700 PwMCI and 4,700 PwD were available. The diagnostic procedures were identified on the basis of the related medical fee schedule items. All diagnostic procedures were used more frequently in PwMCI than in PwD. The drafting of a practice-oriented MCI guideline is an important task for the future.

Pages 931-938
Short Communication

Alessandro Medoro, Silvia Bartollino, Donatella Mignogna, Nicola Marziliano, Carola Porcile, Mario Nizzari, Tullio Florio, Aldo Pagano, Gennaro Raimo, Mariano Intrieri, Claudio Russo
Proteases Upregulation in Sporadic Alzheimer’s Disease Brain
Abstract: Certain proteases are involved in Alzheimer’s disease (AD) and their erroneous control may contribute to the pathology onset and progression. In this study we evaluated the cerebral expression of eight proteases, involved in both AβPP processing and extracellular matrix remodeling. Among these proteases, ADAM10, ADAMTS1, Cathepsin D, and Meprin β show a significantly higher mRNAs expression in sporadic AD subjects versus controls, while ADAMTS1, Cathepsin D, and Meprin β show an increment also at the protein level. These data indicate that transcriptional events affecting brain proteases are activated in AD patients, suggesting a link between proteolysis and AD.

Pages 939-945
Short Communication

Kristen R. Hollinger, Jesse Alt, Rana Rais, Adam I. Kaplin, Barbara S. Slusher (Handling Associate Editor: Weiming Xia)
The NAAG’ing Concerns of Modeling Human Alzheimer’s Disease in mice
Abstract: Studies over the past two decades report significant reductions in brain N-acetylaspartyl glutamate (NAAG) levels in neurodegenerative diseases with associated cognitive impairment, including Alzheimer’s disease (AD). Because NAAG is cleaved by glutamate carboxypeptidase II (GCPII), restoration of brain NAAG levels via GCPII inhibition is a potential therapeutic strategy for AD. Herein, studies were conducted to identify an appropriate murine model of AD that recapitulates human brain NAAG changes in order to preclinically evaluate the therapeutic benefit of GCPII inhibition. Our opposing findings of brain NAAG changes in human and mouse AD highlights the limited predictive value of AD mouse models.

Pages 947-960
Christian Sandøe Musaeus, Malene Schjønning Nielsen, Peter Høgh
Altered Low-Frequency EEG Connectivity in Mild Cognitive Impairment as a Sign of Clinical Progression
Abstract: Background: Mild cognitive impairment (MCI) is associated with clinical progression to Alzheimer’s disease (AD) but not all patients with MCI convert to AD. However, it is important to have methods that can differentiate between patients with MCI who progress (pMCI) and those who remain stable (sMCI), i.e., for timely administration of disease-modifying drugs. Objective: In the current study, we wanted to investigate whether quantitative EEG coherence and imaginary part of coherency (iCoh) could be used to differentiate between pMCI and sMCI. Methods: 17 patients with AD, 27 patients with MCI, and 38 older healthy controls were recruited and followed for three years and 2nd year was used to determine progression. EEGs were recorded at baseline and coherence and iCoh were calculated after thorough preprocessing. Results: Between pMCI and sMCI, the largest difference in total coherence was found in the theta and delta bands. Here, the significant differences for coherence and iCoh were found in the lower frequency bands involving the temporal-frontal connections for coherence and parietal-frontal connections for iCoh. Furthermore, we found a significant negative correlation between theta coherence and the Addenbrooke’s Cognitive Examination (ACE) (p = 0.0378; rho = -0.2388). Conclusion: These findings suggest that low frequency coherence and iCoh can be used to determine, which patients with MCI will progress to AD and is associated with the ACE score. Low-frequency coherence has previously been associated with increased hippocampal atrophy and degeneration of the cholinergic system and may be an early marker of AD pathology.

Pages 961-968
Heikki Pentikäinen, Kai Savonen, Tiia Ngandu, Alina Solomon, Pirjo Komulainen, Teemu Paajanen, Riitta Antikainen, Miia Kivipelto, Hilkka Soininen, Rainer Rauramaa
Cardiorespiratory Fitness and Cognition: Longitudinal Associations in the FINGER Study
Abstract: Background: Previous studies have found positive associations between cardiorespiratory fitness (CRF) and cognitive performance in older people but data are inconsistent and have methodological limitations. Objective: Our aim was to study the longitudinal associations of CRF with executive functions, processing speed and memory as well as with the overall cognitive function in older people at risk for cognitive impairment. Methods: Participants (n=421), mean age 69.0, were a sub-sample of The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). To be eligible, individuals were required to be 60–77 years old with a CAIDE (Cardiovascular Risk Factors, Aging and Dementia) Dementia Risk Score of at least 6 points and cognition at mean level or slightly lower than expected for age. CRF was assessed as peak oxygen uptake (VO2peak, L/min) measured directly in a symptom-limited maximal exercise test on cycle ergometer at baseline and at 24 months. Cognitive performance was assessed using an extensive neuropsychological test battery (NTB) at baseline and at 24 months. NTB data were standardized to Z scores, and analyzed with the linear mixed model. Results: Over two years, VO2peak was associated with NTB total score (β=0.12, p=0.01), executive functions (β=0.16, p=0.01), and processing speed (β=0.25, p<0.001), but not with memory (β=0.11, p=0.12). Conclusion: Over two years follow-up, CRF was associated with executive functions and processing speed, and was related also to the overall cognitive function.

Pages 969-981
Jason Brandt, Alison Buchholz, Bobbie Henry-Barron, Diane Vizthum, Dimitrios Avramopoulos, Mackenzie C. Cervenka
Preliminary Report on the Feasibility and Efficacy of the Modified Atkins Diet for Treatment of Mild Cognitive Impairment and Early Alzheimer’s Disease
Abstract: Ketone bodies, the products of fat metabolism, are a source of energy for the brain and are available even when glucose supplies are inadequate (such as with severe carbohydrate deprivation) or its metabolism is faulty (as it is in Alzheimer’s disease). This phase I/II randomized clinical trial examined the feasibility of using a modified Atkins diet (MAD) to induce ketogenesis in persons with mild cognitive impairment (MCI) or early AD, and the effect of this diet on memory and other clinical outcomes. In the first 2.5 years of active recruitment, only 27 eligible and willing patients enrolled. After extensive assessment and education, they and their study partners were randomly assigned for 12 weeks to either the MAD or the National Institute on Aging (NIA) recommended diet for seniors. As of April 2018, 9 patients in the MAD arm and 5 in the NIA arm have completed the trial. In spite of extensive teaching, coaching, and monitoring, adherence to both diets was only fair. Among those in the MAD arm who generated at least trace amounts of urinary ketones, there was a large (effect size = 0.53) and statistically significant (p = 0.03) increase in Memory Composite Score between the baseline and week-6 assessment. MAD participants also reported increased energy between baseline and week-6 assessment. Despite challenges to implementing this trial, resulting in a small sample, our preliminary data suggest that the generation of even trace ketones might enhance episodic memory and patient-reported vitality in very early AD.

Pages 983-990
Sung Lee*, Trusha Parekh*, Sarah M. King, Bruce Reed, Helena C. Chui, Ronald M. Krauss, Hussein N. Yassine *These authors contributed equally to this work.
Low-Density Lipoprotein Particle Size Subfractions and Cerebral Amyloidosis
Abstract: Cerebral beta-amyloidosis (CA) is a condition in which amyloid-β (Aβ) proteins are deposited in the cerebral cortex and is a predictor of Alzheimer’s disease (AD). The Aging Brain Study (ABS) investigated risk factors for CA in persons with diabetes and dyslipidemia. In the ABS, we identified that greater levels of LDL cholesterol and lower levels of HDL cholesterol were associated with increased CA. LDL particles comprise multiple species of varying size, density, and protein composition. For example, within a lipoprotein profile characteristic for persons with obesity and diabetic dyslipidemia, larger LDL particles have a greater ApoE to ApoB ratio, enhancing their binding affinity to LDL receptors. The goal of this study was to identify LDL particles that associate with CA in ABS. LDL particle size fractions were measured by ion mobility in plasma samples of 58 participants (40 women and 18 men). CA was assessed using Pittsburgh Compound B index-Positron Emission Tomography (PiB-PET) imaging. Among the LDL subfractions, greater plasma levels of large LDL particles were significantly associated with greater cerebral amyloidosis and lower hippocampal volumes independent of LDL cholesterol or triglyceride levels. Since Aβ is cleared by the LDL receptor family, such as lipoprotein-like receptor 1 (LRP1), one potential mechanism for our findings is competition between ApoE enriched larger LDL particles and brain-derived Aβ on hepatic Aβ clearance and degradation. We conclude that assessing larger LDL particles in persons with atherogenic dyslipidemia may provide a mechanistic biomarker for the extent of CA.

Pages 991-1011
Adam L. Orr*, Chaeyoung Kim*, David Jimenez-Morales, Billy W. Newton, Jeffrey R. Johnson, Nevan J. Krogan, Danielle L. Swaney, Robert W. Mahley (Handling Associate Editor: Russell Swerdlow) *These authors contributed equally to this work.
Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function
Abstract: Apolipoprotein (apo) E4, the major genetic risk factor for Alzheimer’s disease (AD), alters mitochondrial function and metabolism early in AD pathogenesis. When injured or stressed, neurons increase apoE synthesis. Because of its structural difference from apoE3, apoE4 undergoes neuron-specific proteolysis, generating fragments that enter the cytosol, interact with mitochondria, and cause neurotoxicity. However, apoE4’s effect on mitochondrial respiration and metabolism is not understood in detail. Here we used biochemical assays and proteomic profiling to more completely characterize the effects of apoE4 on mitochondrial function and cellular metabolism in Neuro-2a neuronal cells stably expressing apoE4 or apoE3. Under basal conditions, apoE4 impaired respiration and increased glycolysis, but when challenged or stressed, apoE4-expressing neurons had 50% less reserve capacity to generate ATP to meet energy requirements than apoE3-expressing neurons. ApoE4 expression also decreased the NAD+/NADH ratio and increased the levels of reactive oxygen species and mitochondrial calcium. Global proteomic profiling revealed widespread changes in mitochondrial processes in apoE4 cells, including reduced levels of numerous respiratory complex subunits and major disruptions to all detected subunits in complex V (ATP synthase). Also altered in apoE4 cells were levels of proteins related to mitochondrial endoplasmic reticulum–associated membranes, mitochondrial fusion/fission, mitochondrial protein translocation, proteases, and mitochondrial ribosomal proteins. ApoE4-induced bioenergetic deficits led to extensive metabolic rewiring, but despite numerous cellular adaptations, apoE4-expressing neurons remained vulnerable to metabolic stress. Our results provide insights into potential molecular targets of therapies to correct apoE4-associated mitochondrial dysfunction and altered cellular metabolism.

Pages 1013-1027
Tianyi Yan, Yonghao Wang, Zizheng Weng ,Wenying Du, Tiantian Liu, Duanduan Chen, Xuesong Li, Jinglong Wu, Ying Han
Early-Stage Identification and Pathological Development of Alzheimer’s Disease Using Multimodal MRI
Abstract: Alzheimer’s disease (AD) is one of the most common progressive and irreversible neurodegenerative diseases. The study of the pathological mechanism of AD and early-stage diagnosis is essential and important. Subjective cognitive decline (SCD), the first at-risk stage of AD occurring prior to amnestic mild cognitive impairment (aMCI), is of great research value and has gained our interest. To investigate the entire pathological development of AD pathology efficiently, we proposed a machine learning classification method based on a multimodal support vector machine (SVM) to investigate the structural and functional connectivity patterns of the three stages of AD (SCD, aMCI, and AD). Our experiments achieved an accuracy of 98.58% in the AD group, 97.76% in the aMCI group, and 80.24% in the SCD group. Moreover, in our experiments, we identified the most discriminating brain regions, which were mainly located in the default mode network and subcortical structures (SCS). Notably, with the development of AD pathology, SCS regions have become increasingly important, and structural connectivity has shown more discriminative power than functional connectivity. The current study may shed new light on the pathological mechanism of AD and suggests that whole-brain connectivity may provide potential effective biomarkers for the early-stage diagnosis of AD.

Pages 1029-1038
Brenna Cholerton, Michael W. Weiner, Rachel L. Nosheny, Kathleen L. Poston, R. Scott Mackin, Lu Tian, J. Wesson Ashford, Thomas J. Montine
Cognitive Performance in Parkinson’s Disease in the Brain Health Registry
Abstract: The study of cognition in Parkinson’s disease (PD) traditionally requires exhaustive recruitment strategies. The current study examines data collected by the Brain Health Registry (BHR) to determine whether ongoing efforts to improve the recruitment base for therapeutic trials in Alzheimer’s disease may be similarly effective for PD research, and whether online cognitive measurements can discriminate between participants who do and do not report a PD diagnosis. Participants enrolled in the BHR (age ≥ 50) with self-reported PD data and online cognitive testing available were included (n=11,813). Associations between baseline cognitive variables and diagnostic group were analyzed using logistic regression. Linear mixed effects models were used to analyze longitudinal data. A total of 634 participants reported PD diagnosis at baseline with no self-reported cognitive impairment and completed cognitive testing. Measures of visual learning and memory, processing speed, attention, and working memory discriminated between self-reported PD and non-PD participants after correcting for multiple comparisons (p values<0.006). Scores on all cognitive tests improved over time in PD and controls with the exception of processing speed, which remained stable in participants with PD while improving in those without. We demonstrate that a novel online approach to recruitment and longitudinal follow-up of study participants is effective for those with self-reported PD, and that significant differences exist between those with and without a reported diagnosis of PD on computerized cognitive measures. These results have important implications for recruitment of participants with PD into targeted therapeutic trials or large-scale genetic and cognitive studies.

Pages 1039-1049
Jennifer L. Campos, Fiona Höbler, Etty Bitton, Tammy Labreche, Katherine S. McGilton, Walter Wittich (Handling Associate Editor: Manuel Montero-Odasso)
Screening for Vision Impairments in Individuals with Dementia Living in Long-Term Care: A Scoping Review
Abstract: Vision impairments are prevalent, but underdiagnosed in individuals with dementia living in long-term care (LTC). Effective screening tools could identify remediable vision problems. This scoping review was conducted to identify vision screening tests used with individuals with dementia and assesses their suitability for administration by nurses in LTC. A literature search using the Arksey and O’Malley (2005) method included research articles, conference proceedings, and dissertations. Data were included from participants over 65 years of age with a diagnosis of probable dementia. A panel of vision experts evaluated the suitability of the candidate vision tests. The search yielded 179 publications that met the inclusion criteria. Of 134 vision tests that were identified, 19 were deemed suitable for screening by nurses in LTC. Tests screened for acuity (12), visual field (1), anatomy (2), color vision (2), and general visual abilities (2). Tests were excluded because of complexity of interpretation (90), need for specialized training (83), use in research only (57), need for specialized equipment (54), not assessing visual function (44), long test duration (21), uncommonness (13), and needing an act reserved for specialists (7). Psychometric properties were not often reported for tests. Few of the tests identified had been validated for use with individuals with dementia. Based on our review, few tests were deemed suitable for use by nurses to assess this population in LTC. Identifying appropriate tools to screen vision in individuals with dementia is a necessary first step to interventions that could potentially improve functioning and quality of life.

Pages 1051-1059
Lingyan Zhu, Li Gong, Tianlun Yang, Xiangwei Xiao (Handling Associate Editor: Yong Guo)
Calpastatin Mediates Development of Alzheimer’s Disease in Diabetes
Abstract: Aged people have a high chance to develop two prevalent diseases, diabetes and Alzheimer’s disease (AD), which are characterized with hyperglycemia and neurodegeneration, respectively. Interestingly, recent evidence suggest that diabetes is a predisposing factor for AD. Nevertheless, the mechanisms underlying the association of diabetes with AD remain poorly defined. Here, we studied the effects of diabetes on AD in mice. The APP-PS1 mouse, an AD-prone strain, was administrated with streptozotocin (STZ) to destroy 75% beta cell mass to induce sustained hyperglycemia. We found that STZ-treated APP-PS1 mice exhibited poorer performance in the social recognition test, Morris water maze, and plus-maze discriminative avoidance task, compared to saline-treated normoglycemic APP-PS1 mice, likely resulting from increases in brain deposition of amyloid-β peptide aggregates (Aβ). Since formation of Aβ is known to be induced by protein hyperphosphorylation mediated by calpain (CAPN)-induced cleavage of p35 into p25, we examined levels of these proteins in mouse brain. We detected not only increased p35-to-p25 conversion, but also enhanced CAPN1 activity via increased protein but not mRNA levels. The internal CAPN1 inhibitor, calpastatin (CAST), was downregulated in STZ-treated APP-PS1 mouse brain, as a basis for the increase in CAPN1. In vitro, a human neuronal cell line, HCN-2, increased CAPN1 activity and downregulated CAST levels when incubated for 8 days in high glucose level, resulting in increased cell apoptosis. Together, these data suggest that chronic hyperglycemia may promote AD development through downregulating CAST.

Pages 1061-1069
Chloé Manca, Lucie Hopes, Anna Kearney-Schwartz, Véronique Roch, Gilles Karcher, Cédric Baumann, Pierre-Yves Marie, Catherine Malaplate-Armand, Thérèse Rivasseau Jonveaux, Antoine Verger
Assessment of 18F-Florbetaben Amyloid PET Imaging in Patients with Suspected Alzheimer’s Disease and Isolated Increase in Cerebrospinal Fluid Tau Proteins
Abstract: Background/Objective: The aim of this study was to assess, in routine, the rates with which an amyloid deposition was documented by 18F-florbetaben PET in patients with suspected Alzheimer’s disease (AD) but with isolated increases in cerebrospinal fluid (CSF) tau-protein concentrations, and the subsequent impact of these PET results on medical management. Methods: This prospective study included 34 patients with mild neurocognitive disorders (MND) and suspected AD (73±9 years, 16 women) and with abnormal CSF concentrations in total-tau (T-tau) and/or phosphorylated-tau (P-tau) proteins but normal Aβ42 concentration and Aβ42/Aβ40 ratio. These patients were referred to 8F-florbetaben PET from which the PET-related changes in the confidence for AD diagnosis (low, intermediate, or high) and treatments were reported. Results: The PET examinations were positive for amyloid deposition (brain amyloid plaque load, BAPL score >1) in none of the 9 patients with an increase in only T-tau proteins and in 8 among the 25 (32%) with an increase in P-tau proteins (one BAPL score of 2 and seven BAPL scores of 3). Knowledge of the PET results was associated with subsequent changes in diagnostic confidence in 44% of patients (15/34) and in the intention-to-treat with a cholinesterase inhibitor drug in 18% (6/34). Conclusion: In patients with suspected AD and isolated increase in CSF tau protein concentrations, an amyloid deposition is documented by 18F-florbetaben PET in as much as one third of cases when the concentration of P-tau is abnormal, and PET results are associated with significant further changes in medical management.

Pages 1071-1083
Erin J. Aiello Bowles, Paul K. Crane, Rod L. Walker, Jessica Chubak, Andrea Z. LaCroix, Melissa L. Anderson, Dori Rosenberg, C. Dirk Keene, Eric B. Larson (Handling Associate Editor: Ozioma Okonkwo)
Cognitive Resilience to Alzheimer’s Disease Pathology in the Human Brain
Abstract: Background: Past research has focused on risk factors for developing dementia, with increasing recognition of “resilient” people who live to old age with intact cognitive function despite pathological features of Alzheimer’s disease (AD). Objective: To evaluate demographic factors, mid-life characteristics, and non-AD neuropathology findings that may be associated with cognitive resilience to AD pathology. Methods: We analyzed data from 276 autopsy cases with intermediate or high levels of AD pathology from the Adult Changes in Thought study. We defined cognitive resilience as having Cognitive Abilities Screening Instrument scores ≥86 within two years of death and no clinical dementia diagnosis; non-resilient people had dementia diagnoses from AD or other causes before death. We compared mid-life characteristics, demographics, and additional neuropathology findings between resilient and non-resilient people. We used multivariable logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for being resilient compared to not being resilient adjusting for demographic and neuropathology factors. Results: We classified 68 (25%) people as resilient and 208 (75%) as not resilient. A greater proportion of resilient people had a college degree (50%) compared with non-resilient (32%, p=0.01). The odds of being resilient were significantly increased among people with a college education (OR=2.01, 95%CI=1.01-3.99) and significantly reduced among people with additional non-AD neuropathology findings such as hippocampal sclerosis (OR=0.28, 95%CI=0.09-0.89) and microinfarcts (OR=0.34, 95%CI=0.15-0.78). Conclusion: Increased education and absence of non-AD pathology may be independently associated with cognitive resilience, highlighting the importance of evaluating co-morbid factors in future research on mechanisms of cognitive resilience.

Pages 1085-1094
Michelle S. Goodman, Reza Zomorrodi, Sanjeev Kumar, Mera S. Barr, Zafiris J. Daskalakis, Daniel M. Blumberger, Corinne E. Fischer, Alastair Flint, Linda Mah, Nathan Herrmann, Bruce G. Pollock, Christopher R. Bowie, Benoit H. Mulsant, Tarek K. Rajji for PACt-MD Study Group
Changes in Theta but not Alpha Modulation Are Associated with Impairment in Working Memory in Alzheimer’s Disease and Mild Cognitive Impairment
Abstract: While several studies have found that neural oscillations play a key role in the functioning of working memory, the nature of aberrant oscillatory activity underlying working memory impairments in Alzheimer’s disease (AD) and mild cognitive impairment (MCI) remains largely unexplored. These individuals often display structural alterations in brain regions and pathways involved in working memory processes and therefore may also display altered oscillatory activity during memory activation. Electroencephalographic (EEG) activity was recorded during the N-back working memory task in three groups: AD (n=29), MCI (n=100), and healthy controls (HCs; n=40). Theta (4-7 Hz) and alpha (7.5-12 Hz) modulation was measured in response to the stimulus presentation during correct and incorrect responses. This modulation represents the change in EEG activity associated with the stimulus onset and was measured as a ratio of post stimulus power to pre stimulus power. We also assessed the relationship between change in oscillatory power and working memory performance. Compared to HCs, the AD group demonstrated the lowest working memory accuracy and a smaller theta ratio for correct responses on the 2-back condition; the MCI group demonstrated a smaller theta ratio for correct responses on the 3-back condition. Finally, we observed that the theta ratio, but not the alpha ratio, was a significant predictor of working memory performance in the three groups for all conditions. Taken together, these behavioral and electrophysiological results suggest that in addition to impairments in working memory performance, modulation of theta, but not alpha power, may be impaired in MCI and AD.

Pages 1095-1111
Long-Long Cao, Pei-Pei Guan, Yun-Yue Liang, Xue-Shi Huang, Pu Wang (Handling Associate Editor: Marong Fang)
Cyclooxygenase-2 Is Essential for Mediating the Effects of Calcium Ions on Stimulating Phosphorylation of Tau at the Sites of Ser 396 and Ser 404
Abstract: Alzheimer’s disease (AD) is reported to be associated with the accumulation of calcium ions (Ca2+), which is responsible for the phosphorylation of tau. Although a series of evidence have demonstrated this phenomenon, the inherent mechanisms remain unknown. Using tauP301S and cyclooxygenase-2 (COX-2) transgenic mice and neuroblastoma (n)2a cells as in vivo and in vitro experimental models, we found that Ca2+ stimulates the phosphorylation of tau by activating COX-2 in a prostaglandin (PG) E2-dependent EP receptor-activating manner. Specifically, Ca2+ incubation stimulated COX-2 and PGE2 synthase activity, microsomal PGE synthase 1 and the synthesis of PGE2 by activating the transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells in n2a cells. Elevated levels of PGE2 were responsible for phosphorylating tau in an EP-1, -2, and -3 but not EP4-dependent glycogen synthase kinase 3-activating manner. These observations were corroborated by results that showed tau was phosphorylated when it colocalized with activated COX-2 in tauP301S and COX-2 transgenic mice or n2a cells. To further validate these observations, treatment of mice with the COX-2 inhibitor rofecoxib decreased the phosphorylation of tau via EP1-3 but not EP4. Collectively, our observations fill the gaps between Ca2+ and the phosphorylation of tau in a COX-2-dependent mechanism, which potentially provides therapeutic targets for combating AD.

Pages 1113-1123
Lilian Calderón-Garcidueñas, Partha S. Mukherjee, Randy J. Kulesza, Ricardo Torres-Jardón, Jacqueline Hernández-Luna, Rodrigo Ávila-Cervantes, Edgar Macías-Escobedo, Oscar González-González, Angélica González-Maciel, Kevin García-Hernández, Ariatna Hernández-Castillo, Research UVM Group, Rodolfo Villarreal-Ríos
Mild Cognitive Impairment and Dementia Involving Multiple Cognitive Domains in Mexican Urbanites
Abstract: Exposures to fine particulate matter PM2.5 and ozone O3 are associated with Alzheimer’s disease (AD) risk. Mexico City residents have lifetime exposures to PM2.5 and O3 above annual USEPA standards and their brains contain high redox, combustion, and friction-derived magnetite nanoparticles. AD pathological changes with subcortical pre-tangle stages in infancy and cortical tau pre-tangles, NFT Stages I-II, and amyloid phases 1-2 are identified by the 2nd decade. Given their AD continuum, a reliable identification of cognitive impairment is of utmost importance. The Montreal Cognitive Assessment (MoCA) was administered to 517 urbanites, age 21.60±5.88 years, with 13.69±1.28 formal education years, in Mexican PM2.5 polluted cities. MoCA score was 23.92±2.82, and 24.7% and 30.3% scored ≤ 24 and ≤22, respectively (MCI≤24, AD≤22). Cognitive deficits progressively targeted Visuospatial, Executive, Language, and Memory domains, body mass index (BMI) impacting total scores negatively (p=0.0008), aging driving down Executive, Visuospatial, and Language index scores (p<0.0001, 0.0037, and 0.0045), and males performing better in Executive tasks. Average age for AD MoCA scores was 22.38±7.7 years. Residency in polluted cities is associated with progression of multi-domain cognitive impairment affecting 55% of Mexican seemingly healthy youth. Normal BMI ought to be a neuroprotection goal. MoCA provides guidance for further mandatory neuropsychological testing in young populations. Identifying and lowering key neurotoxicants impacting neural risk trajectories in the developing brain and monitoring cognitive performance would greatly facilitate multidisciplinary early diagnosis and prevention of AD in high risk young populations. Cognitive deficits hinder development of those representing the force moving the country in future years.

Pages 1125-1150
Dhiraj Kumar, Pravir Kumar
Integrated Mechanism of Lysine 351, PARK2, and STUB1 in AβPP Ubiquitination
Abstract: Intracellular accumulation of aggregated amyloid-β, misfolded and non-functional proteinopathy, is the hallmark feature in Alzheimer’s disease (AD). There are several mechanisms to clear the amyloid burden in a cell, including transcytosis across the blood-brain barrier, immune mediated, lysosomal pathway associated autophagy, enzymatic degradation by insulin degrading enzyme/neprilysin, and the proteasomal pathway. Among them, the ubiquitin proteasome system (UPS) is playing a critical role to prevent the intracellular amyloid-β deposition and to clear off the cellular burden in association with ubiquitin E3 ligase enzymes in AD. For ubiquitination, lysine moiety in a protein acts like a docking site for the attachment of ubiquitin molecule and different lysine residues act differently in this reaction. Therefore, it is pertinent to understand and link the role of various lysine residues along with their effector molecules, for instance, E3 ligases PARK2 and STUB1 in the ubiquitination cascade. Herein, we 1) modeled the structure of AβPP and determined its topologies and studied the impact of lysine residues in AβPP stability, 2) reported K351 as the most promising target for AβPP ubiquitination, 3) investigated the plausible role of lysine residues in non-covalent interactions mediated ubiquitin positioning in the ubiquitination, 4) detected conserved amino acids that is crucial for AβPP ubiquitination, and 5) identified the key ubiquitination enzymes and their interaction network playing major role in the ubiquitination of AβPP.

Pages 1151-1159
Charisse Somers*, Piotr Lewczuk*, Anne Sieben, Christine Van Broeckhoven, Peter Paul De Deyn, Johannes Kornhuber, Jean-Jacques Martin, Maria Bjerke#, Sebastiaan Engelborghs# (Handling Associate Editor: Henrik Zetterberg) *These authors contributed equally to this work. #Joint last authors
Validation of the Erlangen Score Algorithm for Differential Dementia Diagnosis in Autopsy-Confirmed Subjects
Abstract: Background: Despite decades of research on the optimization of the diagnosis of Alzheimer’s disease (AD), its biomarker-based diagnosis is being hampered by the lack of comparability of raw biomarker data. In order to overcome this limitation, the Erlangen Score (ES), among other approaches, was set up as a diagnostic¬-relevant interpretation algorithm. Objective: To validate the ES algorithm in a cohort of neuropathologically confirmed cases with AD (n=106) and non-AD dementia (n=57). Methods: Cerebrospinal fluid (CSF) biomarker concentrations of Aβ1-42, T-tau, and P-tau181 were measured with commercially available single analyte ELISA kits. Based on these biomarkers, ES was calculated as previously reported. Results: This algorithm proved to categorize AD in different degrees of likelihood, ranging from neurochemically “normal”, “improbably having AD”, “possibly having AD”, to “probably having AD”, with a diagnostic accuracy of 74% using the neuropathology as a reference. Conclusion: The ability of the ES to overcome the high variability of raw CSF biomarker data may provide a useful diagnostic tool for comparing neurochemical diagnoses between different labs or methods used.

Pages 1161-1170
Hyun-Sik Yang, Jasmeer P. Chhatwal, Jishu Xu, Charles C. White, Bernard Hanseeuw, Jennifer S. Rabin, Kathryn V. Papp, Rachel F. Buckley, Aaron P. Schultz, Michael J. Properzi, Jennifer R. Gatchel, Rebecca E. Amariglio, Nancy J. Donovan, Elizabeth C. Mormino, Trey Hedden, Gad A. Marshall, Dorene M. Rentz, Keith A. Johnson, Philip L. De Jager, Reisa A. Sperling (Handling Associate Editor: Andrew Saykin)
An UNC5C Allele Predicts Cognitive Decline and Hippocampal Atrophy in Clinically Normal Older Adults
Abstract: Background: The UNC5C rs3846455G allele has been linked to poor cognitive resilience against age-related neuropathologies, but this association remains to be replicated, and the allele’s effect on hippocampal neurodegeneration needs to be examined. Objective: To further validate the association between rs3846455G and faster cognitive decline, especially among cognitively normal older adults, and to assess whether rs3846455G predicts accelerated hippocampal volume loss in older adults. Methods: We assessed participants in the Harvard Aging Brain Study (HABS), a longitudinal cohort study of older adults who were clinically normal at baseline. To avoid bias from population admixture, analyses were limited to participants of European descent with longitudinal neuroimaging data (n=174). Linear mixed effect models were used to examine the effect of rs3846455G on longitudinal change of the Preclinical Alzheimer Cognitive Composite (PACC) and MRI-measured bilateral hippocampal volume, adjusting for baseline amyloid-β (Aβ) measured by the cortical Pittsburgh Compound B PET distributed volume ratio. We also tested whether hippocampal atrophy mediates the association between rs3846455G and greater PACC decline through a mediation analysis. Results: rs3846455G was associated with greater PACC decline (β=-0.087/year, 95% CI -0.169 to -0.005, p=0.039) after controlling for baseline Aβ. Further, rs3846455G predicted accelerated hippocampal atrophy after controlling for baseline Aβ (β=-57.3 mm3/year, 95% CI -102.8 to -11.9, p=0.014). The association between rs3846455G and greater PACC decline was partially mediated by accelerated hippocampal atrophy (mediated effect (relative scale)=-0.014, 95% CI -0.032 to -6.0×10-4, p=0.039). Conclusion: UNC5C rs3846455G predicts greater cognitive decline and accelerated hippocampal atrophy in clinically normal older adults.

Pages 1171-1184
Sheng-Lan Zhou, Chen-Chen Tan, Xiao-He Hou, Xi-Peng Cao, Lan Tan, Jin-Tai Yu (Handling Associate Editor: Ling-Qiang Zhu)
TREM2 Variants and Neurodegenerative Diseases: A Systematic Review and Meta-Analysis
Abstract: TREM2 (triggering receptor expressed on myeloid cells 2) gene variants were reported to increase the risk of Alzheimer's disease (AD) and even other neurodegenerative diseases (frontotemporal dementia (FTD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS)), but so far, no definite conclusion has been drawn. The aim of our systematic review and meta-analysis was to investigate the role of TREM2 variants in neurodegenerative diseases. A total of 39 papers (including 26 case-control studies and 13 case reports) were retrieved from PubMed, MEDLINE, EMBASE, and the Cochrane library in this study. A fixed effect model was used to pool results in the analysis. Three variants in TREM2 (rs75932628 (R47H), rs2234255 (H157Y), and rs143332484 (R62H)) were significantly associated with AD risk, but the similar associations between rs104894002 (Q33X), rs2234253 (T96K), rs142232675 (D87N), rs2234256 (L211P), and AD were not proven. Rs75932628 also increased risk of PD in North Americans and FTD, but not PD in Europeans or ALS. In the systematic review, 12 biallelic TREM2 mutations (e.g., rs104894002, rs201258663 (T66M), and rs386834144, etc.) have been described to cause Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL) in 14 families. And homozygous mutations also have been reported to cause FTD without typical bone phenotypes in 7 families. This study demonstrates that multiple variants in TREM2 have association with the onset of AD, FTD, and PD in North Americans and also play a key role in the phenotypes of the rare familial genetic disorder.

Pages 1185-1192
Blanka Klimova, Kamil Kuca, Martin Valis, Jakub Hort
Traditional Chinese Medicine as an Effective Complementary Non-Pharmacological Approach to Mild Cognitive Impairment: A Call for Collaboration
Abstract: Currently, there is an increase in the number of older people worldwide. Unfortunately, this demographic trend causes a rise in aging diseases, one of which is dementia. Recent research studies have indicated that mild cognitive impairment (MCI) may serve as a predictor of dementia in many patients. At present, there is no pharmacological treatment against MCI. Therefore, there is constant search for novel alternative non-pharmacological approaches to improve MCI. One of the effective complementary emerging approaches seems to be Traditional Chinese Medicine (TCM), which is nowadays becoming quite popular in the treatment of different disorders. The purpose of this study is to explore the efficacy of TCM as an effective complementary non-pharmacological tool for the improvement and treatment of MCI in older adults. The methods used for this review study included a literature search in the world’s databases: Web of Science, Scopus, PubMed, and Springer. Afterwards, methods of comparison and evaluation of the findings from the selected studies were applied. The results of this review study indicate that TCM might be a beneficial complementary non-pharmacological approach to the improvement and treatment of MCI in older individuals. Nevertheless, more rigorously designed quality randomized clinical trials should be conducted in order to conclusively prove efficacy of TCM on the improvement of MCI among older population groups. In addition, there is an urgent call for a functional collaboration between western and eastern medicinal approaches, which could contribute to the enhancement of the overall quality of life of these aging population groups.

Pages 1193-1209
Kevin N. Hascup, Jesse Britz, Caleigh A. Findley, Shelley Tischkau, Erin R. Hascup
LY379268 Does Not Have Long-Term Procognitive Effects nor Attenuate Glutamatergic Signaling in AβPP/PS1 Mice
Abstract: Chronically elevated basal glutamate levels are hypothesized to attenuate detection of physiological signals thereby inhibiting memory formation and retrieval, while inducing excitotoxicity-mediated neurodegeneration observed in Alzheimer’s disease (AD). However, current medication targeting the glutamatergic system, such as memantine, shows limited efficacy and is unable to decelerate disease progression, possibly because it modulates postsynaptic N-methyl-D-aspartate receptors rather than glutamate release or clearance. To determine if decreasing presynaptic glutamate release leads to long-term procognitive effects, we treated AβPP/PS1 mice with LY379268 (3.0 mg/kg; i.p.), a metabotropic glutamate receptor (mGluR)2/3 agonist from 2-6 months of age when elevated glutamate levels are first observed but cognition is unaffected. C57BL/6J genetic background control mice and another cohort of AβPP/PS1 mice received normal saline (i.p.) as vehicle controls. After 6 months off treatment, mice receiving LY379268 did not show long-term improvement as assessed by the Morris water maze (MWM) spatial learning and memory paradigm. Following MWM, mice were isoflurane anesthetized and a glutamate selective microelectrode was used to measure in vivo basal and stimulus-evoked glutamate release and clearance independently from the dentate, CA3, and CA1 hippocampal subregions. Immunohistochemistry was used to measure hippocampal astrogliosis and plaque pathology. Similar to previous studies, we observed elevated basal glutamate, stimulus evoked glutamate release, and astrogliosis in AβPP/PS1 vehicle mice versus C57BL/6J mice. Treatment with LY379268 did not attenuate these responses nor diminish plaque pathology. The current study builds upon previous research demonstrating hyperglutamatergic hippocampal signaling in AβPP/PS1 mice; however, long-term therapeutic efficacy of LY379268 in AβPP/PS1 was not observed.

Pages 1211-1228
Yen Ying Lim, Nawaf Yassi, Lisa Bransby, Michael Properzi, Rachel Buckley
The Healthy Brain Project: An Online Platform for the Recruitment, Assessment, and Monitoring of Middle-Aged Adults at Risk of Developing Alzheimer’s Disease
Abstract: Background: Characterizing the earliest demonstrable cognitive decline in middle-aged adults at risk of Alzheimer’s disease (AD) will allow for the better understanding of the early disease trajectory, and the provision of therapies prior to clinical symptom onset. We developed an online platform—healthybrainproject.org.au (Healthy Brain Project; HBP)—to recruit, assess, and monitor at-risk middle-aged adults. Objective: Describe the HBP methodology and report baseline characteristics and adherence indices of participants. Methods: Between February 2017 and August 2018, 4,000 community-based middle-aged Australian adults with a first or second-degree family history of dementia enrolled at our website (healthybrainproject.org.au). Participants were directed to complete five modules: “Basics”, “Health History”, “How You Feel”, “How You Live”, and “How You Think”. Of these, 1,816 participants have received a saliva sampling kit for genetic analysis. Results: Participants had a mean (SD) age of 55.5 (6.8) years, 11.8 (3.4) years of education, and annual personal income of AUD$68,830 ($35,044). Participants took 26.4 (49.7) days after enrolment to complete questionnaires and cognitive tests. Most participants were from Victoria (63%), followed by New South Wales (14%). Most participants (74%) were female and 76% identified as Caucasian. Approximately 36% of participants completed all modules (n=1,450), and 56% (n=2,221) completed 4 out of 5 modules. Most saliva kits (89%) had been returned. Conclusion: The HBP joins a handful of online registries worldwide that assess and monitor a large cohort of individuals at risk of AD. Our study extends on these efforts by focusing on midlife, where the earliest signs of cognitive and pathological changes will manifest.

Pages 1229-1241
Paul Zhutovsky, Everard G.B. Vijverberg, Willem B. Bruin, Rajat M. Thomas, Mike P. Wattjes, Yolande A.L. Pijnenburg, Guido A. van Wingen, Annemiek Dols (Handling Associate Editor: Eino Solje)
Individual Prediction of Behavioral Variant Frontotemporal Dementia Development Using Multivariate Pattern Analysis of Magnetic Resonance Imaging Data
Abstract: Background: Patients with behavioral variant of frontotemporal dementia (bvFTD) initially may only show behavioral and/or cognitive symptoms that overlap with other neurological and psychiatric disorders. The diagnostic accuracy is dependent on progressive symptoms worsening and frontotemporal abnormalities on neuroimaging findings. Predictive biomarkers could facilitate the early detection of bvFTD. Objective: To determine the prognostic accuracy of clinical and structural MRI data using a support vector machine (SVM) classification to predict the 2-year clinical follow-up diagnosis in a group of patients presenting late-onset behavioral changes. Methods: Data from 73 patients were included and divided into probable/definite bvFTD (n = 18), neurological (n = 28), and psychiatric (n = 27) groups based on 2-year follow-up diagnosis. Grey-matter volumes were extracted from baseline structural MRI scans. SVM classifiers were used to perform three binary classifications: bvFTD versus neurological and psychiatric, bvFTD versus neurological, and bvFTD versus psychiatric group(s), and one multi-class classification. Classification performance was determined for clinical and neuroimaging data separately and their combination using 5-fold cross-validation. Results: Accuracy of the binary classification tasks ranged from 72-82% (p < 0.001) with adequate sensitivity (67-79%), specificity (77-88%), and area-under-the-receiver-operator-curve (0.80-0.9). Multi-class accuracy ranged between 55-59% (p < 0.001). The combination of clinical and voxel-wise whole brain data showed the best performance overall. Conclusion: These results show the potential for automated early confirmation of diagnosis for bvFTD using machine learning analysis of clinical and neuroimaging data in a diverse and clinically relevant sample of patients.

Pages 1243-1255
Emmanuelle Boscher, Thomas Husson, Olivier Quenez, Annie Laquerrière, Florent Marguet, Kevin Cassinari, David Wallon, Olivier Martinaud, Camille Charbonnier, Gaël Nicolas, Jean-François Deleuze, Anne Boland, Mark Lathrop, Thierry Frébourg, FREX Consortium, Dominique Campion, Sébastien S. Hébert*, Anne Rovelet-Lecrux* *These senior authors contributed equally to this work.
Copy Number Variants in miR-138 as a Potential Risk Factor for Early-Onset Alzheimer’s Disease
Abstract: Early-onset Alzheimer’s disease (EOAD) accounts for 5-10% of all AD cases, with a heritability ranging between 92% to 100%. With the exception of rare mutations in APP, PSEN1, and PSEN2 genes causing autosomal dominant EOAD, little is known about the genetic factors underlying most of the EOAD cases. In this study, we hypothesized that copy number variations (CNVs) in microRNA (miR) genes could contribute to risk for EOAD. miRs are short non-coding RNAs previously implicated in the regulation of AD-related genes and phenotypes. Using whole exome sequencing, we screened a series of 546 EOAD patients negative for autosomal dominant EOAD mutations and 597 controls. We identified 86 CNVs in miR genes of which 31 were exclusive to EOAD cases, including a duplication of the MIR138-2 locus. In functional studies in human cultured cells, we could demonstrate that miR-138 overexpression leads to higher Aβ production as well as tau phosphorylation, both implicated in AD pathophysiology. These changes were mediated in part by GSK-3β and FERMT2, a potential risk factor for AD. Additional disease-related genes were also prone to miR-138 regulation including APP and BACE1. This study suggests that increased gene dosage of MIR138-2 could contribute to risk for EOAD by regulating different biological pathways implicated in amyloid and tau metabolism. Additional studies are now required to better understand the role of miR-CNVs in EOAD.

Pages 1257-1271
Desheng Wang (Handling Associate Editor: Othman Ghribi)
Tumor Necrosis Factor-Alpha Alters Electrophysiological Properties of Rabbit Hippocampal Neurons
Abstract: Previous studies have shown tumor necrosis factor-alpha (TNF-α) may impact neurodegeneration in Alzheimer’s disease (AD) by regulating amyloid-β and tau pathogenesis. However, it is unclear whether TNF-α has a role in a cholesterol-fed rabbit model of AD or TNF-α affects the electrophysiological properties of rabbit hippocampus. This study was designed to investigate whether long-term feeding of cholesterol diet known to induce AD pathology regulates TNF-α expression in the hippocampus and whether TNF-α would modulate electrophysiological properties of rabbit hippocampal CA1 neurons. TNF-α ELISA showed dietary cholesterol increased hippocampal TNF-α expression in a dose-dependent manner. Whole-cell recordings revealed TNF-α altered the membrane properties of rabbit hippocampal CA1 neurons, which was characterized by a decrease in after-hyperpolarization amplitudes; Field potential recordings showed TNF-α inhibited long-term potentiation but did not influence presynaptic function. Interestingly, TNF-α did not significantly affect the after-hyperpolarization amplitudes of hippocampal CA1 neurons from cholesterol fed rabbits compared to normal chow fed rabbits. In conclusion, dietary cholesterol generated an in vivo model of chronic TNF-α elevation and TNF-α may underlie the learning and memory changes previously seen in the rabbit model of AD by acting as a bridge between dietary cholesterol and brain function and directly modulating the electrophysiological properties of hippocampal CA1 neurons.

Pages 1273-1286
Jooske M.F. Boomsma, Lieza G. Exalto, Frederik Barkhof, Esther van den Berg, Jeroen de Bresser, Rutger Heinen, Anna E. Leeuwis, Niels D. Prins, Philip Scheltens, Henry C. Weinstein, Wiesje M. van der Flier, Geert Jan Biessels, on behalf of the TRACE-VCI study group
How Do Different Forms of Vascular Brain Injury Relate to Cognition in a Memory Clinic Population: The TRACE-VCI Study
Abstract: Background: Memory clinic patients frequently present with different forms of vascular brain injury due to different etiologies, often co-occurring with Alzheimer’s disease (AD) pathology. Objective: We studied how cognition was affected by different forms of vascular brain injury, possibly in interplay with AD pathology. Methods: We included 860 memory clinic patients with vascular brain injury on magnetic resonance imaging (MRI), receiving a standardized evaluation including cerebrospinal fluid (CSF) biomarker analyses (n=541). The cognitive profile of patients with different forms of vascular brain injury on MRI (moderate/severe white matter hyperintensities (WMH) (n=398), microbleeds (n=368), lacunar (n=188) and non-lacunar (n=96) infarct(s), macrobleeds (n=16)) was assessed by: 1) comparison of all these different forms of vascular brain injury with a reference group (patients with only mild WMH (n=205) without other forms of vascular brain injury), using linear regression analyses also stratified for CSF biomarker AD profile and 2) multivariate linear regression analysis. Results: The cognitive profile was remarkably similar across groups. Compared to the reference group effect sizes on all domains were

Pages 1287-1307
Pol Andrés-Benito, Ellen Gelpi, Mónica Povedano, Karina Ausín, Joaquín Fernández-Irigoyen, Enrique Santamaría, Isidro Ferrer
Combined Transcriptomics and Proteomics in Frontal Cortex Area 8 in Frontotemporal Lobar Degeneration Linked to C9ORF72 Expansion
Abstract: Background: Frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP) may appear as sporadic (sFTLD-TDP) or linked to mutations in various genes including expansions of the non-coding region of C9ORF72 (c9FTLD). Objective: Analysis of differential mRNA and protein expression in the frontal cortex in c9FLTD and evaluation with previous observations in frontal cortex in sFTLD-TDP and amyotrophic lateral sclerosis with TDP-43 inclusions. Methods: Microarray hybridization and mass spectrometry-based quantitative proteomics followed by RT-qPCR, gel electrophoresis, and western blotting in frontal cortex area 8 in 19 c9FTLD cases and 14 age- and gender-matched controls. Results: Microarray hybridization distinguish altered gene transcription related to DNA recombination, RNA splicing regulation, RNA polymerase transcription, myelin synthesis, calcium regulation, and ubiquitin-proteasome system in c9FTLD; proteomics performed in the same tissue samples pinpoints abnormal protein expression involving apoptosis, inflammation, metabolism of amino acids, metabolism of carbohydrates, metabolism of membrane lipid derivatives, microtubule dynamics, morphology of mitochondria, neuritogenesis, neurotransmission, phagocytosis, receptor-mediated endocytosis, synthesis of reactive oxygen species, and calcium signaling in c9FTLD. Conclusion: Transcriptomics and proteomics, as well as bioinformatics processing of derived data, reveal similarly altered pathways in the frontal cortex in c9FTLD, but different RNAs and proteins are identified by these methods. Combined non-targeted ‘-omics’ is a valuable approach to deciphering altered molecular pathways in FTLD provided that observations are approached with caution when assessing human postmortem brain samples.