Volume 80, Number 3, IN PRESS

Review
Guimei Zhang, Yaru Zhang, Yanxin Shen, Yongchun Wang, Meng Zhao, Li Sun (Handling Associate Editor: Jin-Tai Yu)
The Potential Role of Ferroptosis in Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is the most prevalent cause of dementia, accounting for approximately 60%-80% of all cases. Although much effort has been made over the years, the precise mechanism of AD has not been completely elucidated. Recently, great attention has shifted to the roles of iron metabolism, lipid peroxidation, and oxidative stress in AD pathogenesis. We also note that these pathological events are the vital regulators of a novel regulatory cell death, termed ferroptosis—an iron-dependent, oxidative, non-apoptotic cell death. Ferroptosis differs from apoptosis, necrosis, and autophagy with respect to morphology, biochemistry, and genetics. Mounting evidence suggests that ferroptosis may be involved in neurological disorders, including AD. Here, we review the underlying mechanisms of ferroptosis; discuss the potential interaction between AD and ferroptosis in terms of iron metabolism, lipid peroxidation, and the glutathione/glutathione peroxidase 4 axis; and describe some associated studies that have explored the implication of ferroptosis in AD.

Review
Khushnoo K. Indorewalla, Maureen K. O’Connor, Andrew E. Budson, Christina Guess (DiTerlizzi), Jonathan Jackson
Modifiable Barriers for Recruitment and Retention of Older Adult Participants from Underrepresented Minorities in Alzheimer’s Disease Research
Abstract: Clinical Alzheimer’s disease (AD) trials currently face a critical shortfall of thousands of eligible participants, which inflates the duration and cost of the clinical study as well as threatens the scientific merit of promising clinical interventions. This recruitment crisis is further compounded by the fact that underrepresented and marginalized populations—particularly those identifying as a racial or ethnic minority, those with low socioeconomic status, or living in rural areas—have been historically underrepresented in ongoing AD clinical trials despite overwhelming evidence that such populations are at increased risk for developing dementia. As a result of various recruitment barriers, current AD clinical studies frequently reflect a decreasingly representative segment of the US population, which threatens the overall generalizability of these findings. The current narrative review provides an updated examination and critique of common recruitment barriers and potential solutions, as well as a discussion of theoretical approaches that may address barriers disproportionately experienced by underrepresented communities. AD clinical researchers are encouraged to take purposive action aimed at increasing diversity of enrolled AD clinical trial cohorts by actively identifying and quantifying barriers to research participation—especially recruitment barriers and health disparities that disproportionately prevent underrepresented and marginalized populations from participating in research. Furthermore, researchers are encouraged to closely track which individuals who express interest in AD research ultimately enroll in research studies to examine whether AD research participation is appropriately representative of the intended population for whom these new and novel AD interventions are being designed.

Review
Mijoo Chung, Weon Kuu Chung
Clinical Approach of Low-Dose Whole-Brain Ionizing Radiation Treatment in Alzheimer’s Disease Dementia Patients
Abstract: Our research team recently published two relevant papers. In one study, we have seen the acute effect of low-dose ionizing irradiation (LDIR) did not reduce the amyloid-β (Aβ) protein concentration in brain tissue, yet significantly improved synaptic degeneration and neuronal loss in the hippocampus and cerebral cortex. Surprisingly, in another study, we could see late effect that the LDIR-treated mice showed significantly improved learning and memory skills compared with those in the sham group. In addition, Aβ concentrations were significantly decreased in brain tissue. Furthermore, the pro-inflammatory cytokine tumor necrosis factor-α was decreased and the anti-inflammatory cytokine transforming growth factor-β was increased in the brain tissue of 5xFAD mice treated with LDIR. Definitive clinical results for the safety and efficacy of LDIR have not yet been published and, despite the promising outcomes reported during preclinical studies, LDIR can only be applied to patients with Alzheimer's disease dementia when clinical results are made available. In addition, in the case of LDIR, additional large-scale clinical studies are necessary to determine the severity of Alzheimer's disease dementia, indications for LDIR, the total dose to be irradiated, fraction size, and intervals of LDIR treatment. The purpose of this review is to summarize the mechanism of LDIR based on existing preclinical results in a way that is useful for conducting subsequent clinical research.

Review
Yang-Yang Wang, Zhen-Ting Huang, Ming-Hao Yuan, Feng Jing, Ruo-Lan Cai, Qian Zou, Yin-Shuang Pu, Sheng-Yuan Wang, Fei Chen, Wen-Min Yi, Hui-Ji Zhang, Zhi-You Cai
Role of Hypoxia Inducible Factor-1α in Alzheimer’s Disease
Abstract: Amyloid-β (Aβ) peptides and hyperphosphorylated tau protein are the most important pathological markers of Alzheimer’s disease (AD). Neuroinflammation and oxidative stress are also involved in the development and pathological mechanism of AD. Hypoxia inducible factor-1α (HIF-1α) is a transcriptional factor responsible for cellular and tissue adaption to low oxygen tension. Emerging evidence has revealed HIF-1α as a potential medicinal target for neurodegenerative diseases. On the one hand, HIF-1α increases AβPP processing and Aβ generation by promoting β/γ-secretases and suppressing α-secretases, inactivates microglia and reduces their activity, contributes to microglia death and neuroinflammation, which promotes AD pathogenesis. On the other hand, HIF-1α could resist the toxic effect of Aβ, inhibits tau hyperphosphorylation and promotes microglial activation. In summary, this review focuses on the potential complex roles and the future perspectives of HIF-1α in AD, in order to provide references for seeking new drug targets and treatment methods for AD.

Review
He Jin, Rong Wang
Alzheimer-Associated Neuronal Thread Protein: Research Course and Prospects for the Future
Abstract: Alzheimer’s disease (AD) is the leading cause of dementia. With aging societies, the prevalence of AD is increasing dramatically worldwide. The onset of AD is often not identified, and currently no available treatments are capable of stopping the disease process and its effect on cognitive decline. Thus, well-validated biomarkers of the preclinical stages of AD are needed. Alzheimer-associated neuronal thread protein (AD7c-NTP) is a member of the neuronal thread protein family and has a molecular weight of approximately 41 kD. AD7c-NTP has been identified as a biomarker for its specifically elevated levels in putative brain domains, cerebrospinal fluid (CSF), and the urine of AD and mild cognitive impairment (MCI) patients. Since the urine test is non-invasive, easy to perform, and patients accept it more easily than other methods, the urinary AD7c-NTP concentration has been recommended as a practical diagnostic tool for diagnosing AD and MCI. AD7c-NTP has undergone nearly 25 years of research course from its initial discovery to pathological verification, multi-center clinical evaluation, improvement of detection methods, epidemiological investigation, and combined application with other biomarkers. However, as a fluid biomarker, AD7c-NTP can be detected in urine instead of the traditional biomarker sources—CSF or blood, which has made the use of AD7c-NTP as a biomarker controversial. In this article, we review the research course of AD7c-NTP and suggest directions for future research.

Short Communication
Hesam Khodadadi, Évila Lopes Salles, Abbas Jarrahi, Vincenzo Costigliola, MB Khan, Jack C. Yu, John C. Morgan, David C. Hess, Kumar Vaibhav, Krishnan M. Dhandapani, Babak Baban
Cannabidiol Ameliorates Cognitive Function via Regulation of IL-33 and TREM2 Upregulation in a Murine Model of Alzheimer’s Disease
Abstract: There is a dire need for due innovative therapeutic modalities to improve outcomes of AD patients. In this study, we tested whether cannabidiol (CBD) improves outcomes in a translational model of familial AD and to investigate if CBD regulates interleukin (IL)-33 and triggering receptor expressed on myeloid cells 2 (TREM2), which are associated with improved cognitive function. CBD was administered to 5xFAD mice, which recapitulate early onset, familial AD. Behavioral tests and immunoassays were used to evaluate cognitive and motor outcomes. Our findings suggest that CBD treatment enhanced IL-33 and TREM2 expression, ameliorated the symptoms of AD, and retarded cognitive decline.

Short Communication
Filippo Cieri*, Zhengshi Yang*, Dietmar Cordes, Jessica Z.K. Caldwell for the Alzheimer’s Disease Neuroimaging Initiative *These authors contributed equally to this work.
Sex Differences of Brain Functional Topography Revealed in Normal Aging and Alzheimer’s Disease Cohort
Abstract: We applied graph theory analysis on resting-state functional magnetic resonance imaging data to evaluate sex differences of brain functional topography in normal controls (NCs), early mild cognitive impairment (eMCI), and AD patients. These metrics were correlated with RAVLT verbal learning and memory scores. The results show NCs have better functional connectivity (FC) metrics than eMCI and AD, and NC women show worse FC metrics compared to men, despite performing better on the RAVLT. FC differences between men and women diminished in eMCI and disappeared in AD. Within women, better FC metrics relate to better RAVLT learning in NCs and eMCI groups.

Short Communication
Vanesa Pytel, Laura Hernández-Lorenzo, Laura Torre-Fuentes, Raúl Sanz, Nieves González, María Nieves Cabrera-Martín, Alfonso Delgado-Álvarez, Ulises Gómez-Pinedo, Jorge Matías-Guiu, Jordi A Matias-Guiu
Whole-Exome Sequencing and C9orf72 Analysis in Primary Progressive Aphasia
Abstract: Primary progressive aphasia (PPA) is mainly considered a sporadic disease and few studies have systematically analyzed its genetic basis. We here report the analyses of C9orf72 genotyping and whole-exome sequencing data in a consecutive and well-characterized cohort of 50 patients with PPA. We identified three pathogenic GRN variants, one of them unreported, and two cases with C9orf72 expansions. In addition, one likely pathogenic variant was found in the SQSTM1 gene. Overall, we found 12% of patients carrying pathogenic or likely pathogenic variants. These results support the genetic role in the pathophysiology of a proportion of patients with PPA.

Emma Rhodes, Philip S. Insel, Meryl A. Butters, Ruth Morin, David Bickford, Duygu Tosun, Devon Gessert, Howie J. Rosen, Paul Aisen, Rema Raman, Susan Landau, Andrew Saykin, Arthur Toga, Clifford R. Jack Jr., Michael W. Weiner, Craig Nelson, R. Scott Mackin on behalf of the Alzheimer’s Disease Neuroimaging Initiative and the ADNI Depression Project (Handling Associate Editor: Francesco Panza)
The Impact of Amyloid Burden and APOE on Rates of Cognitive Impairment in Late Life Depression
Abstract: Background: Cognitive impairment (CI) is a key feature of late life depression (LLD), but the contribution of underlying neurodegenerative pathology remains unclear. Objective: To evaluate cognitive dysfunction in LLD relative to a sample of nondepressed (ND) older adults with matched levels of memory impairment and amyloid-β (Aβ) burden. Methods: Participants included 120 LLD and 240 ND older adults matched on age, education, sex, Mini-Mental State Exam, mild cognitive impairment diagnosis, and PET Aβ burden. Results: LLD showed higher rates of impairment relative to ND with 54.6% of the LLD sample demonstrating impairment in at least one cognitive domain compared to 42.9% of controls (H = 7.13, p = 0.008). LLD had poorer performance and higher rates of impairment on Rey Auditory Verbal Learning Test learning and memory compared to controls. In the overall sample, Aβ positivity was associated with worse performance on Logical Memory I (p = 0.044), Logical Memory II (p = 0.011), and Trail Making Test – B (p = 0.032), and APOE ε4 genotype was associated with worse performance on Logical Memory I (p = 0.022); these relationships did not differ between LLD and ND. Conclusion: LLD showed higher rates of CI driven by focal deficits in verbal learning and memory. Alzheimer’s disease (AD) biomarkers were associated with worse performance on timed set-shifting and story learning and memory, and these relationships were not impacted by depression status. These findings suggest that AD may account for a portion of previously reported multi-domain CI in LLD and highlight the potential for AD to confound studies of cognition in LLD.

Sylwia Libard, Jochen Walter, Irina Alafuzoff
In vivo Characterization of Biochemical Variants of Amyloid-β in Subjects with Idiopathic Normal Pressure Hydrocephalus and Alzheimer’s Disease Neuropathological Change
Abstract: Background: Stepwise occurrence of biochemically modified amyloid-β (Aβ) in the brain of subjects with Alzheimer’s disease (AD) has been suggested to be of significance for cognitive impairment. Our previous reports have shown that Aβ is observed in 63% of all subjects with idiopathic normal pressure hydrocephalus (iNPH) suggesting that the majority of iNPH subjects with Aβ are indeed also suffering from AD. Objective: We assessed the occurrence of biochemically modified Aβ variants, in vivo, in subjects with iNPH and in a cohort of postmortem brain samples from patients with dementia. Methods: We assessed Aβ proteins in 127 diagnostic brain biopsies obtained from subjects with iNPH and in a cohort of subjects with dementia by means of immunohistochemistry. Results: The pyroglutamylated Aβ (pyAβ) precedes the aggregation of phosphorylated Aβ (pAβ) during the AD neuropathological change progression; moreover, these modified variants of Aβ correlate with hyperphosphorylated tau in the frontal cortical area of human brain. Our results confirm the existence of the suggested biochemical stages of Aβ aggregation that might be of significance for neurodegeneration leading to cognitive impairment. Conclusion: The observation that both pyAβ and pAβ are seen in vivo in iNPH subjects is intriguing. It has been reported that most of the iNPH subjects with Aβ in the brain biopsy indeed develop AD with time. Based on our current and previous results, it is clinically merited to obtain a diagnostic biopsy from a subject with iNPH. When Aβ is observed in the biopsy, the biochemical characterization is of interest.

Adrienne L. Johnson, Naomi C. Nystrom, Megan E. Piper, Jessica Cook, Derek L. Norton, Megan Zuelsdorff, Mary F. Wyman, Susan Flowers Benton, Nickolas H. Lambrou, John O'Hara, Nathaniel A. Chin, Sanjay Asthana, Cynthia Carlsson, Carey E. Gleason (Handling Associate Editor: Matthew Pase)
Cigarette Smoking Status, Cigarette Exposure, and Duration of Abstinence Predicting Incident Dementia and Death: A Multistate Model Approach
Abstract: Background: To fully characterize the risk for dementia associated with cigarette smoking, studies must consider competing risks that hinder the observation of dementia or modify the chance that dementia occurs (i.e., death). Extant research examining the competing risks fails to account for the occurrence of death following dementia, limiting our understanding of the relation between smoking and dementia. Objective: Examine the impact of smoking status, lifetime smoking exposure, and duration of abstinence on incident dementia, death following dementia, and death without dementia. Methods: Multi-state models estimated hazard ratios (HR) for 95% confidence interval (CI) of 10,681 cognitively healthy adults for transition from baseline to dementia, baseline to death, and dementia to death based on smoking status, lifetime cigarette exposure, and abstinence duration. Results: Compared to never smokers, current smokers had increased risk of dementia (HR=1.66; 95%CI 1.18-2.32; p=0.004), and death from baseline (HR=2.98; 95%CI 2.24-3.98; p<0.001) and incident dementia (HR=1.88; 95%CI 1.08-3.27; p=0.03). Pack years increased risk of death from baseline (HR=1.01; 95%CI 1.00-1.01; p<0.001), but not dementia risk (HR=1.00; 95%CI 1.00-1.00; p=0.78) or death following dementia (HR=1.01; 95%CI 1.00-1.01; p=0.05). Recent quitters (quit <10 years), compared to never smokers, had increased risk of death after baseline (HR=2.31; 95%CI 1.55-3.43; p<0.001), but not dementia (HR=1.17; 95%CI 0.73-1.88; p=0.52) or death following dementia (HR=1.01; 95%CI 0.42-2.41; p=0.99). Conclusion: Current smoking increases the risk for dementia and death, but dementia is better attributed to smoking recency than lifetime exposure. Smoking cessation at any age might reduce these risks for cognitively healthy individuals.

Sara Arlati, Simona Gabriella Di Santo, Flaminia Franchini, Marta Mondellini, Beatrice Filiputti, Matilde Luchi, Federica Ratto, Giancarlo Ferrigno, Marco Sacco, Luca Greci
Acceptance and Usability of Immersive Virtual Reality in Older Adults with Objective and Subjective Cognitive Decline
Abstract: Background: Virtual reality (VR) has recently emerged as a promising means for the administration of cognitive training of seniors at risk of dementia. Immersive VR could result in increased engagement and performances; however, its acceptance in older adults with cognitive deficits still has to be assessed. Objective: To assess acceptance and usability of an immersive VR environment requiring real walking and active participants’ interaction. Methods: 58 seniors with mild cognitive impairment (MCI, n=24) or subjective cognitive decline (SCD, n=31) performed a shopping task in a virtual supermarket displayed through a head-mounted display. Subjective and objective outcomes were evaluated. Results: Immersive VR was well-accepted by all but one participant (TAM3 positive subscales >5.33), irrespective of the extent of cognitive decline. Participants enjoyed the experience (spatial presence 3.51 ± 0.50, engagement 3.85 ± 0.68, naturalness 3.85 ± 0.82) and reported negligible side-effects (SSQ: 3.74; q1-q3: 0-16.83). The environment was considered extremely realistic, such as to induce potentially harmful behaviors: one participant fell while trying to lean on a virtual shelf. Older participants needed more time to conclude trials. Participants with MCI committed more errors in grocery items’ selection and experienced less “perceived control” over the environment. Conclusion: Immersive VR was acceptable and enjoyable for older adults in both groups. Cognitive deficits could induce risky behaviors, and cause issues in the interactions with virtual items. Further studies are needed to confirm acceptance of immersive VR in individuals at risk of dementia, and to extend the results to people with more severe symptoms.

Bingyu Li, Jiefeng Bi, Chang Wei, Feng Sha (Handling Associate Editor: Jinping Xu)
Specific Activities and the Trajectories of Cognitive Decline Among Middle-Aged and Older Adults: A Five-Year Longitudinal Cohort Study
Abstract: Background: How specific activities influence cognitive decline among different age groups, especially the late middle-aged and the early old, remains inadequately studied. Objective: To examine the association between specific activities with trajectories of cognitive functions in different age groups in China. Methods: A longitudinal cohort study was conducted based on data from the China Health and Retirement Longitudinal Study (CHARLS). Mixed effects growth models were applied to analyze the association between specific activities and cognitive functions. Results: Interacting with friends (infrequent: β = 0.13, confidence interval [CI] = 0.03 to 0.22; daily: β = 0.19, CI = 0.09 to 0.28), playing Mah-jong or other games (infrequent: β = 0.12, CI = 0.02 to 0.22; daily: β = 0.26 , CI = 0.10 to 0.42), infrequent providing help to others (β = 0.24, CI = 0.11 to 0.37), and going to a sport (infrequent: β = 0.31, CI = 0.08 to 0.54); daily: β = 0.22, CI = 0.05 to 0.38) are significantly associated with participants’ memory. Infrequently playing Mah-jong or other games (β = 0.30, CI = 0.17 to 0.43) and daily sports (β = 0.24, CI = 0.03 to 0.45) are significantly associated with better mental status. Effect of each activity varies among population of different age, education level, gender, and residence. Conclusion: This study identifies four social activities that are associated with better cognitive functions, and provides a comprehensive, in-depth understanding on the specific protective effect of each activity among different subgroups.

Julia Klein, Xinyu Yan, Aubrey Johnson, Zeljko Tomljanovic, James Zou, Krista Polly, Lawrence S. Honig, Adam M. Brickman, Yaakov Stern, D.P. Devanand, Seonjoo Lee, William C. Kreisl (Handling Associate Editor: Brian Gordon)
Olfactory Impairment Is Related to Tau Pathology and Neuroinflammation in Alzheimer’s Disease
Abstract: Background: Olfactory impairment is evident in Alzheimer’s disease (AD); however, its precise relationships with clinical biomarker measures of tau pathology and neuroinflammation are not well understood. Objective: To determine if odor identification performance measured with the University of Pennsylvania Smell Identification Test (UPSIT) is related to in vivo measures of tau pathology and neuroinflammation. Methods: Cognitively normal and cognitively impaired participants were selected from an established research cohort of adults aged 50 and older who underwent neuropsychological testing, brain MRI, and amyloid PET. Fifty-four participants were administered the UPSIT. Forty-one underwent 18F-MK-6240 PET (measuring tau pathology) and fifty-three underwent 11C-PBR28 PET (measuring TSPO, present in activated microglia). Twenty-three participants had lumbar puncture to measure CSF concentrations of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-β (Aβ42). Results: Low UPSIT performance was associated with greater18F-MK-6240 binding in medial temporal cortex, hippocampus, middle/inferior temporal gyri, inferior parietal cortex, and posterior cingulate cortex (p<0.05). Similar relationships were seen for 11C-PBR28. These relationships were primarily driven by amyloid-positive participants. Lower UPSIT performance was associated with greater CSF concentrations of t-tau and p-tau (p<0.05). Amyloid status and cognitive status exhibited independent effects on UPSIT performance (p<0.01). Conclusion: Olfactory identification deficits are related to extent of tau pathology and neuroinflammation, particularly in those with amyloid pathophysiology. The independent association of amyloid-positivity and cognitive impairment with odor identification suggests that low UPSIT performance may be a marker for AD pathophysiology in cognitive normal individuals, although impaired odor identification is associated with both AD and non-AD related neurodegeneration.

Paloma Monllor*, Esther Giraldo*, Mari-Carmen Badia, Jose Garcia de la Asuncion, Maria-Dolores Alonso, Ana Lloret, Jose Vina *These authors contributed equally to this work.
Serum Levels of Clusterin, PKR, and RAGE Correlate with Amyloid Burden in Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is the most common form of dementia and biomarkers are essential to help in the diagnosis of this disease. Image techniques and cerebrospinal fluid (CSF) biomarkers are limited in their use because they are expensive or invasive. Thus, the search for blood-borne biomarkers is becoming central to the medical community. Objective: The main objective of this study is the evaluation of three serum proteins as possible biomarkers in AD patients. Methods: We recruited 27 healthy controls, 19 mild cognitive impairment patients, and 17 AD patients. Using the recent A/T/N classification we split our population into two groups (AD and control). We used ELISA kits to determine Aβ42, tau, and p-tau in CSF and clusterin, PKR, and RAGE in serum. Results: The levels of serum clusterin, PKR, and RAGE were statistically different in the AD group compared to controls. These proteins showed a statistically significant correlation with CSF Aβ42. So, they were selected to generate an AD detection model showing an AUC-ROC of 0.971 (CI 95%, 0.931–0.998). Conclusion: The developed model based on serum biomarkers and other co-variates could reflect the AD core pathology. So far, not one single blood-biomarker has been described, with effectiveness offering high sensitivity and specificity. We propose that the complexity of AD pathology could be reflected in a set of biomarkers also including clinical features of the patients.

Sanjay Nagaraj, Tim Q. Duong
Deep Learning and Risk Score Classification of Mild Cognitive Impairment and Alzheimer’s Disease
Abstract: Background: Many neurocognitive and neuropsychological tests are used to classify early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI), and Alzheimer’s disease (AD) from cognitive normal (CN). This can make it challenging for clinicians to make efficient and objective clinical diagnoses. It is possible to reduce the number of variables needed to make a reasonably accurate classification using machine learning. Objective: The goal of this study was to develop a deep learning algorithm to identify a few significant neurocognitive tests that can accurately classify these four groups. We also derived a simplified risk-stratification score model for diagnosis. Methods: Over 100 variables that included neuropsychological/neurocognitive tests, demographics, genetic factors, and blood biomarkers were collected from 383 EMCI, 644 LMCI, 394 AD patients, and 516 cognitive normal from the Alzheimer’s Disease Neuroimaging Initiative database. A neural network algorithm was trained on data split 90% for training and 10% testing using 10-fold cross-validation. Prediction performance used area under the curve (AUC) of the receiver operating characteristic analysis. We also evaluated five different feature selection methods. Results: The five feature selection methods consistently yielded the top classifiers to be the Clinical Dementia Rating Scale - Sum of Boxes, Delayed total recall, Modified Preclinical Alzheimer Cognitive Composite with Trails test, Modified Preclinical Alzheimer Cognitive Composite with Digit test, and Mini-Mental State Examination. The best classification model yielded an AUC of 0.984, and the simplified risk-stratification score yielded an AUC of 0.963 on the test dataset. Conclusion: The deep-learning algorithm and simplified risk score accurately classifies EMCI, LMCI, AD and CN patients using a few common neurocognitive tests.

Michael D. Devous, Sr., Adam S. Fleisher, Michael J. Pontecorvo, Ming Lu, Andrew Siderowf, Michael Navitsky, Ian Kennedy, Sudeepti Southekal, Thomas S. Harris, Mark A. Mintun
Relationships Between Cognition and Neuropathological Tau in Alzheimer’s Disease Assessed by 18F Flortaucipir PET
Abstract: Background: Tau neurofibrillary tangle burden increases with Alzheimer’s disease (AD) stage and correlates with degree of cognitive impairment. Tau PET imaging could facilitate understanding the relationship between tau pathology and cognitive impairment. Objective: Evaluate the relationship between 18F flortaucipir uptake patterns and cognition across multiple cognitive domains. Methods: We acquired flortaucipir PET scans in 84 amyloid-positive control, mild cognitive impairment (MCI), and AD subjects. Flortaucipir standardized uptake value ratio (SUVr) values were obtained from a neocortical volume of interest (VOI), a precuneus VOI, and VOIs defined by the correlation between flortaucipir SUVr images and domain-specific cognitive tests. Cognitive assessments included Mini-Mental State Exam (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog), and a neuropsychological test battery (i.e., Wechsler Memory Scale-Revised Logical Memory (WMS-R), Trail Making Test, Boston Naming Test, Digit Symbol Substitution Test, Animal List Generation, WMS-R Digit Span, American National Adult Reading Test, Clock Drawing Test, Judgment of Line Orientation, and WMS-R Logical Memory II (Delayed Recall)) and the Functional Activities Questionnaire (FAQ). Correlation analyses compared regional and voxel-wise VOIs to cognitive scores. Results: Subjects included 5 controls, 47 MCI, and 32 AD subjects. Significant correlations were seen between both flortaucipir and florbetapir SUVrs and MMSE, ADAS-Cog, and FAQ. Cognitive impairment was associated with increased flortaucipir uptake in regionally specific patterns consistent with the neuroanatomy underlying specific cognitive tests. Conclusion: Flortaucipir SUVr values demonstrated significant inverse correlations with cognitive scores in domain-specific patterns. Findings support the hypothesis that PET imaging of neuropathologic tau deposits may reflect underlying neurodegeneration in AD.

Stefania Merighi, Enrica Battistello, Ilaria Casetta, Daniela Gragnaniello, Tino Emanuele Poloni, Valentina Medici, Alice Cirrincione, Katia Varani, Fabrizio Vincenzi, Pier Andrea Borea, Stefania Gessi
Upregulation of Cortical A2A Adenosine Receptors Is Reflected in Platelets of Patients with Alzheimer’s Disease
Abstract: Background: Alzheimer's disease (AD) is a neurodegenerative pathology covering about 70% of all cases of dementia. Adenosine, a ubiquitous nucleoside, plays a key role in neurodegeneration, through interaction with four receptor subtypes. The A2A receptor is upregulated in peripheral blood cells of patients affected by Parkinson’s and Huntington’s diseases, reflecting the same alteration found in brain tissues. However, whether these changes are also present in AD pathology has not been determined. Objective: In this study we verified any significant difference between AD cases and controls in both brain and platelets and we evaluated whether peripheral A2A receptors may reflect the status of neuronal A2A receptors. Methods: We evaluated the expression of A2A receptors in frontal white matter, frontal gray matter, and hippocampus/entorhinal cortex, in postmortem AD patients and control subjects, through [3H]ZM 241385 binding experiments. The same analysis was performed in peripheral platelets from AD patients versus controls. Results: The expression of A2A receptors in frontal white matter, frontal gray matter, and hippocampus/entorhinal cortex, revealed a density (Bmax) of 174±29, 219±33, and 358±84 fmol/mg of proteins, respectively, in postmortem AD patients in comparison to 104±16, 103±19, and 121±20 fmol/mg of proteins in controls (p<0.01). The same trend was observed in peripheral platelets from AD patients versus controls (Bmax of 214±17 versus 95±4 fmol/mg of proteins, respectively, p<0.01). Conclusion: AD subjects show significantly higher A2A receptor density than controls. Values on platelets seem to correlate with those in the brain supporting a role for A2A receptor as a possible marker of AD pathology and drug target for novel therapies able to modify the progression of dementia.

Jerry M. Cuttler, Eslam Abdellah, Yael Goldberg, Sarmad Al-Shamaa, Sean P. Symons, Sandra E. Black, Morris Freedman (Handling Associate Editor: Amos Korczyn)
Low Doses of Ionizing Radiation as a Treatment for Alzheimer’s Disease: A Pilot Study
Abstract: Background: In 2015, a patient in hospice with Alzheimer’s disease (AD) was treated with ionizing radiation to her brain using repeated CT scans. Improvement in cognition, speech, movement, and appetite was observed. These improvements were so momentous that she was discharged from the hospice to a long-term care home. Based on this case, we conducted a pilot clinical trial to examine the effect of low-dose ionizing radiation (LDIR) in severe AD. Objective: To determine whether the previously reported benefits of LDIR in a single case with AD could be observed again in other cases with AD when the same treatments are given. Methods: In this single-arm study, four patients were treated with three consecutive treatments of LDIR, each spaced two weeks apart. Qualitative changes in communication and behavior with close relatives were observed and recorded. Quantitative measures of cognition and behavior were administered pre and post LDIR treatments. Results: Minor improvements on quantitative measures were noted in three of the four patients following treatment. However, the qualitative observations of cognition and behavior suggested remarkable improvements within days post-treatment, including greater overall alertness. One patient showed no change. Conclusion: LDIR may be a promising, albeit controversial therapy for AD. Trials of patients with less severe AD, double-blind and placebo-controlled, should be carried out to determine the benefits of LDIR. Quantitative measures are needed that are sensitive to the remarkable changes induced by LDIR, such as biological markers of oxidative stress that are associated with AD.

Clinton B. Wright, Janet T. DeRosa, Michelle P. Moon, Kevin Strobino, Charles DeCarli, Ying Kuen Cheung, Stephanie Assuras, Bonnie Levin, Yaakov Stern, Xiaoyan Sun, Tatjana Rundek, Mitchell S.V. Elkind, Ralph L. Sacco
Race/Ethnic Disparities in Mild Cognitive Impairment and Dementia: The Northern Manhattan Study
Abstract: Background: Variability in dementia rates across racial and ethnic groups has been estimated at 60%. Studies suggest disparities in Caribbean Hispanic and Black populations, but community-based data are limited. Objective: Estimate the prevalence of mild cognitive impairment (MCI) and dementia in the racially and ethnically diverse community-based Northern Manhattan Study cohort and examine sociodemographic, vascular risk factor, and brain imaging correlates. Methods: Cases of MCI and dementia were adjudicated by a team of neuropsychologists and neurologists and prevalence was estimated across race/ethnic groups. Ordinal proportional odds models were used to estimate race/ethnic differences in the prevalence of MCI or dementia adjusting for sociodemographic variables (model 1), model 1 plus potentially modifiable vascular risk factors (model 2), and model 1 plus structural imaging markers of brain integrity (model 3). Results: There were 989 participants with cognitive outcome determinations (mean age 69 ± 9 years; 68% Hispanic, 16% Black, 14% White; 62% women; mean (±SD) follow-up five (±0.6) years). Hispanic and Black participants had greater likelihood of MCI (20%) and dementia (5%) than White participants accounting for age and education differences. Hispanic participants had greater odds of MCI or dementia than both White and Black participants adjusting for sociodemographic variables, vascular risk factors, and brain imaging factors. White matter hyperintensity burden was significantly associated with greater odds of MCI or dementia (OR=1.3, 1.1 to 1.6), but there was no significant interaction by race/ethnicity. Conclusion: In this diverse community-based cohort, cross-sectional data revealed significant race/ethnic disparities in the prevalence of MCI and dementia. Longer follow-up and incidence data are needed to further clarify these relationships.

Sara A. Galle*, Silvan Licher, Maarten M. Milders, Jan Berend Deijen, Erik J.A. Scherder, Madeleine L. Drent, M. Arfan Ikram, Cornelia M. van Duijn (Handling Associate Editor: Yadong Huang)
Plasma Brain-Derived Neurotropic Factor Levels Are Associated with Aging and Smoking But Not with Future Dementia in the Rotterdam Study
Abstract: Background: Brain-derived neurotropic factor (BDNF) plays a vital role in neuronal survival and plasticity and facilitates long-term potentiation, essential for memory. Alterations in BDNF signaling have been associated with cognitive impairment, dementia, and Alzheimer’s disease. Although peripheral BDNF levels are reduced in dementia patients, it is unclear whether changes in BDNF levels precede or follow dementia onset. Objective: In the present study, we examined the association between BDNF plasma levels and dementia risk over a follow-up period of up to 16 years. Methods: Plasma BDNF levels were assessed in 758 participants of the Rotterdam Study. Dementia was assessed from baseline (1997-1999) to follow-up until January 2016. Associations of plasma BDNF and incident dementia were assessed with Cox proportional hazards models, adjusted for age and sex. Associations between plasma BDNF and lifestyle and metabolic factors are investigated using linear regression. Results: During a follow up of 3,286 person-years, 131 participants developed dementia, of whom 104 had Alzheimer’s disease. We did not find an association between plasma BDNF and risk of dementia (adjusted hazard ratio 0.99; 95% CI 0.84-1.16). BDNF levels were positively associated with age (B = 0.003, SD = 0.001, p = 0.002), smoking (B = 0.08, SE = 0.01, p = < 0.001), and female sex (B = 0.03, SE = 0.01, p = 0.03), but not with physical activity level (B = -0.01, SE = 0.01, p = 0.06). Conclusion: The findings suggest that peripheral BDNF levels are not associated with an increased risk of dementia.

Barbara Hinteregger, Tina Loeffler, Stefanie Flunkert, Joerg Neddens, Thomas A. Bayer, Tobias Madl, Birgit Hutter-Paier (Handling Associate Editor: Javier Vitorica)
Metabolic, Phenotypic, and Neuropathological Characterization of the Tg4-42 Mouse Model for Alzheimer’s Disease
Abstract: Background: Preclinical Alzheimer’s disease (AD) research strongly depends on transgenic mouse models that display major symptoms of the disease. Although several AD mouse models have been developed representing relevant pathologies, only a fraction of available mouse models, like the Tg4-42 mouse model, display hippocampal atrophy caused by the death of neurons as the key feature of AD. The Tg4-42 mouse model is therefore very valuable for use in preclinical research. Furthermore, metabolic biomarkers which have the potential to detect biochemical changes, are crucial to gain deeper insights into the pathways, the underlying pathological mechanisms and disease progression. Objective: We thus performed an in-depth characterization of Tg4-42 mice by using an integrated approach to analyze alterations of complex biological networks in this AD in vivo model. Methods: Therefore, untargeted NMR-based metabolomic phenotyping was combined with behavioral tests and immunohistological and biochemical analyses. Results: Our in vivo experiments demonstrate a loss of body weight increase in homozygous Tg 4-42 mice over time as well as severe impaired learning behavior and memory deficits in the Morris water maze behavioral test. Furthermore, we found significantly altered metabolites in two different brain regions and metabolic changes of the glutamate/4-aminobutyrate-glutamine axis. Based on these results, downstream effects were analyzed showing increased Aβ42 levels, increased neuroinflammation as indicated by increased astro- and microgliosis as well as neuronal degeneration and neuronal loss in homozygous Tg4-42 mice. Conclusion: Our study provides a comprehensive characterization of the Tg4-42 mouse model which could lead to a deeper understanding of pathological features of AD. Additionally this study reveals changes in metabolic biomarker which set the base for future preclinical studies or drug development.

Desirée Lopis,Thibault Le Pape, Céline Manetta, Laurence Conty
Sensory Cueing of Autobiographical Memories in Normal Aging and Alzheimer’s Disease: A Comparison Between Visual, Auditory, and Olfactory Information
Abstract: Background: Alzheimer’s disease (AD) is a chronic, neurodegenerative disease resulting in a progressive decline of autobiographical memories (AMs) which favors the development of psycho-behavioral disorders. One of the most popular psychosocial interventions in dementia care, Reminiscence Therapy, commonly uses sensory cueing to stimulate AMs retrieval. However, few empirical studies have investigated the impact of sensory stimulation on AMs retrieval in AD. Objective: Our goal was to determine the most relevant cue for AMs retrieval in patients with early to mild AD when comparing odors, sounds and pictures. Methods: Sixty AD patients, 60 healthy older adults (OA), and 60 healthy young adults (YA) participated in our study. Participants were presented with either 4 odors, 4 sounds, or 4 pictures. For each stimulus, they were asked to retrieve a personal memory, to rate it across 3 dimensions (emotionality, vividness, rarity) and then to date it. Results: Overall, results showed no clear dominance of one sensory modality over the others in evoking higher-quality AMs. However, they show that using pictures is the better way to stimulate AD patients’ AM, as it helps to retrieve a higher number of memories that are also less frequently retrieved, followed by odors. By contrast, auditory cueing with environmental sounds presented no true advantage. Conclusion: Our data should help dementia care professionals to increase the efficiency of Reminiscence Therapy using sensory elicitors. Other clinical implications and future directions are also discussed.

Silvia Chapman, Preeti Sunderaraman, Jillian L. Joyce, Martina Azar, Leigh E. Colvin, Megan S. Barker, Ian McKeague, William C. Kreisl, Stephanie Cosentino
Optimizing Subjective Cognitive Decline to Detect Early Cognitive Dysfunction
Abstract: Background: The utility of subjective cognitive decline (SCD) as an indicator of preclinical AD is overshadowed by its inconsistent association with objective cognition. Objective: This study examines if manipulations of SCD measurement affect its association with early cognitive dysfunction characteristic of preclinical AD. Methods: Cognitively healthy older adults (n=110) completed SCD questionnaires that elicited complaints in general, compared to 5 years ago (retrospective SCD) and compared to their peers (age-anchored SCD) in binary and Likert scales. Outcome cognitive tasks included an associative memory task (Face-Name Test), a visual short-term memory binding task (STMB test), and a clinical neuropsychological list learning test (Selective Reminder Test). Results: SCD complaints, when compared to age-matched peers (age-anchored SCD) was endorsed less frequently than complaints compared to 5 years ago (retrospective SCD) (p<0.01). In demographically adjusted regressions, age-anchored ordinal-rated SCD was associated with short term memory binding (β=-0.22, p=0.040, CI=-0.45, -0.01), associative memory (β=-0.26, p=0.018, CI=-0.45, -0.06), and list learning (β=-0.31, p=0.002, CI=-0.51, -0.12). Retrospective and general ordinal-rated SCD was associated with associative memory (β=-0.25, p=0.012, CI=-0.44, -0.06; β=-0.29, p=0.003, CI=-0.47, -0.10) and list learning only (β=-0.25, p=0.014, CI=-0.45, -0.05; β=-0.28, p=0.004, CI=-0.48, -0.09). Conclusion: Ordinal age-anchored SCD appears better suited than other SCD measurements to detect early cognitive dysfunction characteristic of preclinical AD.

Soyeon Kim*, Kiwon Kim*, Kwangsik Nho, Woojae Myung, Hong-Hee Won *These authors contributed equally to this work.
Shared Genetic Background Between Cerebrospinal Fluid Biomarkers and Risk for Alzheimer’s Disease: A Two-Sample Mendelian Randomization Study
Abstract: Background: Whether the epidemiological association of amyloid-β (Aβ) and tau pathology in late-onset Alzheimer’s disease (LOAD) is causal remains unclear. Objective: We aimed to investigate the shared genetic background between the cerebrospinal fluid (CSF) biomarkers for Aβ and tau pathology and the risk of LOAD. Methods: We conducted a two-sample Mendelian randomization (MR) analysis. We used summary statistics of genome-wide association studies for CSF biomarkers (Aβ1-42 [Aβ], phosphorylated tau181 [p-tau], and total tau [t-tau]) in 3,146 individuals and for LOAD in 21,982 cases and 41,944 controls. We tested the association between changes in the genetically predicted CSF biomarkers and LOAD risk. Results: We found a decrease in LOAD risk per one-standard-deviation (SD) increase in the genetically predicted CSF Aβ (odds ratio [OR], 2.87× 10–3 for AD; 95% confidence interval [CI], 1.54× 10–4 –0.05; p = 8.91× 10–5). Conversely, we observed an increase in LOAD risk per one-SD increase in the genetically predicted CSF p-tau (OR, 19.46; 95% CI, 1.50–2.52×102; p = 0.02) and t-tau (OR, 33.80; 95% CI, 1.57–7.29×102; p = 0.02). However, only the association between p-tau and the risk for LOAD remained significant after the exclusion of the APOE variant (rs769449). Conclusion: We found the causal association between CSF biomarkers and the risk for LOAD. Our results suggest that the etiology of LOAD involves multiple biological processes, including the pathways of Aβ and tau proteins. Further MR studies using large-scale data of multiple candidate biomarkers are needed to elucidate the pathophysiology of LOAD.

Chuan Huang, Minos Kritikos, Sean A.P. Clouston, Yael Deri, Mario Serrano-Sosa, Lev Bangiyev, Stephanie Santiago-Michels, Sam Gandy, Mary Sano, Evelyn J. Bromet, Benjamin J. Luft
White Matter Connectivity in Incident Mild Cognitive Impairment: A Diffusion Spectrum Imaging Study of World Trade Center Responders at Midlife
Abstract: Background: Individuals who participated in response efforts at the World Trade Center (WTC) following 9/11/2001 are experiencing elevated incidence of mild cognitive impairment (MCI) at midlife. Objective: We hypothesized that white matter connectivity measured using diffusion spectrum imaging (DSI) would be restructured in WTC responders with MCI versus cognitively unimpaired responders. Methods: Twenty responders (mean age 56; 10 MCI/10 unimpaired) recruited from an epidemiological study were characterized using NIA-AA criteria alongside controls matched on demographics (age/sex/occupation/race/education). Axial DSI was acquired on a 3T Siemen’s Biograph mMR scanner (12-channel head coil) using a multi-band diffusion sequence. Connectometry examined whole-brain tract-level differences in white matter integrity. Fractional anisotropy (FA), mean diffusivity (MD), and quantified anisotropy were extracted for region of interest (ROI) analyses using the Desikan-Killiany atlas. Results: Connectometry identified both increased and decreased connectivity within regions of the brains of responders with MCI identified in the corticothalamic pathway and cortico-striatal pathway that survived adjustment for multiple comparisons. MCI was also associated with higher FA values in five ROIs including in the rostral anterior cingulate; lower MD values in four ROIs including the left rostral anterior cingulate; and higher MD values in the right inferior circular insula. Analyses by cognitive domain revealed nominal associations in domains of response speed, verbal learning, verbal retention, and visuospatial learning. Conclusions: WTC responders with MCI at midlife showed early signs of neurodegeneration characterized by both increased and decreased white matter diffusivity in regions commonly affected by early-onset Alzheimer’s disease.

Tamara Shiner, Anat Mirelman, Yevgenia Rosenblum, Gitit Kavé, Mali Gana Weisz, Anat Bar-Shira, Orly Goldstein, Avner Thaler, Tanya Gurevich, Avi Orr-Urtreger, Nir Giladi, Noa Bregman
The Effect of GBA Mutations and APOE Polymorphisms on Dementia with Lewy Bodies in Ashkenazi Jews
Abstract: Background: Glucocerebrosidase (GBA) gene mutations and APOE polymorphisms are common in dementia with Lewy bodies (DLB), however their clinical impact is only partially elucidated. Objective: To explore the clinical impact of mutations in the GBA gene and APOE polymorphisms separately and in combination, in a cohort of Ashkenazi Jewish (AJ) patients with DLB. Methods: One hundred consecutively recruited AJ patients with clinically diagnosed DLB underwent genotyping for GBA mutations and APOE polymorphisms, and performed cognitive and motor clinical assessments. Results: Thirty-two (32%) patients with DLB were carriers of GBA mutations and 33 (33%) carried an APOE ε4 allele. GBA mutation carriers had a younger age of onset (mean [SD] age, 67.2 years [8.9] versus 71.97 [5.91]; p=0.03), poorer cognition as assessed by the Mini-Mental State Examination (21.41 [6.9] versus 23.97 [5.18]; p<0.005), and more severe parkinsonism as assessed with the Unified Parkinson’s Disease Rating Scale motor part III (34.41 [13.49] versus 28.38 [11.21]; p=0.01) compared to non-carriers. There were statistically significant interactions between the two genetic factors, so that patients who carried both a mild GBA mutation and the APOE ε4 allele (n=9) had more severe cognitive (p = 0.048) and motor dysfunction (p = 0.037). Conclusion: We found a high frequency of both GBA mutations and the APOE ε4 allele among AJ patients with DLB, both of which have distinct effects on the clinical disease phenotype, separately and in combination.

Amy Jenkins, Jeremy Tree, Andrea Tales
Distinct Profile Differences in Subjective Cognitive Decline in the General Public Are Associated with Metacognition, Negative Affective Symptoms, Neuroticism, Stress, and Poor Quality of Life
Abstract: Background: Subjective cognitive decline (SCD) is increasingly recognized in both the clinical and research arenas as a risk factor for mild cognitive impairment (MCI) and dementia. Although SCD is etiologically heterogeneous and potentially treatable, in comparison to MCI and Alzheimer’s disease, SCD remains poorly characterized with its clinical relevance often questioned. Objective: This study’s aim was to improve the characterization of SCD within the general public. Methods: Individuals with SCD were compared to those without via a battery of measures. Results: Both the SCD and the non-SCD group correlational analysis identified significant relationships between worse SCD, worse metacognitive dysfunction, negative affective symptoms, and greater levels of stress. The SCD group displayed additional correlational relationships between Cognitive Change Index (Self report) (CCI-S) scores, higher neuroticism scores, and poorer quality of life (QoL). Partial correlation analysis in the SCD group suggests CCI-S scores, anxiety, depression, and metacognition are intercorrelated. Ad hoc analyses using metacognition as the grouping variable found that those experiencing worse metacognitive dysfunction were significantly more likely to experience poorer SCD, psychological and social QoL, greater levels of anxiety, depression, stress, and neuroticism. Conclusion: The emerging pattern from the analysis indicates that SCD appears associated with sub-clinical negative affective difficulties, metacognitive, and other psycho-social issues, and poorer QoL. Dysfunctional cognitive control at a meta-level may impact someone’s ability to rationally identify cognitive changes, increase worry about cognitive changes, and allow such changes to impact their lives more than those with superior metacognitive control. Findings could impact SCD assessment, monitoring, early intervention, and ultimately reducing risk of further decline.

Sephira G. Ryman, Maya Yutsis, Lu Tian, Victor W. Henderson, Thomas J. Montine, David P. Salmon, Douglas Galasko, Kathleen L. Poston (Handling Associate Editor: Brittany Dugger)
Cognition at Each Stage of Lewy Body Disease with Co-occurring Alzheimer’s Disease Pathology
Abstract: Background: Alzheimer’s disease neuropathologic change (ADNC) may contribute to dementia in patients with Lewy body disease (LBD) pathology. Objective: To examine how co-occurring ADNC impacts domain specific cognitive impairments at each pathologic stage (brainstem, limbic, cerebral cortical) of LBD. Methods: 2,433 participants with antemortem longitudinal neuropsychological assessment and postmortem neuropathological assessment from the National Alzheimer’s Coordinating Center’s Uniform Data Set were characterized based on the evaluation of ADNC and LBD. Longitudinal mixed-models were used to derive measures of cumulative cognitive deficit for each cognitive domain at each pathologic stage of LBD (brainstem, limbic, and cerebral cortical). Results: 111 participants with a pathologic diagnosis of LBD, 741 participants with combined LBD and ADNC, 1,357 participants with ADNC only, and 224 with no pathology (healthy controls) were included in the analyses. In the executive/visuospatial domain, combined LBD and ADNC showed worse deficits than LBD only when Lewy bodies were confined to the brainstem, but no difference when Lewy bodies extended to the limbic or cerebral cortical regions. The cerebral cortical LBD only group exhibited greater executive/visuospatial deficits than the ADNC only group. By contrast, the ADNC only group and the combined pathology group both demonstrated significantly greater cumulative memory deficits relative to Lewy body disease only, regardless of stage. Conclusion: The impact of co-occurring ADNC on antemortem cumulative cognitive deficits varies not only by domain but also on the pathological stage of Lewy bodies. Our findings stress the cognitive impact of different patterns of neuropathological progression in Lewy body diseases.

Xiaolei Liu*, Xinjie Chen*, Xianbo Zhou*, Yajun Shang, Fan Xu, Junyan Zhang, Jingfang He, Feng Zhao, Bo Du, Xuan Wang, Qi Zhang, Weishan Zhang, Michael F. Bergeron, Tao Ding, J. Wesson Ashford, Lianmei Zhong (Handling Associate Editor: David Loewenstein) *These authors contributed equally to this study.
Validity of the MemTrax Memory Test Compared to the Montreal Cognitive Assessment in the Detection of Mild Cognitive Impairment and Dementia due to Alzheimer’s Disease in a Chinese Cohort
Abstract: Background: A valid, reliable, accessible, engaging, and affordable digital cognitive screen instrument for clinical use is in urgent demand. Objective: To assess the clinical utility of the MemTrax memory test for early detection of cognitive impairment in a Chinese cohort. Methods: The 2.5-minute MemTrax and the Montreal Cognitive Assessment (MoCA) were performed by 50 clinically diagnosed cognitively normal (CON), 50 mild cognitive impairment due to AD (MCI-AD), and 50 Alzheimer’s disease (AD) volunteer participants. The percentage of correct responses (MTx-%C), the mean response time (MTx-RT), and the composite scores (MTx-Cp) of MemTrax and the MoCA scores were comparatively analyzed and receiver operating characteristic (ROC) curves generated. Results: Multivariate linear regression analyses indicated MTx-%C, MTx-Cp, and the MoCA score were significantly lower in MCI-AD versus CON and in AD versus MCI-AD groups (all with p≤0.001). For the differentiation of MCI-AD from CON, an optimized MTx-%C cutoff of 81% had 72% sensitivity and 84% specificity with an area under the curve (AUC) of 0.839, whereas the MoCA score of 23 had 54% sensitivity and 86% specificity with an AUC of 0.740. For the differentiation of AD from MCI-AD, MTx-Cp of 43.0 had 70% sensitivity and 82% specificity with an AUC of 0.799, whereas the MoCA score of 20 had 84% sensitivity and 62% specificity with an AUC of 0.767. Conclusion: MemTrax can effectively detect both clinically diagnosed MCI and AD with better accuracy as compared to the MoCA based on AUCs in a Chinese cohort.

Ryan J. Piers, Yulin Liu, Ting F.A. Ang, Qiushan Tao, Rhoda Au, Wendy Q. Qiu
Association Between Elevated Depressive Symptoms and Cognitive Function Moderated by APOE4 Status: Framingham Offspring Study
Abstract: Background: Depression and Apolipoprotein E4 (APOE4) are associated with decreased cognitive function and differences in brain structure. Objective: This study investigated whether APOE4 status moderates the association between elevated depressive symptoms, cognitive function, and brain structure. Methods: Stroke- and dementia-free participants (n=1,968) underwent neuropsychological evaluation, brain MRI, and depression screening. Linear and logistic regression was used to examine all associations. Secondary analyses were performed using interaction terms to assess effect modification by APOE4 status. Results: Elevated depressive symptoms were associated with lower cognitive performance in several domains. In stratified analyses, elevated depressive symptoms were associated with poorer visual short- and long-term memory performance for APOE4+ participants. Elevated depressive symptoms were not associated with any brain structure in this study sample. Conclusion: Elevated depressive symptoms impact cognitive function in non-demented individuals. Having the APOE4 allele may exacerbate the deleterious effects of elevated depressive symptoms on visual memory performance. Screening for elevated depressive symptoms in both research studies and clinical practice may be warranted to avoid false positive identification of neurodegeneration, particularly among those who are APOE4+.

Keith W. VanDusen, Yi-Ju Li, Victor Cai, Ashley Hall, Sarah Hiles, J. Will Thompson, M. Arthur Moseley, Mary Cooter, Leah Acker, Jerrold H. Levy, Kamrouz Ghadimi, Quintin J. Quiñones, Michael J. Devinney, Stacey Chung, Niccolò Terrando, Eugene W. Moretti, Jeffrey N. Browndyke, Joseph P. Mathew, Miles Berger for the MADCO-PC Investigators
Cerebrospinal Fluid Proteome Changes in Older Non-Cardiac Surgical Patients with Postoperative Cognitive Dysfunction
Abstract: Background: Postoperative cognitive dysfunction (POCD), a syndrome of cognitive deficits occurring 1-12 months after surgery primarily in older patients, is associated with poor postoperative outcomes. POCD is hypothesized to result from neuroinflammation; however, the pathways involved remain unclear. Unbiased proteomic analyses have been used to identify neuroinflammatory pathways in multiple neurologic diseases and syndromes but have not yet been applied to POCD. Objective: To utilize unbiased mass spectrometry-based proteomics to identify potential neuroinflammatory pathways underlying POCD. Methods: Unbiased LC-MS/MS proteomics was performed on immunodepleted cerebrospinal fluid (CSF) samples obtained before, 24 hours after, and 6 weeks after major non-cardiac surgery in older adults who did (n=8) or did not develop POCD (n=6). Linear mixed models were used to select peptides and proteins with intensity differences for pathway analysis. Results: Mass spectrometry quantified 8,258 peptides from 1,222 proteins in >50% of patient samples at all three time points. Twelve peptides from 11 proteins showed differences in expression over time between patients with versus without POCD (q<0.05), including proteins previously implicated in neurodegenerative disease pathophysiology. Additionally, 283 peptides from 182 proteins were identified with trend-level differences (q<0.25) in expression over time between these groups. Among these, pathway analysis revealed that 50 were from 17 proteins mapping to complement and coagulation pathways (q=2.44*10-13). Conclusion: These data demonstrate the feasibility of performing unbiased mass spectrometry on perioperative CSF samples to identify pathways associated with POCD. Additionally, they provide hypothesis-generating evidence for CSF complement and coagulation pathway changes in patients with POCD.

Zhiyong Zhao*, Huaying Cai*, Weihao Zheng, Tingting Liu, Di Sun, Guocan Han, Yi Zhang, Dan Wu *These authors contributed equally to this work.
Atrophic Pattern of Hippocampal Subfields in Post-Stroke Demented Patient
Abstract: Background: Previous studies have demonstrated that hippocampal atrophy is a hallmark of dementia and can be used to predict the outcome of post-stroke demented (PSD) patients. The hippocampus consists of several subfields but their involvement in the pathophysiology of the PSD remains unclear. Objective: The present study aimed to investigate volumetric alterations of hippocampal subfields in patients with PSD. Methods: High-resolution T1-weighted images were collected from 27 PSD and 28 post-stroke nondemented (PSND) patients who recovered from ischemic stroke, and 17 age-matched normal control (NC). We estimated the volumes of the hippocampal subfields using FreeSurfer 6.0 which segmented the hippocampus into 12 subfields in each hemisphere. The volumetric differences between the groups were evaluated by the two-sample tests after regressing out the age, sex, education, and total intracranial volume. Results: Compared with NC group, PSD group showed smaller volumes in the entire hippocampus and its subfields, and such differences were not found in PSND group. Moreover, we found the dementia-specific atrophy in the left granule cell layer of dentate gyrus (GC-DG) and CA4 in the PSD patients compared with NC and PSND. Regression analysis showed positive correlations between the changes of cognitive performance and the asymmetry index in the CA3/4 and GC-DG of the PSD group. Furthermore, we found that the volumes of hippocampal subfields provided a better classification performance than the entire hippocampus. Conclusion: Our findings suggest that the hippocampus is reduced in the PSD patients and it presents a selective subfield involvement.

Na An, Yu Fu, Jie Shi, Han-Ning Guo, Zheng-Wu Yang, Yong-Chao Li, Shan Li, Yin Wang, Zhi-Jun Yao, Bin Hu, Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Zhanjun Zhang)
Synergistic Effects of APOE and CLU May Increase the Risk of Alzheimer's Disease: Acceleration of Atrophy in the Volumes and Shapes of the Hippocampus and Amygdala
Abstract: Background: The volume loss of the hippocampus and amygdala in non-demented individuals has been reported to increase the risk of developing Alzheimer’s disease (AD). Many neuroimaging genetics studies mainly focused on the individual effects of APOE and CLU on neuroimaging to understand their neural mechanisms, whereas their interaction effects have been rarely studied. Objective: To assess whether APOE and CLU have synergetic effects, we investigated the epistatic interaction and combined effects of the two genetic variants on morphological degeneration of hippocampus and amygdala in the non-demented elderly at baseline and 2-year follow-up. Methods: Besides the widely-used volume indicator, the surface-based morphometry method was also adopted in this study to evaluate shape alterations. Results: Our results showed a synergistic effect of homozygosity for the CLU risk allele C in rs11136000 and APOE ε4 on the hippocampal and amygdalar volumes during a 2-year follow-up. Moreover, the combined effects of APOE ε4 and CLU C were stronger than either of the individual effects in the atrophy progress of the amygdala. Conclusion: These findings indicate that brain morphological changes are caused by more than one gene variant, which may help us to better understand the complex endogenous mechanism of AD.

Jure Mur, Daniel L. McCartney, Daniel I. Chasman, Peter M. Visscher, Graciela Muniz-Terrera, Simon R. Cox, Tom C. Russ, Riccardo E. Marioni (Handling Associate Editor: M. Arfan Ikram)
Variation in VKORC1 Is Associated with Vascular Dementia
Abstract: Background: The genetic variant rs9923231 (VKORC1) is associated with differences in the coagulation of blood and consequentially with sensitivity to the drug warfarin. Variation in VKORC1 has been linked in a gene-based test to dementia/Alzheimer’s disease in the parents of participants, with suggestive evidence for an association for rs9923231 (p=1.8x10-7), which was included in the genome-wide significant KAT8 locus. Objective: Our study aimed to investigate whether the relationship between rs9923231 and dementia persists only for certain dementia sub-types, and if those taking warfarin are at greater risk. Methods: We used logistic regression and data from 238,195 participants from UK Biobank to examine the relationship between VKORC1, risk of dementia, and the interplay with warfarin use. Results: Parental history of dementia, APOE variant, atrial fibrillation, diabetes, hypertension, and hypercholesterolemia all had strong associations with vascular dementia (p<4.6x10-6). The T-allele in rs9923231 was linked to a lower warfarin dose (βper T-allele=-0.29, p<2x10-16) and risk of vascular dementia (OR=1.17, p=0.010), but not other dementia sub-types. However, the risk of vascular dementia was not affected by warfarin use in carriers of the T-allele. Conclusion: Our study reports for the first time an association between rs9923231 and vascular dementia, but further research is warranted to explore potential mechanisms and specify the relationship between rs9923231 and features of vascular dementia.