Volume 72, Number 4, IN PRESS

Commentary
Ruth F. Itzhaki
A Turning Point in Alzheimer's Disease Research: Microbes Matter

Review
Federica Cioffi, Rayan Hassan Ibrahim Adam, Kerensa Broersen
Molecular Mechanisms and Genetics of Oxidative Stress in Alzheimer’s Disease
Abstract: Alzheimer’s disease is the most common neurodegenerative disorder that can cause dementia in elderly over 60 years of age. One of the disease hallmarks is oxidative stress which interconnects with other processes such as amyloid-β deposition, tau hyperphosphorylation, and tangle formation. This review discusses current thoughts on molecular mechanisms that may relate oxidative stress to Alzheimer’s disease and identifies genetic factors observed from in vitro, in vivo, and clinical studies that may be associated with Alzheimer’s disease-related oxidative stress.

Review
Rebecca Parodi-Rullán*, Je Yeong Sone*, Silvia Fossati (Handling Associate Editor: Benedict Albensi) *These authors have contributed equally.
Endothelial Mitochondrial Dysfunction in Cerebral Amyloid Angiopathy and Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is the most prevalent form of dementia. Cerebrovascular dysfunction is one of the earliest events in the pathogenesis of AD, as well as in vascular and mixed dementias. Cerebral amyloid angiopathy (CAA), the deposition of amyloid around cerebral vessels, is observed in up to 90% of AD patients and in approximately 50% of elderly individuals over 80 years of age. CAA is a strong contributor to vascular dysfunction in AD. CAA-laden brain vessels are characterized by dysfunctional hemodynamics and leaky blood-brain barrier (BBB), contributing to clearance failure and further accumulation of amyloid-β (Aβ) in the cerebrovasculature and brain parenchyma. Mitochondrial dysfunction is increasingly recognized as an important early initiator of the pathogenesis of AD and CAA. The objective of this review is to discuss the effects of Aβ on cerebral microvascular cell function, focusing on its impact on endothelial mitochondria. After introducing CAA and its etiology and genetic risk factors, we describe the pathological relationship between cerebrovascular amyloidosis and brain microvascular endothelial cell dysfunction, critically analyzing its roles in disease progression, hypoperfusion, and BBB integrity. Then, we focus on discussing the effect of Aβ challenge on endothelial mitochondrial dysfunction pathways, and their contribution to the progression of neurovascular dysfunction in AD and dementia. Finally, we report potential pharmacological and non-pharmacological mitochondria-targeted therapeutic strategies which may help prevent or delay cerebrovascular failure.

Commentary
Maurits van den Noort, Katrien Vermeire, Heike Staudte, Benoît Perriard, Peggy Bosch, Sabina Lim (Handling Associate Editor: Gali Weissberger)
The Relationship Between Linguistic Ability, Multilingualism, and Dementia
Abstract: In a recent article of the Journal of Alzheimer’s Disease, Hack et al. (2019) argue that linguistic ability rather than multilingualism is a significant predictor of dementia. In their longitudinal study, they investigated 325 religious sisters who were older than 75 years of age. Self-reports were used in order to determine multilingualism. They found that speaking two or three languages did not delay the onset of dementia. However, they did find that individuals speaking four or more languages were less likely to suffer from dementia than those speaking only one language and concluded that having linguistic ability was a more significant predictor of dementia than being multilingual. However, more research is needed in order to identify the characteristics of multilingualism most salient for the risk of dementia. In this commentary, we raise several important methodological and statistical issues that are likely to have affected the findings of Hack et al.’s study. As a result, although their study makes an important contribution to the research field, drawing a conclusion at this time that linguistic ability is more a predictor of dementia than multilingualism would be premature; moreover, their preliminary results cannot be generalized to the general population.

Imane Lejri*, Amandine Grimm* François Hallé, Mustapha Abarghaz, Christian Klein, Michel Maitre, Martine Schmitt, Jean-Jacques Bourguignon, Ayikoe Guy Mensah-Nyagan, Frederic Bihel, Anne Eckert (Handling Associate Editor: Benedict Albensi) *These authors contributed equally to this work.
TSPO Ligands Boost Mitochondrial Function and Pregnenolone Synthesis
Abstract: Translocator protein 18 kDa (TSPO) is located in the mitochondrial outer membrane and plays an important role in steroidogenesis and cell survival. In the central nervous system (CNS), its expression is upregulated in neuropathologies such as Alzheimer’s disease (AD). Previously, we demonstrated that two new TSPO ligands based on an imidazoquinazolinone termed 2a and 2b, stimulated pregnenolone synthesis and ATP production in vitro. In the present study, we compared their effects to those of TSPO ligands described in the literature (XBD173, SSR-180,575, and Ro5-4864) by profiling the mitochondrial bioenergetic phenotype before and after treatment and investigating the protective effects of these ligands after oxidative injury in a cellular model of AD overexpressing amyloid-β (Aβ). Of note, ATP levels increased with rising pregnenolone levels suggesting that the energetic performance of mitochondria is linked to an increased production of this neurosteroid via TSPO modulation. Our results further demonstrate that the TSPO ligands 2a and 2b exerted neuroprotective effects by improving mitochondrial respiration, reducing reactive oxygen species and thereby decreasing oxidative stress-induced cell death as well as lowering Aβ levels. The compounds 2a and 2b show similar or even better functional effects than those obtained with the reference TSPO ligands XBD173 and SSR-180.575. These findings indicate that the new TSPO ligands modulate mitochondrial bioenergetic phenotype and protect against oxidative injury probably through the de novo synthesis of neurosteroids, suggesting that these compounds could be potential new therapeutic tools for the treatment of neurodegenerative disease.

Karol Dowjat*, Tatyana Adayev*, Urszula Wojda, Katarzyna Brzozowska, Anna Barczak, Tomasz Gabryelewicz, Yu-Wen Hwang (Handling Associate Editor: Piotr Lewczuk) *These authors contributed equally to this work.
Abnormalities of DYRK1A-Cytoskeleton Complexes in the Blood Cells as Potential Biomarkers of Alzheimer’s Disease
Abstract: Background: DYRK1A is implicated in mental retardation and Alzheimer’s disease (AD) dementia of Down syndrome (DS) individuals. The protein is associated with cytoskeleton and altered expression has been shown to impair the cytoskeletal network via dosage effect. Objective: Our original observations of marked reduction of cytoskeletal proteins associated with DYRK1A in brains and lymphoblastoid cell lines from DS and AD prompted an investigation whether cytoskeleton abnormalities could potentially be used as biomarkers of AD. Methods: Our assay relied on quantification of co-immunoprecipitated cytoskeletal proteins with DYRK1A (co-IP assay) and analysis of the profile of G- and F-actin fractions obtained by high-speed centrifugations (spin-down assay). Results: In co-IP assay, both DS and AD samples displayed reduced abundance of associated cytoskeletal proteins. In spin-down assay, G-actin fractions of controls displayed two closely spaced bands of actin in SDS-PAGE; while in AD and DS, only the upper band of the doublet was present. In both assays, alterations of actin cytoskeleton were present in DS, sporadic and familial AD cases, and in asymptomatic persons who later progressed to confirmed AD, but not in non-AD donors. In blind testing involving six AD and six controls, the above tests positively identified ten cases. Analysis of blood samples revealed the diversity of mild cognitive impairment (MCI) cases regarding the presence of the AD biomarker allowing distinction between likely prodromal AD and non-AD MCI cases. Conclusions: Both brain tissue and lymphocytes from DS and AD displayed similar semi-quantitative and qualitative alterations of actin cytoskeleton. Their specificity for AD-type dementia and the presence before clinical onset of the disease make them suitable biomarker candidates for early and definite diagnosis of AD. The presence of alterations in peripheral tissue points to systemic underlying mechanisms and suggests that early dysfunction of cytoskeleton may be a predisposing factor in the development of AD.

Monica Emili Garcia-Segura, Corinne E. Fischer, Tom A. Schweizer, David G. Munoz
APOE ε4/ε4 Is Associated with Aberrant Motor Behavior Through Both Lewy Body and Cerebral Amyloid Angiopathy Pathology in High Alzheimer’s Disease Pathological Load
Abstract: Background: Aberrant motor behavior (AMB) is a neuropsychiatric symptom (NPS) prevalent in Alzheimer’s disease (AD), known to cause great distress to both patients and caregivers. Apolipoprotein E4 (APOE4) is the most important genetic predictor of AD, and it has been associated with high NPS prevalence. Objective: To investigate the neuropathological substrates and risk factors associated with AMB in AD patients. Methods: Cases with Braak stage I-II and CERAD 0-1 were classified as Low AD (LAD), while Braak stage III-IV and CERAD 2 were grouped as Intermediate AD (IAD). Cases with Braak stage V-VI and CERAD 3 were classified as High AD (HAD) in accordance with NIA-Reagan criteria. All cases were stratified by APOE genotype, yielding No ε4 & ε4 and ε4/ε4 groups depending on ε4 copy number within APOE. Presence of AMB was assessed using NPI-Q. Results and Conclusion: AMB increased in parallel with CERAD and Braak & Braak scores. Hypercholesterolemia, but no other cardiovascular risk factors, was associated with AMB in HAD. AMB prevalence in HAD was significantly increased in the presence of two APOE ε4 alleles as compared to No ε4 & ε4. The relationship between homozygous APOE4 and AMB was strongly associated with the presence of both Lewy bodies and cerebral amyloid angiopathy pathologies in both sexes.

Camilla Ferrari, Cristina Polito, Valentina Berti, Gemma Lombardi, Giulia Lucidi, Valentina Bessi, Silvia Bagnoli, Irene Piaceri, Benedetta Nacmias, Sandro Sorbi
High Frequency of Crossed Aphasia in Dextral in an Italian Cohort of Patients with Logopenic Primary Progressive Aphasia
Abstract: Background: Primary progressive aphasia (PPA) has been described as a neurodegenerative language disorder mainly affecting the left hemisphere. Few cases of right hemisphere damage in right-handed PPA subjects have been reported. This condition, named crossed aphasia in dextral (CAD), is relatively rare and probably related to an alteration during neurodevelopment of language networks. Objective: To explore the prevalence of CAD in an Italian cohort of 68 PPA patients, in order to evaluate whether right hemisphere language lateralization could be a risk factor for PPA. Methods: Clinical-demographic and cerebral [18F]-fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) scan were analyzed, resulting in 23 logopenic variant (lvPPA) patients, 26 non-fluent variant (nfvPPA) patients, and 19 semantic variant (svPPA) patients. SPM single subject routine was performed for diagnostic purposes in order to identify the hypometabolic pattern of each patient. Based on brain metabolic profile, PPA patients were divided in right and left lvPPA, nfvPPA, and svPPA. [18F]FDG-PET group analyses were performed with SPM two-sample t-test routine. Results: 26% of lvPPA cases were identified as CAD based on right hypometabolic pattern. CAD patients did not differ from left lvPPA regarding demographic features and general cognitive performance; however, they performed better in specific working memory tasks and showed brain hypometabolism limited to the superior, middle, and supramarginal temporal gyri. Conclusion: Atypical lateralization of language function could determine a vulnerability of the phonological language loop and in that way could be a risk factor for lvPPA.

Sweilem B. Al Rihani, Renny S. Lan, Amal Kaddoumi (Handling Associate Editor: Fabien Gosselet)
Granisetron Alleviates Alzheimer’s Disease Pathology in TgSwDI Mice Through Calmodulin-Dependent Protein Kinase II/cAMP-Response Element Binding Protein Pathway
Abstract: Alzheimer's disease (AD) is characterized by a compromised blood-brain barrier (BBB) and disrupted intracellular calcium homeostasis in the brain. Therefore, rectifying the BBB integrity and restoring calcium homeostasis could provide an effective strategy to treat AD. Recently, we developed a high throughput-screening assay to screen for compounds that enhance a cell-based BBB model integrity, which identified multiple hits among which is granisetron, a Food and Drug Administration approved drug. Here, we evaluated the therapeutic potential of granisetron against AD. Granisetron was tested in C57Bl/6J young and aged wild-type mice, and in a transgenic mouse model of AD namely TgSwDI for its effect on BBB intactness and amyloid-β (Aβ)-related pathology. Our study findings showed that granisetron enhanced BBB integrity in both aged and TgSwDI mice. This effect was associated with an overall reduction in Aβ load and neuroinflammation in TgSwDI mice brains. In addition, and supported by proteomics analysis, granisetron significantly reduced Aβ induced calcium influx in vitro, and rectified calcium dyshomeostasis in TgSwDI mice brains by restoring calmodulin-dependent protein kinase II/cAMP-response element binding protein pathway, which was associated with cognitive improvement. These results support granisetron repurposing as a potential drug to hold, slow, and/or treat AD.

Julia Christl, Sandra Verhülsdonk, Francesca Pessanha, Til Menge, Rüdiger J. Seitz, Milenko Kujovic, Barbara Höft, Tillmann Supprian, Christian Lange-Asschenfeldt
Association of Cerebrospinal Fluid S100B Protein with Core Biomarkers and Cognitive Deficits in Prodromal and Mild Alzheimer’s Disease
Abstract: Background: Increased expression of the astroglial Ca2+-binding protein S100B has been observed in various neurodegenerative diseases and also seems to play a role in the unfolding of pathophysiological events at early stages of Alzheimer’s disease (AD). Objective: To examine the association of cerebrospinal fluid (CSF) levels of S100B with 1) established CSF core biomarkers total tau (tau), hyperphosphorylated tau (p-tau), and amyloid β1-42 (Aβ1-42) as well as neuron-specific enolase (NSE) CSF levels and 2) cognition in early AD and mild cognitive impairment (MCI) due to AD (MCI-AD). Methods: Retrospective study assessing 49 pooled charts of Memory Clinic and inpatients diagnosed with AD (N = 26) and MCI-AD (N = 23) according to the National Institute of Aging and Alzheimer’s Disease Association (NIA-AA) criteria. Neuropsychological testing was performed with the Consortium to Establish a Registry for AD (CERAD)-Plus battery. Results: CSF levels of S100B correlated with NSE, but not the other CSF parameters. Stepwise multiple linear regression, adjusted for age, sex, and educational level, revealed that only increased CSF S100B was independently associated with lower CERAD-Plus total and Mini-Mental Status Examination scores together with poorer performance in wordlist learning (delayed recall and overall performance). We found no independent associations with other CSF biomarkers or cognitive domains. Conclusion: Our data suggest that CSF S100B may have a diagnostic value particularly at early stages of AD reflecting the significance of neuroinflammatory/astroglial processes. Thus, CSF S100B may complement the established array of available AD biomarkers to improve early stage diagnosis.

Ana Pozueta, Carmen Lage, María García-Martínez, Martha Kazimierczak, María Bravo, Sara López-García, Javier Riancho, Andrea González-Suarez, José Luis Vázquez-Higuera, María de Arcocha-Torres, Ignacio Banzo, Julio Jimenez-Bonilla, José Berciano, Eloy Rodríguez-Rodríguez, Pascual Sánchez-Juan
Cognitive and Behavioral Profiles of Left and Right Semantic Dementia: Differential Diagnosis with Behavioral Variant Frontotemporal Dementia and Alzheimer’s Disease
Abstract: Background: Semantic dementia (SD) is a subtype of frontotemporal dementia (FTD) characterized by semantic memory loss and preserved abilities of other cognitive functions. The clinical manifestations of SD require a differential diagnosis with Alzheimer’s disease (AD), especially those with early onset, and behavioral variant FTD (bvFTD). Objective: The present study aimed to compare cognitive performances and neuropsychiatric symptoms in a population of AD, bvFTD, and left and right SD defined with the support of molecular imaging (amyloid and 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography) and assessed the accuracy of different neuropsychological markers in distinguishing these neurodegenerative diseases. Methods: Eighty-seven participants (32 AD, 20 bvFTD, and 35 SD (17 Left-SD and 18 Right-SD) completed a comprehensive neuropsychological battery that included memory, language, attention and executive functions, visuospatial function, visuoconstructional skills, and tasks designed specifically to evaluate prosopagnosia and facial emotions recognition. The Neuropsychiatric Inventory was administered to assess neuropsychiatric symptoms. Results: An episodic memory test that included semantic cues, a visuospatial test (both impaired in AD), a naming test and a prosopagnosia task (both impaired in SD) were the four most valuable cognitive metrics for the differential diagnosis between groups. Several behavioral abnormalities were differentially present, of which aggression, self-care (both more frequent in bvFTD), and eating habits, specifically overeating and altered dietary preference (more frequent in SD), were the most valuable in group discrimination. Conclusion: Our study highlights the value of a comprehensive neuropsychological and neuropsychiatric evaluation for the differential diagnosis between FTD syndromes and AD.

Suyun Li, Wenjun Sun, Dongfeng Zhang
Association of Zinc, Iron, Copper, and Selenium Intakes with Low Cognitive Performance in Older Adults: A Cross-Sectional Study from National Health and Nutrition Examination Survey (NHANES)
Abstract: Background: The association of zinc, iron, copper, and selenium intakes with cognitive function is poorly understood so far. Objective: To examine the associations of dietary and total zinc, iron, copper, and selenium intakes with low cognitive performance. Methods: Cross-sectional study data from the National Health and Nutrition Examination Survey (NHANES) 2011–2014 was used. Zinc, iron, copper, and selenium intakes from foods and supplements were estimated from two non-consecutive 24-hour diet recalls. Cognitive function was measured by the Consortium to Establish a Registry for Alzheimer’s disease (CERAD) Word Learning sub-test, Animal Fluency test, and Digit Symbol Substitution test (DSST). For each cognitive measurement, people whose score were lower than the age group stratified lowest quartile were defined as low cognitive performance. Logistic regression and restricted cubic spline models were applied to examine the associations of dietary and total zinc, iron, copper, and selenium intakes with different measures of low cognitive performance. Results: A total of 2,332 adults aged 60 years or older were included. The association between zinc, iron, copper, and selenium intake and low cognitive performance was significant in different test. Compared with the lowest quartile of total copper intake, the weighted multivariate adjusted ORs (95% CI) of the highest quartile were 0.34 (0.16–0.75) for low cognitive performance in DSST. L-shaped associations between total copper or selenium and low cognitive performance in DSST and animal fluency were found. Conclusion: Dietary and total zinc, copper, and selenium intakes might be inversely associated with the prevalence of low cognitive performance.

Cinzia Bussè, Ilaria Pettenuzzo, Sara Pompanin, Beatrice Roiter, Gian Antonio di Bernardo, Giovanni Zorzi, Federica Fragiacomo, Gianmarco Gazzola, Diego Cecchin, Giorgio Pigato, Annachiara Cagnin
Psychiatric Phenocopy Syndrome of Behavioral Frontotemporal Dementia: Behavioral and Cognitive Fingerprint
Abstract: Behavioral and cognitive variables predicting behavioral frontotemporal dementia (bvFTD) versus primary psychiatric disorders mimicking bvFTD (phenocopy syndrome: bvFTD-PS) were studied. Forty-one probable/definite bvFTD and 16 bvFTD-PS patients were evaluated with cognitive battery, Neuropsychiatric Inventory, and Stereotypic and Ritualistic Behavior-revised questionnaires. Twenty-seven healthy subjects served as control. Severity of cognitive impairment/behavioral symptoms and profile of cognitive deficits were similar, with bvFTD-PS showing impaired executive abilities and memory. However, phonemic fluency was impaired only in bvFTD (p<0.001). Depression was worse in bvFTD-PS, while apathy, disinhibition, and dietary changes characterized bvFTD. Phonemic fluency and depression accounted for the best predictive diagnostic model. A structured psychiatric screening of bvFTD mimickers may often yield a psychiatric diagnosis with predominant depressive symptoms and therefore a potentially treatable condition.

Mohammad Abdullah, Noriyuki Kimura, Hiroyasu Akatsu, Yoshio Hashizume, Taslima Ferdous, Takuto Tachita, Shinsuke Iida, Kun Zou, Etsuro Matsubara, Makoto Michikawa
Flotillin is a Novel Diagnostic Blood Marker of Alzheimer’s Disease
Abstract: Currently, best-characterized indicators for Alzheimer’s disease (AD) diagnosis are the decreased levels of amyloid-β protein 42 and increased levels of phosphorylated tau in cerebrospinal fluid (CSF). The positron emission tomography (PET) imaging with Pittsburgh compound B (PiB) is also used in AD diagnosis by visualizing amyloid deposition in the brain. These methods are invasive or expensive; therefore, less invasive and easily detectable blood biomarkers are required. Because our previous study showed that flotillin release, a marker of exosomes, was attenuated by Aβ, we designed the present study to determine whether flotillin level could be reduced in CSF and/or serum of patients with AD. In this study, we analyzed flotillin levels in CSF and serum of non-AD controls, patients with AD and mild cognitive impairment (MCI) by western blotting. Flotillin levels in cerebroventricular fluid (CVF) and serum of AD, vascular dementia (VaD), and non-AD autopsy cases were also analyzed. Flotillin levels significantly decreased in the CSF and serum of AD patients compared with those of non-AD controls, respectively. Moreover, in patients with MCI due to AD determined by PiB-PET, CSF and serum flotillin levels significantly decreased compared with those of patients with MCI due to non-AD. Flotillin levels remained unchanged in CVF and serum of autopsy cases diagnosed as VaD. Serum flotillin level is negatively associated with brain amyloid deposition indicated as PiB uptake. These results demonstrate that serum flotillin level can serve as one of the blood markers for estimation of brain amyloid deposition and early diagnosis of AD.

Ariana Gatt, David R. Whitfield, Clive Ballard, Patrick Doherty, Gareth Williams
Alzheimer’s Disease Progression in the 5xFAD Mouse Captured with a Multiplex Gene Expression Array
Abstract: Background: Alzheimer’s disease (AD) is an incurable complex neurodegenerative condition with no new therapies licensed in the past 20 years. AD progression is characterized by the up- and downregulation of distinct biological processes that can be followed through the expression level changes of associated genes and gene networks. Objective: Our study aims to establish a multiplex gene expression tracking platform to follow disease progression in an animal model facilitating the study of treatment paradigms. Methods: We have established a multiplex platform covering 47 key genes related to immunological, neuronal, mitochondrial, and autophagy cell types and processes that capture disease progression in the 5xFAD mouse model. Results: We show that the immunological response is the most pronounced change in aged 5xFAD mice (8 months and above), and in agreement with early stage human disease samples, observe an initial downregulation of microglial genes in one-month-old animals. The less dramatic downregulation of neuronal and mitochondrial gene sets is also reported. Conclusion: This study provides the basis for a quantitative multi-dimensional platform to follow AD progression and monitor the efficacy of treatments in an animal model.

Federico Massa*, Lucia Farotti*, Paolo Eusebi, Elisabetta Capello, Massimo E. Dottorini, Cristina Tranfaglia, Matteo Bauckneht, Silvia Morbelli, Flavio Nobili, Lucilla Parnetti(Handling Associate Editor: Laura Bonanni) *These authors contributed equally to this work.
Reciprocal Incremental Value of 18F-FDG-PET and Cerebrospinal Fluid Biomarkers in Mild Cognitive Impairment Patients Suspected for Alzheimer’s Disease and Inconclusive First Biomarker
Abstract: Background: In Alzheimer’s disease (AD) diagnosis, both cerebrospinal fluid (CSF) biomarkers and FDG-PET sometimes give inconclusive results. Objective: To evaluate the incremental diagnostic value of FDG-PET over CSF biomarkers, and vice versa, in patients with mild cognitive impairment (MCI) and suspected AD, in which the first biomarker resulted inconclusive. Methods: A consecutive series of MCI patients was retrospectively selected from two Memory Clinics where, as per clinical routine, either the first biomarker choice is FDG-PET and CSF biomarkers are only used in patients with uninformative FDG-PET, or vice versa. We defined criteria of uncertainty in interpretation of FDG-PET and CSF biomarkers, according to current evidence. The final diagnosis was established according to clinical-neuropsychological follow-up of at least one year (mean 4.4±2.2). Results: When CSF was used as second biomarker after FDG-PET, 14 out of 36 (39%) received informative results. Among these 14 patients, 11 (79%) were correctly classified with respect to final diagnosis, thus with a relative incremental value of CSF over FDG-PET of 30.6%. When FDG-PET was used as second biomarker, 26 out of 39 (67%) received informative results. Among these 26 patients, 15 (58%) were correctly classified by FDG-PET with respect to final diagnosis, thus with a relative incremental value over CSF of 38.5%. Conclusion: Our real-world data confirm the added values of FDG-PET (or CSF) in a diagnostic pathway where CSF (or FDG-PET) was used as first biomarkers in suspected AD. These findings should be replicated in larger studies with prospective enrolment according to a Phase III design.

Ryuji Ochiai, Katsuyoshi Saitou, Chika Suzukamo, Noriko Osaki, Takashi Asada
Effect of Chlorogenic Acids on Cognitive Function in Mild Cognitive Impairment: A Randomized Controlled Crossover Trial
Abstract: Background: Mild cognitive impairment (MCI) is a global-scale issue, due in large part to the rapidly growing elderly population. The main polyphenol contained in coffee beans, chlorogenic acid (CGA), improves attention in healthy individuals. The utility of CGAs for treating MCI, however, has not been evaluated. Objective: To determine the effects of continuous CGA intake on cognitive function, especially attention, in patients diagnosed with MCI. Methods: The study was a randomized controlled crossover trial including 34 patients with MCI. Participants were randomly divided into two groups: Those who first ingested a placebo beverage and those who first ingested an active beverage containing CGAs (553.6 mg/bottle) twice daily for 12 weeks. After a 4-week washout period, the subjects ingested the other beverage (i.e., placebo or active beverage) in the same manner. Endpoint measures included scores on the Japanese version of the Mini-Mental State Examination (MMSE), the Japanese version of the Alzheimer's Disease Assessment Scale-cognitive component (ADAS-cog) testing overall cognitive function, and the Japanese version of the Trail Making Test (TMT-A, TMT-B) testing attention, along with the results of blood tests to evaluate safety. Results: In the TMT-B test, participants had a significantly reduced number of errors while ingesting the CGA beverage as compared with the placebo beverage (p < 0.05), although there was no difference in test completion time. Scores in the MMSE, ADAS-cog, and TMT-A did not differ significantly between conditions. Conclusion: Continuous intake of CGAs appears to improve attention and executive function among cognitive functions in MCI.

Zhao-Jun Wang*, Fang Zhao*, Chen-Fang Wang, Xiu-Min Zhang, Yi Xiao, Fang Zhou, Mei-Na Wu, Jun Zhang, Jin-Shun Qi, Wei Yang (Handling Associate Editor: Xinglong Wang) *These authors contributed equally to this work.
Xestospongin C, a Reversible IP3 Receptor Antagonist, Alleviates the Cognitive and Pathological Impairments in APP/PS1 Mice of Alzheimer’s Disease
Abstract:
Exaggerated Ca2+ signaling might be one of primary causes of neural dysfunction in Alzheimer’s disease (AD). And the intracellular Ca2+ overload has been closely associated with amyloid-β (Aβ)-induced endoplasmic reticulum (ER) stress and memory impairments in AD. Here we showed for the first time the neuroprotective effects of Xestospongin C (XeC), a reversible IP3 receptor antagonist, on the cognitive behaviors and pathology of APP/PS1 AD mice. Male APP/PS1-AD mice (n=20) were injected intracerebroventricularly with XeC (3 μmol) via Alzet osmotic pumps for four weeks, followed by cognition tests, Aβ plaque examination, and ER stress-related protein measurement. The results showed that XeC pretreatment significantly improved the cognitive behavior of APP/PS1-AD mice, raising the spontaneous alteration accuracy in Y maze, decreasing the escape latency and increasing the target quadrant swimming time in Morris water maze; XeC pretreatment also reduced the number of Aβ plaques and the overexpression of ER stress proteins 78 kDa glucose-regulated protein (GRP-78), caspase-12, and CAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) in the hippocampus of APP/PS1 mice. In addition, in vitro experiments showed that XeC effectively ameliorated Aβ1-42-induced early neuronal apoptosis and intracellular Ca2+ overload in the primary hippocampal neurons. Taken together, IP3R-mediated Ca2+ disorder plays a key role in the cognitive deficits and pathological damages in AD mice. By targeting the IP3R, XeC might be considered as a novel therapeutic strategy in AD.

Robert H. Unger, Patrick M. Flanigan, Mitra Khosravi, James B. Leverenz, Babak Tousi
Clinical and Imaging Characteristics Associated with Color Vision Impairment in Lewy Body Disease
Abstract: Background: Color vision impairment (CVI) has been reported in dementia with Lewy bodies (DLB) and prodromal Lewy body disease (pro-LBD). Objective: In order to better characterize the diagnostic value of CVI testing, we compared the prevalence of CVI patients with Lewy body disease compared to Alzheimer’s disease (AD), and we examined clinical and imaging characteristics associated with CVI in patients with DLB and suspected pro-LBD. Methods: We retrospectively reviewed medical records, dopamine transporter (DaT-SPECT) imaging, and volumetric MRI from patients with AD, DLB, and suspected pro-LBD who underwent an online Farnsworth D-15 color vision test. Results: 111 patients (62 DLB, 25 pro-LBD, and 24 AD) were included with a median age of 75 years. Newly diagnosed CVI was present in 67% of patients with DLB, 44% of patients with pro-LBD, and 18% of patients with AD. In patients with DLB, CVI was associated with lower Montreal Cognitive Assessment (MoCA) scores and lower sub-scores in visuospatial/executive function, naming, and language. In a multivariable logistic regression model, a diagnosis of DLB or pro-LBD compared to AD, and a lower combined MoCA score in visuospatial/executive function, naming, and language were associated with CVI controlling for age and gender. Among 17 DLB patients who underwent volumetric MRI, patients with CVI (n = 9) demonstrated lower normative volumetric percentiles in the right transverse superior temporal lobe. Conclusion: We provide further evidence that CVI can help differentiate DLB from AD, and we suggest that CVI may be an indicator of cognitive decline and disease progression in DLB.

Alessandra Danese, Angela Federico, Alice Martini, Elisa Mantovani, Chiara Zucchella, Matteo Tagliapietra, Stefano Tamburin, Tiziana Cavallaro, Vincenzo Marafioti, Salvatore Monaco, Giulia Turri
QTc Prolongation in Patients with Dementia and Mild Cognitive Impairment: Neuropsychological and Brain Imaging Correlations
Abstract: The QTc interval is the electrocardiographic manifestation of ventricular depolarization and repolarization. This marker is often prolonged in acute and chronic neurological conditions. The cause of the cerebrogenic QT prolongation remains unclear. The aim of the study was to analyze the relation between QTc interval and the degree of cognitive impairment and structural brain imaging changes in patients with dementia and mild cognitive impairment (MCI). To this aim, 269 patients were screened, of whom 61 met one or more exclusion criteria. The remaining 208 patients (56 control subjects, 44 patients with MCI, and 108 with dementia) were recruited. Eighty-five patients using drugs causing prolongation of QT interval were further excluded. The QT interval was measured manually in all 12 leads by a single blinded observer, assuming the longest QT value adjusted for heart rate by using the Bazett’s formula. All patients underwent a structural brain imaging and the following measures were obtained: the bicaudate ratio and the periventricular hyperintensity and deep white matter hyperintensity using the modified Fazekas scale. Prolonged QTc interval was prevalent in 1) patients with dementia, especially in those with moderate-severe degree; 2) subjects with impairment of praxis and attention, low functional status, and behavioral symptoms; 3) patients with global and temporal atrophy and with higher scores on the Fazekas or leukoaraiosis scales. Degenerative and vascular processes might play a main role in QTc interval prolongation because of the damage to brain areas involved in the control of the autonomic cardiac nervous system.

Hugo Lövheim, Maria Gustafsson, Ulf Isaksson, Stig Karlsson, Per-Olof Sandman
Gottfries’ Cognitive Scale for Staff Proxy Rating of Cognitive Function Among Nursing Home Residents
Abstract: Background: For research purposes, there is a need for tools to assess an individual’s level of cognitive function. For survey-based investigations in nursing home contexts, proxy ratings allow the assessment also of individuals with severe cognitive impairment. Objective: The aim of this study was to describe the feasibility and psychometric properties of Gottfries’ cognitive scale when used in a nursing home context for proxy rating of cognitive function. Method: The psychometric properties of Gottfries’ cognitive scale were investigated in a sample of 8,492 nursing home residents in Västerbotten County, Sweden, using item response theory and classic scale theory-based approaches. Results: Cognitive function could be scored in 97.1% of the assessed individuals. The scale had a negligible floor effect, it had items with a large spread in difficulties, it appeared linear, and it distributed the assessed individuals equally over the scale. Internal consistency (Cronbach’s alpha) was 0.967, and an exploratory factor analysis revealed three factors of the scale – interpreted to represent orientation to time, to place, and to person. Conclusion: Gottfries’ cognitive scale is a feasible tool for grading cognitive function among nursing home residents using staff proxy ratings. The scale has excellent psychometric properties with a very high internal consistency, a favorable distribution of item difficulties producing an almost rectangular distribution of scores, and a negligible floor effect. The scale thus can be recommended for use in survey-based investigations in nursing home contexts.

IL Han Choo, Ari Chong, Ji Yeon Chung, Hoowon Kim (Handling Associate Editor: Sang Won Seo)
Association of Subjective Memory Complaints with the Left Parahippocampal Amyloid Burden in Mild Cognitive Impairment
Abstract: Background: Subjective memory complaints (SMC) are a risk factor for Alzheimer’s disease. Objective: We aimed to explore the association between SMC and regional amyloid-β (Aβ) deposition in mild cognitive impairment (MCI). Methods: Sixty-eight individuals with MCI were recruited. [18F]Florbetaben PET scans were performed. T1-weighted 3D volumes were also acquired for co-registration with PET and for defining the regions of interest (ROI). Two step exploratory partial correlation analyses between SMC and Aβ deposition were performed with covariates of age, sex, education, and depression. Furthermore, for the priori ROI that had the most significant partial correlation, we investigated the correlation between the SMC and regional Aβ burden using a multiple linear regression model controlling for depression, age, sex, and education. Results: Significant positive correlations between the SMC and Aβ burden was found in the medial temporal ROI (first step) and in the left parahippocampus ROI (second step). In the priori left parahippocampus, we found significant correlation between the SMC and Aβ burden (R2 = 0.473, p = 0.014). Conclusions: Our study suggested that the SMC was associated with amyloid accumulation, especially in the left parahippocampus, in individuals with MCI.

Anne G. Ording, Katalin Veres, Erzsébet Horváth-Puhó, M. Maria Glymour, Mikael Rørth, Victor W. Henderson, Henrik T. Sørensen (Handling Associate Editor: David Knopman)
Alzheimer’s and Parkinson’s Diseases and the Risk of Cancer: A Cohort Study
Abstract: Observational studies have shown inverse associations between neurological diseases, particularly dementia, and subsequent cancer risk, but is unknown whether this association is valid or arises from bias. We conducted a Danish nationwide cohort study using population-based health registries (1980–2012). The study included patients with dementia (n=173,434) and with Parkinson’s disease (n=28,835). We followed patients for 10 years to assess subsequent cancer diagnoses. We computed absolute reduction in cancer risk attributable to dementia or Parkinson’s disease (expected minus the observed number of cancer cases divided by the person time) and standardized incidence rate ratios (SIRs) as the observed to expected number of cancers, based on sex-, age-, and calendar year-standardized national incidence rates. During 10 years, the reduction in cancer cases were 79.9 per 10,000 person-years for Alzheimer’s disease [SIR= 0.68 (95% CI: 0.66, 0.70)], 74.4 per 10,000 person-years for vascular dementia [SIR=0.71 (95% CI: 0.67, 0.74)], 55.8 per 10,000 person-years [SIR=0.77 (95% CI: 0.75, 0.78)] for all-cause dementia, and 4.0 per 10,000 person-years [SIR= 0.98 (95% CI: 0.95, 1.02) for Parkinson’s disease. Associations were nearly similar for solid tumors diagnosed at localized, regional, or distant stages. We found an inverse association between dementia and cancer risk, with similar associations when considering only cancers diagnosed at distant stage. The cancer risk varied by type of dementia, with a gradient toward a stronger protective effect associated with Alzheimer’s disease and vascular dementia, which may favor a biological explanation. Overall results do not show an inverse association between Parkinson’s disease and cancer.

Marzena Ułamek-Kozioł, Stanisław J. Czuczwar, Janusz Kocki, Sławomir Januszewski, Jacek Bogucki, Anna Bogucka-Kocka, Ryszard Pluta
Dysregulation of Autophagy, Mitophagy, and Apoptosis Genes in the CA3 Region of the Hippocampus in the Ischemic Model of Alzheimer’s Disease in the Rat
Abstract: There is currently no knowledge about the expression profile of the autophagy (BECN1), mitophagy (BNIP3), and apoptosis (CASP3) genes in the CA3 region of the hippocampus after cerebral ischemia. In addition, it is unknown whether genes for BECN1, BNIP3, and CASP3 have any effect on the neuronal death in the CA3 area of the hippocampus due to ischemia. In this study, for the first time, we present, by means of a quantitative PCR protocol with reverse transcriptase, the expression of BECN1 and CASP3 genes in the neuronal CA3 region of the hippocampus with the co-expression of the mitochondrial BNIP3 gene, which genes are associated with Alzheimer's disease, in the ischemic model of Alzheimer's disease in the rat. The present study showed that after ischemia, the CASP3 gene was significantly expressed within 7-30 days, the BECN1 gene was significantly overexpressed on the thirtieth day, and the BINP3 gene was lowered below control values during post-ischemic follow-up period. The caspase-dependent neuronal death in the CA3 region of the hippocampus after ischemia is not accompanied by overexpression of the BNIP3 gene. Our data may therefore suggest a new insight into the BNIP3 gene in the regulation of neuronal mitophagy in neurodegeneration in the CA3 region of the hippocampus after ischemia. This indicates no involvement of the BNIP3 gene along with the CASP3 gene in the CA3 region of the hippocampus in delayed neuronal death after brain ischemia.

Natalia Valech-Torres*, Gonzalo Sánchez-Benavides*, Adrià Tort-Merino, Nina Coll-Padrós, Jaume Olives, María León, Carles Falcon, José Luis Molinuevo, Lorena Rami *These authors contributed equally to this work.
Associations Between the Subjective Cognitive Decline-Questionnaire’s Scores, Gray Matter Volume, and Amyloid-β Levels
Abstract: Background: Exploring the relationship between Alzheimer’s disease (AD) biomarkers and subjective cognitive decline (SCD) is needed for better defining its clinical meaning in preclinical AD (preAD). Objective: To assess the association between the Subjective Cognitive Decline Questionnaire (SCD-Q), gray matter (GM), and cerebrospinal fluid amyloid-β (Aβ). Methods: 56 cognitively healthy older adults and their informants answered the SCD-Q. Correlations between GM and SCD-Q scores were explored using structural voxel-based morphometry models including Aβ levels. SCD-Q*Aβ vectors were calculated with higher scores reflecting higher SCD and cerebral amyloid, simultaneously. Subjects were classified according to their perception of cognitive worsening in the last two years, exploring for GM differences between-groups. Results: Higher self-reported SCD-Q scores correlated with reduced GM in the right frontal lobe and increased volumes in the occipital lobe, calcarine sulcus, fusiform gyrus, and cerebellum, while higher informant’s scores correlated with increased GM in the right middle temporal gyrus. Correlations were more significant for SCD-Q language items, self-complaints, and more positive than negative correlations were found. The SCD-Q*Aβ vectors were negatively associated with GM both in self and informant’s reports. Finally, lower Aβ levels related to lower GM in subjects who noticed cognitive worsening, but related to higher GM in subjects who have not noticed this decline. Conclusions: Our results suggest that SCD-Q scores relate with incipient brain changes that may be due to preAD. Independent studies are needed to confirm our observations.

Amanda Douglass, Mark Walterfang, Dennis Velakoulis, Larry Abel
Visual Search in Behavioral Variant Frontotemporal Dementia
Abstract: Background: Changes to visual search have shown specific patterns in a number of dementia subtypes. The cortical regions involved in the control of visual search overlap with the regions affected in behavioral variant frontotemporal dementia (bvFTD). Previous literature has examined visual search in bvFTD with smaller array sizes. Objective: To examine the pattern of behavior shown by bvFTD patients while undertaking visual search in the presence of larger numbers of distractors to model increased cognitive load. Methods: 15 bvFTD and 17 control participants undertook three visual search tasks: color, orientation, and conjunction searches. A wide range of array sizes was used, from 16 to 100 items arranged as a square. Behavior was quantified using accuracy, response time, and eye movements. Results: bvFTD participants displayed a reduction in accuracy and an increased response time across all task types. bvFTD participants displayed an increase in number of objects examined and number of fixations made for color and conjunction tasks. Fixation duration was increased for orientation and conjunction (the more difficult tasks) but not color search. Results indicated the increase in fixation duration to be due to an increased intercept, with no significant difference in slope for the different tasks. Conclusion: bvFTD participants display a pattern of visual search behavior consisting of a decrease in accuracy, an increase in response time, and a corresponding increase in the number and length of eye movements made during visual search. The pattern seen corresponds to studies of frontal lobe damage, while differing in pattern from that seen in a range of other cognitive conditions.

Jianping Jia, Yong Ji, Tao Feng, Qinyong Ye, Dantao Peng, Weihong Kuang, Yuping Ning, Zhihou Liang, Dongsheng Fan, Wenshi Wei, Yansheng Li, Shifu Xiao
Sixteen-Week Interventional Study to Evaluate the Clinical Effects and Safety of Rivastigmine Capsules in Chinese Patients with Alzheimer’s Disease
Abstract: Background: Rivastigmine is a cholinesterase inhibitor, approved for the treatment of mild-to-moderate dementia of Alzheimer's type. Objective: To explore the efficacy and safety of the maximal tolerated dose of rivastigmine capsules in Chinese patients with mild-to-moderate Alzheimer’s disease (AD). Methods: The study was a multicenter, open-label, single-arm, phase IV clinical study in mild-to-moderate drug-naïve AD patients treated with rivastigmine capsules. The primary endpoint was the changes in the total scores of Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) from baseline to week 16. Secondary endpoints included changes in the scores of the following assessment scales and safety: Alzheimer’s Disease Cooperative Study; Activities of Daily Living; Mini-Mental Status Examination (MMSE); Neuropsychiatry Index (NPI), and Caregiver Burden Inventory. Results: 222 patients were enrolled. Of these, 136 (75.1%) patients received and maintained the effective dose (≥6 mg/d) of rivastigmine for at least 4 weeks. The ADAS-Cog scale score improved in rivastigmine-treated patients at week 16 compared with baseline (p<0.001) by 2.0 (95% CI: –3.0 to –1.1) points, which met the pre-defined superiority criteria. NPI-10 and NPI-12 scores improved by 3.6 and 4.0 points at week 16 (p=0.001, p<0.001), respectively. A total of 107 patients (59.1%) experienced adverse effects (AEs) during the study; common AEs included nausea (20.5%), vomiting (16.6%), anorexia (7.8%), dizziness (7.7%), and diarrhea (7.2%). Conclusion: This was the first phase IV study on rivastigmine in mainland China. The study preliminarily demonstrated that rivastigmine capsules showed good tolerability and efficacy in mild-to-moderate AD patients with the maximal tolerated dose.

Farhan Ali, Stephanie L. Baringer, Arianna Neal, Esther Y. Choi, Alex C. Kwan (Handling Associate Editor: Oliver Wirths)
Parvalbumin-Positive Neuron Loss and Amyloid-β Deposits in the Frontal Cortex of Alzheimer’s Disease-Related Mice
Abstract: Alzheimer’s disease (AD) has several hallmark features including amyloid-β (Aβ) plaque deposits and neuronal loss. Here, we characterized Aβ plaque aggregation and parvalbumin-positive (PV) GABAergic neurons in 6–9-month-old 5xFAD mice harboring mutations associated with familial AD. We used immunofluorescence staining to compare three regions in the frontal cortex—prelimbic (PrL), cingulate (Cg, including Cg1 and Cg2), and secondary motor (M2) cortices—along with primary somatosensory (S1) cortex. We quantified the density of Aβ plaques, which showed significant laminar and regional vulnerability. There were more plaques of larger sizes in deep layers compared to superficial layers. Total plaque burden was higher in frontal regions compared to S1. We also found layer- and region-specific differences across genotype in the density of PV interneurons. PV neuron density was lower in 5xFAD mice than wild-type, particularly in deep layers of frontal regions, with Cg (-50%) and M2 (-39%) exhibiting the largest reduction. Using in vivo two-photon imaging, we longitudinally visualized the loss of frontal cortical PV neurons across four weeks in the AD mouse model. Overall, these results provide information about Aβ deposits and PV neuron density in a widely used mouse model for AD, implicating deep layers of frontal cortical regions as being especially vulnerable.

Caroline Liechti*, Marco P. Caviezel*, Stephan Müller*, Carolin F. Reichert, Pasquale Calabrese, Christoph Linnemann, Tobias Melcher, Thomas Leyhe (Handling Associate Editor: Panos Alexopoulos) *These authors contributed equally to this work.
Correlation Between Hippocampal Volume and Autobiographical Memory Depending on Retrieval Frequency in Healthy Individuals and Patients with Alzheimer’s Disease
Abstract: The hippocampus plays an indispensable role in episodic memory, particularly during the consolidation process. However, its precise role in retrieval of episodic memory is still ambiguous. In this study, we investigated the correlation of hippocampal morphometry and the performance in an autobiographical memory task in 27 healthy controls and 24 patients suffering from Alzheimer’s disease (AD). Most importantly, correlations were defined separately and comparatively for memory contents with different retrieval frequency in the past. In healthy subjects, memory performance for seldom retrieved autobiographical events was significantly associated with gray matter density in the bilateral hippocampus, whereas this correlation was not present for events with high retrieval frequency. This pattern of findings confirms that retrieval frequency plays a critical role in the consolidation of episodic autobiographical memories, thereby making them more independent of the hippocampal system. In AD patients, on the other hand, successful memory retrieval appeared to be related to hippocampal morphometry irrespective of the contents’ retrieval frequency, comprising events with high retrieval frequency, too. The observed differences between patients and control subjects suggest that AD-related neurodegeneration not only impairs the function, but also decreases the functional specialization of the hippocampal memory system, which, thus, may be considered as marker for AD.

Shao-Yang Wang*, Wei Chen*, Wei Xu, Jie-Qiong Li, Xiao-He Hou, Ya-Nan Ou, Jin-Tai Yu, Lan Tan (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
Neurofilament Light Chain in Cerebrospinal Fluid and Blood as a Biomarker for Neurodegenerative Diseases: A Systematic Review and Meta-Analysis
Abstract: Background: Neurofilament light chain (NFL) as a potential biomarker of neurodegenerative diseases has been studied in a number of studies. Thus, a comprehensive meta-analysis is warranted to assess NFL performance in neurodegenerative diseases. Objective: To assess the performance of NFL in blood and cerebrospinal fluid (CSF) as a biomarker for neurodegenerative diseases. Methods: A total of 36 studies with comparison of NFL level between individuals with neurodegenerative diseases and controls were retrieved from PubMed, Web of Science and Science Direct, and the ratio of means method and delta method based on the random-effect model were used to analyze the differentiation of NFL between patients and controls. Results: Differentiation of CSF NFL between patients with neurodegenerative diseases and controls showed significant results. Although a few studies on blood NFL available were included in the meta-analysis, the results still showed a distinct possibility that NFL could be a potential biomarker for neurodegenerative diseases. NFL levels were increased significantly in dementias, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, and Huntington’s disease. By contrast, NFL levels were not increased in Parkinson’s disease (PD), although they were increased significantly in PD-related disorders (multiple system atrophy and progressive supranuclear palsy). Conclusions: In our study, in addition to PD, NFL was suggested to be a global diagnostic biomarker for neurodegenerative diseases. Moreover, it could be used in differential diagnosis of PD and PD-related disorders. However, it was worth noting that NFL was not appropriate for diagnosis or differential diagnosis without clinical symptoms and other auxiliary examinations.

Book Review
Jack C. Lennon
Review of Dementia Reimagined: Building a Life of Joy and Dignity from Beginning to End by Tia Powell
Abstract: This review of Dementia Reimagined: Building a Life of Joy and Dignity from Beginning to End by Dr. Tia Powell describes its unique, scientifically-informed approach to the topics of caring for family members with dementia within the confines of the current United States healthcare system and preparing for their long-term care. Her book serves to provide an important account of many difficulties confronted along the course of dementia, ultimately seeking compassionate, dignified care for a loved one during the many years following diagnosis that allow for the experiencing of life’s joys that are unique to each individual. This book is tailored to a broad readership, providing information for all individuals caring for people with dementia, and maintains a candid voice as it relates to our pursuit of curative treatments for an incurable illness. This review raises further questions related to how autonomy and beneficence can be amplified when interdisciplinary conflicts arise, as well as how education reform may improve patient care.