Volume 73, Number 3, IN PROGRESS

Review
Xiaoni Wang*, Yu Sun*, Taoran Li, Yanning Cai, Ying Han (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
Amyloid-β as a Blood Biomarker for Alzheimer's Disease: A Review of Recent Literature

Abstract: Alzheimer’s disease (AD), the main cause of dementia, is characterized by the aggregation of amyloid-β (Aβ). This pathophysiological process starts many years to decades before the onset of clinical symptoms. Cerebrospinal fluid analysis and amyloid positron emission tomography scans are two standard methods to measure brain Aβ, but their invasive nature and expense limit their usage as screening tools. Therefore, peripheral Aβ studies have grown exponentially during the past few years. In this review, we discuss recent studies on plasma Aβ and its potential as a reliable biomarker of AD.

Review
Gada Musa, Andrea Slachevsky, Carlos Muñoz-Neira, Carolina Méndez, Roque Villagra, Christian González-Billault, Agustín Ibáñez, Michael Hornberger, Patricia Lillo (Handling Associate Editor: Paulo Caramelli)
Alzheimer’s Disease or Behavioral Variant Frontotemporal Dementia? Review of Key Points Toward an Accurate Clinical and Neuropsychological Diagnosis
Abstract:
Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the most common neurodegenerative early-onset dementias. Despite the fact that both conditions have a very distinctive clinical pattern, they present with an overlap in their cognitive and behavioral features that may lead to misdiagnosis or delay in diagnosis. The current review intends to summarize briefly the main differences at the clinical, neuropsychological, and behavioral levels, in an attempt to suggest which aspects would facilitate an adequate diagnosis in a clinical setting, especially in Latin American and low- and middle-income countries, where the resources needed for a differential diagnosis (such as MRI or biomarkers) are not always available. A timely diagnosis of AD and FTD have significant implications for the medical management and quality of life of patients and careers.

Review
Miao Sun*, Kai Ma*, Jie Wen, Guangxian Wang, Changliang Zhang, Qi Li, Xiaofeng Bao, Hui Wang *These authors contributed equally to this work.
A Review of the Brain-Gut-Microbiome Axis and the Potential Role of Microbiota in Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is a neurodegenerative process characterized by loss of neurons in the hippocampus and cerebral cortex, leading to progressive cognitive decline. Pathologically, the hallmark of AD is accumulation of “senile” plaques composed of amyloid-β (Aβ) protein surrounding neurons in affected regions. Despite extensive research into AD pathogenesis and therapeutic targets, there remains no breakthroughs in its management. In recent years, there has been a spark of interest in the connection between the brain and gastrointestinal tract, referred to as the brain-gut axis, and its potential implications for both metabolic and neurologic disease. Moreover, the gastrointestinal flora, referred to as the microbiome, appears to exert significant influence over the brain-gut axis. With the need for expanded horizons in understanding and treating AD, many have turned to the brain-gut-microbiome axis for answers. Here we provide a review of the brain-gut-microbiome axis and discuss the evidence supporting alterations of the axis in the pathogenesis of AD. Specifically, we highlight the role for the microbiome in disruption of Aβ metabolism/clearance, increased permeability of the blood-brain barrier and modulation of the neuroinflammatory response, and inhibition of hippocampal neurogenesis. The majority of the above described findings are the result of excellent, albeit basic and pre-clinical studies. Therefore, we conclude with a brief description of documented clinical support for brain-gut-microbiome axis alteration in AD, including potential microbiome-based therapeutics for AD. Collectively, these findings suggest that the brain-gut-microbiome axis may be a “lost link” in understanding and treating AD and call for future work.

Short Communication
Sally Fowler-Davis, Deborah Barnett, John Kelley, David Curtis
Potential for Digital Monitoring to Enhance Wellbeing at Home for People with Mild Dementia and Their Family Carers
Abstract: Digital technologies have the potential to assist people with dementia to monitor day to day activities and mitigate the risks of living independently. This purposive pilot study surveyed participants for frailty, wellbeing, and perceived carer burden using the 3Rings™ digital plug. 30 paired participants used the digital device for four months. People with dementia reported a decline in wellbeing and increased frailty. Family carers reported a decline in wellbeing but 18 reported a reduction in burden. The use of digital monitoring by family carers demonstrated a reduction in their perceived burden and the device was acceptable to people with mild dementia living alone.

Seok Jong Chung*, Seun Jeon*, Han Soo Yoo, Yang Hyun Lee, Mijin Yun, Seung-Koo Lee, Phil Hyu Lee, Young Ho Sohn, Alan C. Evans, Byoung Seok Ye (Handling Associate Editor: Sang Won Seo) *These authors contributed equally to this work.
Neural Correlates of Cognitive Performance in Alzheimer’s Disease- and Lewy Bodies-Related Cognitive Impairment
Abstract: Background: Clinicopathological studies have demonstrated that the neuropsychological profiles and outcomes are different between two dementia subtypes, namely Alzheimer’s disease (AD) and Lewy bodies-related disease. Objective: We investigated the neural correlates of cognitive dysfunction in patients with AD-related cognitive impairment (ADCI) and those with Lewy bodies-related cognitive impairment (LBCI). Methods: We enrolled 216 ADCI patients, 183 LBCI patients, and 30 controls. Cortical thickness and diffusion tensor imaging analyses were performed to correlate gray matter and white matter (WM) abnormalities to cognitive composite scores for memory, visuospatial, and attention/executive domains in the ADCI spectrum (ADCI patients and controls) and the LBCI spectrum (LBCI patients and controls) separately. Results: Memory dysfunction correlated with cortical thinning and increased mean diffusivity in the AD-prone regions, particularly the medial temporal region, in ADCI. Meanwhile, it only correlated with increased mean diffusivity in the WM adjacent to the anteromedial temporal, insula, and basal frontal cortices in LBCI. Visuospatial dysfunction correlated with cortical thinning in posterior brain regions in ADCI, while it correlated with decreased fractional anisotropy in the corpus callosum and widespread WM regions in LBCI. Attention/executive dysfunction correlated with cortical thinning and WM abnormalities in widespread brain regions in both disease spectra; however, ADCI had more prominent correlation with cortical thickness and LBCI did with fractional anisotropy values. Conclusions: Our study demonstrated that ADCI and LBCI have different neural correlates with respect to cognitive dysfunction. Cortical thinning had greater effects on cognitive dysfunction in the ADCI, while WM disruption did in the LBCI.

Takashi Waki, Sachiko Tanaka-Mizuno, Naoyuki Takashima, Hajime Takechi, Takehito Hayakawa, Katsuyuki Miura, Hirotsugu Ueshima, Yoshikuni Kita, Hiroko H. Dodge (Handling Associate Editor: Jessica Kirkland Caldwell)
Waist Circumference and Domain-Specific Cognitive Function Among Non-Demented Japanese Older Adults Stratified by Sex: Results from the Takashima Cognition Study
Abstract: Background: While being obese in mid-life is associated with an increased risk of dementia and cognitive decline in late-life, being obese in late-life is shown to be associated with a lower risk of these outcomes in some studies. This phenomenon is known as the “obesity paradox”, but the underlying reasons and potential sex difference have not been well understood. Objective: To investigate the association between cognition and waist circumference (WC), an alternative measure of body fat which can be measured easier than body mass index (BMI), among older adults in each generation of late-life for men and women separately. Methods: Three hundred thirty-five participants were used in the current study who were identified by random sampling of residents aged 65-74, 75-84, and 85+ years in Takashima County, Shiga Prefecture, Japan during 2005-2006. Associations between WC and domain-specific cognitive functions measured by 12 neuropsychological tests were examined using multivariable linear regression models with covariates: age, education, and hypertension. Results: Larger WC was associated with better attention/working memory among 65-74-year old women and with better learning/acquisition among 65-74-year-old men, while larger WC was associated with worse learning/acquisition, memory, attention/working memory, and language/fluency among 75-84-year old men. Conclusion: We found age and sex differences in the association between WC and domain-specific cognitive functions. Among older old men (age 75-84) larger WC had negative effects on various domains including memory, attention, language, and executive functions, while we did not find any negative effects of larger WC on cognition among women in any age groups.

Nawaf Yassi, Saima Hilal, Ying Xia, Yen Ying Lim, Rosie Watson, Hugo Kuijf, Christopher Fowler, Paul Yates, Paul Maruff, Ralph Martins, David Ames, Christopher Chen, Christopher Rowe, Victor Villemagne, Olivier Salvado, Patricia M. Desmond, Colin L. Masters (Handling Associate Editor: Greg Kennedy)
Influence of Comorbidity of Cerebrovascular Disease and Amyloid-β on Alzheimer’s Disease
Abstract: Background: Quantifying the contribution of cerebrovascular disease to the clinical and pathological profile of Alzheimer’s disease is challenging. Objective: We aimed to determine the influence of cerebrovascular disease, amyloid-β (Aβ), and their comorbidity on cognitive decline, hippocampal atrophy, and Aβ deposition, by evaluating data from the Australian Imaging, Biomarker and Lifestyle Study of Ageing. Methods: Two-hundred and eighteen participants underwent Aβ PET, MRI, and cognitive assessment at 18-month intervals for up to 90 months. Aβ status was determined on baseline PET. Participants were also classified as V+ on baseline MRI if they had ≥1 large cortical infarcts, subcortical infarcts, or cortical cerebral microinfarcts; or white matter hyperintensity volume greater than the 90th percentile of healthy controls. Linear mixed models were conducted comparing slopes of change in cognition, hippocampal volume, and Aβ load between the four resultant groups. Results: Mean age at baseline was 74 years (range 59-96). One-hundred and fifteen participants were cognitively normal, 54 had mild cognitive impairment, and 49 had Alzheimer’s disease. Compared to the Aβ-/V- group, the Aβ+/V- and Aβ+/V+ groups showed significantly faster cognitive decline and hippocampal atrophy over 90 months. V+ status was associated with greater cognitive decline (Cohen’s d=0.85, p<0.001) and hippocampal atrophy (d=2.05, p<0.001) in the Aβ+ group but not in the Aβ- group. V+ status was not associated with Aβ accumulation in any group. Conclusion: Comorbidity of cerebrovascular disease and Aβ was associated with cognitive decline and neurodegeneration. Cerebrovascular disease was not associated with the rate of Aβ accumulation.

Ruihua Sun, Huayuan Wang, Yingying Shi, Zhikun Sun, Haisong Jiang, Jiewen Zhang
Changes in the Morphology, Number, and Pathological Protein Levels of Plasma Exosomes May Help Diagnose Alzheimer's Disease
Abstract: Exosomes are nano-sized extracellular vesicles that are secreted by cells and usually found in body fluids. Since they freely cross the blood-brain barrier, neuronal exosomes respond directly to changes in the brain’s environment. Recent studies have shown that exosomes contain both amyloid-β (Aβ) and tau proteins and have a controversial role in the Alzheimer’s disease (AD) process. In this study, enzyme-linked immunosorbent assay was used to detect the levels of P-S396-tau and Aβ1-42 in plasma exosomes. We found that levels of P-S396-tau and Aβ1-42 in plasma exosomes of AD patients were significantly higher compared to those in matched healthy controls. The difference between plasma exosomes of AD patients and those of matched healthy controls was determined using transmission electron microscopy and nanoparticle tracking analysis. Exosomes from AD patients were smaller and lower in quantity. These data together may provide a basis for early diagnosis of AD.

Yanying Liu, Hongmin Wang
Modeling Sporadic Alzheimer’s Disease by Efficient Direct Reprogramming of the Elderly Derived Disease Dermal Fibroblasts into Neural Stem Cells
Abstract: Alzheimer’s disease (AD) is a devastating neurodegenerative disorder, neuropathologically characterized by hyperphosphorylation of tau and formation of amyloid plaques. Most AD cases are sporadic with no clear cause. Cell models play an important role in understanding the pathogenesis of sporadic AD, and the cell reprogramming and epigenetic techniques have provided new avenue to model the disorder. However, since most sporadic AD patients are late-onset, it poses a challenge to reprogram elderly somatic cells into stem cells. Here, we report that combination of overexpressing a single transcription factor, hSOX, with nine small molecules, was able to directly reprogram elderly (55-75 years of age) sporadic AD and the age-matched healthy individual dermal fibroblasts into the induced neural stem cells (iNSCs). These cells possessed the typical neural stem cell properties and were able to be further differentiated into neurons and glia in vitro and in vivo. More importantly, AD iNSC-derived neurons showed hyperphosphorylation at several sites of tau and increased release of Aβ into culture medium, indicating the replication of the major neuropathological hallmarks. Thus, we described a new technique to directly convert elderly AD dermal fibroblasts into iNSCs that may serve as a useful tool for studying the pathogenesis of sporadic AD and for drug discovery to treat the disorder.

Thabat Khatib, David R. Chisholm, Andrew Whiting, Bettina Platt, Peter McCaffery
Decay in Retinoic Acid Signaling in Varied Models of Alzheimer’s Disease and In-Vitro Test of Novel Receptor Acid Receptor Ligands (RAR-Ms) to Regulate Protective Genes
Abstract: Retinoic acid has been previously proposed in the treatment of Alzheimer’s disease (AD). Here, five transgenic mouse models expressing AD and frontotemporal dementia risk genes (i.e., PLB2APP, PLB2TAU, PLB1Double, PLB1Triple, and PLB4) were used to investigate if consistent alterations exist in multiple elements of the retinoic acid signaling pathway in these models. Many steps of the retinoic acid signaling pathway including binding proteins and metabolic enzymes decline, while the previously reported increase in RBP4 was only consistent at late (6 months) but not early (3 month) ages. The retinoic acid receptors were exceptional in their consistent decline in mRNA and protein with transcript decline of retinoic acid receptors β and γ by 3 months, before significant pathology, suggesting involvement in early stages of disease. Decline in RBP1 transcript may also be an early but not late marker of disease. The decline in the retinoic acid signaling system may therefore be a therapeutic target for AD and frontotemporal dementia. Thus, novel stable retinoic acid receptor modulators (RAR-Ms) activating multiple genomic and non-genomic pathways were probed for therapeutic control of gene expression in rat primary hippocampal and cortical cultures. RAR-Ms promoted the non-amyloidogenic pathway, repressed lipopolysaccharide induced inflammatory genes and induced genes with neurotrophic action. RAR-Ms had diverse effects on gene expression allowing particular RAR-Ms to be selected for maximal therapeutic effect. Overall the results demonstrated the early decline of retinoic acid signaling in AD and frontotemporal dementia models and the activity of stable and potent alternatives to retinoic acid as potential therapeutics.

Mattias Göthlin, Marie Eckerström, Magnus Lindwall, Sindre Rolstad, Carl Eckerström, Michael Jonsson, Petronella Kettunen, Johan Svensson, Anders Wallin
Latent Cognitive Profiles Differ Between Incipient Alzheimer’s Disease and Dementia with Subcortical Vascular Lesions in a Memory Clinic Population
Abstract: Background: It is unclear if latent cognitive profiles can distinguish between dementia with subcortical vascular lesions and Alzheimer's disease (AD) at the incipient stage, and if the differ in performance from the Petersen subtypes. Objective: To identify latent cognitive profiles in a naturalistic population of patients from a memory clinic sample, and investigate the derived classes not only in terms of conversion to AD, but also in terms of conversion to dementia with subcortical vascular lesions. Another objective was to compare the derived classes to the Petersen subtypes. Methods: We performed a latent profile analysis (LPA) on standardized neuropsychological test scores from 476 memory clinic patients (age 64 ± 8) without dementia, and analyzed progression to dementia after 2 years. Results: The LPA resulted in two classes with impaired cognition (Amnestic and Slow/Dysexecutive) and two classes with normal cognition (Normal-Low and Normal-High cognition). Belonging to the Amnestic class predicted progression to all-cause dementia and to AD; belonging to the Slow/Dysexecutive class predicted progression to all-cause dementia, AD, and dementia with subcortical vascular lesions. Of the Petersen MCI subtypes, only amnestic multi-domain MCI predicted progression to all-cause dementia, AD, and dementia with subcortical vascular lesions. Conclusion: Latent cognitive profiles separated between AD and dementia with subcortical vascular lesions, while the Petersen subtypes did not. However, similar to the Petersen subtypes, LPA classes work better for ruling out progression to dementia than for case finding.

Minh Tuan Hoang, Ingemar Kåreholt, Mia von Euler, Linus Jönsson, Lena von Koch, Maria Eriksdotter, Sara Garcia-Ptacek
Costs of Inpatient Rehabilitation for Ischemic Stroke in Patients with Dementia: A Cohort Swedish Register-Based Study
Abstract: Background: Stroke and dementia are frequent comorbidities. Dementia possibly increases total costs of stroke care, especially cost of institutionalization and informal medical care. However, stroke rehabilitation costs in dementia patients are understudied. Objective: To estimate inpatient stroke rehabilitation costs for Swedish dementia patients in comparison with non-dementia patients. Methods: A longitudinal cohort study with linked data from the Swedish Dementia Register and the Swedish Stroke Register was conducted. Patients diagnosed with dementia who suffered a first ischemic stroke between 2010 and 2014 (n = 138) were compared with non-dementia patients (n = 935). Cost analyses were conducted from a Swedish health care perspective. The difference of rehabilitation costs between the two groups was examined via simple linear regression (before and after matching by propensity scores of dementia) and multiple linear regression. Results: Mean inpatient rehabilitation costs for dementia and non-dementia patients were SEK 103,693/$11,932 and SEK 130,057/$14,966, respectively (median SEK 92,183/$10,607 and SEK 106,365/$12,239) (p = 0.001). Dementia patients suffered from more comorbidities and experienced lower functioning, compared to non-dementia patients. The inpatient rehabilitation costs for patients with known dementia was 0.84 times the cost in non-dementia individuals. Conclusion: Dementia status was significantly associated with lower inpatient stroke rehabilitation costs. This might be explained by physician’s beliefs on the limited effectiveness of rehabilitation in dementia patients. Further research on cost-effectiveness of stroke rehabilitation and patients’ satisfaction with stroke rehabilitation is necessary.

Takayuki Okano, Yosuke Yamamoto, Akira Kuzuya, Naohiro Egawa, Koji Kawakami, Ichiro Furuta, Kayoko Mizuno, Kiyohiro Fujino, Ken Kojima, Koichi Omori
Development of the Reading Cognitive Test Kyoto (ReaCT Kyoto) for Early Detection of Cognitive Decline in Patients with Hearing Loss
Abstract: Background: Early detection of cognitive decline allows timely intervention to delay progression of dementia. However, current cognitive evaluation tools often include items delivered via verbal forms of instruction, which can cause poor performance in patients with hearing loss. Objective: To develop and validate a cognitive screening battery, the Reading Cognitive Test Kyoto (ReaCT Kyoto), comprising test items given through non-verbal instruction. Methods: A cross-sectional and multi-center study was conducted in the three medical institutes. ReaCT Kyoto was designed to evaluate domains of “registration,” “repetition,” “delayed recall,” “visuospatial recognition,” “orientation in time and place,” and “executive function.” The Japanese version of the Mini-Mental State Examination Test (MMSE-J) and ReaCT Kyoto were applied by experienced psychotherapists. Concurrent validity was evaluated between the ReaCT Kyoto Test and MMSE-J and between the ReaCT Kyoto Test and physician-diagnosed dementia. Results: ReaCT Kyoto was validated in a sample of 115 participants. The mean age of subjects was 81.0 ± 6.4 years, and the sample comprised 53.0% females. The area under the receiver operating curves was 0.95 for detecting physician-diagnosed dementia. When classifying patients in accordance with presence or absence of hearing loss, the AUCs were 0.93 and 0.97 for those with and without hearing loss, respectively. With a cut-off score of < 29 points for suspected dementia, ReaCT Kyoto correctly classified 90.4% of the subjects as belonging to the group with or without physician-diagnosed dementia. Conclusion: ReaCT Kyoto provides an appropriate solution for detection of cognitive impairment in persons with or without hearing loss.

Zhe Ma*, Bin Jing*, Yuxia Li, Huagang Yan, Zhaoxia Li, Xiangyu Ma, Zhizheng Zhuo, Lijiang Wei, Haiyun Li and for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Tianyi Yan) *These authors contributed equally to this work.
Identifying Mild Cognitive Impairment with Random Forest by Integrating Multiple MRI Morphological Metrics
Abstract:
Mild cognitive impairment (MCI) exhibits a high risk of progression to Alzheimer’s disease (AD), and it is commonly deemed as the precursor of AD. It is important to find effective and robust ways for the early diagnosis of MCI. In this paper, a random forest-based method combining multiple morphological metrics was proposed to identify MCI from normal controls (NC). Voxel-based morphometry, deformation-based morphometry, and surface-based morphometry were utilized to extract morphological metrics such as gray matter volume, Jacobian determinant value, cortical thickness, gyrification index, sulcus depth, and fractal dimension. An initial discovery dataset (56 MCI/55 NC) from the ADNI were used to construct classification models and the performances were testified with 10-fold cross validation. To test the generalization of the proposed method, two extra validation datasets including longitudinal ADNI data (30 MCI/16 NC) and collected data from Xuanwu Hospital (27 MCI/32 NC) were employed respectively to evaluate the performance. No matter whether testing was done on the discovery dataset or the extra validation datasets, the accuracies were about 80% with the combined morphological metrics, which were significantly superior to single metric (accuracy: 45%~76%) and also displayed good generalization across datasets. Additionally, gyrification index and cortical thickness derived from surface-based morphometry outperformed other features in MCI identification, suggesting they were some key morphological biomarkers for early MCI diagnosis. Combining the multiple morphological metrics together resulted in a significantly better and reliable identification model, which may be helpful to assist in the clinical diagnosis of MCI.

Steffi Witter, Ago Samoson, Raivo Vilu, Raiker Witter
Screening of Nutraceuticals and Plant Extracts for Inhibition of Amyloid-β Fibrillation
Abstract: Fluorescence spectroscopy for in vitro amyloid-β (Aβ) fibrillation diagnosis and spectral fluorescence signature for the identification of bioactive compounds were applied to study traditional Ayurvedic nutraceuticals—Brahmi, Ashwagandha, Shanka pushpi, and Gotu kola—as well as their plant extracts for possible treatment of Alzheimer’s disease. All samples manifest as inhibitors on three different variants of the Aβ peptide: methionine Aβ1-40, Aβ1-40, and Aβ1-42. The main compounds within the nutraceuticals were identified. Since related medicals are known to have reduced negative post- and side-effects and even may introduce further positive health impacts by preventing pathogen plaque formation and reducing free Aβ to a natural level, such treatment approaches could be of further interest.

Eva Zupanic, Milica G. Kramberger, Mia von Euler, Bo Norrving, Bengt Winblad, Juraj Secnik, Johan Fastbom, Maria Eriksdotter, Sara Garcia-Ptacek
Secondary Stroke Prevention After Ischemic Stroke in Patients with Alzheimer’s Disease and Other Dementia Disorders
Abstract: Background: Recurrent ischemic stroke (IS) increases the risk of cognitive decline. To lower the risk of recurrent IS, secondary prevention is essential. Objective: Our aim was to compare post-discharge secondary IS prevention and its maintenance up to 3 years after first IS in patients with and without Alzheimer’s disease and other dementia disorders. Methods: Prospective open-cohort study 2007–2014 from the Swedish national dementia registry (SveDem) and the Swedish national stroke registry (Riksstroke). Patients with dementia who experienced an IS (n=1410; 332 [23.5%] with Alzheimer’s disease) were compared with matched non-dementia IS patients (n=7150). We analyzed antiplatelet, anticoagulant, blood pressure lowering, and statin treatment as planned medication initiation at discharge and actual dispensation of medications at first, second, and third year post-stroke. Results: At discharge, planned initiation of medication was higher in patients with dementia compared to non-dementia patients for antiplatelets (OR with 95% CI for fully adjusted models 1.23 [1.02-1.48]) and lower for blood pressure lowering medication (BPLM; 0.57 [0.49-0.67]), statins (0.57 [0.50-0.66]), and anticoagulants (in patients with atrial fibrillation – AF; 0.41 [0.32-0.53]). When analysis for antiplatelets was stratified according to the presence of AF, ORs for receiving antiplatelets remained significant only in the presence of AF (in the presence of AF 1.56 [1.21-2.01], in patients without AF 0.99 [0.75-1.33]). Similar trends were observed in 1st, 2nd, and 3rd year post-stroke. Conclusions: Dementia was a predictor of lower statin and BPLM use. Patients with dementia and AF were more likely to be prescribed antiplatelets and less likely to receive anticoagulants.

Andrew J. Surmak, Koon-Pong Wong, Graham B. Cole, Kenji Hirata, Alexander A. Aabedi, Omid Mirfendereski, Payam Mirfendereski, Amy S. Yu, Sung-Cheng Huang, John M. Ringman, David S. Liebeskind, Jorge R. Barrio
Probing Estrogen Sulfotransferase-Mediated Inflammation with [11C]-PiB in the Living Human Brain
Abstract: Background: 2-(4’-[11C]Methylaminophenyl)-6-hydroxybenzothiazole ([11C]-PiB), purportedly a specific imaging agent for cerebral amyloid-β plaques, is a specific, high affinity substrate for estrogen sulfotransferase (SULT1E1), an enzyme that regulates estrogen homeostasis. Objective: In this work, we use positron emission tomography (PET) imaging with [11C]-PiB to assess the functional activity of SULT1E1 in the brain of moyamoya disease patients. Methods: Ten moyamoya subjects and five control patients were evaluated with [11C]-PiB PET and structural MRI scans. Additionally, a patient with relapsing-remitting multiple sclerosis (RRMS) received [11C]-PiB PET scans before and after steroidal and immunomodulatory therapy. Parametric PET images were established to assess SULT1E1 distribution in the inflamed brain tissue. Results: Increased [11C]-PiB SRTM DVR in the thalamus, pons, corona radiata, and internal capsule of moyamoya cohort subjects was observed in comparison with controls (p < 0.005). This was observed in patients without treatment, with collateralization, and also after radiation. The post-treatment [11C]-PiB PET scan in one RRMS patient also revealed substantially reduced subcortical brain inflammation. In validation studies, [11C]-PiB autoradiography signal in the peri-infarct area of the rat middle cerebral arterial occlusion stroke model was shown to correlate with SULT1E1 immunohistochemistry. Conclusion: Strong [11C]-PiB PET signal associated with intracranial inflammation in the moyamoya syndrome cohort and a single RRMS patient appears consistent with functional imaging of SULT1E1 activity in the human brain. This preliminary work offers substantial and direct evidence that significant [11C]-PiB PET focal signals can be obtained from the living human brain with intracranial inflammation, signals not attributable to amyloid-β plaques.

Sebastián Cogliati, Victoria Clementi, Marcos Francisco, Cira Crespo, Federico Argañaraz, Roberto Grau
Bacillus subtilis Delays Neurodegeneration and Behavioral Impairment in the Alzheimer’s Disease Model Caenorhabditis elegans
Abstract: Multiple causes, apart from genetic inheritance, predispose to the production and aggregation of amyloid-β (Aβ) peptide and Alzheimer’s disease (AD) development in the older population. There is currently no therapy or medicine to prevent or delay AD progression. One novel strategy against AD might involve the use of psychobiotics, probiotic gut bacteria with specific mental health benefits. Here, we report the neuronal and behavioral protective effects of the probiotic bacterium Bacillus subtilis in a Caenorhabditis elegans AD model. Aging and neuronal deterioration constitute important risk factors for AD development, and we showed that B. subtilis significantly delayed both detrimental processes in the wild-type C. elegans strain N2 compared with N2 worms colonized by the non-probiotic Escherichia coli OP50 strain. Importantly, B. subtilis alleviated the AD-related paralysis phenotype of the transgenic C. elegans strains CL2120 and GMC101 that express, in body wall muscle cells, the toxic peptides Aβ3-42 and Aβ1-42, respectively. B. subtilis-colonized CL2355 worms were protected from the behavioral deficits (e.g., poor chemotactic response and decreased body bends) produced by pan-neuronal Aβ1-42 expression. Notably, B. subtilis restored the lifespan level of C. elegans strains that express Aβ to values similar to the life expectancy of the wild-type strain N2 fed on E. coli OP50 cells. The B. subtilis proficiencies in quorum-sensing peptide (i.e., the Competence Sporulation Factor, CSF) synthesis and gut-associated biofilm formation (related to the anti-aging effect of the probiotic) play a crucial role in the anti-AD effects of B. subtilis. These novel results are discussed in the context of how B. subtilis might exert its beneficial effects from the gut to the brain of people with or at risk of developing AD.

Cheuk Ni Kan*, Bibek Gyanwali*, Saima Hilal, Kok Pin Ng, Narayanaswamy Venketasubramanian, Christopher Li-Hsian Chen, Xin Xu *These authors contributed equally to this work.
Neuropsychiatric Correlates of Small Vessel Disease Progression in Incident Cognitive Decline: Independent and Interactive Effects
Abstract: Background: Cerebral small vessel disease (SVD) and neuropsychiatric symptoms (NPS) independently increase the risk of cognitive decline. While their co-existence has been reported in the preclinical stage of dementia, longitudinal data establishing the prognosis of their associations, especially in an Asian context remains limited. Objective: This study investigated the role of SVD and NPS progressions on cognitive outcomes over 2 years in a dementia-free elderly cohort. Methods: 170 dementia-free elderly with baseline and 2-year neuropsychological assessments and MRI scans were included in this study. White matter hyperintensities (WMH), lacunes, and microbleeds (CMBs) were graded as markers of SVD. The Neuropsychiatric Inventory (NPI) was used to measure NPS. Generalized estimating equations modelling evaluated the relationship between NPI change and SVD progression. Logistic regression evaluated the risk of incident cognitive decline with both SVD and NPS. All models were adjusted for demographics, baseline cerebrovascular diease, and medial temporal lobe atrophy. Results: Higher NPI scores were associated with higher SVD burden at baseline. Subjects with WMH progression had greater increase in total NPI (β[SE]=0.46[0.19], p=0.016), driven by hyperactivity subsyndrome (β[SE]=0.88[0.34], p=0.007). Subjects with incident CMBs had greater increase in psychosis subsyndrome (β[SE]=0.89[0.30], p<0.001). Subjects with progressions in both SVD and NPS were more likely to develop cognitive decline over 2 years (OR[95% CI]=4.17[1.06-16.40], p<0.05). Conclusion: Our findings support worsening of NPS as a clinical indicator of SVD progression and are associated with cognitive decline over 2 years. Early detection of NPS and targeted interventions on SVD burden may improve NPS outcomes.

Andrea R. Zammit, David A. Bennett, Charles B. Hall, Richard B. Lipton, Mindy J. Katz, Graciela Muniz-Terrera
A Latent Transition Analysis Model to Assess Change in Cognitive States over Three Occasions: Results from the Rush Memory and Aging Project
Abstract: Background: Conceptualizing cognitive aging as a step-sequential process is useful in identifying particular stages of cognitive function and impairment. Objective: We applied latent transition analysis (LTA) to determine 1) whether the underlying structure of cognitive profiles found at every measurement occasion are uniform across three waves of assessment, 2) whether class-instability is predictive of distal outcomes, and 3) whether class-reversions from impaired to non-impaired using latent modelling is lower than when using clinical criteria of mild cognitive impairment (MCI). Methods: A mover-stayer LTA model with dementia as a distal outcome was specified to model transitions of ten neuropsychological measures over three annual waves in the Rush Memory and Aging Project (n = 1,661). The predictive validity of the mover-stayer status for incident Alzheimer’s disease (AD) was then assessed. Results: We identified a five-class model across the three time-points: Mixed-Domain Impairment, Memory-Specific Impairment, Frontal Impairment, Average, and Superior Cognition. None of the individuals in the Impairment classes reverted to the Average or Superior classes. Conventional MCI classification identified 26.4% and 14.1% at Times 1 and 2 as false-positive cases. “Movers” had 87% increased risk of developing dementia compared to those classified as “Stayers”. Conclusion: Our findings support the use of latent variable modelling that incorporates comprehensive neuropsychological assessment to identify and classify cognitive impairment.

Rosalía A. Santos-Mandujano, Natalie S. Ryan, Lucía Chávez-Gutiérrez, Carmen Sánchez-Torres, Marco Antonio Meraz-Ríos (Handling Associate Editor: Caroline Dallaire-Théroux)
Clinical Association of White Matter Hyperintensities Localization in a Mexican Family with Spastic Paraparesis Carrying the PSEN1 A431E Mutation
Abstract: Presenilin 1 gene (PSEN1) mutations are the most common cause of familial Alzheimer’s disease (FAD). One of the most abundant FAD mutations, PSEN1 A431E, has been reported to be associated with spastic paraparesis in about half of its carriers, but the determining mechanisms of this phenotype are still unknown. In our study we characterized three A431E mutation carriers, one symptomatic and two asymptomatic, from a Mexican family with a history of spastic paraparesis in all of its affected members. At cognitive assessment and MRI, the symptomatic subject showed an atypical non-amnestic mild cognitive impairment with visuospatial deficits, olfactory dysfunction and significant parieto-occipital brain atrophy. Furthermore, we found several periventricular white matter hyperintensities whose progression pattern and localization correlated with their motor impairment, cognitive profile, and non-motor symptoms. Together, our data suggests that in this family the A431E mutation leads to a divergent neurological disorder in which cognitive deterioration was clinically exceeded by motor impairment and that it involves early glial and vascular pathological changes.

Stan Chamberlain, Hoda Gabriel, Warren Strittmatter, John Didsbury
Handling Associate Editor: Gary Small)
An Exploratory Phase IIa Study of the PPAR delta/gamma Agonist T3D-959 Assessing Metabolic and Cognitive Function in Subjects with Mild to Moderate Alzheimer’s Disease
Abstract: Background: T3D-959 is a chemically unique, brain penetrant, dual PPAR delta/gamma agonist with 15-fold higher PPAR delta selectivity. Ubiquitous brain expression of PPAR delta, its critical role in regulating glucose and lipid metabolism, and the Alzheimer’s disease (AD)-like phenotype of PPAR delta null mice motivated this study. Objective: To determine safety and tolerability of multiple doses of T3D-959 in subjects with mild to moderate AD, examine systemic and central drug pharmacology and in an exploratory manner, perform cognitive assessments. Methods: Thirty-four subjects with mild-to-moderate AD were orally administered 3, 10, 30, or 90 mg of T3D-959 daily for 14 days. There was no inclusion of a placebo arm. Safety and tolerability were monitored. Systemic drug pharmacology was examined via plasma metabolomics LC-MS-MS analysis, cerebral drug pharmacology via FDG-PET measures of changes in Relative CMRgl (R CMRgl, AD-effected regions relative to brain reference regions), and cognitive function assessed before and after drug treatment and again one week after completion of drug treatment, by ADAS-cog11 and the Digit Symbol Substitution Test (DSST). Results: T3D-959 was in general safe and well tolerated. Single point pharmacokinetics at the Tmax showed dose dependent exposure. Plasma metabolome profile changes showed dose-dependent systemic effects on lipid metabolism and metabolism related to insulin sensitization. Relative FDG-PET imaging demonstrated dose-dependent, regional, effects of T3D-959 on R CMRgl based on the use of multiple reference regions. ADAS-cog11 and DSST cognitive assessments showed improvements with possible ApoE genotype association and pharmacodynamics related to the mechanism of drug action. Conclusions: Exploratory data from this Phase IIa clinical trial supports further clinical investigation of T3D-959 in a larger placebo-controlled clinical study.

Cheng Xu, Jing Guo, Li Li, Xin Wang, Qiuzhi Zhou, Dongsheng Sun, Shujuan Zhang, Shihong Li, Jinwang Ye, Yanchao Liu, Enjie Liu, Peng Zeng, Xiaochuan Wang, Ying Yang, Jian-Zhi Wang (Handling Associate Editor: Xiongwei Zhu)
Co-Expression of Three Wild-Type 3R-Tau Isoforms Induces Memory Deficit via Oxidation-Related DNA Damage and Cell Death: A Promising Model for Tauopathies
Abstract: The three isoforms of 3R-tau are predominantly deposited in neurons bearing neurofibrillary tangles in Alzheimer’s disease (AD), while only 3R-tau accumulation has been detected in Pick’s disease (PiD), suggesting the involvement of 3R-tau in neurodegeneration. However, both the role and the molecular mechanism of 3R-tau in neurodegeneration are elusive. Here, we co-expressed three isoforms of human wild-type 3R-tau in adult mouse hippocampal to mimic the pathologic tau accumulating observed in PiD patients. We found that co-expressing three 3R-tau isoforms induced hyperphosphorylation and accumulation of tau proteins; simultaneously, the mice showed remarkable neuron death with synapse and memory deficits. Further in vitro and in vivo studies demonstrated that co-expressing 3R-tau isoforms caused oxidative stress evidenced by an increased malondialdehyde, and the decreased superoxide dismutase and glutathione peroxidase; the 3R-tau accumulation also induced significant glial activation and DNA double-strand breaks (DSBs). Notably, the toxic effects of 3R-tau accumulation were efficiently reversed by administration of antioxidants Vitamin E (VitE) and Vitamin C (VitC), respectively. These data reveal that intracellular accumulation of 3R-tau isoforms in adult brain induces significant neuron death and memory deficits with the mechanism involving oxidation-mediated DSBs; and the antioxidants VitE and VitC can efficiently attenuate the toxicities of 3R-tau. Given that no significant cell death has been detected in the currently available wild-type tau-accumulating models, co-expressing 3R-tau isoforms could be a promising model for drug development of tauopathies, such as PiD.

Hanxiang Liu, Gavin P. Reynolds, Xianwen Wei
Uric Acid and High-Density Lipoprotein Cholesterol Are Differently Associated with Alzheimer’s Disease and Vascular Dementia
Abstract: Uric acid (UA) is a major contributor to naturally-occurring antioxidant activity and is thought to have protective effects against neurodegenerative processes. However, UA is also implicated as a risk factor in vascular, including cerebrovascular, disease. Its association with, and role in, dementia and its component diseases including Alzheimer’s disease (AD) and vascular dementia (VaD) remains unclear and inconsistently studied. Changes in blood lipids, particularly cholesterol measures, have also been implicated in dementias although the relationship or interactions with UA have been little studied. We have measured plasma UA and lipids taken from 187 subjects first attending a general hospital neurology department for symptoms associated with dementia, and from a series of 79 healthy control subjects. Diagnoses of AD and VaD were made following neuroimaging; laboratory measures were compared between dementia and control groups and between AD and VaD subgroups. No overall change in UA was seen in dementia, although a substantial and highly significant reduction was found in the AD patients. Reduced values in total cholesterol, HDL, and LDL were found in dementia, independent of statin treatment. Further investigation found a significant reduction of HDL only in the VaD group, while total cholesterol was significantly reduced in both AD and VaD subjects. These findings indicate that in our Chinese sample, UA deficits are specifically associated with AD, while deficits in HDL cholesterol found in dementia tend to be greater in VaD.

Alberto Benussi, Valentina Dell’Era, Valentina Cantoni, Maria Sofia Cotelli, Maura Cosseddu, Marco Spallazzi, Antonella Alberici, Alessandro Padovani, Barbara Borroni (Handling Associate Editor: Andrea Arighi)
Neurophysiological Correlates of Positive and Negative Symptoms in Frontotemporal Dementia
Abstract: Background: The neural correlates of behavioral symptoms in frontotemporal dementia (FTD) are still to be elucidated. Neurotransmitter abnormalities could be correlated to the pathophysiology of negative and positive symptoms in FTD. Objective: To evaluate if the imbalance between inhibitory and excitatory cortical circuits, evaluated with transcranial magnetic stimulation (TMS), correlate with the magnitude of negative and positive symptoms, as measured by Frontal Behavioral Inventory (FBI) scores, in patients with FTD. Methods: Paired-pulse TMS was used to investigate the activity of different intracortical circuits in 186 FTD patients (130 bvFTD, 35 avPPA, 21 svPPA). We applied short interval intracortical inhibition (SICI - GABAAergic transmission), intracortical facilitation (ICF - glutamatergic transmission), long interval intracortical inhibition (LICI - GABABergic transmission), and short latency afferent inhibition (SAI - cholinergic transmission). Linear and stepwise multiple regression analysis were used to determine the contribution of each neurophysiological measures to the total variance of FBI scores. Results: At the stepwise multivariate analysis, we observed a significant negative correlation between FBI-A scores (negative symptoms) and ICF (β=-0.57, p<0.001, adjusted R2=0.32). For FBI-B scores (positive symptoms), we observed a significant positive correlation for SICI (β=0.84, p<0.001, adjusted R2=0.56). Significant correlations were observed for single items of the FBI-A score with ICF and FBI-B scores with SICI, with a medium-large size effect for several items. Conclusions: The present study shows that the imbalance between inhibitory and excitatory intracortical circuits, evaluated with TMS, correlated with the magnitude of negative and positive symptoms in FTD, respectively.

Corinne E. Fischer, Zahinoor Ismail, James M. Youakim, Byron Creese, Sanjeev Kumar, Nicolas Nuñez, Ryan R. Darby, Antonella Di Vita, Fabrizia D’Antonio, Carlo de Lena, William J. McGeown, Ravona Ramit, Jill Rasmussenn, Joanne Bello, Huali Wangp, Marie-Andrée Bruneau, Peter K. Panegyres, Krista L. Lanctôt, Luis Agüera-Ortiz, Kostas Lyketsos, Jeffrey Cummings, Dilip V. Jeste, Mary Sano, Dev P. Devanand, Robert A. Sweet, Clive Ballard
Revisiting Criteria for Psychosis in Alzheimer’s Disease and Related Dementias: Toward Better Phenotypic Classification and Biomarker Research
Abstract: Background: Psychotic symptoms are common in Alzheimer’s disease (AD) and related neurodegenerative disorders and are associated with more rapid disease progression and increased mortality. It is unclear to what degree existing criteria are utilized in clinical research and practice. Objective: To establish research criteria for the diagnosis of psychosis in AD. Methods: The International Society to Advance Alzheimer’s Research and Treatment (ISTAART) Neuropsychiatric Symptoms (NPS) Professional Interest Area (PIA) psychosis subgroup reviewed existing criteria for psychosis in AD and related dementias. Through a series of in person and on-line meetings, a priority checklist was devised to capture features necessary for current research and clinical needs. PubMed, Medline and other relevant databases were searched for relevant criteria. Results: Consensus identified three sets of criteria suitable for review including those of Jeste and Finkel, Lyketsos, and the Diagnostic and Statistical Manual for Mental Disorders, 5th edition. It was concluded that existing criteria could be augmented by including a more specific differentiation between delusions and hallucinations, address overlap with related conditions (agitation in particular), adding the possibility of symptoms emerging in the preclinical and prodromal phases, and building on developing research in disease biomarkers. Conclusion: We propose criteria, developed to improve phenotypic classification of psychosis in AD, and advance the research agenda in the field to improve epidemiological, biomarker, and genetics research in the field. These criteria serve as a complement to the International Psychogeriatric Association criteria for psychosis in neurocognitive disorders.

Qing Cao, Chen-Chen Tan, Wei Xu, Hao Hu, Xi-Peng Cao, Qiang Dong, Lan Tan, Jin-Tai Yu (Handling Associate Editor: Ling-Qiang Zhu)
The Prevalence of Dementia: A Systematic Review and Meta-Analysis
Abstract: Dementia is a severe neurodegenerative disorder and it can be categorized into several subtypes by different pathogenic causes. We sought to comprehensively analyzed the prevalence of dementia from perspectives of geographic region (Asia, Africa, South America, and Europe/North America), age, and gender. We searched PubMed and EMBASE for relevant articles on dementia published from January 1985 to August 2019. In these studies, analyses were stratified by geographic region, age, and gender. Meta-regression was conducted to identify if there were significant differences between groups. We included forty-seven studies. Among the individuals aged 50 and over in the community, the pooled prevalence for all-cause dementia, Alzheimer’s disease, and vascular dementia were 697 (CI95%: 546-864) per 10,000 persons, 324 (CI95%: 228-460) per 10,000 persons, and 116 (CI95%: 86-157) per 10,000 persons, respectively. In our study, the prevalence of all-type dementia in individuals aged 100 years and older (6,592 per 10,000 cases) is 2.415 times higher than in those aged 50-59 (27 per 10,000 cases). The number of people living with dementia approximately doubles every five years. The prevalence was greater in women than in men (788 cases versus 561 cases per 10,000 persons) in overall analysis. In individuals aged 60 to 69 years, AD prevalence in females was 1.9 times greater than that in males (108 cases versus 56 cases per 10,000 persons), while the prevalence of VaD was 1.8 times greater in males than in females (56 cases versus 32 cases per 10,000 persons). Prevalence rate was higher in Europe and North America than in Asia, Africa, and South America.

Vasiliy A. Devyatkin, Olga E. Redina, Nataliya G. Kolosova, Natalia A. Muraleva
Single-Nucleotide Polymorphisms Associated with the Senescence-Accelerated Phenotype of OXYS Rats: A Focus on Alzheimer’s Disease-Like and Age-Related-Macular-Degeneration-Like Pathologies
Abstract: Alzheimer’s disease (AD) and age-related macular degeneration (AMD) are two complex incurable neurodegenerative disorders the common pathogenesis of which is actively discussed. There are overlapping risk factors and molecular mechanisms of the two diseases; at the same time, there are arguments in favor of the notion that susceptibility to each of these diseases is associated with a distinct genetic background. Here we identified single-nucleotide polymorphisms (SNPs) that are specific for senescence-accelerated OXYS rats, which simulate key characteristics of both sporadic AD and AMD. Transcriptomes of the hippocampus, prefrontal cortex, and retina (data of RNA-Seq) were analyzed. We detected SNPs in genes Rims2, AABR07072639.2, Lemd2, and AABR07045405.1, which thus can express significantly truncated proteins lacking functionally important domains. Additionally, 33 mutations in genes—which are related to various metabolic and signaling pathways—cause nonsynonymous amino acid substitutions presumably leading to disturbances in protein structure or functions. Some of the genes carrying these SNPs are associated with aging, neurodegenerative, and mental diseases. Thus, we revealed the SNPs can lead to abnormalities in protein structure or functions and affect the development of the senescence-accelerated phenotype of OXYS rats. Our data are consistent with the latest results of genome-wide association studies that highlight the importance of multiple pathways for the pathogenesis of AD and AMD. Identified SNPs can serve as promising research objects for further studies on the molecular mechanisms underlying this particular rat model as well as for the prediction of potential biomarkers of AD and AMD.

Jennifer C. Palmer*, Hannah M. Tayler*, Laurence Dyer, Patrick G. Kehoe, Julian F.R. Paton, Seth Love *These authors contributed equally to this work.
Zibotentan, an Endothelin Alzheimer’s Disease Receptor Antagonist, Prevents Amyloid-β-Induced Hypertension and Maintains Cerebral Perfusion
Abstract: Cerebral blood flow is reduced in Alzheimer’s disease (AD), which is associated with mid-life hypertension. In people with increased cerebral vascular resistance due to vertebral artery or posterior communicating artery hypoplasia, there is evidence that hypertension develops as a protective mechanism to maintain cerebral perfusion. In AD, amyloid-β (Aβ) accumulation may similarly raise cerebral vascular resistance by upregulation of the cerebral endothelin system. The level of endothelin-1 in brain tissue correlates positively with Aβ load and negatively with markers of cerebral hypoperfusion such as increased vascular endothelial growth factor. We previously showed that cerebroventricular infusion of Aβ40 exacerbated pre-existing hypertension in Dahl rats. We have investigated the effects of 28-day cerebral infusion of Aβ40 on blood pressure and heart rate and their variability; carotid flow; endothelin-1; and markers of cerebral oxygenation, in the (normotensive) Wistar rat, and the modulatory influence of the endothelin A receptor antagonist Zibotentan (ZD4054). Cerebral infusion of Aβ caused progressive rise in blood pressure (p < 0.0001) (paired t-test: increase of 3 (0.1-5.6) mmHg (p = 0.040)), with evidence of reduced baroreflex responsiveness, and accumulation of Aβ and elevated endothein-1 in the vicinity of the infusion. Oral Zibotentan (3 mg/kg/d, administered for 31 d) abrogated the effects of Aβ40 infusion on baroreflex responsiveness and blood pressure, which declined, although without reduction in carotid blood flow, and Zibotentan caused uncoupling of the positive linear relationship between endothelin-1 and vascular endothelial growth factor, which as a sensor of tissue oxygenation would be expected to increase if there were hypoperfusion.