Journal of Alzheimer's Disease - Volume 86, issue 3

Authors: Diaz-Pacheco, Valeria | Vargas-Medrano, Javier | Tran, Eric | Nicolas, Meza | Price, Diamond | Patel, Richa | Tonarelli, Silvina | Gadad, Bharathi S.

Article Type: Review Article

Abstract: Mild traumatic brain injury (mTBI) is the most prevalent type of TBI (80–90%). It is characterized by a loss consciousness for less than 30 minutes, post-traumatic amnesia for less than 24 hours, and Glasgow Coma Score of 13–15. Accurately diagnosing mTBIs can be a challenge because the majority of these injuries do not show noticeable or visible changes on neuroimaging studies. Appropriate determination of mTBI is tremendously important because it might lead in some cases to post-concussion syndrome, cognitive impairments including attention, memory, and speed of information processing problems. The scientists have studied different methods to improve mTBI diagnosis and …enhanced approaches that would accurately determine the severity of the trauma. The present review focuses on discussing the role of biomarkers as potential key factors in diagnosing mTBI. The present review focuses on 1) protein based peripheral and CNS markers, 2) genetic biomarkers, 3) imaging biomarkers, 4) neurophysiological biomarkers, and 5) clinical trials in mTBI. Each section provides information and characteristics on different biomarkers for mTBI. Show more

Keywords: Biomarkers, genetics, mild traumatic brain injury, neuroimaging, neurophysiology, proteomics

DOI: 10.3233/JAD-215158

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 943-959, 2022

Authors: Ticinesi, Andrea | Mancabelli, Leonardo | Carnevali, Luca | Nouvenne, Antonio | Meschi, Tiziana | Del Rio, Daniele | Ventura, Marco | Sgoifo, Andrea | Angelino, Donato

Article Type: Review Article

Abstract: Animal studies increasingly indicate that the gut microbiota composition and function can be involved in the pathophysiology and progression of Alzheimer’s disease (AD) at multiple levels. However, few studies have investigated this putative gut-brain axis in human beings, and none of them considered diet as a determinant of intestinal microbiota composition. Epidemiological studies highlight that a high intake of fruit and vegetables, such as that typical of the Mediterranean diet, can modulate AD progression. Thus, nutritional interventions are being increasingly studied as a possible non-pharmacological strategy to slow down the progression of AD. In particular, polyphenols and fibers represent the …nutritional compounds with the higher potential of counterbalancing the pathophysiological mechanisms of dementia due to their antioxidant, anti-inflammatory, and anti-apoptotic properties. These actions are mediated by the gut microbiota, that can transform polyphenols and fibers into biologically active compounds including, among others, phenyl-γ-valerolactones, urolithins, butyrate, and other short-chain fatty acids. In this review, the complex mechanisms linking nutrition, gut microbiota composition, and pathophysiology of cognitive decline in AD are discussed, with a particular focus on the role of polyphenols and fibers. The gaps between pre-clinical and clinical studies are particularly emphasized, as well as the urgent need for studies comprehensively evaluating the link between nutrition, microbiome, and clinical aspects of AD. Show more

Keywords: Aging, butyrate, cognitive impairment, short-chain fatty acids

DOI: 10.3233/JAD-215493

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 961-982, 2022

Authors: Huang, Yu-Yuan | Chen, Shi-Dong | Leng, Xin-Yi | Kuo, Kevin | Wang, Zuo-Teng | Cui, Mei | Tan, Lan | Wang, Kai | Dong, Qiang | Yu, Jin-Tai

Article Type: Review Article

Abstract: Stroke, characterized as a neurological deficit of cerebrovascular cause, is very common in older adults. Increasing evidence suggests stroke contributes to the risk and severity of cognitive impairment. People with cognitive impairment following stroke often face with quality-of-life issues and require ongoing support, which have a profound effect on caregivers and society. The high morbidity of post-stroke cognitive impairment (PSCI) demands effective management strategies, in which preventive strategies are more appealing, especially those targeting towards modifiable risk factors. In this review article, we attempt to summarize existing evidence and knowledge gaps on PSCI: elaborating on the heterogeneity in current definitions, …reporting the inconsistent findings in PSCI prevalence in the literature, exploring established or less established predictors, outlining prevention and treatment strategies potentially effective or currently being tested, and proposing promising directions for future research. Show more

Keywords: Cognitive dysfunction, epidemiology, prevention, screening, stroke, treatment

DOI: 10.3233/JAD-215644

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 983-999, 2022

Authors: Rice, Michaela | Davalos, Deana | Thomas, Michael L.

Article Type: Systematic Review

Abstract: Background: There is a critical need to develop effective interventions for cognitive impairments associated with dementia-related disorders (i.e., Alzheimer’s disease, frontotemporal dementia, mild cognitive impairment). Prospective memory (PM), or the ability to create and carry out future intentions, is one cognitive domain that is impaired in individuals with dementia-related disorders. Effective treatment of PM could significantly improve daily functioning, level of independence, and quality of life. Objective: To date, there have been a number of studies investigating potential interventions, but these interventions have not been comprehensively reviewed and compared across the stages of dementia-related disorders, as is the …aim of the current review. Methods: This review examined 21 studies on the success of intervention strategies for prospective memory in patients with dementia-related disorders. Results: All the studies demonstrated positive effects of intervention on PM abilities, but there are questions concerning ecological validity, length of positive effects on PM, and a lack of diversity of interventions across the different stages of dementia-related disorders. Conclusion: Future research should address these issues by incorporating daily functioning activities and caregiver support into the intervention process, as well as investigating these interventions at more severe stages of dementia-related disorders. Show more

Keywords: Alzheimer’s disease, dementia, intervention, mild cognitive impairment, prospective memory

DOI: 10.3233/JAD-215473

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1001-1024, 2022

Authors: Cipriano, Lorenzo | Saracino, Dario | Oliva, Mariano | Campana, Vito | Puoti, Gianfranco | Conforti, Renata | Fulgione, Ludovica | Signoriello, Elisabetta | Bonavita, Simona | Coppola, Cinzia

Article Type: Systematic Review

Abstract: Background: Cerebral microbleeds (CMBs) are small round/oval lesions seen in MRI-specific sequences. They are divided in deep and lobar according to their location. Lobar CMBs (L-CMBs) are commonly associated with amyloid angiopathy. Although CMBs have been considered clinically silent for a long time, a growing body of evidence has shown that they could play a crucial role in cognitive functioning. Objective: The aim of this systematic review was to estimate the role of L-CMBs in cognitive performance. Methods: We selected, from the Cochrane Library, Embase, PubMed, and ScienceDirect databases, clinical studies, published from January 2000 to …January 2020 and focused on the association between L-CMBs and cognitive functions. The inclusion criteria were: 1) participants grouped according to presence or absence of CMBs, 2) extensive neuropsychological examination, 3) CMBs differentiation according to topographical distribution, and 4) MRI-based CMB definition (< 10 mm and low signal in T2* /SWI). The impact of L-CMBs was separately assessed for executive functions, visuospatial skills, language, and memory. Results: Among 963 potentially eligible studies, six fulfilled the inclusion criteria. Four studies reported a greater reduction in executive performances in participants with L-CMB and two studies showed a statistically significant association between visuospatial dysfunction and L-CMBs. No association was found between hippocampal memory or language abilities and L-CMBs. Conclusion: Lobar CMBs are associated with a reduction of processing speed and visuospatial performances, thus suggesting the contribution of vascular amyloid deposition to this cognitive profile. This occurrence enables us to suspect an underlying Alzheimer’s disease pathology even in absence of typical hippocampal memory impairment. Show more

Keywords: Alzheimer’s disease, cerebral microbleeds, cognitive impairment, executive functions, hippocampal memory

DOI: 10.3233/JAD-215323

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1025-1035, 2022

Authors: Kelberman, Michael A. | Anderson, Claire R. | Chlan, Eli | Rorabaugh, Jacki M. | McCann, Katharine E. | Weinshenker, David

Article Type: Research Article

Abstract: Background: The locus coeruleus (LC) is one of the earliest brain regions to accumulate hyperphosphorylated tau, but a lack of animal models that recapitulate this pathology has hampered our understanding of its contributions to Alzheimer’s disease (AD) pathophysiology. Objective: We previously reported that TgF344-AD rats, which overexpress mutant human amyloid precursor protein and presenilin-1, accumulate early endogenous hyperphosphorylated tau in the LC. Here, we used TgF344-AD rats and a wild-type (WT) human tau virus to interrogate the effects of endogenous hyperphosphorylated rat tau and human tau in the LC on AD-related neuropathology and behavior. Methods: Two-month-old …TgF344-AD and WT rats received bilateral LC infusions of full-length WT human tau or mCherry control virus driven by the noradrenergic-specific PRSx8 promoter. Rats were subsequently assessed at 6 and 12 months for arousal (sleep latency), anxiety-like behavior (open field, elevated plus maze, novelty-suppressed feeding), passive coping (forced swim task), and learning and memory (Morris water maze and fear conditioning). Hippocampal microglia, astrocyte, and AD pathology were evaluated using immunohistochemistry. Results: In general, the effects of age were more pronounced than genotype or treatment; older rats displayed greater hippocampal pathology, took longer to fall asleep, had reduced locomotor activity, floated more, and had impaired cognition compared to younger animals. TgF344-AD rats showed increased anxiety-like behavior and impaired learning and memory. The tau virus had negligible influence on most measures. Conclusion: Effects of hyperphosphorylated tau on AD-like neuropathology and behavioral symptoms were subtle. Further investigation of different forms of tau is warranted. Show more

Keywords: Alzheimer’s disease, behavior, cognition, locus coeruleus, rat, tau, transgenic

DOI: 10.3233/JAD-215546

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1037-1059, 2022

Authors: Gallucci, Maurizio | Cenesi, Leandro | White, Céline | Antuono, Piero | Quaglio, Gianluca | Bonanni, Laura

Article Type: Research Article

Abstract: Background: The most significant biomarkers that are included in the Alzheimer’s disease (AD) research framework are amyloid-β plaques deposition, p-tau, t-tau, and neurodegeneration. Although cerebrospinal fluid (CSF) biomarkers are included in the most recent AD research criteria, their use is increasing in the routine clinical practice and is applied also to the preclinical phases of AD, including mild cognitive impairment. The role of these biomarkers is still unclear concerning the preclinical stage of AD diagnosis, the CSF methodology, and the costs-benefits of the biomarkers’ tests. The controversies regarding the use of biomarkers in the clinical practice are related to …the concepts of analytical validity, clinical validity, and clinical utility and to the question of whether they are able to diagnose AD without the support of AD clinical phenotypes. Objective: The objective of the present work is to expose the strengths and weaknesses of the use of CSF biomarkers in the diagnosis of AD in a clinical context. Methods: We used PubMed as main source for articles published and the final reference list was generated on the basis of relevance to the topics covered in this work. Results: The use of CSF biomarkers for AD diagnosis is certainly important but its indication in routine clinical practice, especially for prodromal conditions, needs to be regulated and also contextualized considering the variety of possible clinical AD phenotypes. Conclusion: We suggest that the diagnosis of AD should be understood both as clinical and pathological. Show more

Keywords: Alzheimer’s disease, analytical validity, ATN model, clinical utility, clinical validity, CSF biomarkers, diagnosis, mild cognitive impairment, probabilistic model

DOI: 10.3233/JAD-215432

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1061-1072, 2022

Authors: de Paula França Resende, Elisa | Ketelle, Robin | Karydas, Anna | Allen, Isabel | Grinberg, Lea T. | Spina, Salvatore | Seeley, William W. | Perry, David C. | Miller, Bruce | Naasan, Georges

Article Type: Research Article

Abstract: Background: The association between lifetime alcohol abuse and a higher risk to develop dementia is well known. However, it is unknown whether older adults who begin abusing alcohol late in life have an underlying neurodegenerative disease. Objective: Identify the frequency of lifelong alcohol abuse (L-AA), late-onset alcohol abuse (LO-AA), and alcohol abuse as a first symptom of dementia (AA-FS) in patients with neurodegenerative diseases. Methods: Cross-sectional retrospective study of patients evaluated at an academic referral center with a clinical diagnosis of behavioral variant frontotemporal dementia (bvFTD), Alzheimer-type dementia (AD), and semantic variant primary progressive aphasia (svPPA) …(n  = 1,518). The presence of alcohol abuse was screened with the National Alzheimer’s Coordinating Center questionnaire. L-AA was defined as onset < 40 years, LO-AA as onset ≥40 years, and AA-FS was defined when the abuse started within the first three years from symptom onset. Results: The frequency of LO-AA was 2.2% (n  = 33/1,518). LO-AA was significantly more frequent in patients with bvFTD than AD (7.5%, n  = 13/173 versus 1.3%, n  = 16/1,254, CI:1.0;11.4%), but not svPPA (4.4%, n  = 4/91, CI: –4.4;10.7%). Similarly, AA-FS was more frequent in bvFTD patients than AD (5.7%, n  = 10/173 versus 0.7%, n  = 9/1,254, CI:0.5%;9.5%), but not svPPA (2.2%, n  = 2/91, CI:–2.4;9.1%). Conclusion: LO-AA can be a presenting symptom of dementia, especially bvFTD. Alcohol abuse onset later in life should prompt a clinical investigation into the possibility of an underlying neurodegenerative process because delay in diagnosis and treatment may increase patient and caregiver burden. The results need to be interpreted with caution due to the limitations of the study. Show more

Keywords: Alcohol-related problems, Alzheimer’s dementia, dementia, frontotemporal dementia

DOI: 10.3233/JAD-215369

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1073-1080, 2022

Authors: Yassi, Nawaf | Pase, Matthew P. | Buckley, Rachel F. | Rosenich, Emily | Watson, Rosie | Maruff, Paul | Lim, Yen Ying

Article Type: Research Article

Abstract: Background: Midlife cardiovascular risk factors (CVRF) are associated with reduced cognition and an increased risk of dementia. Objective: To further investigate this association using remote unsupervised online assessment of cognition and cardiovascular risk in middle-aged adults; and to explore the extent to which the association is altered by carriage of the APOE ɛ4 allele. Methods: The Healthy Brain Project is an online cohort of middle-aged cognitively unimpaired adults (40–70 years) who have undergone cognitive assessment and provided self-reports of demographic and health history. Cardiovascular risk was determined by ascertaining history of hypertension, hypercholesterolemia, diabetes mellitus, …overweight (body mass index≥25), and current cigarette smoking. Participants (n  = 2,480) were then grouped based on the number of reported CVRF into no CVRF, 1, 2, and≥3 CVRF. Associations between the number of CVRF as a continuous variable, CVRF group, and each individual CVRF with composite measures of attention, memory and subjective cognitive function were investigated. Results: Higher number of CVRF was associated with poorer attention (β= –0.042, p  = 0.039) and memory (β= –0.080, p  < 0.001), but not with subjective cognitive function. When considered individually, current smoking (β= –0.400, p  = 0.015), diabetes (β= –0.251, p  = 0.023), and hypercholesterolemia (β= –0.109, p  = 0.044) were independently associated with poorer memory performance. APOE ɛ4 carriers with≥1 CVRF performed worse on memory than ɛ4 carriers with no CVRFs (β(SE) = 0.259(0.077), p  = 0.004). This was not observed in ɛ4 non-carriers. Conclusion: In cognitively normal middle-aged adults, CVRF were associated with poorer cognition, particularly in the memory domain. These results support feasibility of online assessment of cardiovascular risk for cognitive impairment. Show more

Keywords: Alzheimer’s disease, cardiovascular risk factors, diabetes mellitus, dyslipidemias, smoking

DOI: 10.3233/JAD-215375

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1081-1091, 2022

Authors: Tanaka, Tomotaka | Gyanwali, Bibek | Villaraza, Steven Gayoles | Saridin, Francis N. | Vrooman, Henri | Ihara, Masafumi | Reilhac, Anthonin | Chen, Christopher L.H. | Hilal, Saima

Article Type: Research Article

Abstract: Background: P-wave terminal force in lead V1 (PTFV1) on electrocardiography has been associated with atrial fibrillation and ischemic stroke. Objective: To investigate whether PTFV1 is associated with cerebral small vessel disease (CSVD) markers and etiological subtypes of cognitive impairment and dementia. Methods: Participants were recruited from ongoing memory clinic study between August 2010 to January 2019. All participants underwent physical and medical evaluation along with an electrocardiography and 3 T brain magnetic resonance imaging. Participants were classified as no cognitive impairment, cognitive impairment no dementia, vascular cognitive impairment no dementia, and dementia subtypes (Alzheimer’s …disease and vascular dementia). Elevated PTFV1 was defined as > 4,000μV×ms and measured manually on ECG. Results: Of 408 participants, 78 (19.1%) had elevated PTFV1 (37 women [47%]; mean [SD] age, 73.8 [7.2] years). The participants with elevated PTFV1 had higher burden of lacunes, cerebral microbleeds (CMB), and cortical microinfarcts. As for the CMB location, persons with strictly deep CMB and mixed CMB had significantly higher PTFV1 than those with no CMB (p  = 0.005, p  = 0.007). Regardless of adjustment for cardiovascular risk factors and/or heart diseases, elevated PTFV1 was significantly associated with presence of CMB (odds ratio, 2.26; 95% CI,1.33–3.91). Conclusion: Elevated PTFV1 was associated with CSVD, especially deep CMB. PTFV1 in vascular dementia was also higher compared to Alzheimer’s disease. Thus, PTFV1 might be a potential surrogate marker of brain-heart connection and vascular brain damage. Show more

Keywords: Cerebral microbleeds, cerebral small vessel diseases, cognitive impairment, electrocardiography, P-wave

DOI: 10.3233/JAD-215413

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1093-1105, 2022

Authors: Wang, Ying | Huang, Xuan | Feng, Yueting | Luo, Qiong | He, Yemeng | Guo, Qihao | Feng, Yanmei | Wang, Hui | Yin, Shankai

Article Type: Research Article

Abstract: Background: In recent years, there have been several meaningful advances in the understanding of the cognitive effects of vestibular loss. However, there has not yet been an investigation exploring the early biomarkers of preclinical cognitive decline in individuals with age-related vestibular loss. Objective: We aim to explore the “early biomarkers” of preclinical cognitive decline based on altered cortical activity (resting-state electroencephalography (EEG) and P300) with a multichannel EEG system in individuals with age-related vestibular loss. Method: This is a case-control study. A total of 21 patients with age-related vestibular loss (66.50±5.79 years, 13 [62% ] …females), 19 patients with cognitive decline (68.42±5.82 years, 13 [68% ] females), and 21 age- and sex-matched healthy controls were recruited. All participants underwent a comprehensive battery of neuropsychological tests, audio-vestibular evaluations, resting-state EEG and P300 recordings. Results: Significant visuo-spatial, executive, and attention hypofunction were observed in the age-related vestibular group, reflected by decreased subscale scores. Reduced gamma functional connectivity between the right cuneus (Brodmann area 19, BA19) and the left superior parietal gyrus (BA7) was observed in both the age-related vestibular group and the cognitive impairment group. Smaller P300 amplitudes were observed in the age-related vestibular group (1.43±3.69μV) and cognitive impairment group (1.15±4.24μV) than in the healthy control group (3.97±2.38μV). Conclusion: Decreased P300 amplitude and functional connectivity between the right BA19 and the left BA7 were “early biomarkers” observed in individuals with age-related vestibular loss; these biomarkers may contribute to visuospatial, executive, and attention hypofunction. Show more

Keywords: Age-related vestibular loss, cognitive decline, early biomarker, EEG, P300

DOI: 10.3233/JAD-215467

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1107-1121, 2022

Authors: Alkeridy, Walid A. | Al Khalifah, Reem Abdullah | Mohammedin, Ahmed S. | Khallaf, Roaa | Muayqil, Taim | Bucks, Romola S.

Article Type: Research Article

Abstract: Background: There are few Arabic language functional scales for patients with dementia. The Bristol Activity of Daily Living Scale (BADLS) was designed and validated for use in patients with dementia. Objective: Our study aimed to translate, cross-culturally adapt, and validate the BADLS to the Arabic language for people with neurocognitive decline and dementia. Methods: The original BADLS scale was translated to the Arabic language followed by face validity assessment through a pilot testing in five Arabic countries. The Arabic BADLS was assessed in a sample of 139 participants and their caregivers for concurrent and convergent validity. …Results: The Arabic BADLS had excellent internal consistency, Cronbach’s alpha 0.95 (95% CI 0.93–0.96). Likewise, the Arabic BADLS had strong convergent validity with the Montreal Cognitive Assessment (r  = –0.82, p  < 0.001). Conclusion: The Arabic BADLS is a valid scale that can used to assess the functional performance of people living with dementia. Show more

Keywords: Bristol activities of daily living scale, dementia, reliability, scale validation

DOI: 10.3233/JAD-215489

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1123-1130, 2022

Authors: Doraiswamy, P. Murali | Goldberg, Terry E. | Qian, Min | Linares, Alexandra R. | Nwosu, Adaora | Nino, Izael | D’Antonio, Jessica | Phillips, Julia | Ndouli, Charlie | Hellegers, Caroline | Michael, Andrew M. | Petrella, Jeffrey R. | Andrews, Howard | Sneed, Joel | Devanand, Davangere P.

Article Type: Research Article

Abstract: Background: Digital cognitive tests offer several potential advantages over established paper-pencil tests but have not yet been fully evaluated for the clinical evaluation of mild cognitive impairment. Objective: The NeuroCognitive Performance Test (NCPT) is a web-based, self-directed, modular battery intended for repeated assessments of multiple cognitive domains. Our objective was to examine its relationship with the Alzheimer’s Disease Assessment Scale-Cognition Subscale (ADAS-Cog) and Mini-Mental State Examination (MMSE) as well as with established paper-pencil tests of cognition and daily functioning in mild cognitive impairment (MCI). Methods: We used Spearman correlations, regressions and principal components analysis followed by …a factor analysis (varimax rotated) to examine our objectives. Results: In MCI subjects, the NCPT composite is significantly correlated with both a composite measure of established tests (r  = 0.78, p  < 0.0001) as well as with the ADAS-Cog (r  = –0.55, p  < 0.0001). Both NCPT and paper-pencil test batteries had a similar factor structure that included a large “g” component with a high eigenvalue. The correlation for the analogous tests (e.g., Trails A and B, learning memory tests) were significant (p  < 0.0001). Further, both the NCPT and established tests significantly (p  < 0.0001) predicted the University of California San Diego Performance-Based Skills Assessment and Functional Activities Questionnaire, measures of daily functioning. Conclusion: The NCPT, a web-based, self-directed, computerized test, shows high concurrent validity with established tests and hence offers promise for use as a research or clinical tool in MCI. Despite limitations such as a relatively small sample, absence of control group and cross-sectional nature, these findings are consistent with the growing literature on the promise of self-directed, web-based cognitive assessments for MCI. Show more

Keywords: Alzheimer’s disease, clinical trials, computerized cognitive tests, neurocognitive performance test

DOI: 10.3233/JAD-220015

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1131-1136, 2022

Authors: Atayde, Adrienne L. | Fischer, Corinne E. | Schweizer, Tom A. | Munoz, David G.

Article Type: Research Article

Abstract: Background: The temporal relationship between sleep, Alzheimer’s disease (AD), and cognitive impairment remains to be further elucidated. Objective: First, we aim to determine whether the Neuropsychiatric Inventory–Questionnaire (NPI-Q) assessed nighttime behaviors prior to cognitive decline influence the rate of cognitive deterioration in pathologically confirmed AD, and second, to assess the possible interactions with APOE allele and cerebral amyloid angiopathy (CAA). Methods: The rate of cognitive decline between cognitively asymptomatic participants from the National Alzheimer Coordinating Center who eventually received a neuropathologic diagnosis of AD with (+NTB) or without (−NTB) nighttime behaviors were …compared using independent samples t -test. Participants were stratified by APOE carrier and CAA status. Demographic and patient characteristics were assessed using descriptive statistics, and the independent samples t -test was used for continuous variables and chi-square test for categorical variables. The significance level was set at p ≤0.05. Results: The rate of cognitive decline was greater in +NTB (n  = 74; 3.30 points/year) than −NTB (n  = 330; 2.45 points/year) (p  = 0.016), even if there was no difference in cognitive status at onset. This difference was restricted to APOE ɛ4 carriers (p  = 0.049) and positive CAA participants (p  = 0.020). Significance was not reached in non-carriers (p  = 0.186) and negative CAA (p  = 0.364). APOE and CAA were not differentially distributed between the NTB groups. Conclusion: NPI-Q assessed nighttime behaviors, a surrogate for sleep disturbances, are associated with more rapidly deteriorating cognition in patients with AD neuropathology who are also carriers of APOE ɛ4 or show CAA. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E, cerebral amyloid angiopathy, cognitive decline, neuropsychiatric symptoms, sleep

DOI: 10.3233/JAD-215276

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1137-1147, 2022

Authors: Marcum, Zachary A. | Li, Yongmei | Lee, Sei J. | Steinman, Michael A. | Graham, Laura | Jing, Bocheng | Fung, Kathy | Peralta, Carmen A. | Odden, Michelle C.

Article Type: Research Article

Abstract: Background: Certain classes of antihypertensive medication may have different associations with cognitive impairment. Objective: To examine the association between prevalent use of antihypertensive medications that stimulate (thiazides, dihydropyridine calcium channel blockers, angiotensin type I receptor blockers) versus inhibit (angiotensin-converting enzyme inhibitors, beta-blockers, non-dihydropyridine calcium channel blockers) type 2 and 4 angiotensin II receptors on cognitive impairment among older adults residing in Veterans Affairs (VA) nursing homes for long-term care. Methods: Retrospective cohort study. Long-term care residents aged 65 + years admitted to a VA nursing home from 2012 to 2019 using blood pressure medication and without cognitive impairment …at admission. Main exposure was prevalent use of angiotensin II receptor type 2 and 4-‘stimulating’ (N  = 589), ‘inhibiting’ (N  = 3,219), or ‘mixed’ (N  = 1,715) antihypertensive medication regimens at admission. Primary outcome was any cognitive impairment (Cognitive Function Scale). Results: Over an average of 5.4 months of follow-up, prevalent use of regimens containing exclusively ‘stimulating’ antihypertensives was associated with a lower risk of any incident cognitive impairment as compared to prevalent use of regimens containing exclusively ‘inhibiting’ antihypertensives (HR 0.83, 95% CI 0.74–0.93). Results for the comparison between ‘mixed’ versus ‘inhibiting’ regimens were in the same direction but not statistically significant (HR 0.96, 95% CI 0.88–1.06). Conclusion: For residents without cognitive impairment at baseline, prevalent users of regimens containing exclusively antihypertensives that stimulate type 2 and 4 angiotensin II receptors had lower rates of cognitive impairment as compared to prevalent users of regimens containing exclusively antihypertensives that inhibit these receptors. Residual confounding cannot be ruled out. Show more

Keywords: Aged, antihypertensive drugs, antihypertensives, cognitive dysfunction

DOI: 10.3233/JAD-215393

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1149-1158, 2022

Authors: Biju, Kevin | Oh, Esther | Rosenberg, Paul | Xue, Qian-Li | Dash, Paul | Burhanullah, M. Haroon | Agrawal, Yuri

Article Type: Research Article

Abstract: Background: Patients with Alzheimer’s disease (AD) are at high risk for falls. Vestibular dysfunction predicts balance impairment in healthy adults; however, its contribution to falls in patients with AD is not well known. Objective: The objective of this study was to assess whether vestibular function contributes to balance and fall risk in patients with AD. Methods: In this prospective observational study, we assessed vestibular function using measures of semicircular canal (vestibulo-ocular reflex (VOR) gain) and saccular function (cervical vestibular-evoked myogenic (cVEMP) response), and we assessed balance function using the Berg Balance Scale and quantitative posturography. We …evaluated falls incidence for a mean 1-year follow-up period (range 3–21 months) in 48 patients with mild-moderate AD. Results: Relative to matched controls, AD patients exhibited increased medio-lateral (ML) sway in eyes-open (0.89 cm versus 0.69 cm; p  = 0.033) and eyes-closed (0.86 cm versus 0.65 cm; p  = 0.042) conditions. Among AD patients, better semicircular canal function was associated with lower ML sway and antero-posterior (AP) sway in the eyes-closed condition (β= –2.42, 95% CI (–3.89, –0.95), p  = 0.002; β= –2.38, 95% CI (–4.43, –0.32), p  = 0.025, respectively). Additionally, better saccular function was associated with lower sway velocity (β= –0.18, 95% CI (–0.28, –0.08); p  = 0.001). Finally, we observed that better semicircular canal function was significantly associated with lower likelihood of falls when adjusted for age, sex, and MMSE score (HR = 0.65; p  = 0.009). Conclusion: These results support the vestibular system as an important contributor to balance and fall risk in AD patients and suggest a role for vestibular therapy. Show more

Keywords: Alzheimer’s disease, cognitive aging, falls, postural balance, vestibular function tests

DOI: 10.3233/JAD-215366

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1159-1168, 2022

Authors: Freedman, Morris | Binns, Malcolm A. | Serediuk, Fidelma | Wolf, M. Uri | Danieli, Einat | Pugh, Bradley | Galet, Deb | Abdellah, Eslam | Teleg, Ericka | Halper, Mindy | Masci, Lauren | Lee, Adrienne | Kirstein, Anne

Article Type: Research Article

Abstract: Background: Patients with severe neuropsychiatric symptoms (NPS) due to dementia are often uprooted from their familiar environments in long-term care or the community and transferred to emergency departments, acute care hospitals, or specialized behavioral units which can exacerbate NPS. To address this issue, we developed the Virtual Behavioural Medicine Program (VBM), an innovative model of virtual care designed to support management of patients with NPS in their own environment. Objective: To determine efficacy of VBM in reducing admission to a specialized inpatient neurobehavioral unit for management of NPS. Methods: We reviewed outcomes in the first consecutive …95 patients referred to VBM. Referrals were classified into two groups. In one group, patients were referred to VBM with a simultaneous application to an inpatient Behavioural Neurology Unit (BNU). The other group was referred only to VBM. The primary outcome was reduction in proportion of patients requiring admission to the BNU regardless of whether they were referred to the BNU or to VBM alone. Results: For patients referred to VBM plus the BNU, the proportion needing admission to the BNU was reduced by 60.42%. For patients referred to VBM alone, it was 68.75%. Conclusion: VBM is a novel virtual neurobehavioral unit for treatment of NPS. Although the sample size was relatively small, especially for the VBM group, the data suggest that this program is a game changer that can reduce preventable emergency department visits and acute care hospital admissions. VBM is a scalable model of virtual care that can be adopted worldwide. Show more

Keywords: Behavioural and psychological symptoms of dementia, dementia, models of care, neuropsychiatric symptoms, responsive behaviors, telehealth, virtual care

DOI: 10.3233/JAD-215403

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1169-1184, 2022

Authors: Suárez-Méndez, Isabel | Bruña, Ricardo | López-Sanz, David | Montejo, Pedro | Montenegro-Peña, Mercedes | Delgado-Losada, María Luisa | Marcos Dolado, Alberto | López-Higes, Ramón | Maestú, Fernando

Article Type: Research Article

Abstract: Background: Recent studies demonstrated that brain hypersynchrony is an early sign of dysfunction in Alzheimer’s disease (AD) that can represent a proxy for clinical progression. Conversely, non-pharmacological interventions, such as cognitive training (COGTR), are associated with cognitive gains that may be underpinned by a neuroprotective effect on brain synchrony. Objective: To study the potential of COGTR to modulate brain synchrony and to eventually revert the hypersynchrony phenomenon that characterizes preclinical AD. Methods: The effect of COGTR was examined in a sample of healthy controls (HC, n  = 41, 22 trained) and individuals with subjective cognitive decline (SCD, …n  = 49, 24 trained). Magnetoencephalographic activity and neuropsychological scores were acquired before and after a ten-week COGTR intervention aimed at improving cognitive function and daily living performance. Functional connectivity (FC) was analyzed using the phase-locking value. A mixed-effects ANOVA model with factors time (pre-intervention/post-intervention), training (trained/non-trained), and diagnosis (HC/SCD) was used to investigate significant changes in FC. Results: We found an average increase in alpha-band FC over time, but the effect was different in each group (trained and non-trained). In the trained group (HC and SCD), we report a reduction in the increase in FC within temporo-parietal and temporo-occipital connections. In the trained SCD group, this reduction was stronger and showed a tentative correlation with improved performance in different cognitive tests. Conclusion: COGTR interventions could mitigate aberrant increases in FC in preclinical AD, promoting brain synchrony normalization in groups at a higher risk of developing dementia. Show more

Keywords: Cognitive decline, functional neuroimaging, intervention study, longitudinal studies, magnetoencephalography

DOI: 10.3233/JAD-215406

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1185-1199, 2022

Authors: Owens, Lauren | Bracewell, Joshua | Benedetto, Alexandre | Dawson, Neil | Gaffney, Christopher | Parkin, Edward

Article Type: Research Article

Abstract: Background: The Alzheimer’s disease (AD)-associated amyloid-beta protein precursor (AβPP) can be cleaved by β-site AβPP cleaving enzyme 1 (BACE1) and the γ -secretase complex to yield neurotoxic amyloid-β (Aβ) peptides. However, AβPP can also be cleaved in a ‘non-amyloidogenic’ manner either by α -secretase to produce soluble AβPP alpha (sAβPPα ) (a fragment with neuroprotective/neurogenic functions) or through alternative BACE1-mediated ‘beta prime’ activity yielding soluble AβPP beta prime (sAβPPβ’). Objective: To determine whether sAβPPα depletion, as opposed to Aβ peptide accumulation, contributes to cytotoxicity in AD-relevant SH-SY5Y neuroblastoma cell models. Methods: AβPP proteolysis was characterized …by immunoblotting in mock-, wild-type AβPP (wtAβPP)-, BACE1-, and Swedish mutant AβPP (SweAβPP)-transfected cells. AβPP beta prime cleavage was confirmed through secretase inhibitor studies and C-terminal fragment analysis. The roles of sAβPPα and sAβPPβ’ in cell viability were confirmed by overexpression studies. Results: Despite producing enhanced Aβ peptide levels, wtAβPP- and SweAβPP-transfected cells did not exhibit reduced viability whereas BACE1-transfected cells did. sAβPPα generation in SH-SY5Y-BACE1 cells was virtually ablated in lieu of BACE1-mediated sAβPPβ’ production. sAβPPα overexpression in SH-SY5Y-BACE1 cells restored viability whereas sAβPPβ’ overexpression decreased viability further. The anti-AβPP 6E10 antibody was shown to cross-react with sAβPPβ’. Conclusion: sAβPPα depletion and/or sAβPPβ’ accumulation, but not elevated Aβ peptide levels, represent the cytotoxic mechanism following BACE1 overexpression in SH-SY5Y cells. These data support the novel concept that competitive sAβPPα depletion by BACE1 beta prime activity might contribute to AD. The cross-reactivity of 6E10 with AβPPβ’also questions whether previous studies assessing sAβPPα as a biomarker using this antibody should be revisited. Show more

Keywords: Alpha-secretase, Alzheimer’s disease, amyloid-beta protein precursor, beta-secretase, beta prime

DOI: 10.3233/JAD-215457

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1201-1220, 2022

Authors: Thompson, Richard E. | Tuchman, Alan J. | Alkon, Daniel L.

Article Type: Research Article

Abstract: Background: In pre-clinical studies of Alzheimer’s disease (AD) transgenic mice, bryostatin restored synaptic connections, prevented neuronal death, reduced amyloid plaques, and reduced neurofibrillary tangles. Objective: Within pre-specified cohorts of advanced AD patients in two double-blind placebo-controlled bryostatin Phase II trials, to conduct exploratory statistical analyses of patients with identical conditions of enrollment and treatment. Methods: Severe Impairment Battery (SIB) scores above baseline at 5, 9, and 13 weeks were analyzed initially in the complete cases, with multiple imputation methods based on an iterative Markov chain Monte Carlo algorithm used for missing SIB scores. To mitigate confounding …by a chance imbalance of 4.9 SIB baseline scores (Study #203), each patient was used as their own control with differences in 13-week SIB from baseline in single trial and pooled analyses to measure benefit at 13 weeks using general estimating equations (GEE) modeling. Results: Patients treated with bryostatin pre-specified at Mini-Mental State Examination scores 10–14, without memantine, showed baseline balance, complete safety, and SIB improvements at 13 weeks with multiple imputation analysis: Study #203 = 4.1 SIB points above baseline (p  = 0.005), and Study #202 = 4.2 SIB points above baseline (p  = 0.016). An increased power (N  = 95) “pooled analysis” showed an increased SIB over time and a higher mean SIB at 13 weeks in the bryostatin treatment group (p  < 0.001) but not significant (NS) for the placebo patients. Conclusion: Pre-specified exploratory analyses for the individual trials and the pooled trials confirmed significant bryostatin-induced improvement over baseline (treatment p  < 0.001, placebo NS). Show more

Keywords: Alzheimer’s disease, bryostatin, cognitive improvement above baseline, double-blind, pooled analysis, randomized trials, therapeutics

DOI: 10.3233/JAD-215545

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1221-1229, 2022

Authors: Grothe, Jessica | Luppa, Melanie | Dietzel, Jens | Schomerus, Georg | Sommerlad, Andrew | Riedel-Heller, Steffi G. | Röhr, Susanne

Article Type: Research Article

Abstract: Background: Dementia is one of the most common and most severe disorder in old age. In addition to cognitive decline and functional impairment, changes in social functioning occur in the course of dementia. Currently, there is no valid instrument in German language to assess social functioning in individuals with dementia. Objective: We aim to adapt and psychometrically evaluate a German version of the Social Functioning in Dementia Scale (SF-DEM). Methods: First, a multi-step and team-based translation process based on the TRAPD model was performed. Second, we interviewed dyads of individuals with mild dementia and caregivers to …test the internal consistency, test-retest reliability, interrater reliability, construct validity, and acceptance of the German version of the SF-DEM. Results: The internal consistency of the patient-rated (α = 0.72) and the caregiver-rated (α = 0.76) SF-DEM is at an acceptable level. The interrater reliability was excellent for both versions (patients: ICC = 0.98, CI [0.95–0.99]; caregiver: ICC = 0.95, CI [0.89–0.98]) and the test-retest reliability was moderate (patients: ICC = 0.57, CI [0.26–0.77]; caregiver: ICC = 0.58, CI [0.27–0.78]). Caregiver-rated SF-DEM correlated strong with LSNS-6 (rs  = 0.60, p  < 0.01), QoL-AD (marriage: rs  = 0.61, p  < 0.01; friends: rs  = 0.51, p  = 0.01). In addition, the SF-DEM was accepted by the participants. Conclusion: The German SF-DEM is a valid, reliable, and acceptable instrument to assess social functioning in individuals with dementia. Further research should address the psychometric properties in individuals with more severe dementia. Show more

Keywords: Acceptance, dementia, measure, psychometrics, questionnaire, reliability, scale, SF-DEM, social functioning, validity

DOI: 10.3233/JAD-215557

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1231-1241, 2022

Authors: O’Bryant, Sid E. | Zhang, Fan | Petersen, Melissa | Hall, James R. | Johnson, Leigh A. | Yaffe, Kristine | Braskie, Meredith | Vig, Rocky | Toga, Arthur W. | Rissman, Robert A. | for the HABS-HD Study Team

Article Type: Research Article

Abstract: Background: Hispanics are expected to experience the largest increase in Alzheimer’s disease (AD) and AD related dementias over the next several decades. However, few studies have examined biomarkers of AD among Mexican Americans, the largest segment of the U.S. Hispanic population. Objective: We sought to examine proteomic profiles of an MRI-based marker of neurodegeneration from the AT(N) framework among a multi-ethnic, community-dwelling cohort. Methods: Community-dwelling Mexican Americans and non-Hispanic white adults and elders were recruited. All participants underwent comprehensive assessments including an interview, functional exam, clinical labs, informant interview, neuropsychological testing, and 3T MRI of the …brain. A neurodegeneration MRI meta-ROI biomarker for the AT(N) framework was calculated. Results: Data was examined from n  = 1,291 participants. Proteomic profiles were highly accurate for detecting neurodegeneration (i.e., N +) among both Mexican Americans (AUC = 1.0) and non-Hispanic whites (AUC = 0.98). The proteomic profile of N  + was different between ethnic groups. Further analyses revealed that the proteomic profiles of N  + varied by diagnostic status (control, MCI, dementia) and ethnicity (Mexican American versus non-Hispanic whites) though diagnostic accuracy was high for all classifications. Conclusion: A proteomic profile of neurodegeneration has tremendous value and point towards novel diagnostic and intervention opportunities. The current findings demonstrate that the underlying biological factors associated with neurodegeneration are different between Mexican Americans versus non-Hispanic whites as well as at different levels of disease progression. Show more

Keywords: Alzheimer’s disease, biomarkers, diversity, hispanic, mexican american, mild cognitive impairment, neurodegeneration

DOI: 10.3233/JAD-210543

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1243-1254, 2022

Authors: Wang, Jia | Ma, Si-Fei | Yun, Qi | Liu, Wen-Jun | Zhai, Hong-Ru | Shi, Hou-Zhen | Xie, Lan-Gui | Qian, Jin-Jun | Zhao, Chun-Jie | Zhang, Wei-Ning

Article Type: Research Article

Abstract: Background: Several recent findings have revealed that targeting of cell cycle reentry and (or) progression may provide an opportunity for the therapeutic intervention of Alzheimer’s disease (AD). FOXG1 has been shown to play important roles in pattern formation, cell proliferation, and cell specification. Thus far, the roles of FoxG1 and its involvement in AD are largely unknown. Objective: Our study aimed to explore the intervention effect of FOXG1 on AD pathology and its potential mechanism with a particular focus on cell cycle regulation. Methods: We investigated the association of Foxg1 gene variants with AD-like behavioral …deficits, p21 expression, neuronal apoptosis, and amyloid-β (Aβ) aggregate formation; we further determined whether targeting FOXG1-regulated cell cycle has therapeutic potential in AD. Results: Paralleling AD-like behavioral abnormalities, neuronal apoptosis, and Aβ deposits, a significant reduction in the expression of FOXG1 was observed in APP/PS1 mice at 6 months of age. Using the APP/PS1;Foxg1fl /f l -CreAAV mouse line, we found that FOXG1 potentially antagonized cell cycle reentry by negatively regulating the levels of p21-activated kinase (PAK3). By reducing p21cip 1 -mediated arrest at the G2 stage and regulating cyclin A1- and cyclin B-dependent progression patterns of the cell cycle, FOXG1 blocked neuronal apoptosis and Aβ deposition. Conclusion: These results indicate that FOXG1 contributes to the regulation of the neuronal cell cycle, thereby affecting brain abnormalities in AD. An elevation of the FOXG1 level, either pharmacologically or through other means, could present a therapeutic strategy for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β deposits, apoptosis, cell cycle, FOXG1, p21cip1

DOI: 10.3233/JAD-215144

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1255-1273, 2022

Authors: Tian, Qu | Bilgel, Murat | Moghekar, Abhay R. | Ferrucci, Luigi | Resnick, Susan M.

Article Type: Research Article

Abstract: Background: Olfactory deficits are early features of preclinical Alzheimer’s disease (AD). Whether olfaction is associated with PET biomarkers among community-dwelling older adults is less clear. Objective: Investigate cross-sectional and longitudinal associations of olfaction with mild cognitive impairment (MCI) and amyloid-β (Aβ) and tau deposition. Methods: We analyzed 364 initially cognitively normal participants (58% women, 24% black) who had baseline olfaction data and subsequent cognitive assessments during an average 2.4-year. A subset of 129 had PET-PiB (Aβ) (n  = 72 repeated) and 105 had 18 F-flortaucipir (FTP)-PET (tau) (n  = 44 repeated). Olfaction was measured using a 16-item Sniffin’ …Sticks Odor Identification Test. The association of olfaction with incident MCI was examined using Cox regression. Associations with PiB-distribution volume ratio (DVR) and FTP-standardized uptake value ratio (SUVR) were examined using partial correlation. We tested whether PiB+/–status modified these associations. Analyses were adjusted for demographics and olfactory test version. Results: 17 (5%) participants developed MCI. Each unit lower odor identification score was associated with 22% higher risk of developing MCI (p  = 0.04). In the PET subset, lower scores were associated with higher mean cortical DVR and DVR in orbitofrontal cortex (OFC), precuneus, and middle temporal gyrus (p ≤0.04). The “olfaction*PiB+/–” interaction in OFC DVR was significant (p  = 0.03), indicating the association was limited to PiB positive individuals. Greater decline in odor identification score was associated with greater increase in anterior OFC DVR and entorhinal tau SUVR (p ≤0.03). Conclusion: Among community-dwelling older adults, poorer olfaction predicts incident MCI and is associated with overall and regional Aβ. Greater olfaction decline is associated with faster Aβ and tau accumulation in olfaction-related regions. Whether olfaction predicts AD-related neurodegenerative changes warrants further investigations. Show more

Keywords: Amyloid-β, olfaction, PET biomarkers, tau

DOI: 10.3233/JAD-210636

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1275-1285, 2022

Authors: Hang, Zhongci | Cai, Shanglin | Lei, Tong | Zhang, Xiaoshuang | Xiao, Zhuangzhuang | Wang, Donghui | Li, Yingxian | Bi, Wangyu | Yang, Yanjie | Deng, Shiwen | Wang, Li | Li, Quanhai | Du, Hongwu

Article Type: Research Article

Abstract: Background: Fecal microbiota transplant (FMT) is a potential treatment approach for many diseases. Alzheimer’s disease (AD) and cancer have been proven to have a specific antagonistic relationship to FMT. Objective: This article aims to explore whether intestinal flora transplantation from cancer individuals can ameliorate cognitive impairment. Methods: Morris water maze and object recognition tests were performed to assess cognitive function after the fecal flora from tumor-bearing and WT mice were transplanted into AD mice by gavage. The effect of flora transplantation on AD was analyzed by thioflavin T staining, western blot, and 16S RNA sequencing. …Results: AD mice with FMT significantly improved short-term memory level and cognitive ability compared with Tg + NaCl group. Inflammatory factors in the plasma were regulated, and Aβ plaques burden in the hippocampus and cortex were decreased. FMT in the tumor-bearing group showed a higher significant amelioration in symptoms compared to the healthy group. 16S RNA sequencing revealed that FMT treatments could reverse the increased Firmicutes and Prevotella and the decreased Bacteroidetes , Bacteroides , and Sutterella in AD mice. AD mice transplanted with tumor-bearing mice feces additionally increased the density of Oscillospira , Odoribacter , and AF12 . Furthermore, the predicted functional analyses showed that the metabolism of inorganic and organic salts in the intestinal flora of AD mice was also reversed by FMT. Conclusion: Intestinal flora transplantation from tumor-bearing mice can ameliorate the cognitive impairment of AD mice. Show more

Keywords: Alzheimer’s disease, cancer, fecal microbiota transplants, intestinal flora

DOI: 10.3233/JAD-215495

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1287-1300, 2022

Authors: Soares, Jelena Zugic | Valeur, Jørgen | Šaltytė Benth, Jūratė | Knapskog, Anne-Brita | Selbæk, Geir | Arefi, Golchin | Gilfillan, Gregor D. | Tollisen, Anita | Bogdanovic, Nenad | Pettersen, Renate

Article Type: Research Article

Abstract: Background: Vitamin D insufficiency has been suggested as a dementia risk factor. Objective: In this cross-sectional, explorative study we investigated whether levels of vitamin D in cerebrospinal fluid (CSF) are lower in patients with positive biomarkers of Alzheimer’s disease (AD) compared to cognitively healthy controls and whether polymorphisms of the vitamin D receptor (VDR) gene, FokI, BsmI, ApaI, and TaqI, are associated with levels of vitamin D in CSF and cognition. Methods: We included 100 patients≥65 years assessed for cognitive impairment and 76 cognitively healthy controls. Levels of 25-hydroxyvitamin D (25(OH)D) in both serum and CSF, …and VDR polymorphisms were analyzed. Results: The mean level of 25(OH)D in serum was 78.6 (SD 28.9) nmol/l. While serum levels of 25(OH)D were not significantly different between the groups, CSF levels of 25(OH)D were significantly lower in patients with positive AD core biomarkers (p  = 0.001) compared to patients without such biomarkers. Individuals with the BsmI major homozygote genotype had significantly lower results on a 10-word delayed recall test (p  = 0.044) and verbal fluency test (p  = 0.013), and individuals with the TaqI major homozygote genotype had significantly lower results on a verbal fluency test (p  = 0.030) compared to individuals with the corresponding minor homozygote genotype. Conclusion: Patients with positive AD core biomarkers have low CSF levels of 25(OH)D, despite sufficient serum levels. CSF levels of 25(OH)D do not seem to be affected by any of the four VDR gene polymorphisms. TaqI and BsmI major homozygote genotypes might be at increased risk for development of cognitive decline. Show more

Keywords: Alzheimer’s disease, blood-brain barrier, cerebrospinal fluid, cognitive function, dementia, polymorphism, single nucleotide, vitamin D, vitamin D3 receptor

DOI: 10.3233/JAD-215536

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1301-1314, 2022

Authors: Wang, Jing | Ding, Ding | Wu, Bei

Article Type: Research Article

Abstract: Background: There has been a rich body of literature on informal caregivers of persons with dementia (PWD). However, little has been discussed on how to facilitate person-centered dementia care in home settings with spouses as primary caregivers. We tend to take it for granted that spouses provide person-centered care for PWD. However, being spouses of PWD and living with them for several decades does not necessarily mean that it is easier for them to provide person-centered dementia care and maintain valued and healthy relationships. Objective: The current study aimed to explore dyadic experiences of PWD and their spousal …caregivers and develop a culturally and contextually-sensitive understanding of person-centered dementia care in home-based settings. Methods: A total of 20 dyads of PWD and their care partners were selected for this study. A trained qualitative interviewer conducted a one-on-one interview with each participant with dementia and their care partners separately. We adopted both conventional and directed content analyses. Results: Our findings provide examples of care partners provide person-centered care, resulting in a profound positive impact on their wellbeing. Adaptive leadership and collaborative work emerged as a key finding in facilitating person-centered dementia care. Cultural relevancy of person-centered dementia care was also interpreted from the data. The study findings provide implications for the evolving of person-centered dementia care model in home-based settings. Conclusion: Findings from this study highlight the significance of facilitating person-centered dementia care in home-based settings between PWD and their primary family caregivers. Show more

Keywords: Dementia care, informal caregivers, person-centered care, theoretical model

DOI: 10.3233/JAD-215612

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1315-1322, 2022

Authors: Saji, Naoki | Murotani, Kenta | Sato, Naoyuki | Tsuduki, Tsuyoshi | Hisada, Takayoshi | Shinohara, Mitsuru | Sugimoto, Taiki | Niida, Shumpei | Toba, Kenji | Sakurai, Takashi

Article Type: Research Article

Abstract: Background: Previous studies have demonstrated associations between gut microbiota, microbial metabolites, and cognitive decline. However, relationships between these factors and neurofilament light chain (NfL; a disease-nonspecific biomarker of neural damage) remain controversial. Objective: To evaluate the associations between plasma NfL, gut microbiota, and cognitive function. Methods: We performed a cross-sectional sub-analysis of data from our prospective cohort study that was designed to investigate the relationship between gut microbiota and cognitive function. Patients who visited our memory clinic were enrolled and demographics, dementia-related risk factors, cognitive function, brain imaging, gut microbiomes, and microbial metabolites were assessed. We …evaluated the relationships between the gut microbiome, microbial metabolites, and plasma NfL. Moreover, the relationships between plasma NfL and cognitive function were assessed using multivariable logistic regression analyses. Results: We analyzed 128 participants (women: 59%, mean age: 74 years). Participants with high (above the median) plasma NfL concentrations tended to be older, women, and hypertensive and have a history of stroke, chronic kidney disease, and dementia. Plasma NfL was also associated with cerebral small vessel disease. However, plasma NfL levels were not significantly correlated with gut microbial metabolites. Multivariable analyses revealed that a higher plasma NfL concentration was independently associated with the presence of dementia (odds ratio: 9.94, 95% confidence interval: 2.75–48.2, p  < 0.001). Conclusion: High plasma NfL concentration was independently associated with the presence of dementia as previously reported. However, plasma NfL levels were not significantly correlated with gut microbial metabolites in this preliminary study. Show more

Keywords: Biomarkers, cerebral small vessel disease, cognitive decline, dementia, gut microbiota

DOI: 10.3233/JAD-215141

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1323-1335, 2022

Authors: Álvarez-Sánchez, Lourdes | Peña-Bautista, Carmen | Baquero, Miguel | Cháfer-Pericás, Consuelo

Article Type: Research Article

Abstract: Background: Single molecule array (SIMOA) and other ultrasensitive detection technologies have allowed the determination of blood-based biomarkers of Alzheimer’s disease (AD) for diagnosis and monitoring, thereby opening up a promising field of research. Objective: To review the published bibliography on plasma biomarkers in AD using new ultrasensitive techniques. Methods: A systematic review of the PubMed database was carried out to identify reports on the use of blood-based ultrasensitive technology to identify biomarkers for AD. Results: Based on this search, 86 works were included and classified according to the biomarker determined. First, plasma amyloid-β showed …satisfactory accuracy as an AD biomarker in patients with a high risk of developing dementia. Second, plasma t-Tau displayed good sensitivity in detecting different neurodegenerative diseases. Third, plasma p-Tau was highly specific for AD. Fourth, plasma NfL was highly sensitive for distinguishing between patients with neurodegenerative diseases and healthy controls. In general, the simultaneous determination of several biomarkers facilitated greater accuracy in diagnosing AD (Aβ42 /Aβ40 , p-Tau181/217). Conclusion: The recent development of ultrasensitive technology allows the determination of blood-based biomarkers with high sensitivity, thus facilitating the early detection of AD through the analysis of easily obtained biological samples. In short, as a result of this knowledge, pre-symptomatic and early AD diagnosis may be possible, and the recruitment process for future clinical trials could be more precise. However, further studies are necessary to standardize levels of blood-based biomarkers in the general population and thus achieve reproducible results among different laboratories. Show more

Keywords: Alzheimer’s disease, biomarker, blood, digital immunoassay, ELISA, plasma, protein, SIMOA

DOI: 10.3233/JAD-215093

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1337-1369, 2022

Authors: Weinstein, Galit | O’Donnell, Adrienne | Davis-Plourde, Kendra | Zelber-Sagi, Shira | Ghosh, Saptaparni | DeCarli, Charles S. | Thibault, Emma G. | Sperling, Reisa A. | Johnson, Keith A. | Beiser, Alexa S. | Seshadri, Sudha

Article Type: Research Article

Abstract: Background: Liver steatosis and fibrosis are emerging as risk factors for multiple extrahepatic health conditions; however, their relationship with Alzheimer’s disease pathology is unclear. Objective: To examine whether non-alcoholic fatty liver disease (NAFLD) and FIB-4, a non-invasive index of advanced fibrosis, are associated with brain amyloid-β (Aβ) and tau pathology. Methods: The study sample included Framingham Study participants from the Offspring and Third generation cohorts who attended exams 9 (2011–2014) and 2 (2008–2011), respectively. Participants underwent 11 C-Pittsburgh Compound-B amyloid and 18 F-Flortaucipir tau positron emission tomography (PET) imaging and abdomen computed tomography, or had information …on all components of the FIB-4 index. Linear regression models were used to assess the relationship of NAFLD and FIB-4 with regional tau and Aβ, adjusting for potential confounders and multiple comparisons. Results: Of the subsample with NAFLD information (N = 169; mean age 52±9 y; 57% males), 57 (34%) had NAFLD. Of the subsample with information on liver fibrosis (N = 177; mean age 50±10 y; 51% males), 34 (19%) had advanced fibrosis (FIB-4 > 1.3). Prevalent NAFLD was not associated with Aβ or tau PET. However, FIB-4 index was significantly associated with increased rhinal tau (β= 1.03±0.33, p  = 0.002). Among individuals with prevalent NAFLD, FIB-4 was related to inferior temporal, parahippocampal gyrus, entorhinal and rhinal tau (β= 2.01±0.47, p  < 0.001; β= 1.60±0.53, p  = 0.007, and β= 1.59±0.47, p  = 0.003 and β= 1.60±0.42, p  = 0.001, respectively) and to Aβ deposition overall and in the inferior temporal and parahippocampal regions (β= 1.93±0.47, p  < 0.001; β= 1.59±0.38, p  < 0.001, and β= 1.52±0.54, p  = 0.008, respectively). Conclusion: This study suggests a possible association between liver fibrosis and early Alzheimer’s disease pathology, independently of cardio-metabolic risk factors. Show more

Keywords: Alzheimer’s disease, amyloid-β, liver fibrosis, non-alcoholic fatty liver disease, positron emission tomography

DOI: 10.3233/JAD-215409

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1371-1383, 2022

Authors: Liu, Ziming | Paek, Eun Jin | Yoon, Si On | Casenhiser, Devin | Zhou, Wenjun | Zhao, Xiaopeng

Article Type: Research Article

Abstract: Background: People with Alzheimer’s disease (AD) often demonstrate difficulties in discourse production. Referential communication tasks (RCTs) are used to examine a speaker’s capability to select and verbally code the characteristics of an object in interactive conversation. Objective: In this study, we used contextualized word representations from Natural language processing (NLP) to evaluate how well RCTs are able to distinguish between people with AD and cognitively healthy older adults. Methods: We adapted machine learning techniques to analyze manually transcribed speech transcripts in an RCT from 28 older adults, including 12 with AD and 16 cognitively healthy older …adults. Two approaches were applied to classify these speech transcript samples: 1) using clinically relevant linguistic features, 2) using machine learned representations derived by a state-of-art pretrained NLP transfer learning model, Bidirectional Encoder Representation from Transformer (BERT) based classification model. Results: The results demonstrated the superior performance of AD detection using a designed transfer learning NLP algorithm. Moreover, the analysis showed that transcripts of a single image yielded high accuracies in AD detection. Conclusion: The results indicated that RCT may be useful as a diagnostic tool for AD, and that the task can be simplified to a subset of images without significant sacrifice to diagnostic accuracy, which can make RCT an easier and more practical tool for AD diagnosis. The results also demonstrate the potential of RCT as a tool to better understand cognitive deficits from the perspective of discourse production in people with AD. Show more

Keywords: Alzheimer’s disease, early diagnosis, natural language processing, transfer learning

DOI: 10.3233/JAD-215137

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1385-1398, 2022

Authors: Hua, Xue | Church, Kevin | Walker, William | L’Hostis, Philippe | Viardot, Geoffrey | Danjou, Philippe | Hendrix, Suzanne | Moebius, Hans J.

Article Type: Research Article

Abstract: Background: Fosgonimeton (ATH-1017) is being developed as a first-in-class regenerative therapy for people with Alzheimer’s disease (AD) and dementia; potentially improving dementia symptoms and altering disease progression by reversing synaptic disconnection and neuronal loss. Objective: This randomized, double-blind, placebo-controlled phase I trial (NCT03298672) evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of fosgonimeton. Methods: Fosgonimeton was administered once daily via subcutaneous injection to 88 subjects. The single ascending dose study enrolled healthy young male subjects (n  = 48; age, 33.4±6.3 years; dose, 2, 6, 20, 40, 60, or 90 mg); the multiple ascending dose study enrolled healthy elderly subjects …(n  = 29; age, 63.8±4.0 years; dose, 20, 40, 60, or 80 mg; 9-day duration); and the fixed-dose study enrolled AD subjects (n  = 11; age, 69.2±7.1 years; dose, 40 mg; 9-day duration). Quantitative electroencephalogram (qEEG) and event-related potential (ERP) P300 measured neurophysiological signals following fosgonimeton treatment, supporting brain penetration and target engagement. Results: Fosgonimeton and placebo were shown to be safe and well-tolerated across all doses. Pharmacokinetic results for fosgonimeton were dose-proportional, with no sex effect or accumulation over 9 days. The main effect of fosgonimeton on qEEG was acute and sustained gamma power induction. In AD subjects, there was a significant effect toward ERP P300 latency normalization compared with placebo (p  = 0.027; n  = 7 at 40 mg fosgonimeton versus n  = 4 placebo). Conclusion: These results support the continued development of fosgonimeton as a novel therapeutic for people with AD and dementia. The fast-onset normalization of ERP P300 latency in AD subjects suggests enhancement of synaptic function and potential procognitive effects. Show more

Keywords: ATH-1001, ATH-1017, Alzheimer’s disease, dementia, fosgonimeton, hepatocyte growth factor, electroencephalography, event-related potentials, P300 component, neurotrophic factor

DOI: 10.3233/JAD-215511

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1399-1413, 2022

Authors: Chan, Carol K. | Pettigrew, Corinne | Soldan, Anja | Zhu, Yuxin | Wang, Mei-Cheng | Albert, Marilyn | Rosenberg, Paul B. | and the BIOCARD Research Team

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms (NPS) among cognitively normal older adults are increasingly recognized as risk factors for cognitive decline and impairment. However, the underlying mechanisms remain unclear. Objective: To examine whether biomarkers of Alzheimer’s disease (amyloid burden) and cerebrovascular disease (white matter hyperintensity (WMH) volume) modify the association between NPS and cognitive decline among cognitively unimpaired older adults. Methods: Analyses included 193 cognitively unimpaired participants (M age = 70 years) from the BIOCARD study, including 148 with PET amyloid and WMH biomarker data. NPS were measured with Neuropsychiatric Inventory and Geriatric Depression Scale scores. Linear mixed effects models …were used to examine the association between baseline NPS and longitudinal cognitive trajectories (M follow-up = 3.05 years), using separate models for global, episodic memory, and executive function cognitive composite scores. In a subset of individuals with biomarker data, we evaluated whether WMH or cortical amyloid burden modified the relationship between NPS and cognitive change (as indicated by the NPS×biomarker×time interactions). Results: Higher baseline NPS were associated with lower executive function scores, but not a faster rate of decline in executive function. NPS symptoms were unrelated to the global or episodic memory composite scores, and there was little evidence of a relationship between NPS symptoms and cognitive change over time. The associations between NPS and cognitive decline did not differ by amyloid or WMH burden, and NPS were unrelated to amyloid and WMH burden. Conclusion: These results suggest that the effect of neuropsychiatric symptoms on executive dysfunction may occur through mechanisms outside of amyloid and cerebrovascular disease. Show more

Keywords: Alzheimer’s disease, amyloid, depression, mild behavioral impairment, neuropsychiatric symptoms, white matter hyperintensities

DOI: 10.3233/JAD-215267

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1415-1426, 2022

Authors: Tsamou, Maria | Carpi, Donatella | Pistollato, Francesca | Roggen, Erwin L.

Article Type: Research Article

Abstract: Background: A complex network of aging-related homeostatic pathways that are sensitive to further deterioration in the presence of genetic, systemic, and environmental risk factors, and lifestyle, is implicated in the pathogenesis of progressive neurodegenerative diseases, such as sporadic (late-onset) Alzheimer’s disease (sAD). Objective: Since sAD pathology and neurotoxicity share microRNAs (miRs) regulating common as well as overlapping pathological processes, environmental neurotoxic compounds are hypothesized to exert a risk for sAD initiation and progression. Methods: Literature search for miRs associated with human sAD and environmental neurotoxic compounds was conducted. Functional miR analysis using PathDip was performed to …create miR-target interaction networks. Results: The identified miRs were successfully linked to the hypothetical starting point and key events of the earlier proposed tau-driven adverse outcome pathway toward memory loss. Functional miR analysis confirmed most of the findings retrieved from literature and revealed some interesting findings. The analysis identified 40 miRs involved in both sAD and neurotoxicity that dysregulated processes governing the plausible adverse outcome pathway for memory loss. Conclusion: Creating miR-target interaction networks related to pathological processes involved in sAD initiation and progression, and environmental chemical-induced neurotoxicity, respectively, provided overlapping miR-target interaction networks. This overlap offered an opportunity to create an alternative picture of the mechanisms underlying sAD initiation and early progression. Looking at initiation and progression of sAD from this new angle may open for new biomarkers and novel drug targets for sAD before the appearance of the first clinical symptoms. Show more

Keywords: Adverse outcome pathway, Alzheimer’s disease, key events, miRs, neurotoxicity

DOI: 10.3233/JAD-215434

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1427-1457, 2022

Authors: Aksnes, Mari | Aass, Hans Christian D. | Tiiman, Ann | Terenius, Lars | Bogdanović, Nenad | Vukojević, Vladana | Knapskog, Anne-Brita

Article Type: Research Article

Abstract: Background: Neuroinflammation is a central component of Alzheimer’s disease (AD) and correlates closely with amyloid pathology. Markers of inflammation such as cytokines, and amyloidogenic aggregates, so-called nanoplaques, are both promising biomarker candidates for AD. We have previously shown that there is a relationship between the levels of nanoplaques and cytokines in cerebrospinal fluid, but it is unknown whether this association extends to serum. Objective: Investigate in a naturalistic memory clinic cohort whether the associations between nanoplaques and cytokines in the cerebrospinal fluid extends to serum. Methods: We collected serum from 49 patients assessed for cognitive complaints …at the Oslo University Hospital Memory Clinic (15 with clinical AD). We assessed the levels of serum nanoplaques with the novel Thioflavin-T fluorescence correlation spectroscopy (ThT-FCS) assay. Serum levels of nine cytokines (eotaxin-1, granulocyte colony-stimulating factor [G-CSF], interleukin [IL]-6, IL-7, IL-8, monocyte chemoattractant protein-1 (MCP-1), gamma induced protein 10 (IP-10), macrophage inflammatory protein [MIP]-1α, and MIP-1β) were quantified with a multiplex assay and read on a Luminex IS 200 instrument. Results: Serum nanoplaques were not increased in clinical AD patients compared to non-AD memory clinic patients and nanoplaques were not associated with any cytokines. The cytokines IL-8 and G-CSF were increased in patients with clinical AD compared to non-AD patients. Conclusion: In this small pilot study, serum nanoplaques were not associated with serum cytokines. Nanoplaque levels could not be used to separate clinical AD patients from non-AD patients in this unselected memory clinic cohort. Show more

Keywords: Alzheimer’s disease, amyloid, amyloid-β peptide, biomarkers, cytokines, fluorescence, serum, Thioflavin T

DOI: 10.3233/JAD-215504

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1459-1470, 2022

Authors: Kundu, Payel | Zimmerman, Benjamin | Quinn, Joseph F. | Kaye, Jeffrey | Mattek, Nora | Westaway, Shawn K. | Raber, Jacob

Article Type: Research Article

Abstract: Background: α-klotho might play a role in neurodegenerative diseases. Objective: To determine levels of α-klotho and apoE in serum and cerebrospinal fluid (CSF) samples and their relationship with the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR). Methods: All subjects were between age 39 to 83+ (n  = 94). CDR and MMSE were administered to all participants. CSF was collected in the early afternoon by lumbar puncture. Results: Serum and CSF levels of α-klotho are positively correlated and both predict scores on the MMSE and CDR, regardless of sex or apoE4 status. …Conclusion: Our results demonstrate that α-klotho may be an important biomarker of cognitive health and neurodegeneration, and that relatively non-invasive sampling of α-klotho from serum is likely highly reflective of CSF levels. Show more

Keywords: α-klotho, apoE, cerebrospinal fluid, Clinical Dementia Rating, Mini-Mental State Examination, serum

DOI: 10.3233/JAD-215719

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1471-1481, 2022

Article Type: Correction

DOI: 10.3233/JAD-229002

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1483-1483, 2022