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

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