Journal of Alzheimer's Disease - Volume 84, issue 3

Authors: Fu, Yan | Wang, Zuo-Teng | Qu, Yi | Wang, Xiao-Tong | Ma, Ya-Hui | Bi, Yan-Lin | Dong, Qiang | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: The associations between sleep characteristics and cognition are complicated. Alzheimer’s disease (AD) pathologies have been proven to be associated with sleep characteristics. Objective: We aimed to investigate the associations between sleep characteristics and cognitive function and examine the roles of AD pathologies in modulating the association of sleep duration with cognition. Methods: A total of 974 participants who had measurements of cerebrospinal fluid (CSF) amyloid-β (Aβ), phosphorylated tau (P-tau), total tau proteins (T-tau), cognitive function, and sleep characteristics were included from the Chinese Alzheimer’s Biomarker and Lifestyle (CABLE) study. Linear regression analyses …were utilized to explore the associations of sleep characteristics with cognition. Non-linear regression analyses were utilized to explore the associations of sleep habits with cognition. Causal mediation analyses were conducted to explore the mediation effects of AD pathologies on cognition. Results: The Pittsburgh Sleep Quality Index (PSQI) total score was significantly negatively correlated with Montreal Cognitive Assessment (MoCA) score (p  = 0.0176). Long latency (p  = 0.0054) and low efficiency (p  = 0.0273) were associated with cognitive impairment. Habitual nap behavior was associated with lower MoCA scores (p  = 0.0045). U-shaped associations were observed between sleep habits (bedtime and nocturnal sleep duration) and cognition. A causal mediation analysis indicated that P-tau/Aβ42 mediated the association of sleep duration with cognition. Conclusion: These findings showed sleep characteristics were associated with cognitive functions. Sleep habits (duration, bedtime) had U-shaped associations with cognition. AD core pathologies might partially mediate the influence of sleep duration on cognitive impairments. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, cognition, montreal cognitive assessment, sleep

DOI: 10.3233/JAD-215017

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1029-1038, 2021

Authors: Jakubowski, Hieronim | Zioła-Frankowska, Anetta | Frankowski, Marcin | Perła-Kaján, Joanna | Refsum, Helga | de Jager, Celeste A. | Smith, A. David

Article Type: Research Article

Abstract: Background: Metals, silicon, and homocysteine are linked to Alzheimer’s disease. B vitamin therapy lowers homocysteine and slows brain atrophy and cognitive decline in mild cognitive impairment (MCI). Objective: Examine metals and silicon as predictors of cognition/brain atrophy in MCI, their interaction with homocysteine and cysteine, and how B vitamins affect these relationships. Methods: MCI participants (n  = 266, 77.6-year-old, 60.7% female) in VITACOG trial were randomized to receive daily folic acid (0.8 mg)/vitamin B12 (0.5 mg)/vitamin B6 (20 mg) (n  = 133) or placebo for two years. At baseline and end-of-study, cranial MRIs were obtained from 168 participants, cognition …was analyzed by neuropsychological tests, and serum iron, copper, arsenic, aluminum, and silicon quantified by inductively-coupled plasma mass spectrometry in 196 participants. Data were analyzed by bivariate and multiple regression. Results: Baseline iron, cysteine, and homocysteine were significantly associated with brain atrophy rate. Homocysteine effects on brain atrophy rate were modified by iron and cysteine. At baseline, iron, copper, aluminum, and silicon were significantly associated with one or more domains of cognition: semantic memory, verbal episodic memory, attention/processing speed, and executive function. At end-of-study, baseline iron, copper, aluminum, and silicon predicted cognition in at least one domain: semantic memory, verbal episodic memory, visuospatial episodic memory, attention/processing speed, and global cognition in the placebo but not the B vitamin group. Conclusion: Disparate effects of serum iron, copper, aluminum, silicon, and homocysteine on cognition and brain atrophy in MCI suggest that cognitive impairment is independent of brain atrophy. These factors showed domain-specific associations with cognition, which were abrogated by B vitamin therapy. Show more

Keywords: Aluminum, brain atrophy, cognitive decline, copper, cysteine, homocysteine, iron, silicon

DOI: 10.3233/JAD-215085

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1039-1055, 2021

Authors: Wang, Luwen | Liu, Mengyu | Gao, Ju | Smith, Amber M. | Fujioka, Hisashi | Liang, Jingjing | Perry, George | Wang, Xinglong

Article Type: Research Article

Abstract: Background: Abnormalities of mitochondrial fission and fusion, dynamic processes known to be essential for various aspects of mitochondrial function, have repeatedly been reported to be altered in Alzheimer’s disease (AD). Neurofibrillary tangles are known as a hallmark feature of AD and are commonly considered a likely cause of neurodegeneration in this devastating disease. Objective: To understand the pathological role of mitochondrial dynamics in the context of tauopathy. Methods: The widely used P301S transgenic mice of tauopathy (P301S mice) were crossed with transgenic TMFN mice with the forced expression of Mfn2 specifically in neurons …to obtain double transgenic P301S/TMFN mice. Brain tissues from 11-month-old non-transgenic (NTG), TMFN, P301S, and P301S/TMFN mice were analyzed by electron microscopy, confocal microscopy, immunoblot, histological staining, and immunostaining for mitochondria, tau pathology, and tau pathology-induced neurodegeneration and gliosis. The cognitive function was assessed by the Barnes maze. Results: P301S mice exhibited mitochondrial fragmentation and a consistent decrease in Mfn2 compared to age-matched NTG mice. When P301S mice were crossed with TMFN mice (P301S/TMFN mice), neuronal loss, as well as mitochondria fragmentation were significantly attenuated. Greatly alleviated tau hyperphosphorylation, filamentous aggregates, and thioflavin-S positive tangles were also noted in P301S/TMFN mice. Furthermore, P301S/TMFN mice showed marked suppression of neuroinflammation and improved cognitive performance in contrast to P301S mice. Conclusion: These in vivo findings suggest that promoted mitochondrial fusion suppresses toxic tau accumulation and associated neurodegeneration, which may protect against the progression of AD and related tauopathies. Show more

Keywords: Cognitive decline, Mfn2, mitochondrial dynamics, mitochondrial fusion, neurodegeneration, neuroinflammation, tau pathology

DOI: 10.3233/JAD-215175

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1057-1069, 2021

Authors: Shafiee, Neda | Dadar, Mahsa | Ducharme, Simon | Collins, D. Louis | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: While both cognitive and magnetic resonance imaging (MRI) data has been used to predict progression in Alzheimer’s disease, heterogeneity between patients makes it challenging to predict the rate of cognitive and functional decline for individual subjects. Objective: To investigate prognostic power of MRI-based biomarkers of medial temporal lobe atrophy and macroscopic tissue change to predict cognitive decline in individual patients in clinical trials of early Alzheimer’s disease. Methods: Data used in this study included 312 patients with mild cognitive impairment from the ADNI dataset with baseline MRI, cerebrospinal fluid amyloid-β, cognitive test scores, and a …minimum of two-year follow-up information available. We built a prognostic model using baseline cognitive scores and MRI-based features to determine which subjects remain stable and which functionally decline over 2 and 3-year follow-up periods. Results: Combining both sets of features yields 77%accuracy (81%sensitivity and 75%specificity) to predict cognitive decline at 2 years (74%accuracy at 3 years with 75%sensitivity and 73%specificity). When used to select trial participants, this tool yields a 3.8-fold decrease in the required sample size for a 2-year study (2.8-fold decrease for a 3-year study) for a hypothesized 25%treatment effect to reduce cognitive decline. Conclusion: When used in clinical trials for cohort enrichment, this tool could accelerate development of new treatments by significantly increasing statistical power to detect differences in cognitive decline between arms. In addition, detection of future decline can help clinicians improve patient management strategies that will slow or delay symptom progression. Show more

Keywords: Alzheimer’s disease, cognitive decline, machine learning, magnetic resonance imaging, prognostics, random forest, sample size, statistical model

DOI: 10.3233/JAD-210664

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1071-1078, 2021

Authors: Filippone, Alessia | Li, Jian-Guo | Praticò, Domenico

Article Type: Research Article

Abstract: Background: The vacuolar protein sorting 35 (VPS35) is the main component of the retromer recognition core complex system which regulates intracellular cargo protein sorting and trafficking. Downregulation of VPS35 has been linked to the pathogenesis of neurodegenerative disorders such Alzheimer’s and Parkinson’s diseases via endosome dysregulation. Objective: Here we show that the genetic manipulation of VPS35 affects intracellular degradation pathways. Methods: A neuronal cell line expressing human APP Swedish mutant was used. VPS35 silencing was performed treating cells with VPS35 siRNA or Ctr siRNA for 72 h. Results: Downregulation of VPS35 was associated with alteration …of autophagy flux and intracellular accumulation of acidic and ubiquitinated aggregates suggesting that dysfunction of the retromer recognition core leads to a significant alteration in both pathways. Conclusion: Taken together, our data demonstrate that besides cargo sorting and trafficking, VPS35 by supporting the integral function of the retromer complex system plays an important role also as a critical regulator of intracellular degradation pathways. Show more

Keywords: Alzheimer’s disease, autophagy, endosomal system, proteosome, retromer complex

DOI: 10.3233/JAD-210701

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1079-1089, 2021

Authors: Lengu, Ketrin | Ryan, Shannon | Peltier, Scott J. | Tyszkowski, Troy | Kairys, Anson | Giordani, Bruno | Hampstead, Benjamin M.

Article Type: Research Article

Abstract: Background: Prior research, primarily with young adults, suggests transcranial direct current stimulation (tDCS) effects are driven by the primary excitatory and/or inhibitory neurotransmitters, glutamate, and gamma-aminobutyric acid (GABA), respectively. Objective: We examined the neurometabolic mechanisms of tDCS in older adults with and without mild cognitive impairment (MCI). Methods: We used data from a double-blind, cross-over, randomized controlled trial (NCT01958437) in 32 older adults to evaluate high definition (HD)-tDCS-induced changes in glutamate and GABA via magnetic resonance spectroscopy (MRS). Participants underwent MRS following two counterbalanced HD-tDCS sessions (one active, one sham) that targeted the right superior parietal …cortex (center anode at P2) and delivered 2mA for 20 minutes. Results: Relative to sham, and when co-varying for MRS voxel overlap and right superior parietal volume, active HD-tDCS significantly increased GABA and decreased the ratio of glutamate to GABA. No changes were observed in a left prefrontal control MRS voxel. Although we did not find a significant correlation between strength of delivered current (measured via MRI-based computational modeling) and neurometabolite change, there was a robust positive relationship between the volume of right superior parietal cortex and neurometabolite change. Conclusion: Our preliminary findings of increased GABA and reduced glutamate/GABA ratio raise the possibility that (HD-)tDCS effects differ by age. Moreover, age- and disease-related regional brain volume loss may be especially important to consider when planning future studies. Replication would emphasize the importance of developing population-specific tDCS parameters that consider structural and physiologic changes associated with “normal” and pathological aging. Show more

Keywords: Aging, magnetic resonance spectroscopy, mild cognitive impairment, neuromodulation, neurotransmitters, transcranial electrical stimulation

DOI: 10.3233/JAD-201091

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1091-1102, 2021

Authors: Washida, Kazuo | Kitajima, Erika | Tanaka, Tomotaka | Ikeda, Shuhei | Chiba, Tetsuya | Noda, Kotaro | Yoshimoto, Takeshi | Fukuma, Kazuki | Saito, Satoshi | Ihara, Masafumi

Article Type: Research Article

Abstract: Background: Poststroke dementia (PSD) is a serious problem for stroke survivors. However, there is still limited data on the real-world state and clinical management of PSD worldwide, and several countries already have a super-aged society. Objective: We conducted a nationwide questionnaire survey to examine the real-world state and management of PSD in Japan. Methods: A survey was conducted in the top 500 Japanese hospitals regarding the number of stroke patients treated between July 2018 and August 2019. Thirteen questions regarding PSD were mailed to doctors responsible for stroke management. Results: Responses were obtained from …251 hospitals (50.2%). The chief doctors responsible for stroke management answered the questionnaires. The median numbers of patients admitted annually with stroke in the departments of neurology and neurosurgery in the hospitals were 281.0 (interquartile range [IQR], 231.8–385.3) and 253.5 (IQR, 210.0–335.3), respectively, and most hospitals were acute care hospitals. Executive dysfunction was the most common cognitive dysfunction (10.9%), followed by amnesia (9.5%) and apathy (4.1%). Surprisingly, many stroke survivors lived alone at home (23.7%). Montreal Cognitive Assessment was significantly uncommon compared to Mini-Mental State Examination (p  < 0.01). Furthermore, objective evaluation tests for behavioral and psychological symptoms of dementia were not often performed. Cognitive rehabilitation treatments were performed more often and earlier than drug treatments. The first drug of choice for PSD was predominantly donepezil (79.1%), followed by galantamine (6.1%), cilostazol (4.9%), memantine (2.5%), and rivastigmine (1.8%). Conclusion: Our study provides real-world evidence for the state of clinical practice related to PSD in Japan. Show more

Keywords: Donepezil, executive dysfunction, living alone, Montreal Cognitive Assessment, poststroke dementia

DOI: 10.3233/JAD-215006

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1103-1114, 2021

Authors: Höbler, Fiona | McGilton, Katherine S. | Wittich, Walter | Dupuis, Kate | Reed, Marilyn | Dumassais, Shirley | Mick, Paul | Pichora-Fuller, M. Kathleen

Article Type: Research Article

Abstract: Background: Hearing loss is highly prevalent in older adults, particularly among those living with dementia and residing in long-term care homes (LTCHs). Sensory declines can have deleterious effects on functioning and contribute to frailty, but the hearing needs of residents are often unrecognized or unaddressed. Objective: To identify valid and reliable screening measures that are effective for the identification of hearing loss and are suitable for use by nursing staff providing care to residents with dementia in LTCHs. Methods: Electronic databases (Embase, Medline, PsycINFO, CENTRAL, and CINAHL) were searched using comprehensive search strategies, and a stepwise …approach based on Arksey & O’Malley’s scoping review and appraisal process was followed. Results: There were 193 scientific papers included in the review. Pure-tone audiometry was the most frequently reported measure to test hearing in older adults living with dementia. However, measures including self- or other-reports and questionnaires, review of medical records, otoscopy, and the whisper test were found to be most suitable for use by nurses working with older adults living with dementia in LTCHs. Conclusion: Although frequently used, the suitability of pure-tone audiometry for use by nursing staff in LTCHs is limited, as standardized audiometry presents challenges for many residents, and specific training is needed to successfully adapt test administration procedures and interpret results. The whisper test was considered to be more suitable for use by staff in LTCH; however, it yields a limited characterization of hearing loss. There remains an urgent need to develop new approaches to screen hearing in LTCHs. Show more

Keywords: Aging, cognitive impairment, dementia, hard-of-hearing, hearing impairment, hearing screening, long-term care home, nursing, scoping review

DOI: 10.3233/JAD-215087

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1115-1138, 2021

Authors: Shukla, Deepika | Mandal, Pravat K. | Mishra, Ritwick | Punjabi, Khushboo | Dwivedi, Divya | Tripathi, Manjari | Badhautia, Vaishali

Article Type: Research Article

Abstract: Background: Oxidative stress plays a major role in Alzheimer’s disease (AD) pathogenesis, and thus, antioxidant glutathione (GSH) has been actively investigated in mitigating the oxidative load. Significant hippocampal GSH depletion has been correlated with cognitive impairment in AD. Furthermore, postmortem studies indicated alterations in cellular-energy metabolism and hippocampal pH change toward alkalinity in AD. Objective: Concurrent analysis of hippocampal GSH and pH interplay in vivo on the same individual is quite unclear and hence requires investigation to understand the pathological events in AD. Methods: Total 39 healthy old (HO), 22 mild cognitive impairment (MCI), and …37 AD patients were recruited for hippocampal GSH using 1 H-MRS MEGA-PRESS and pH using 2D 31 P-MRSI with dual tuned (1 H/31 P) transmit/receive volume head coil on 3T-Philips scanner. All MRS data processing using KALPANA package and statistical analysis were performed MedCalc, respectively and NINS-STAT package. Results: Significant GSH depletion in the left and right hippocampus (LH and RH) among MCI and AD study groups as compared to HO was observed, whereas pH increased significantly in the LH region between HO and AD. Hippocampal GSH level negatively correlated with pH in both patient groups. The ROC analysis on the combined effect of GSH and pH in both hippocampal regions give accuracy for MCI (LH: 78.27%; RH: 86.96%) and AD (LH: 88%; RH: 78.26%) groups differentiating from HO. Conclusion: Outcomes from this study provide further insights to metabolic alterations in terms of concurrent assessment of hippocampal GSH and pH levels in AD pathogenesis, aiding in early diagnosis of MCI and AD. Show more

Keywords: Alzheimer’s disease, glutathione, 1H/31P multi-nuclear MRS, hippocampus, pH, mild cognitive impairment

DOI: 10.3233/JAD-215032

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1139-1152, 2021

Authors: de Boer, Sterre C.M. | Riedl, Lina | van der Lee, Sven J. | Otto, Markus | Anderl-Straub, Sarah | Landin-Romero, Ramon | Sorrentino, Federica | Fieldhouse, Jay L.P. | Reus, Lianne M. | Vacaflor, Blanca | Halliday, Glenda | Galimberti, Daniela | Diehl-Schmid, Janine | Ducharme, Simon | Piguet, Olivier | Pijnenburg, Yolande A.L.

Article Type: Research Article

Abstract: Background: Reported sex distributions differ between frontotemporal dementia (FTD) cohorts. Possible explanations are the evolving clinical criteria of FTD and its subtypes and the discovery of FTD causal genetic mutations that has resulted in varying demographics. Objective: Our aim was to determine the sex distribution of sporadic and genetic FTD cases and its subtypes in an international cohort. Methods: We included 910 patients with behavioral variant frontotemporal dementia (bvFTD; n  = 654), non-fluent variant primary progressive aphasia (nfvPPA; n  = 99), semantic variant primary progressive aphasia (svPPA; n  = 117), and right temporal variant frontotemporal dementia (rtvFTD; n  = 40). …We compared sex distribution between genetic and sporadic FTD using χ 2 -tests. Results: The genetic FTD group consisted of 51.2% males, which did not differ from sporadic FTD (57.8% male, p  = 0.08). In the sporadic bvFTD subgroup, males were predominant in contrast to genetic bvFTD (61.6% versus 52.9% males, p  = 0.04). In the other clinical FTD subgroups, genetic cases were underrepresented and within the sporadic cases the sex distribution was somewhat equal. Conclusion: The higher male prevalence in sporadic bvFTD may provide important clues for its differential pathogenesis and warrants further research. Show more

Keywords: Behavioral variant frontotemporal dementia, genetic, non-fluent variant primary progressive aphasia, right temporal variant frontotemporal dementia, semantic variant primary progressive aphasia, sex differences, sex distribution, sporadic

DOI: 10.3233/JAD-210688

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1153-1161, 2021