Journal of Alzheimer's Disease - Volume 97, issue 1

Authors: Hao, Ning | Bai, Xue | Hu, An | Zhao, Gaofeng | Chen, Yansheng | Zhao, Jianhe | Ling, Qiong | Li, Xiangyu | Cai, Chuipu | Wang, Qi | Wang, Zhaojun | Fang, Jiansong

Article Type: Research Article

Abstract: Background: Obesity significantly increases Alzheimer’s disease (AD) and dementia risk. Understanding the link between a high body mass index (BMI) and these conditions is crucial for effective management and prevention. Objective: We aimed to estimate the burden of AD and other dementias attributed to high BMI from 1990 to 2019 based on sex, age, and socio-demographic indicators (SDI) at global, regional, and national levels. Methods: We collected data on deaths, disability-adjusted life years (DALYs), age-standardized mortality rates (ASMR), and age-standardized DALY rates (ASDR) from the 2019 Global Burden of Disease study for AD and dementia attributed …to high BMI. We explored the correlation between SDI levels and ASDR. Results: In 2019, there were 198,476.2 deaths (95% UI: 32,695.4–593,366.4) and 3,159,912.4 DALYs (848,330.5–8,042,531) attributed to high BMI. Numbers of deaths, DALYs, ASMR, and ASDR increased since 1990. Females had higher deaths, ASMR, and ASDR than males. Mortality and DALYs rates increased with age. ASMR and ASDR increased across five SDI levels, with the highest rise in Low-middle SDI. High-income North America had the most deaths [30,993.9 (5,101.7–89,912.9)], while North Africa and the Middle East had the highest ASMR [4.61 (0.79–13.64)] and ASDR [72.56 (20.98–181.16)] in 2019. Conclusions: The burden of AD and other dementias attributed to high BMI increased since 1990 globally and is still heaviest in developed regions. Females accounted predominantly for the burden than males. Timely measures are needed to against high BMI. Show more

Keywords: Alzheimer’s disease and other dementias, body mass index, death, Global Burden of Disease, age-standardized rates

DOI: 10.3233/JAD-230827

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 293-307, 2024

Authors: Angelidou, Ioanna Antigoni | Stocker, Hannah | Beyreuther, Konrad | Teichmann, Birgit

Article Type: Research Article

Abstract: Background: Attitudes, motivations, and barriers to pre-symptomatic screening for Alzheimer’s disease (AD) in the general population are unclear, and validated measurement tools are lacking. Objective: Translation and validation of the German version of the “Perceptions regarding pRE-symptomatic Alzheimer’s Disease Screening” (PRE-ADS) questionnaire. Methods: A convenience sample (N  = 256) was recruited via an online platform. Validation of the PRE-ADS-D consisted of assessments of reliability, structural validity using Principal Component Analysis (PCA) and Exploratory Factor Analysis (EFA) and construct validity using known-group tests. A subscale “Acceptability of Screening”, with 5 PRE-ADS-D items, was extracted to measure acceptance of …screening in clinical practice. The STROBE checklist was used for reporting. Results: EFA revealed a three-factor model for the PRE-ADS-D. Acceptable to good internal consistency was found for the 25-item scale (α = 0.78), as well as for the three factors “Concerns about Screening” (α = 0.85), “Intention to be Screened” (α = 0.87), and “Preventive Health Behaviors” (α = 0.81). Construct validity was confirmed for both the 25-item PRE-ADS-D and the “Acceptability of Screening” scale (α = 0.91). Overall, 51.2% of the participants showed a preference for screening. Non-parametric tests were conducted to further explore group differences of the sample. Conclusions: The PRE-ADS-D is a reliable and valid tool to measure attitudes, motives, and barriers regarding pre-symptomatic dementia screening in the German-speaking general population. Additionally, the subscale “Acceptability of Screening” demonstrated good construct validity and reliability, suggesting its promising potential as a practical tool in clinical practice. Show more

Keywords: Alzheimer’s disease, attitude, biomarker, psychometrics, screening, validity

DOI: 10.3233/JAD-230961

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 309-325, 2024

Authors: Bruno, Jennifer L. | Shaw, Jacob S. | Hosseini, S. M. Hadi

Article Type: Research Article

Abstract: Background: Cognitive training holds potential as a non-pharmacological intervention to decrease cognitive symptoms associated with Alzheimer’s disease (AD), but more research is needed to understand individual differences that may predict maximal training benefits. Objective: We conducted a pilot study using a six-month training regimen in healthy aging adults with no cognitive decline. We investigated the effects of baseline performance and age on training and transfer improvements. Methods: Out of 43 participants aged 65–84 years, 31 successfully completed cognitive training (BrainHQ ) in one of three cognitive domains: processing speed (N = 13), inhibitory control (N = 9), or episodic memory …(N = 9). We used standardized assessments to measure baseline performance and transfer effects. Results: All 31 participants improved on the cognitive training regimen and age was positively associated with training improvement (p  = 0.039). The processing speed group improved significantly across many near- and far-transfer tasks. In the inhibitory control group, individuals with lower baseline performance improved more on inhibitory control and cognitive flexibility tasks. In the episodic memory group, older individuals improved most on a memory task while younger individuals improved most on an executive function far-transfer task. Conclusions: Individual differences are predictive of cognitive training gains, and the impact of individual differences on training improvements is specific to the domain of training. We provide initial insight regarding how non-pharmacological interventions can be optimized to combat the onset of cognitive decline in older adults. With future research this work can inform the design of effective cognitive interventions for delaying cognitive decline in preclinical AD. Show more

Keywords: Age, Alzheimer’s disease, baseline performance, cognitive training, compensation effect, inhibition, processing speed, working memory

DOI: 10.3233/JAD-230619

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 327-343, 2024

Authors: LoBue, Christian | Stopschinski, Barbara E. | Saez Calveras, Nil | Douglas, Peter M. | Huebinger, Ryan | Cullum, C. Munro | Hart, John | Gonzales, Mitzi M.

Article Type: Research Article

Abstract: Background: Traumatic brain injury (TBI) has been linked to multiple pathophysiological processes that could increase risk for Alzheimer’s disease and related dementias (ADRD). However, the impact of prior TBI on blood biomarkers for ADRD remains unknown. Objective: Using cross-sectional data, we assessed whether a history of TBI influences serum biomarkers in a diverse cohort (approximately 50% Hispanic) with normal cognition, mild cognitive impairment, or dementia. Methods: Levels of glial fibrillary acidic protein (GFAP), neurofilament light (NFL), total tau (T-tau), and ubiquitin carboxy-terminal hydrolase-L1 (UCHL1) were measured for participants across the cognitive spectrum. Participants were categorized based …on presence and absence of a history of TBI with loss of consciousness, and study samples were derived through case-control matching. Multivariable general linear models compared concentrations of biomarkers in relation to a history of TBI and smoothing splines modelled biomarkers non-linearly in the cognitively impaired groups as a function of time since symptom onset. Results: Each biomarker was higher across stages of cognitive impairment, characterized by clinical diagnosis and Mini-Mental State Examination performance, but these associations were not influenced by a history of TBI. However, modelling biomarkers in relation to duration of cognitive symptoms for ADRD showed differences by history of TBI, with only GFAP and UCHL1 being elevated. Conclusions: Serum GFAP, NFL, T-tau, and UCHL1 were higher across stages of cognitive impairment in this diverse clinical cohort, regardless of TBI history, though longitudinal investigation of the timing, order, and trajectory of the biomarkers in relation to prior TBI is warranted. Show more

Keywords: Alzheimer’s disease, brain injury, dementia, cognitive dysfunction, serum marker

DOI: 10.3233/JAD-231027

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 345-358, 2024

Authors: Da, Xiao | Hempel, Evan | Ou, Yangming | Rowe, Olivia Elizabeth | Malchano, Zach | Hajós, Mihály | Kern, Ralph | Megerian, Jonathan Thomas | Cimenser, Aylin

Article Type: Research Article

Abstract: Background: Patients with Alzheimer’s disease (AD) demonstrate progressive white matter atrophy and myelin loss. Restoring myelin content or preventing demyelination has been suggested as a therapeutic approach for AD. Objective: Herein, we investigate the effects of non-invasive, combined visual and auditory gamma-sensory stimulation on white matter atrophy and myelin content loss in patients with AD. Methods: In this study, we used the magnetic resonance imaging (MRI) data from the OVERTURE study (NCT03556280), a randomized, controlled, clinical trial in which active treatment participants received daily, non-invasive, combined visual and auditory, 40 Hz stimulation for six months. A subset …of OVERTURE participants who meet the inclusion criteria for detailed white matter (N = 38) and myelin content (N = 36) assessments are included in the analysis. White matter volume assessments were performed using T1-weighted MRI, and myelin content assessments were performed using T1-weighted/T2-weighted MRI. Treatment effects on white matter atrophy and myelin content loss were assessed. Results: Combined visual and auditory gamma-sensory stimulation treatment is associated with reduced total and regional white matter atrophy and myelin content loss in active treatment participants compared to sham treatment participants. Across white matter structures evaluated, the most significant changes were observed in the entorhinal region. Conclusions: The study results suggest that combined visual and auditory gamma-sensory stimulation may modulate neuronal network function in AD in part by reducing white matter atrophy and myelin content loss. Furthermore, the entorhinal region MRI outcomes may have significant implications for early disease intervention, considering the crucial afferent connections to the hippocampus and entorhinal cortex. Show more

Keywords: Alzheimer’s disease, dementia, myelin, white matter

DOI: 10.3233/JAD-230506

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 359-372, 2024

Authors: Grothe, Jessica | Kropidlowski, Adam | Luppa, Melanie | Elgner, Melanie | Funke, Katja | Pabst, Alexander | Schomerus, Georg | Dietzel, Jens | Saur, Dorothee | Sommerlad, Andrew | Riedel-Heller, Steffi G. | Luck, Tobias

Article Type: Research Article

Abstract: Background: Activities of daily living (ADL) functioning are important in the diagnosis of neurocognitive disorders (NCD), yet no standardized and validated instrument exist based on international classification systems. Objective: We aimed to psychometrically evaluate the differentiated assessment of ADL and instrumental ADL (IADL) impairments due to NCD according to DSM-5 criteria (Instrument für die Erfassung von A lltagsbeeinträchtigungen bei N eurok ognitiven S törungen ; A-NKS). Methods: We conducted a pilot study involving 92 participant-informant dyads of participants with mild or major NCDs, cognitively healthy individuals, and an informant, to test acceptability, internal consistency, and convergent …validity with similar measures. Results: Both A-NKS versions demonstrated excellent internal consistency (α= 0.95 –0.99) and correlate with other instrumental ADL instruments (participant [informant ]: Barthel Index: rs  = –0.26, p ≤0.05 [rs  = –0.30, p ≤0.01]; Amsterdam IADL: rs  = 0.59, p ≤0.01 [rs  = 0.48, p ≤0.01]; SIDAM ADL: rs  = 0.46, p ≤0.001 [rs  = 0.47, p ≤0.001]). Additionally, there are correlations with the scale autonomy of the WHOQOL-OLD (rs = -0.50, p ≤0.001 [rs  = –0.37, p ≤0.001]) and physical, as well as cognitive activities (rs = -0.39, p ≤0.001 [rs  = –0.50, p ≤0.001]). They were well-accepted by participants and informants. Conclusions: The A-NKS is an instrument with acceptable psychometric properties to assess ADL due to neurodegenerative decline in healthy individuals, and those with mild or major NCD. Further research is needed to confirm reliability and validity and investigate the factor structure. Show more

Keywords: A-NKS, activities of daily living, dementia, measure, neurocognitive disorders, psychometrics, questionnaire, reliability, scale, validity

DOI: 10.3233/JAD-230627

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 373-394, 2024

Authors: Ge, Yingying | AlObaidi, Alya S. | Kuchel, George A. | Bartley, Jenna M. | Smith, Phillip P. | He, Wanxia | Hu, Xiangyou

Article Type: Research Article

Abstract: Background: While symptoms related to lower urinary tract dysfunction (LUTD) are common in individuals with Alzheimer’s disease (AD), pathophysiological links between AD and LUTD remain unclear. Objective: This study aimed to investigate whether AD neuropathology would cause autonomic dysfunction along the spinal cord-bladder axis, which could result in alterations in bladder muscle kinetics. Methods: We utilized APPNL -G -F /NL -G -F knock-in (APP KI) and APPwt/wt (wild-type) mice at two different ages, 4- and 10-month-old, to investigate how AD impacts bladder tissue function by immunohistochemistry, western blotting, and pharmacomyography. …Results: We showed that the mucosal layer partially separated from the detrusor in 10-month-old APP KI mouse bladders. Although there was no detectable amyloid deposition in the APP KI bladder, we found amyloid plaques in APP KI lumbar spinal cord. Further immunoblot analysis revealed that tyrosine hydroxylase protein levels were significantly reduced in both 4- and 10-month-old bladder tissues, suggesting reduction of norepinephrine synthesis in APP KI mouse bladders. In contrast, the level of β2 adrenergic receptor was increased in 4-month-old but not 10-month-old APP KI bladders. In bladder strips, the adrenergic agonist isoproterenol induced increased relaxation in 4- but not 10-month-old APP KI bladders. With 10 Hz electrical field stimulation, 10-month-old APP KI bladder strips were more responsive than wild-type controls, with no differences observed in 4-month-old APP KI bladders. Conclusions: APP KI mice exhibit LUTD, which is likely arising from amyloid pathology in the spinal cord, and results in maturational declines in presynaptic activity combined with compensatory postsynaptic upregulation. Show more

Keywords: Alzheimer’s disease, amyloid plaque, bladder, bladder dysfunction, bladder pharmacomyography, lower urinary tract dysfunction, neurotransmitters

DOI: 10.3233/JAD-230547

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 395-408, 2024

Authors: Yang, Mengli | Gan, Jinghuan | Liu, Shuai | Yang, Yaqi | Han, Jiuyan | Meng, Qingbo | Yang, Fan | Ji, Yong

Article Type: Research Article

Abstract: Background: Constipation is a common symptom in dementia, and the cause is controversial. Rare clinical studies focused on plasma orexin-A levels and constipation in dementia. Objective: To evaluate the associations between orexin-A and constipation in patients with cognitive impairment. Methods: A total of 21 patients with mild cognitive impairment (MCI), 142 with Alzheimer’s disease (AD), and 57 with Lewy body dementia (LBD) were conducted. Besides informant-based history, neurological examinations or neuropsychological assessments, plasma levels of orexin-A, and constipation were assessed. The associations between orexin-A and constipation were evaluated by logistic regression models. Results: There …were 47/220 (21.36%) cognitive impairment patients having constipation, and the proportion of constipation in LBD (61.40%) was significantly higher than AD (5.63%) and MCI (19.05%). No significant age or sex differences in the prevalence of constipation were found in the MCI, AD, and LBD groups. We found the cognitive impairment patients with constipation had lower levels of plasma orexin-A [1.00 (0.86, 1.28) versus 1.29 (1.01, 1.50) ng/ml, p  < 0.001] than those without. And the plasma levels of orexin-A were significantly associated with the occurrence of constipation after adjusting for all variables in all patients with cognitive impairment (OR = 0.151, 95% CI: 0.042–0.537, p  = 0.003). And the same finding was more prominent in the LBD group (p  = 0.048). Conclusions: The decrease of plasma level of orexin-A is closely associated with the occurrence of constipation. Orexin-A has an intestinal protective effect and is involved in the gastrointestinal symptoms of patients with cognitive impairment. Show more

Keywords: Alzheimer’s disease, brain-gut axis, constipation, intestinal epithelial barrier, Lewy body dementia, orexin-A

DOI: 10.3233/JAD-230625

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 409-419, 2024

Authors: Malotaux, Vincent | Colmant, Lise | Quenon, Lisa | Huyghe, Lara | Gérard, Thomas | Dricot, Laurence | Ivanoiu, Adrian | Lhommel, Renaud | Hanseeuw, Bernard

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) pathology can be disclosed in vivo using amyloid and tau imaging, unlike non-AD neuropathologies for which no specific markers exist. Objective: We aimed to compare brain hypometabolism and tauopathy to unveil non-AD pathologies. Methods: Sixty-one patients presenting cognitive complaints (age 48–90), including 32 with positive AD biomarkers (52%), performed [18 F]-Fluorodeoxyglucose (FDG)-PET (brain metabolism) and [18 F]-MK-6240-PET (tau). We normalized these images using data from clinically normal individuals (n  = 30), resulting in comparable FDG and tau z-scores. We computed between-patients correlations to evaluate regional associations. For each patient, a predominant biomarker …(i.e., Hypometabolism > Tauopathy or Hypometabolism≤Tauopathy) was determined in the temporal and frontoparietal lobes. We computed within-patient correlations between tau and metabolism and investigated their associations with demographics, cognition, cardiovascular risk factors (CVRF), CSF biomarkers, and white matter hypointensities (WMH). Results: We observed negative associations between tau and FDG in 37 of the 68 cortical regions-of-interest (average Pearson’s r  = –0.25), mainly in the temporal lobe. Thirteen patients (21%) had Hypometabolism > Tauopathy whereas twenty-five patients (41%) had Hypometabolism≤Tauopathy. Tau-predominant patients were more frequently females and had greater amyloid burden. Twenty-three patients (38%) had Hypometabolism≤Tauopathy in the temporal lobe, but Hypometabolism > Tauopathy in the frontoparietal lobe. This group was older and had higher CVRF than Tau-predominant patients. Patients with more negative associations between tau and metabolism were younger, had worse cognition, and greater amyloid and WMH burdens. Conclusions: Tau-FDG comparison can help suspect non-AD pathologies in patients presenting cognitive complaints. Stronger Tau-FDG correlations are associated with younger age, worse cognition, and greater amyloid and WMH burdens. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, mixed dementias, positron emission tomography

DOI: 10.3233/JAD-230696

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 421-433, 2024

Authors: Li, Wenyi | Jiang, Jiwei | Yin, Xiangchang | Zhang, Yuan | Zou, Xinying | Sun, Mengfan | Jia, Jianjun | Ma, Baiping | Xu, Jun

Article Type: Research Article

Abstract: Background: Gut microbiota could affect the onset and development of vascular cognitive impairment (VCI) through modulating metabolic and immune pathways. However, the vascular mechanisms involved remain unclear. Objective: To investigate the gut microbiota associated with VCI and examine the mediating effects of regional cerebral blood flow (CBF) to explore potential therapeutic targets for VCI. Methods: This prospective study enrolled patients with VCI (n  = 16) and healthy controls (n  = 18) from the Chinese Imaging, Biomarkers, and Lifestyle study between January 1 and June 30, 2022. The gut microbiota composition and diversity were determined by …16 S ribosomal RNA gene sequencing. The association between gut microbiota and Montreal Cognitive Assessment (MoCA) scores was determined using Spearman’s correlation analysis. Regional CBF was calculated using pseudo-continuous arterial spin labeling. The mediating effects of regional CBF on the relationship between specific gut microbiota and cognition in VCI were investigated using mediation analysis. Results: Compared to healthy controls, patients with VCI had significantly greater abundance of Bifidobacterium, Veillonella, R uminococcus gnavus , Fusobacterium, and Erysipelatoclostridium and smaller abundance of Collinsella . The abundance of Ruminococcus gnavus was negatively associated with MoCA scores in patients with VCI, with the CBF in the left hypothalamus, right hypothalamus, and left amygdala accounting for 63.96%, 48.22%, and 36.51%, respectively, of this association after adjusting for confounders. Conclusions: Ruminococcus gnavus is associated with cognition in VCI, which is strongly mediated by CBF in the bilateral hypothalamus and left amygdala. These findings highlight the potential regulatory roles of nutrition and metabolism-related areas of the brain in VCI. Show more

Keywords: Alzheimer’s disease, cerebral blood flow, cerebral small vessel diseases, gut microbiota, mediation analysis, Ruminococcus gnavus

DOI: 10.3233/JAD-230709

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 435-445, 2024