Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Boulares, Ayoub | Fabre, Claudine | Cherni, Ala | Jdidi, Hela | Gaied Chortane, Sabri | Trompetto, Carlo | Puce, Luca | Bragazzi, Nicola Luigi

Article Type: Research Article

Abstract: Background: Aging often leads to cognitive function decline, sensory structure deterioration, and musculoskeletal system weakening. This impacts postural control during static and dynamic activities like walking, increasing the fall risk among the elderly. Older adults with mild cognitive impairment (MCI) face an elevated fall risk and cognitive decline, magnifying the public health concern. Objective: This study aimed to explore solutions by investigating the effects of a multi-component physical activity program on cognitive and motor functions in MCI patients. Methods: Twenty-three participants were enrolled in the study and assigned into two groups: an intervention group (n  = 13; …age = 85.7±5.5 years) and a control group (n  = 9; age = 85±6.7 years). The study spanned two months, with participants engaging in three 60-minute weekly physical exercise sessions. The intervention focused on improving proprioception, muscle strength, and balance. Results: Results demonstrated significant enhancements in physical performance, fall risk reduction, and balance (p  < 0.05). Various tests, including the timed up and go test, Unipedal Stance test, Tinetti test, Short Physical Performance Battery, and 6-minute walking test, indicated these improvements. Cognitive function was evaluated with the Mini-Mental State Examination, revealing non-significant progress (p  > 0.05). Predictive models for outcomes were developed using linear regression analysis during the follow-up stage. Conclusions: This study underscores the effectiveness of a multi-component physical activity program encompassing balance, proprioception, and muscle-strengthening exercises as a non-pharmaceutical approach in improving balance skills and playing a key role in mitigating the risk of falls among old adults with MCI. Show more

Keywords: Alzheimer’s disease, balance, cognitive functions, fall risk, mild cognitive impairment, motor functions, multi-component physical exercise, older adults, proprioception

DOI: 10.3233/JAD-230305

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2023

Authors: Wang, Jiao | Wang, Chun | Li, Xuan | Guo, Jie | Dove, Abigail | Cui, Zhuang | Xu, Weili

Article Type: Research Article

Abstract: Background: The association of anemia with cognitive function and dementia remains unclear. Objective: We aimed to investigate the association of anemia with cognitive function and dementia risk and to explore the role of inflammation in these associations. Methods: Within the UK Biobank, 207,203 dementia-free participants aged 60+ were followed for up to 16 years. Hemoglobin (HGB) and C-creative protein (CRP) were measured from blood samples taken at baseline. Anemia was defined as HGB <13 g/dL for males and <12 g/dL for females. Inflammation was categorized as low or high according to the median CRP level (1.50 mg/L). A subset …of 18,211 participants underwent cognitive assessments (including global and domain-specific cognitive). Data were analyzed using linear mixed-effects model, Cox regression, and Laplace regression. Results: Anemia was associated with faster declines in global cognition (β= –0.08, 95% confidence interval [CI]: –0.14, –0.01) and processing speed (β= –0.10, 95% CI: –0.19, –0.01). During the follow-up of 9.76 years (interquartile range 7.55 to 11.39), 6,272 developed dementia. The hazard ratio of dementia was 1.57 (95% CI: 1.38, 1.78) for people with anemia, and anemia accelerated dementia onset by 1.53 (95% CI: 1.08, 1.97) years. The risk of dementia tended to be higher in people with both anemia and high CRP (1.89, 95% CI: 1.60, 2.22). There was a statistically significant interaction between anemia and CRP on dementia risk (p-interaction = 0.032). Conclusions: Anemia is associated with cognitive decline (specifically for processing speed) and increased risk of dementia, especially in people with high inflammation. Show more

Keywords: Alzheimer’s disease, anemia, cognitive function, dementia, inflammation, UK Biobank

DOI: 10.3233/JAD-230483

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2023

Authors: Hammers, Dustin B. | Lin, Joshua H. | Polsinelli, Angelina J. | Logan, Paige E. | Risacher, Shannon L. | Schwarz, Adam J. | Apostolova, Liana G.

Article Type: Research Article

Abstract: Background: Utilization of NIA-AA Research Framework requires dichotomization of tau pathology. However, due to the novelty of tau-PET imaging, there is no consensus on methods to categorize scans into “positive” or “negative” (T+ or T–). In response, some tau topographical pathologic staging schemes have been developed. Objective: The aim of the current study is to establish criterion validity to support these recently-developed staging schemes. Methods: Tau-PET data from 465 participants from the Alzheimer’s Disease Neuroimaging Initiative (aged 55 to 90) were classified as T+ or T– using decision rules for the Temporal-Occipital Classification (TOC), Simplified TOC …(STOC), and Lobar Classification (LC) tau pathologic schemes of Schwarz, and Chen staging scheme. Subsequent dichotomization was analyzed in comparison to memory and learning slope performances, and diagnostic accuracy using actuarial diagnostic methods. Results: Tau positivity was associated with worse cognitive performance across all staging schemes. Cognitive measures were nearly all categorized as having “fair” sensitivity at classifying tau status using TOC, STOC, and LC schemes. Results were comparable between Schwarz schemes, though ease of use and better data fit preferred the STOC and LC schemes. While some evidence was supportive for Chen’s scheme, validity lagged behind others—likely due to elevated false positive rates. Conclusions: Tau-PET staging schemes appear to be valuable for Alzheimer’s disease diagnosis, tracking, and screening for clinical trials. Their validation provides support as options for tau pathologic dichotomization, as necessary for use of NIA-AA Research Framework. Future research should consider other staging schemes and validation with other outcome benchmarks. Show more

Keywords: Alzheimer’s disease, amyloid, learning, memory, mild cognitive impairment, tau

DOI: 10.3233/JAD-230512

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2023

Authors: Verde, Federico | Aiello, Edoardo Nicolò | Adobbati, Laura | Poletti, Barbara | Solca, Federica | Tiloca, Cinzia | Sangalli, Davide | Maranzano, Alessio | Muscio, Cristina | Ratti, Antonia | Zago, Stefano | Ticozzi, Nicola | Frisoni, Giovanni Battista | Silani, Vincenzo

Article Type: Short Communication

Abstract: We describe a case of amyotrophic lateral sclerosis (ALS) associated with Alzheimer’s disease (AD) and review the literature about the coexistence of the two entities, highlighting the following: mean age at onset is 63.8 years, with slight female predominance; ALS tends to manifest after cognitive impairment and often begins in the bulbar region; average disease duration is 3 years; cognitive phenotype is mostly amnestic; the pattern of brain involvement is, in most cases, consistent with AD. Our case and the reviewed ones suggest that patients with ALS and dementia lacking unequivocal features of FTD should undergo additional examinations in order …to recognize AD. Show more

Keywords: Alzheimer’s disease, amyotrophic lateral sclerosis, neurodegeneration, neuropsychology

DOI: 10.3233/JAD-230562

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2023

Authors: Watts, Amber | Haneline, Stephen | Welsh-Bohmer, Kathleen A. | Wu, Jingtao | Alexander, Robert | Swerdlow, Russell H. | Burns, Daniel K. | Saunders, Ann M.

Article Type: Research Article

Abstract: Background: TOMM40 ‘523 has been associated with cognitive performance and risk for developing Alzheimer’s disease independent of the effect of APOE genotype. Few studies have considered the longitudinal effect of this genotype on change in cognition over time. Objective: Our objective was to evaluate the relationship between TOMM40 genotype status and change in cognitive performance in the TOMMORROW study, which was designed to prospectively evaluate an algorithm that includes TOMM40 ‘523 for genetic risk for conversion to mild cognitive impairment. Methods: We used latent growth curve models to estimate the effect …of TOMM40 allele carrier (short, very long) status on the intercept and slope of change in cognitive performance in four broad cognitive domains (attention, memory, executive function, and language) and a combined overall cognitive score over 30 months. Results: TOMM40 very long allele carriers had significantly lower baseline performance for the combined overall cognitive function score (B = –0.088, p  = 0.034) and for the executive function domain score (B = –0.143, p  = 0.013). Slopes for TOMM40 VL carriers had significantly greater increases over time for the executive function domain score only. In sensitivity analyses, the results for executive function were observed in participants who remained clinically stable, but not in those who progressed clinically over the study duration. Conclusions: Our results add to the growing body of evidence that TOMM40, in the absence of APOE ɛ 4, may contribute to cognitive changes with aging and dementia and support the view that mitochondrial function is an important contributor to AD risk. Show more

Keywords: Alzheimer’s disease, APOE , cognition, executive function, longitudinal, TOMM40

DOI: 10.3233/JAD-230066

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2023

Authors: Sejunaite, Karolina | Gaucher, Frederic | Lanza, Claudia | Riepe, Matthias W.

Article Type: Research Article

Abstract: Background: Clock Drawing Test (CDT) is a commonly used screening tool for cognitive disorders, known for its ease of administration and scoring. Despite frequent use by clinicians, CDT is criticized for its poor predictive value in mild cases of impairment. Objective: To evaluate CDT as a screening tool for early stage of cognitive impairment in biomarker-verified Alzheimer’s disease (AD) and depressive disorder (DD). Methods: We analyzed CDT of 172 patients with verified AD, 70 patients with DD, in whom neurodegenerative disorder was excluded using cerebrospinal fluid biomarkers, and 58 healthy older adults. CDT …was scored using the semi-quantitative (Shulman) and itemized criteria (adapted from Mendez). Results: Logistic regression showed that for both DD and AD patients with high Mini-Mental State Examination (MMSE) scores (27 and above) the significant predicting variable is uneven number spacing. As MMSE deteriorates (24-26 points), an additional error of setting clock hands is predictive of the disease. In the low MMSE condition, CDT showed an acceptable discrimination for AD (AUC itemized 0.740, Shulman 0.741) and DD (AUC itemized 0.827, Shulman 0.739) using both scoring methods. In the high MMSE condition, discrimination rates were acceptable using itemized scoring but poor using Shulman scoring for both AD (AUC itemized 0.707, Shulman 0.677) and DD (AUC itemized 0.755, Shulman 0.667) groups. Conclusion: Ideally, modern diagnostic process should take place before the cognitive performance drops beneath the healthy range. This makes CDT of little use when screening patients with very mild cognitive deficits. Show more

Keywords: Alzheimer’s disease, dementia, depressive disorder, mental status and dementia tests, screening

DOI: 10.3233/JAD-230110

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2023

Authors: Yang, Yanyan | Li, Mengfan | Leng, Bing | Yao, Ran | Xue, Song | Tan, Ming | Sun, Hairong | Zhang, Jinbiao

Article Type: Research Article

Abstract: Background: Cognitive impairment is common in patients with obstructive sleep apnea (OSA). Previous studies indicated that intermittent hypoxia, sleep fragmentation, and depressive symptoms were associated with cognitive impairment in OSA patients. Objective: The study aimed to investigate whether sleep characteristics and depressive symptoms affected cognitive abilities mediated by Alzheimer’s disease (AD) biomarkers and complement proteins in OSA patients without dementia. Methods: A total of 317 subjects without dementia who had undergone polysomnography, cognitive and neuropsychological evaluations, were recruited. Neuronal-derived exosomes (NDEs) levels for amyloid-β (Aβ), total tau (T-tau), and tau phosphorylated 62 at threonine 181 (P-T181-tau) …and astrocyte-derived exosomes (ADEs) levels for complement proteins were measured. Mediation analysis were performed to explore the mediation effects of AD biomarkers (Aβ42 , T-tau, P-T181-tau) and complement proteins (C3b and C5b-9) on cognition. Results: The findings revealed that the association between sleep fragmentation and cognition was mediated by Aβ42 (the percentage varied from 18.25% to 30.6%), P-T181-tau (the percentage varied from 24.36% to 32.3%), and C5b-9 (the percentage varied from 30.88% to 60.7%). The influence of depressive symptoms on cognition was only mediated via C3b (the percentage varied from 24.1% to 36.6%). Conclusions: In OSA patients without dementia, Aβ42 and P-T181-tau levels in NDEs, and C5b-9 levels in ADEs mediated the impact of sleep fragmentation on cognitive impairment, and C3b levels in ADEs mediated the impact of depressive symptoms on cognitive impairment. Show more

Keywords: Alzheimer’s disease biomarkers, cognition function, complement proteins, depressive symptoms, obstructive sleep apnea, sleep characteristics

DOI: 10.3233/JAD-221288

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2023

Authors: Nik Akhtar, Shayan | Lu, Qun

Article Type: Research Article

Abstract: Background: RhoA signaling is widely reported to be dysregulated in Alzheimer’s disease (AD), but its therapeutic targeting demonstrated mixed outcomes. We hypothesize that the activation and inactivation states of RhoA and LIMK are different in the cortex and in subregions of hippocampus along the rostral-caudal dimensions. Objective: We intended to elucidate the plane and spatial dependent RhoA signaling in association with AD. Methods: We applied antibody pRhoA that recognizes an inactive state of RhoA (S188 phosphorylation) and antibody pLIMK against an active state of LIMK (T508 phosphorylation) to investigate RhoA signaling in wildtype (WT) and triple …transgenic AD (3xTg-AD) mouse model. We prepared serial sections from the rostral to caudal coronal planes of the entire mouse brain followed by immunofluorescence staining with pRhoA and pLIMK antibodies. Results: Both pRhoA and pLIMK elicited a shift of expression pattern from rostral to caudal planes. Additionally, pRhoA demonstrated dynamic redistribution between the nucleus and cytoplasm. pLIMK did not show such nucleus and cytoplasm redistribution but the expression level was changed from rostral to caudal planes. At some planes, pRhoA showed an increasing trend in expression in the cortex but a decreasing trend in the dentate gyrus of the 3xTg-AD mouse hippocampus. pLIMK tends to decrease in the cortex but increase in the dentate gyrus of 3xTg-AD mouse hippocampus. Conclusions: RhoA activation is dysregulated in both human and mouse AD brains, and the RhoA-LIMK signaling axis reveals spatial dysregulation along the rostral-caudal plane dimensions. Show more

Keywords: Alzheimer’s disease, cell signaling, LIM kinase, mouse models, planar distribution, Rho GTPases, spatial expression

DOI: 10.3233/JAD-230408

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2023

Authors: Blusztajn, Jan Krzysztof | Aytan, Nurgul | Rajendiran, Thekkelnaycke | Mellott, Tiffany J. | Soni, Tanu | Burant, Charles F. | Serrano, Geidy E. | Beach, Thomas G. | Lin, Honghuang | Stein, Thor D.

Article Type: Research Article

Abstract: Background: Multiple studies have reported brain lipidomic abnormalities in Alzheimer’s disease (AD) that affect glycerophospholipids, sphingolipids, and fatty acids. However, there is no consensus regarding the nature of these abnormalities, and it is unclear if they relate to disease progression. Objective: Monogalactosyl diglycerides (MGDGs) are a class of lipids which have been recently detected in the human brain. We sought to measure their levels in postmortem human brain and determine if these levels correlate with the progression of the AD-related traits. Methods: We measured MGDGs by ultrahigh performance liquid chromatography tandem mass spectrometry in postmortem dorsolateral …prefrontal cortex gray matter and subcortical corona radiata white matter samples derived from three cohorts of participants: the Framingham Heart Study, the Boston University Alzheimer’s Disease Research Center, and the Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program (total n  = 288). Results: We detected 40 molecular species of MGDGs (including diacyl and alkyl/acyl compounds) and found that the levels of 29 of them, as well as total MGDG levels, are positively associated with AD-related traits including pathologically confirmed AD diagnosis, clinical dementia rating, Braak and Braak stage, neuritic plaque score, phospho-Tau AT8 immunostaining density, levels of phospho-Tau396 and levels of Aβ40 . Increased MGDG levels were present in both gray and white matter, indicating that they are widespread and likely associated with myelin-producing oligodendrocytes—the principal cell type of white matter. Conclusions: Our data implicate the MGDG metabolic defect as a central correlate of clinical and pathological progression in AD. Show more

Keywords: Alzheimer’s disease, cerebral cortex, cerebrosides, gray matter, lipidomics, monogalactosyldiacylglycerol, white matter

DOI: 10.3233/JAD-230543

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2023

Authors: Guieysse, Thomas | Lamothe, Roxane | Houot, Marion | Razafimahatratra, Solofo | Medani, Takfarinas | Lejeune, François-Xavier | Dreyfus, Gérard | Klarsfeld, André | Pantazis, Dimitrios | Koechlin, Etienne | Andrade, Katia

Article Type: Research Article

Abstract: Background: Though not originally developed for this purpose, the Healthy Aging Brain Care Monitor (HABC-M) seems a valuable instrument for assessing anosognosia in Alzheimer’s disease (AD). Objectives: Our study aimed at 1) investigating the validity of the HABC-M (31 items), and its cognitive, psychological, and functional subscales, in discriminating AD patients from controls; 2) exploring whether the HABC-M discrepancy scores between the self-reports of patients/controls in these different domains and the respective ratings provided by their caregivers/informants correlate with an online measure of self-awareness; 3) determining whether the caregiver burden level, also derived from the HABC-M, could …add additional support for detecting anosognosia. Methods: The HABC-M was administered to 30 AD patients and 30 healthy controls, and to their caregivers/informants. A measure of online awareness was established from subjects’ estimation of their performances in a computerized experiment. Results: The HABC-M discrepancy scores distinguished AD patients from controls. The cognitive subscale discriminated the two groups from the prodromal AD stage, with an AUC of 0.88 [95% CI: 0.78;0.97]. Adding the caregiver burden level raised it to 0.94 [0.86;0.99]. Significant correlations between the HABC-M and online discrepancy scores were observed in the patients group, providing convergent validity of these methods. Conclusions: The cognitive HABC-M (six items) can detect anosognosia across the AD spectrum. The caregiver burden (four items) may corroborate the suspicion of anosognosia. The short-hybrid scale, built from these 10 items instead of the usual 31, showed the highest sensitivity for detecting anosognosia from the prodromal AD stage, which may further help with timely diagnosis. Show more

Keywords: Alzheimer’s disease, anosognosia assessment, caregiver burden, error-monitoring, HABC-M, timely diagnosis

DOI: 10.3233/JAD-230552

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2023