Journal of Alzheimer's Disease - Volume 94, issue 3

Authors: Ortí-Casañ, Natalia | Wajant, Harald | Kuiperij, H. Bea | Hooijsma, Annelien | Tromp, Leon | Poortman, Isabelle L. | Tadema, Norick | de Lange, Julia H.E. | Verbeek, Marcel M. | De Deyn, Peter P. | Naudé, Petrus J.W. | Eisel, Ulrich L.M.

Article Type: Research Article

Abstract: Background: Tumor necrosis factor-alpha (TNF-α ) is a master cytokine involved in a variety of inflammatory and neurological diseases, including Alzheimer’s disease (AD). Therapies that block TNF-α proved ineffective as therapeutic for neurodegenerative diseases, which might be explained by the opposing functions of the two receptors of TNF (TNFRs): while TNFR1 stimulation mediates inflammatory and apoptotic pathways, activation of TNFR2 is related to neuroprotection. Despite the success of targeting TNFR2 in a transgenic AD mouse model, research that better mimics the human context is lacking. Objective: The aim of this study is to investigate whether stimulation of …TNFR2 with a TNFR2 agonist is effective in activating human TNFR2 and attenuating AD neuropathology in the J20xhuTNFR2-k/i mouse model. Methods: Transgenic amyloid-β (Aβ)-overexpressing mice containing a human extracellular TNFR2 domain (J20xhuTNFR2-k/i) were treated with a TNFR2 agonist (NewStar2). After treatment, different behavioral tests and immunohistochemical analysis were performed to assess different parameters, such as cognitive functions, plaque deposition, synaptic plasticity, or microglial phagocytosis. Results: Treatment with NewStar2 in J20xhuTNFR2-k/i mice resulted in a drastic decrease in plaque load and beta-secretase 1 (BACE-1) compared to controls. Moreover, TNFR2 stimulation increased microglial phagocytic activity, leading to enhanced Aβ clearance. Finally, activation of TNFR2 rescued cognitive impairments and improved synaptic plasticity. Conclusion: Our findings demonstrate that activation of human TNFR2 ameliorates neuropathology and improves cognitive functions in an AD mouse model. Moreover, our study confirms that the J20xhuTNFR2-k/i mouse model is suitable for testing human TNFR2-specific compounds. Show more

Keywords: Alzheimer’s disease, humanized mouse model, neurodegeneration, neuroinflammation, TNF, TNFR2 agonist

DOI: 10.3233/JAD-221230

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 977-991, 2023

Authors: Sandison, Heather | Callan, Nini G.L. | Rao, Rammohan V. | Phipps, John | Bradley, Ryan

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a chronic condition marked by progressive objective cognitive impairment (OCI). No monotherapy has substantially altered disease progression, suggesting the disease is multifactorial and may require a multimodal therapeutic approach. Objective: We sought to determine if cognitive function in a sample with OCI would change in response to a multimodal, individualized care plan based on potential contributors to cognitive decline (e.g., nutritional status, infection, etc.). Methods: Participants (n  = 34) were recruited from the San Diego, CA area. The multimodal intervention included lifestyle changes (i.e., movement, diet, and stress management), nutraceutical support, and …medications. It was delivered pragmatically over four clinical visits, and outcome measures were gathered at four study visits, occurring at baseline, one, three, and six months (primary endpoint). Study participants received weekly phone calls for nutrition support throughout study participation. Outcome measures included the Cambridge Brain Sciences (CBS) battery, and the Montreal Cognitive Assessment (MoCA). Results: At 6 months, mean MoCA scores improved from 19.6±3.1 to 21.7±6.2 (p  = 0.013). Significant improvement was observed in mean scores of the CBS memory domain [25.2 (SD 23.3) to 35.8 (SD 26.9); p  < 0.01] and CBS overall composite cognition score [24.5 (SD 16.1) to 29.7 (SD 20.5); p = 0.02]. All CBS domains improved. Conclusion: Multiple measures of cognitive function improved after six months of intervention. Our results support the feasibility and impact of a multimodal, individualized treatment approach to OCI, warranting further research. Show more

Keywords: Alzheimer’s disease, Cambridge Brain Sciences, clinical trial, dementia, mild cognitive impairment, Montreal Cognitive Assessment

DOI: 10.3233/JAD-230004

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 993-1004, 2023

Authors: Mao, He-Jiao | Zhang, Jiang-Xia | Zhu, Wen-Cheng | Zhang, Hao | Fan, Xiang-Min | Han, Fei | Ni, Jun | Zhou, Li-Xin | Yao, Ming | Tian, Feng | Su, Ning | Zhu, Yi-Cheng

Article Type: Research Article

Abstract: Background: The mechanism of gait disorder in patients with cerebral small vessel disease (CSVD) remains unclear. Limited studies have compared the effect of cerebral microbleeds (CMBs) and lacunes on gait disturbance in CSVD patients in different anatomical locations. Objective: To investigate the relationship of quantitative gait parameters with varied anatomically located MRI imaging markers in patients with CSVD. Methods: Quantitative gait tests were performed on 127 symptomatic CSVD patients all with diffuse distributed white matter hyperintensities (WMHs). CMBs and lacunes in regard to anatomical locations and burdens were measured. The correlation between CSVD imaging markers and …gait parameters was evaluated using general linear model analysis. Results: Presence of CMBs was significantly associated with stride length (β= –0.098, p  = 0.0272) and right step length (β= –0.054, p  = 0.0206). Presence of CMBs in basal ganglia (BG) was significantly associated with stride length and step length. Presence of CMBs in brainstem was significantly associated with gait parameters including stride length, step length, step height, and step width. Presence of lacunes in brainstem was significantly associated with gait speed (β= –0.197, p  = 0.0365). However, presence of lacunes in the other areas was not associated with worse gait performances. Conclusion: BG and brain stem located CMBs contributed to gait impairment in symptomatic CSVD patients. Show more

Keywords: Basal ganglia, brainstem, cerebral microbleeds, cerebral small vessel disease, quantitative gait parameters

DOI: 10.3233/JAD-230005

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1005-1012, 2023

Authors: Falkenreck, Julia Maria | Kunkler, Michelle Celine | Ophey, Anja | Weigert, Hannah | Friese, Andrea | Jahr, Petra | Nelles, Gereon | Kalbe, Elke | Polidori, M. Cristina

Article Type: Research Article

Abstract: Background: Cognitive integrity is a fundamental driver of health. The exact structure of strategies against cognitive impairment is still under debate. Objective: To compare the short-term effects of a multicomponent cognitive training (BrainProtect) with those of general health counseling (GHC) on cognitive abilities and health-related quality of life (HRQoL) in healthy adults in Germany. Methods: In this parallel randomized controlled trial (RCT), 132 eligible cognitively healthy adults (age ≥50 years, Beck Depression Inventory ≤9/63; Montreal Cognitive Assessment ≥26/30) were randomized to either GHC (N = 72) or to intervention with BrainProtect (intervention group, IG; N = 60). IG participants received …8 weekly sessions of 90 min of the group-based BrainProtect program focusing on executive functions, concentration, learning, perception, and imagination, plus nutritional and physical exercise units. Before and after intervention, all participants underwent neuropsychological testing and HRQoL evaluation, blinded for pretest. Results: No significant training effect was observed for the primary endpoint of global cognition as assessed by CERAD-Plus-z Total Score (p  = 0.113; η p2  = 0.023). Improvements in several cognitive subtests were shown in the IG (N = 53) compared to the GHC (N = 62) without adverse events. Differences reached significance for verbal fluency (p  = 0.021), visual memory (p  = 0.013), visuo-constructive functions (p  = 0.034), and HRQoL (p  = 0.009). Significance was lost after adjustment, though several changes were clinically relevant. Conclusion: BrainProtect did not significantly impact global cognition in this RCT. Nevertheless, the results of some outcomes indicate clinically meaningful changes, so that a strengthening of the cognitive performance by BrainProtect cannot be excluded. Further studies with larger sample size are needed to confirm these findings. Show more

Keywords: Alzheimer’s disease, cognitive integrity, cognitive training, healthy aging, prevention

DOI: 10.3233/JAD-220619

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1013-1034, 2023

Authors: Chwa, Won Jong | Lopez, Oscar L. | Longstreth Jr, W.T. | Dai, Weiying | Raji, Cyrus A.

Article Type: Research Article

Abstract: Background: Aging and Alzheimer’s disease (AD) are characterized by widespread cortical and subcortical atrophy. Though atrophy patterns between aging and AD overlap considerably, regional differences between these two conditions may exist. Few studies, however, have investigated these patterns in large community samples. Objective: Elaborate longitudinal changes in brain morphometry in relation to aging and cognitive status in a well-characterized community cohort. Methods: Clinical and neuroimaging data were compiled from 72 participants from the Cardiovascular Health Study-Cognition Study, a community cohort of healthy aging and probable AD participants. Two time points were identified for each participant with …a mean follow-up time of 5.36 years. MRI post-processing, morphometric measurements, and statistical analyses were performed using FreeSurfer, Version 7.1.1. Results: Cortical volume was significantly decreased in the bilateral superior frontal, bilateral inferior parietal, and left superior parietal regions, among others. Cortical thickness was significantly reduced in the bilateral superior frontal and left inferior parietal regions, among others. Overall gray and white matter volumes and hippocampal subfields also demonstrated significant reductions. Cortical volume atrophy trajectories between cognitively stable and cognitively declined participants were significantly different in the right postcentral region. Conclusion: Observed volume reductions were consistent with previous studies investigating morphometric brain changes. Patterns of brain atrophy between AD and aging may be different in magnitude but exhibit widespread spatial overlap. These findings help characterize patterns of brain atrophy that may reflect the general population. Larger studies may more definitively establish population norms of aging and AD-related neuroimaging changes. Show more

Keywords: Aging, Alzheimer’s disease, cognition, cognitive dysfunction, neuroimaging

DOI: 10.3233/JAD-230080

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1035-1045, 2023

Authors: Caillaud, Marie | Maltezos, Samantha | Hudon, Carol | Mellah, Samira | Belleville, Sylvie

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) was proposed to identify older adults who complain about their memory but perform within a normal range on standard neuropsychological tests. Persons with SCD are at increased risk of dementia meaning that some SCD individuals experience subthreshold memory decline due to an underlying progression of Alzheimer’s disease (AD). Objective: Our main goal was to determine whether hippocampal volume and APOE4 , which represent typical AD markers, predict inter-individual differences in memory performance among SCD individuals and can be used to identify a meaningful clinical subgroup. Methods: Neuropsychological assessment, structural MRI, and …genetic testing for APOE4 were administered to one hundred and twenty-five older adults over the age of 65 from the CIMAQ cohort: 66 SCD, 29 individuals with mild cognitive impairment (MCI), and 30 cognitively intact controls (CTRLS). Multiple regression models were first used to identify which factor (hippocampal volume, APOE4 allele, or cognitive reserve) best predicted inter-individual differences in a Face-name association memory task within the SCD group. Results: Hippocampal volume was found to be the only and best predictor of memory performance. We then compared the demographic, clinical and cognitive characteristics of two SCD subgroups, one with small hippocampal volume (SCD/SH) and another with normal hippocampal volume (SCD/NH), with MCI and CTRLS. SCD/SH were comparable to MCI on neuropsychological tasks evaluating memory (i.e., test of delayed word recall), whereas SCD/NH were comparable to CTRLS. Conclusion: Thus, using hippocampal volume allows identification of an SCD subgroup with a cognitive profile consistent with a higher risk of conversion to AD. Show more

Keywords: Alzheimer’s disease, hippocampal volume, mild cognitive impairment, neuropsychology, subjective cognitive decline

DOI: 10.3233/JAD-230131

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1047-1056, 2023

Authors: Hautecloque-Raysz, Geoffroy | Sellal, François | Bousiges, Olivier | Phillipi, Nathalie | Blanc, Frédéric | Cretin, Benjamin

Article Type: Research Article

Abstract: Background: The medium term outcome (over more than one year) of epileptic prodromal AD (epAD) patients treated with antiseizure medications (ASMs) is unknown in terms of seizure response, treatment tolerability, and cognitive and functional progression. Objective: To describe such medium term outcome over a mean of 5.1±2.1 years. Methods: We retrospectively compared 19 epAD patients with 16 non-epileptic prodromal AD (nepAD) patients: 1) at baseline for demographics, medical history, cognitive fluctuations (CFs), psychotropic medications, MMSE scores, visually rated hippocampal atrophy, CSF neurodegenerative biomarkers, and standard EEG recordings; 2) during follow-up (FU) for psychotropic medications, MMSE progression, …and conversion to dementia. In the epAD group, we analyzed baseline and FU types of seizures as well as each line of ASM with the corresponding efficacy and tolerability. Results: At baseline, the epAD group had more CFs than the nepAD group (58% versus 20%, p  = 0.03); focal impaired awareness seizures were the most common type (n  = 12, 63.1%), occurring at a monthly to quarterly frequency (89.5%), and were well controlled with monotherapy in 89.5% of cases (including 63.1% seizure-free individuals). During FU, treated epAD patients did not differ significantly from nepAD patients in MMSE progression or in conversion to dementia. Conclusion: Epilepsy is commonly controlled with ASMs over the medium term in epAD patients, with similar functional and cognitive outcomes to nepAD patients. Pathophysiologically, epilepsy is likely to be an ASM-modifiable cognitive aggravating factor at this stage of AD. Show more

Keywords: Alzheimer’s disease, antiseizure medications, cerebrospinal fluid, late-onset epilepsy, mild cognitive impairment

DOI: 10.3233/JAD-221197

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1057-1074, 2023

Authors: Vossel, Keith

Article Type: Article Commentary

Abstract: Epileptic activity is known to exacerbate Alzheimer’s disease (AD) pathology and worsen disease course. However, few studies have assessed whether treating epileptic activity with antiseizure drugs (ASDs) can improve patient outcomes. The current study by Hautecloque-Raysz et al. shows that patients with prodromal AD and epilepsy (epAD) fare well with ASD treatment, achieving seizure control in a large majority of cases using low dosage ASDs in monotherapy. Compared to slowly progressing AD patients without epilepsy, treated epAD patients experienced a similarly slow cognitive decline. These results suggest that ASDs that suppress seizures can improve outcomes in AD patients with epileptic …activity. Show more

Keywords: Alzheimer’s disease, antiseizure drugs, epilepsy, epileptic activity, mild cognitive impairment

DOI: 10.3233/JAD-230613

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1075-1077, 2023

Authors: Beauchet, Olivier | Matskiv, Jacqueline | Gaudreau, Pierrette | Allali, Gilles | Vaillant-Ciszewicz, Anne-Julie | Guerin, Olivier | Gros, Auriane

Article Type: Research Article

Abstract: Background: Frailty is associated with an increased risk of major neurocognitive disorders (MNCD). Objective: This study aims to compare the Fried physical model and the CARE deficit accumulation model for their association with incident major neurocognitive disorders (MNCD), and to examine how the addition of cognitive impairment to these frailty models impacts the incidence in community-dwelling older adults. Methods: A subset of community dwellers (n  = 1,259) who participated in the “Quebec Longitudinal Study on Nutrition and Successful Aging” (NuAge) were selected in this Elderly population-based observational cohort study with 3 years of follow-up. Fried and CARE …frailty stratifications into robust, pre-frail and frail groups were performed using the NuAge baseline assessment. Incident MNCD (i.e., Modified Mini Mental State (3MS) score < 79/100 and Instrumental Activity Daily Living (IADL) score < 6/8) were collected each year over a 3-year follow-up period. Results: A greater association with incident MNCD of the CARE frail state was observed with an increased predictive value when combined with cognitive impairment in comparison to Fried’s one, the highest incidences being observed using the robust state as the reference. Results with the Fried frail state were more heterogenous, with no association with the frail state alone, whereas cognitive impairment alone showed the highest significant incidence. Conclusion: The association of the CARE frail state with cognitive impairment increased the predictive value of MNCD, suggesting that the CARE frailty model may be of clinical interest when screening MCND in the elderly population. Show more

Keywords: Aging, Alzheimer’s disease, cognitive impairment, cohort study, community-dwellers, frailty

DOI: 10.3233/JAD-230006

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1079-1092, 2023

Authors: Chen, Weineng | Lin, Cha | Su, Fengjuan | Fang, Yingying | Liu, Ganqiang | Chen, Yu-Chian | Zhou, Xianbo | Yao, Xiaoli | Ashford, Curtis B. | Li, Feng | Ashford, J. Wesson | Fu, Qing-Ling | Pei, Zhong

Article Type: Research Article

Abstract: Background: Accessible measurements for the early detection of mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) are urgently needed to address the increasing prevalence of AD. Objective: To determine the benefits of a composite MemTrax Memory Test and AD-related blood biomarker assessment for the early detection of MCI-AD in non-specialty clinics. Methods: The MemTrax Memory Test and Montreal Cognitive Assessment were administered to 99 healthy seniors with normal cognitive function and 101 patients with MCI-AD; clinical manifestation and peripheral blood samples were collected. We evaluated correlations between the MemTrax Memory Test and blood biomarkers using …Spearman’s rank correlation analyses and then built discrimination models using various machine learning approaches that combined the MemTrax Memory Test and blood biomarker results. The models’ performances were assessed according to the areas under the receiver operating characteristic curve. Results: The MemTrax Memory Test and Montreal Cognitive Assessment areas under the curve for differentiating patients with MCI-AD from the healthy controls were similar. The MemTrax Memory Test strongly correlated with phosphorylated tau 181 and amyloid-β42/40 . The area under the curve for the best composite MemTrax Memory Test and blood biomarker model was 0.975 (95% confidence interval: 0.950–0.999). Conclusion: Combining MemTrax Memory Test and blood biomarker results is a promising new technique for the early detection of MCI-AD. Show more

Keywords: Alzheimer’s disease, biomarkers, cognitive dysfunction, neuropsychological tests

DOI: 10.3233/JAD-230182

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1093-1103, 2023