Journal of Alzheimer's Disease - Volume 82, issue 2

Authors: Barrio, Jorge R. | Whitehouse, Peter | Alavi, Abass | Høilund-Carlsen, Poul F.

Article Type: Editorial

Keywords: IDEAS study, Alzheimer’s disease, amyloid imaging, clinical usefulness

DOI: 10.3233/JAD-210383

Citation: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 461-462, 2021

Authors: Yang, Hong | Luo, Yinpei | Hu, Qingrong | Tian, Xuelong | Wen, Huizhong

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a serious neurodegenerative disease, which seriously affects the behavior, cognition, and memory of patients. Studies have shown that sensory stimulation can effectively improve the cognition and memory of AD patients, and its role in brain plasticity and neural regulation is initially revealed. This paper aims to review the effect of various sensory stimulation and multisensory stimulation for AD, and to explain the possible mechanism, so as to provide some new ideas for further research in this field. We searched the Web of Science and PubMed databases (from 2000 to October 27, 2020) for literature on the …treatment of AD with sensory and multisensory stimulation, including music therapy, aromatherapy, rhythmic (e.g., visual or acoustic) stimulation, light therapy, multisensory stimulation, and virtual reality assisted therapy, then conducted a systematic analysis. Results show these sensory and multisensory stimulations can effectively ameliorate the pathology of AD, arouse memory, and improve cognition and behaviors. What’s more, it can cause brain nerve oscillation, enhance brain plasticity, and regulate regional cerebral blood flow. Sensory and multisensory stimulation are very promising therapeutic methods, and they play an important role in the improvement and treatment of AD, but their potential mechanism and stimulation parameters need to be explored and improved. Show more

Keywords: Alzheimer’s disease, music therapy, aromatherapy, rhythmic stimulation, light therapy, multisensory stimulation, virtual reality

DOI: 10.3233/JAD-201554

Citation: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 463-484, 2021

Authors: Riegerová, Petra | Brejcha, Jindřich | Bezděková, Dagmar | Chum, Tomáš | Mašínová, Eva | Čermáková, Nikola | Ovsepian, Saak V. | Cebecauer, Marek | Štefl, Martin

Article Type: Short Communication

Abstract: Neuroblastoma cell line SH-SY5Y, due to its capacity to differentiate into neurons, easy handling, and low cost, is a common experimental model to study molecular events leading to Alzheimer’s disease (AD). However, it is prevalently used in its undifferentiated state, which does not resemble neurons affected by the disease. Here, we show that the expression and localization of amyloid-β protein precursor (AβPP), one of the key molecules involved in AD pathogenesis, is dramatically altered in SH-SY5Y cells fully differentiated by combined treatment with retinoic acid and BDNF. We show that insufficient differentiation of SH-SY5Y cells results in AβPP mislocalization.

Keywords: AβPP, Alzheimer’s disease, differentiation, SH-SY5Y, super-resolution microscopy

DOI: 10.3233/JAD-201409

Citation: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 485-491, 2021

Authors: Yerstein, Oleg | Parand, Leila | Liang, Li-Jung | Isaac, Adrienne | Mendez, Mario F.

Article Type: Research Article

Abstract: Background: D. Frank Benson and colleagues first described the clinical and neuropathological features of posterior cortical atrophy (PCA) from patients in the UCLA Neurobehavior Program. Objective: We reviewed the Program’s subsequent clinical experience with PCA, and its potential for clarifying this relatively rare syndrome in comparison to the accumulated literature on PCA. Methods: Using the original criteria derived from this clinic, 65 patients with neuroimaging-supported PCA were diagnosed between 1995 and 2020. Results: On presentation, most had visual localization complaints and related visuospatial symptoms, but nearly half had memory complaints followed by symptoms of …depression. Neurobehavioral testing showed predominant difficulty with visuospatial constructions, Gerstmann’s syndrome, and Balint’s syndrome, but also impaired memory and naming. On retrospective application of the current Consensus Criteria for PCA, 59 (91%) met PCA criteria with a modification allowing for “significantly greater visuospatial over memory and naming deficits.” There were 37 deaths (56.9%) with the median overall survival of 10.3 years (95% CI: 9.6–13.6 years), consistent with a slow neurodegenerative disorder in most patients. Conclusion: Together, these findings recommend modifying the PCA criteria for “relatively spared” memory, language, and behavior to include secondary memory and naming difficulty and depression, with increased emphasis on the presence of Gerstmann’s and Balint’s syndromes. Show more

Keywords: Alzheimer’s disease, balint’s syndrome, gerstmann’s syndrome, posterior cortical atrophy

DOI: 10.3233/JAD-210368

Citation: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 493-502, 2021

Authors: Li, Xian | Tian, Yan | Yang, Yu-Xiang | Ma, Ya-Hui | Shen, Xue-Ning | Chen, Shi-Dong | Dong, Qiang | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Several studies showed that life course adiposity was associated with Alzheimer’s disease (AD). However, the underlying causality remains unclear. Objective: We aimed to examine the causal relationship between life course adiposity and AD using Mendelian randomization (MR) analysis. Methods: Instrumental variants were obtained from large genome-wide association studies (GWAS) for life course adiposity, including birth weight (BW), childhood body mass index (BMI), adult BMI, waist circumference (WC), waist-to-hip ratio (WHR), and body fat percentage (BFP). A meta-analysis of GWAS for AD including 71,880 cases and 383,378 controls was used in this study. MR analyses were …performed using inverse variance weighted (IVW), weighted median, and MR-Egger regression methods. We calculated odds ratios (ORs) per genetically predicted standard deviation (1-SD) unit increase in each trait for AD. Results: Genetically predicted 1-SD increase in adult BMI was significantly associated with higher risk of AD (IVW: OR = 1.03, 95% confidence interval [CI] = 1.01–1.05, p  = 2.7×10–3 ) after Bonferroni correction. The weighted median method indicated a significant association between BW and AD (OR = 0.94, 95% CI = 0.90–0.98, p  = 1.8×10–3 ). We also found suggestive associations of AD with WC (IVW: OR = 1.03, 95% CI = 1.00–1.07, p  = 0.048) and WHR (weighted median: OR = 1.04, 95% CI = 1.00–1.07, p  = 0.029). No association was detected of AD with childhood BMI and BFP. Conclusion: Our study demonstrated that lower BW and higher adult BMI had causal effects on increased AD risk. Show more

Keywords: Alzheimer’s disease, causal relations, life course adiposity, Mendelian randomization

DOI: 10.3233/JAD-210345

Citation: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 503-512, 2021

Authors: Sheng, Can | Lin, Li | Lin, Hua | Wang, Xiaoni | Han, Ying | Liu, Shu-Lin

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) is the earliest symptomatic manifestation of preclinical Alzheimer’s disease (AD). Gut microbiota may serve as a susceptibility factor for AD. Altered gut microbiota has been reported in patients with mild cognitive impairment (MCI) and AD dementia. However, whether gut microbial compositions changed in SCD remains largely unknown. Objective: To characterize the gut microbiota in SCD. Methods: In this study, a total of 105 participants including 38 normal controls (NC), 53 individuals with SCD, and 14 patients with cognitive impairment (CI) were recruited. Gut microbiota of all participants isolated from fecal samples …were investigated using 16S ribosomal RNA (rRNA) Illumina Miseq sequencing technique. The gut microbial compositions were compared among the three groups, and the association between altered gut microbiota and cognitive performance was analyzed. To validate the alteration of gut microbiota in SCD, we conducted amyloid positron emission tomography (PET) in selected participants and further compared the gut microbiota among subgroups. Results: The abundance of phylum Firmicutes , class Clostridia , order Clostridiales , family Ruminococcaceae , and genus Faecalibacterium showed a trend toward a progressive decline from NC to SCD and CI. Specifically, the abundance of the anti-inflammatory genus Faecalibacterium was significantly decreased in SCD compared with NC. In addition, altered bacterial taxa among the three groups were associated with cognitive performance. The findings were validated in SCD participants with positive amyloid evidence. Conclusion: The composition of gut microbiota is altered in individuals with SCD. This preliminary study will provide novel insights into the pathophysiological mechanism of AD. Show more

Keywords: Alzheimer’s disease, gut microbiota, 16S ribosomal RNA, subjective cognitive decline

DOI: 10.3233/JAD-210259

Citation: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 513-526, 2021

Authors: Han, Hui | Wang, Feng | Chen, Juanjuan | Li, Xingxing | Fu, Gaoqing | Zhou, Jiawei | Zhou, Dongsheng | Wu, Wei | Chen, Haimin

Article Type: Research Article

Abstract: Background: Serum homocysteine (Hcy) level is considered to be an important biomarker for Alzheimer’s disease (AD); however, the status of Hcy in brain tissue, and the association between brain and serum levels of Hcy in AD patients remain unclear. Objective: We aimed to examine whether the changes of three thiols are consistent in serum of AD patients and the brain of APP/PS1 mice, and to verify the effectiveness of Hcy as a biomarker for early AD detection. Methods: The levels of Hcy, cysteine (Cys), and glutathione (GSH) in Aβ1–42 -treated PC12 cells, the brain and hippocampus …of APP/PS1 mouse, and the serum of AD patients were evaluated using ethyl (E)-3-(9-chloro-11-oxo-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f] pyrido [3,2,1 -ij] quinolin-10-yl)-2-cyanoacrylate (Probe 1) and ELISA assay or LC-MS. Results: Measurement by Probe 1 revealed a significant increase in Hcy level, and a decrease in Cys and GSH levels in Aβ1–42 -treated PC12 cells and the serum of AD patients. The hippocampus and whole brain of APP/PS1 mice also showed a significant increase in Hcy level alongside the accumulation of age-related AD symptoms. The upregulation of Hcy and the downregulation of Cys and GSH were reversed in the Aβ1–42 -treated PC12 cells and the brain of APP/PS1 mice when supplemented with VB6 . Conclusion: Changes in Hcy, Cys, and GSH levels in the brain of APP/PS1 mice and Aβ1–42 -treated PC12 cells were observed in situ with a new fluorescent probe, which were consistent with the abnormal changes in Hcy, Cys, and GSH levels in the serum of AD patients. VB6 supplementation was successful in ameliorating abnormal increases in Hcy levels. Show more

Keywords: Alzheimer’s disease, biothiols, fluorescent probe, vitamin B6

DOI: 10.3233/JAD-210021

Citation: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 527-540, 2021

Authors: King-Robson, Josh | Wilson, Heather | Politis, Marios | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The roles of amyloid-β and tau in the degenerative process of Alzheimer’s disease (AD) remain uncertain. [18 F]AV-45 and [18 F]AV-1451 PET quantify amyloid-β and tau pathology, respectively, while diffusion tractography enables detection of their microstructural consequences. Objective: Examine the impact of amyloid-β and tau pathology on the structural connectome and cognition, in mild cognitive impairment (MCI) and AD. Methods: Combined [18 F]AV-45 and [18 F]AV-1451 PET, diffusion tractography, and cognitive assessment in 28 controls, 32 MCI, and 26 AD patients. Results: Hippocampal connectivity was reduced to the thalami, right lateral orbitofrontal, and …right amygdala in MCI; alongside the insula, posterior cingulate, right entorhinal, and numerous cortical regions in AD (all p  < 0.05). Hippocampal strength inversely correlated with [18 F]AV-1451 SUVr in MCI (r  = –0.55, p  = 0.049) and AD (r  = –0.57, p  = 0.046), while reductions in hippocampal connectivity to ipsilateral brain regions correlated with increased [18F]AV-45 SUVr in those same regions in MCI (r  = –0.33, p  = 0.003) and AD (r  = –0.31, p  = 0.006). Cognitive scores correlated with connectivity of the right temporal pole in MCI (r  = –0.60, p  = 0.035) and left hippocampus in AD (r  = 0.69, p  = 0.024). Clinical Dementia Rating Scale scores correlated with [18 F]AV-1451 SUVr in multiple areas reflecting Braak stages I-IV, including the right (r  = 0.65, p  = 0.004) entorhinal cortex in MCI; and Braak stages III-VI, including the right (r  = 0.062, p  = 0.009) parahippocampal gyrus in AD. Conclusion: Reductions in hippocampal connectivity predominate in the AD connectome, correlating with hippocampal tau in MCI and AD, and with amyloid-β in the target regions of those connections. Cognitive scores correlate with microstructural changes and reflect the accumulation of tau pathology. Show more

Keywords: Alzheimer’s disease, amyloid, connectome, diffusion tensor imaging, 18F-AV-1451, 18F-AV-45, magnetic resonance imaging, mild cognitive impairment, positron emission tomography, tau protein

DOI: 10.3233/JAD-201457

Citation: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 541-560, 2021

Authors: Gyanwali, Bibek | Cai, Celestine Xue Ting | Chen, Christopher | Vrooman, Henri | Tan, Chuen Seng | Hilal, Saima

Article Type: Research Article

Abstract: Background: Cerebrovascular disease (CeVD) is an underlying cause of cognitive impairment and dementia. Hypertension is a known risk factor of CeVD, but the effects of mean of visit-to-visit blood pressure (BP) on incident CeVD and functional-cognitive decline remains unclear. Objective: To determine the association between mean of visit-to-visit BP with the incidence and progression of CeVD [white matter hyperintensities (WMH), infarcts (cortical infarcts and lacunes), cerebral microbleeds (CMBs), intracranial stenosis, and hippocampal volume] as well as functional-cognitive decline over 2 years of follow-up. Methods: 373 patients from a memory-clinic underwent BP measurements at baseline, year 1, …and year 2. The mean of visit-to-visit systolic BP, diastolic BP, pulse pressure, and mean arterial pressure were calculated. Baseline and year 2 MRI scans were graded for WMH, infarcts, CMBs, intracranial stenosis, and hippocampal volume. Functional-cognitive decline was assessed using locally validated protocol. Logistic and linear regression models with odds ratios, mean difference, and 95%confidence interval were constructed to analyze associations of visit-to-visit BP on CeVD incidence and progression as well as functional-cognitive decline. Results: Higher mean of visit-to-visit diastolic BP was associated with WMH progression. Higher tertiles of diastolic BP was associated with WMH progression and incident CMBs. There was no association between mean of visit-to-visit BP measures with incident cerebral infarcts, intracranial stenosis, change in hippocampal volume, and functional-cognitive decline. Conclusion: These findings suggest the possibility of hypertension-related vascular brain damage. Careful monitoring and management of BP in elderly patients is essential to reduce the incidence and progression of CeVD. Show more

Keywords: Blood pressure, cerebrovascular disease, cognitive decline, magnetic resonance imaging, memory clinic

DOI: 10.3233/JAD-210188

Citation: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 561-573, 2021

Authors: Thomsen, Barbara Blicher | Madsen, Cecilie | Krohn, Katrine Tækker | Thygesen, Camilla | Schütt, Trine | Metaxas, Athanasios | Darvesh, Sultan | Agerholm, Jørgen Steen | Wirenfeldt, Martin | Berendt, Mette | Finsen, Bente

Article Type: Research Article

Abstract: Background: Microglia contribute to Alzheimer’s disease (AD) pathogenesis by clearing amyloid-β (Aβ) and driving neuroinflammation. Domestic dogs with age-related dementia (canine cognitive dysfunction (CCD)) develop cerebral amyloidosis like humans developing AD, and studying such dogs can provide novel information about microglial response in prodromal AD. Objective: The aim was to investigate the microglial response in the cortical grey and the subcortical white matter in dogs with CCD versus age-matched cognitively normal dogs. Methods: Brains from aged dogs with CCD and age-matched controls without dementia were studied. Cases were defined by dementia rating score. Brain sections were …stained for Aβ, thioflavin S, hyperphosphorylated tau, and the microglial-macrophage ionized calcium binding adaptor molecule 1 (Iba1). Results were correlated to dementia rating score and tissue levels of Aβ. Results: Microglial numbers were higher in the Aβ plaque-loaded deep cortical layers in CCD versus control dogs, while the coverage by microglial processes were comparable. Aβ plaques were of the diffuse type and without microglial aggregation. However, a correlation was found between the %Iba1 area and insoluble Aβ 42 and N-terminal pyroglutamate modified Aβ(N3pE)-42. The %Iba1 area was higher in white matter, showing phosphorylation of S396 tau, versus grey matter. Perivascular macrophage infiltrates were abundant in the white matter particularly in CDD dogs. Conclusion: The results from this study of the microglial-macrophage response in dogs with CCD are suggestive of relatively mild microglial responses in the Aβ plaque-loaded deep cortical layers and perivascular macrophage infiltrates in the subcortical white matter, in prodromal AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, animal model, dementia, macrophages, microglia, neuroinflammation

DOI: 10.3233/JAD-210040

Citation: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 575-592, 2021