Journal of Alzheimer's Disease - Volume 85, issue 2

Authors: Kuroda, Takeshi | Honma, Motoyasu | Mori, Yukiko | Futamura, Akinori | Sugimoto, Azusa | Kasai, Hideyo | Yano, Satoshi | Hieda, Sotaro | Kasuga, Kensaku | Ikeuchi, Takeshi | Ono, Kenjiro

Article Type: Research Article

Abstract: Background: Idiopathic normal pressure hydrocephalus (iNPH) is often misdiagnosed as Alzheimer’s disease (AD) due to overlapping pathophysiology and similar imaging characteristics, including ventricular enlargement and increased white matter lesions (WMLs). Objective: To compare the extent and distribution of WMLs directly between iNPH and AD and examine the association with underlying pathophysiology. Methods: Twelve patients with iNPH (mean age: 78.08 years; 5 females), 20 with AD (mean age: 75.40 years; 13 females), and 10 normal cognition (NC) participants (mean age: 76.60 years; 7 females) were recruited. The extent and distribution of WMLs and the lateral ventricular volume …(LV-V) were evaluated on MRI using voxel-based morphometry analysis. Concentrations of cerebrospinal fluid biomarkers, such as amyloid-β protein (Aβ)42 , Aβ40 , Aβ38 , and tau species, were also measured. Risk factors for small vessel disease (SVD) were assessed by blood examination and medical records. Results: The periventricular WML volume (PWML-V) and deep WML volume (DWML-V) were significantly larger in iNPH than in AD and NC. The DWML-V was dominant in iNPH, while the PWML-V was dominant in AD and NC. GM-V was significantly smaller in AD than in iNPH and NC. The LV-V positively correlated with WML-V in all participants. There was a significant negative correlation between LV-V and Aβ38 in iNPH. Furthermore, there was no significant difference in SVD risk factors between the groups. Conclusion: The differences in the extent and distribution of WMLs between iNPH and AD, especially predominance of DWML-V over PWML-V in iNPH, may reflect decreased fluid and Aβ clearance. Show more

Keywords: Alzheimer disease, amyloid, cerebrospinal fluid, glymphatic system, hydrocephalus, white matter

DOI: 10.3233/JAD-215187

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 851-862, 2022

Authors: Bao, Jian | Liang, Zheng | Gong, Xiaokang | Yu, Jing | Xiao, Yifan | Liu, Wei | Wang, Xiaochuan | Wang, Jian-Zhi | Shu, Xiji

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common form of dementia in older adults and extracellular accumulation of amyloid-β (Aβ) is one of the two characterized pathologies of AD. Obesity is significantly associated with AD developing factors. Several studies have reported that high fat diet (HFD) influenced Aβ accumulation and cognitive performance during AD pathology. However, the underlying neurobiological mechanisms have not yet been elucidated. Objective: The objective of this study was to explore the underlying neurobiological mechanisms of HFD influenced Aβ accumulation and cognitive performance during AD pathology. Methods: 2.5-month-old male APP/PS1 mice were randomly …separated into two groups: 1) the normal diet (ND) group, fed a standard diet (10 kcal%fat); and 2) the HFD group, fed a high fat diet (40 kcal%fat, D12492; Research Diets). After 4 months of HFD or ND feeding, mice in the two groups were subjected for further ethological, morphological, and biochemical analyses. Results: A long-term HFD diet significantly increased perirenal fat and impaired dendritic integrity and aggravated neurodegeneration, and augmented learning and memory deficits in APP/PS1 mice. Furthermore, the HFD increased beta amyloid cleaving enzyme 1 (BACE1) dephosphorylation and SUMOylation, resulting in enhanced enzyme activity and stability, which exacerbated the deposition of amyloid plaques. Conclusion: Our study demonstrates that long-term HFD consumption aggravates amyloid-β accumulation and cognitive impairments, and that modifiable lifestyle factors, such as obesity, can induce BACE1 post-modifications which may contribute to AD pathogenesis. Show more

Keywords: Alzheimer’s disease, BACE1, high fat, phosphorylation, SUMOylation

DOI: 10.3233/JAD-215299

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 863-876, 2022

Authors: Zhang, Xiao-Xue | Ma, Ya-Hui | Hu, He-Ying | Ma, Ling-Zhi | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Existed evidence suggests that midlife obesity increases the risk of Alzheimer’s disease (AD), while there is an inverse association between AD and obesity in late life. However, the underlying metabolic changes of AD pathological proteins attributed to obesity in two life stages were not clear. Objective: To investigate the associations of obesity types and obesity indices with AD biomarkers in cerebrospinal fluid (CSF) in different life stages. Methods: We recruited 1,051 cognitively normal individuals (61.94±10.29 years, 59.66%male) from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study with CSF detections for amyloid-β 42 (Aβ42 ), total-tau …(T-tau), and phosphorylated tau (P-tau). We utilized body mass index, waist circumference, waist-to-height ratio, and metabolic risk factors to determine human obesity types. Multiple linear models and interaction analyses were run to assess the impacts of obesity on AD biomarkers. Results: The metabolically unhealthy obesity or healthy obesity might exert a reduced tau pathology burden (p  < 0.05). Individuals with overweight, general obesity, and central obesity presented lower levels of tau-related proteins in CSF than normal controls (p  < 0.05). Specially, for late-life individuals, higher levels of obesity indices were associated with a lower load of tau pathology as measured by CSF T-tau and T-tau/Aβ42 (p  < 0.05). No similar significant associations were observed in midlife. Conclusion: Collectively, late-life general and central obesity seems to be associated with the reduced load of tau pathology, which further consolidates the favorable influence of obesity in specific life courses for AD prevention. Show more

Keywords: Alzheimer’s disease, biomarkers, body mass index, cerebrospinal fluid, obesity, waist circumference, waist-to-height ratio

DOI: 10.3233/JAD-215351

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 877-887, 2022

Authors: Senejani, Alireza G. | Maghsoudlou, Jasmin | El-Zohiry, Dina | Gaur, Gauri | Wawrzeniak, Keith | Caravaglia, Cristina | Khatri, Vishwa A. | MacDonald, Alan | Sapi, Eva

Article Type: Research Article

Abstract: Background: Infections by bacterial or viral agents have been hypothesized to influence the etiology of neurodegenerative diseases. Objective: This study examined the potential presence of Borrelia burgdorferi spirochete, the causative agent of Lyme disease, in brain autopsy tissue of patients diagnosed with either Alzheimer’s (AD) or Parkinson’s diseases. Methods: Brain tissue sections from patients with age-matched controls were evaluated for antigen and DNA presence of B. burgdorferi using various methods. Positive Borrelia structures were evaluated for co-localization with biofilm and AD markers such as amyloid and phospho-tau (p-Tau) using immunohistochemical …methods. Results: The results showed the presence of B. burgdorferi antigen and DNA in patients with AD pathology and among those, one of them was previously diagnosed with Lyme disease. Interestingly, a significant number of Borrelia -positive aggregates with a known biofilm marker, alginate, were found along with the spirochetal structures. Our immunohistochemical data also showed that Borrelia -positive aggregates co-localized with amyloid and phospho-tau markers. To further prove the potential relationship of B. burgdorferi and amyloids, we infected two mammalian cell lines with B. burgdorferi which resulted in a significant increase in the expression of amyloid-β and p-Tau proteins in both cells lines post-infection. Conclusion: These results indicate that B. burgdorferi can be found in AD brain tissues, not just in spirochete but a known antibiotics resistant biofilm form, and its co-localized amyloid markers. In summary, this study provides evidence for a likely association between B. burgdorferi infections and biofilm formation, AD pathology, and chronic neurodegenerative diseases. Show more

Keywords: Alzheimer’s disease, amyloid, biofilm, Lyme neuroborreliosis, tau proteins

DOI: 10.3233/JAD-215398

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 889-903, 2022

Authors: Kothapalli, Satya V.V.N. | Benzinger, Tammie L. | Aschenbrenner, Andrew J. | Perrin, Richard J. | Hildebolt, Charles F. | Goyal, Manu S. | Fagan, Anne M. | Raichle, Marcus E. | Morris, John C. | Yablonskiy, Dmitriy A.

Article Type: Research Article

Abstract: Background: Currently, brain tissue atrophy serves as an in vivo MRI biomarker of neurodegeneration in Alzheimer’s disease (AD). However, postmortem histopathological studies show that neuronal loss in AD exceeds volumetric loss of tissue and that loss of memory in AD begins when neurons and synapses are lost. Therefore, in vivo detection of neuronal loss prior to detectable atrophy in MRI is essential for early AD diagnosis. Objective: To apply a recently developed quantitative Gradient Recalled Echo (qGRE) MRI technique for in vivo evaluation of neuronal loss in human hippocampus. Methods: …Seventy participants were recruited from the Knight Alzheimer Disease Research Center, representing three groups: Healthy controls [Clinical Dementia Rating® (CDR®) = 0, amyloid β (Aβ)-negative, n  = 34]; Preclinical AD (CDR = 0, Aβ-positive, n  = 19); and mild AD (CDR = 0.5 or 1, Aβ-positive, n  = 17). Results: In hippocampal tissue, qGRE identified two types of regions: one, practically devoid of neurons, we designate as “Dark Matter”, and the other, with relatively preserved neurons, “Viable Tissue”. Data showed a greater loss of neurons than defined by atrophy in the mild AD group compared with the healthy control group; neuronal loss ranged between 31% and 43%, while volume loss ranged only between 10% and 19%. The concept of Dark Matter was confirmed with histopathological study of one participant who underwent in vivo qGRE 14 months prior to expiration. Conclusion: In vivo qGRE method identifies neuronal loss that is associated with impaired AD-related cognition but is not recognized by MRI measurements of tissue atrophy, therefore providing new biomarkers for early AD detection. Show more

Keywords: Alzheimer’s disease, brain atrophy, cognitive impairment, hippocampal subfields, hippocampus, magnetic resonance imaging, neurodegeneration, quantitative Gradient Recalled Echo

DOI: 10.3233/JAD-210503

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 905-924, 2022

Authors: Clare, Linda | Martyr, Anthony | Gamble, Laura D. | Pentecost, Claire | Collins, Rachel | Dawson, Eleanor | Hunt, Anna | Parker, Sophie | Allan, Louise | Burns, Alistair | Hillman, Alexandra | Litherland, Rachael | Quinn, Catherine | Matthews, Fiona E. | Victor, Christina

Article Type: Research Article

Abstract: Background: Negative impacts of the COVID-19 pandemic on people with dementia have been widely-documented, but most studies have relied on carer reports and few have compared responses to information collected before the pandemic. Objective: We aimed to explore the impact of the pandemic on community-dwelling individuals with mild-to-moderate dementia and compare responses with pre-pandemic data. Methods: During the second wave of the pandemic, we conducted structured telephone interviews with 173 people with dementia and 242 carers acting as informants, all of whom had previously participated in the IDEAL cohort. Where possible, we benchmarked responses against pre-pandemic …data. Results: Significant perceived negative impacts were identified in cognitive and functional skills and ability to engage in self-care and manage everyday activities, along with increased levels of loneliness and discontinuity in sense of self and a decline in perceived capability to ‘live well’. Compared to pre-pandemic data, there were lower levels of pain, depression, and anxiety, higher levels of optimism, and better satisfaction with family support. There was little impact on physical health, mood, social connections and relationships, or perceptions of neighborhood characteristics. Conclusion: Efforts to mitigate negative impacts of pandemic-related restrictions and restore quality of life could focus on reablement to address the effects on participation in everyday activities, creating opportunities for social contact to reduce loneliness, and personalized planning to reconnect people with their pre-COVID selves. Such efforts may build on the resilience demonstrated by people with dementia and carers in coping with the pandemic. Show more

Keywords: Alzheimer’s disease, quality of life, services, well-being

DOI: 10.3233/JAD-215095

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 925-940, 2022

Authors: Park, Mincheol | Baik, Kyoungwon | Lee, Young-gun | Kang, Sung Woo | Jung, Jin Ho | Jeong, Seong Ho | Lee, Phil Hyu | Sohn, Young H. | Ye, Byoung Seok

Article Type: Correction

DOI: 10.3233/JAD-219020

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 941-941, 2022