Journal of Alzheimer's Disease - Volume 70, issue 2

Authors: Udeh-Momoh, Chinedu T. | Su, Bowen | Evans, Stephanie | Zheng, Bang | Sindi, Shireen | Tzoulaki, Ioanna | Perneczky, Robert | Middleton, Lefkos T. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Elevated cortisol as a measure of hypothalamic-pituitary-adrenal-axis hyperactivity has emerged as a predictor of clinical progression of Alzheimer’s disease (AD), in conjunction with amyloid-β (Aβ) abnormalities. Yet factors exist which have the propensity to delay AD symptomatic expression in the face of an AD-type biomarker-based pathological profile. This study sought to determine whether abnormal cerebrospinal fluid (CSF) Aβ and elevated cortisol levels are associated with clinical transition to mild cognitive impairment (MCI) and AD in cognitively normal (CN) individuals, and if this association is modified by reserve proxies. Data from 91 CN individuals participating in the Alzheimer’s Disease Neuroimaging Initiative …(ADNI) with available morning CSF cortisol and Aβ42 were evaluated. Reserve was modelled as a latent composite score of standardized intracranial volume and lifetime experience proxies. Cox regressions were used to test associations between baseline CSF cortisol/Aβ42 , reserve score and AD progression; adjusting for age, sex, apolipoprotein E genotype, and depressive symptoms. Individuals with elevated cortisol + abnormal Aβ42 levels at baseline showed highest risk of clinical progression. After a median of 84 months follow-up, significant cortisol/Aβ/ reserve interaction for clinical progression was noted (adjusted HR = 0.15, p  < 0.001), suggesting a moderating effect of reserve on the association between cortisol/Aβ+ and clinical progression. Our findings indicate that cortisol hypersecretion accelerates clinical progression in CN individuals presenting with pathological Aβ42 . High reserve reduces the associated AD progression risk in these high-risk individuals. Show more

Keywords: Alzheimer’s disease, amyloid, cognitive reserve, cortisol

DOI: 10.3233/JAD-181030

Citation: Journal of Alzheimer's Disease, vol. 70, no. 2, pp. 553-562, 2019

Authors: Gao, Fulin | Jing, Yuhong | Zang, Peixi | Hu, Xiaojuan | Gu, Cheng | Wu, Ruipeng | Chai, Bingyan | Zhang, Yi

Article Type: Research Article

Abstract: Background: Cerebral small vessel disease (CSVD) can lead to leukodystrophy and cognitive impairment. The inflammatory response mediated by Toll-like receptor 4 (TLR4) is involved in the pathological process of CSVD, but the roles of TLR4 in vascular cognitive impairment (VCI) following CSVD are not clear. Objective: To explore the roles and mechanisms of TLR4 in the development of VCI. Methods: Male spontaneous hypertension rats (SHR) and Wistar Kyoto rats (WKY) were monitored for blood pressure (BP). The spatial learning and memory were assessed every 6 weeks using Morris water maze (MWM). Blood samples from femoral artery …were collected and serum was isolated. Cerebral white matter damage was evaluated using a 3.0T magnetic resonance imaging (MRI) every 12 weeks. After 35 weeks, all rats were decapitated, and the expression of TLR4 in the hippocampus was determined using western blot. The number of positive cells of TLR4, active astrocyte and microglia in hippocampus were measured using immunohistochemistry and immunofluorescence. Results: Compared with WKY, the BP of SHR was maintained at a high level. Spatial learning and memory declined. IL-1β and TNF-α levels were elevated. Cranial coronal scanning with T2-weighted MRI showed high signal intensity in corpus callosum and external capsule of SHR. Furthermore, in SHR, the expression of TLR4, GFAP, and Iba1 in the hippocampus were increased. Conclusion: Hypertension can cause small vascular damage and partial white matter degeneration in the brain. SHR showed cognitive impairment with increasing age. High expression of TLR4 and glial cell response in hippocampus is one of the key mechanisms of this disease. Show more

Keywords: Cerebral small vessel disease, glial cell, neuroinflammation, spontaneous hypertension rats, toll-like receptor 4, vascular cognitive impairment

DOI: 10.3233/JAD-190240

Citation: Journal of Alzheimer's Disease, vol. 70, no. 2, pp. 563-572, 2019

Authors: Xu, Miaojing | Huang, Yingwei | Song, Pingping | Huang, Yaowei | Huang, Wei | Zhang, Han-Ting | Hu, Yafang

Article Type: Research Article

Abstract: Background: Under stress stimulation, p25 is generated by cleavage of p35 and acts as an activator of cyclin-dependent kinase 5 (Cdk5) like p35. Unlike Cdk5/p35, which is important for brain development, aberrant activity of Cdk5/p25 plays a pathological role in neurodegenerative diseases, such as Alzheimer’s disease, by inducing hyperphosphorylation of downstream substrates related to pathological progression. A truncated fragment of the c-terminus of p35, the Cdk5 inhibitory peptide (CIP), selectively inhibits Cdk5/ p25 activity in cultured neurons and in CIP/p25 tetra-transgenic mice. Objective: First, we aimed to establish a p25 overexpression adult mouse model, then to evaluate whether …CIP delivered by adeno-associated virus serotype 9 (AAV9) can ameliorate neuronal toxicity induced by p25. Methods: The p25 overexpression mouse model was established by intracerebroventricular (i.c.v.) injection of AAV8-GFP-p25 in 8-week-old mice. One month later, these mice were i.c.v. injected with AAV9-CIP-T2A-mCherry or AAV9 vector as control. Pathological and behavioral changes were assessed 3-months post-injection in all mice. Results: The p25 overexpression mice displayed hyperphosphorylation of tau at multiple sites, activation of astrocytes, and elevated inflammatory factors, including IL-1 and TNF-α , which were significantly decreased by the administration of CIP. However, Aβ deposition and microgliosis were not obvious in p25 overexpression mice. In addition, a significant learning decline and anxiety-like behavior were induced by p25 toxicity, and CIP treatment improved learning ability in p25 mice. Conclusion: AAV-mediated p25 overexpression mouse model is easy to construct to study p25-induced neuronal toxicity. Application of CIP after p25 insult reverses the pathological changes and behavioral abnormalities. Show more

Keywords: Adeno-associated virus, Cdk5 inhibitory peptide, hyperphosphorylation of tau, neurodegeneration, p25

DOI: 10.3233/JAD-190099

Citation: Journal of Alzheimer's Disease, vol. 70, no. 2, pp. 573-585, 2019

Authors: Tsutsumimoto, Kota | Doi, Takehiko | Nakakubo, Sho | Kim, Minji | Kurita, Satoshi | Ishii, Hideaki | Shimada, Hiroyuki | Kawachi, Ichiro

Article Type: Research Article

Abstract: We investigated the association between social frailty and Alzheimer’s disease (AD) incidence among community-dwelling older adults in Japan. A 53-month follow-up cohort study was conducted in Obu City, Japan. Participants comprised 3,720 community-dwelling older adults (mean age, 71.7 years; 48.4% men). The operational definition of social frailty comprised five items: going out infrequently, rarely visiting friends, feeling unhelpful to friends or family, living alone, and not always talking with someone each day. During follow-up, the cumulative AD incidence risk between socially robust, pre-frail, and frail groups was 4.1%, 5.5%, and 10.7%, respectively. In both crude (HR 2.72, 95% CI 1.90–3.89, …p  < 0.001) and adjusted Cox proportional hazards models (HR 1.53, 95% CI 1.03–2.28, p  = 0.035), social frailty was associated with a significantly higher AD incidence risk. The present study revealed that social frailty is strongly associated with AD incidence among Japanese older adults. Further research should elucidate whether social frailty prevention is effective for decreasing AD risk. Show more

Keywords: Alzheimer’s disease, older adults, social frailty

DOI: 10.3233/JAD-181178

Citation: Journal of Alzheimer's Disease, vol. 70, no. 2, pp. 587-595, 2019

Authors: Palermo, Giovanni | Tommasini, Luca | Aghakhanyan, Gayanè | Frosini, Daniela | Giuntini, Martina | Tognoni, Gloria | Bonuccelli, Ubaldo | Volterrani, Duccio | Ceravolo, Roberto

Article Type: Research Article

Abstract: Background: Dementia in Parkinson’s disease (PDD) is common presumably due to combined neuropathological substrates. Amyloid-β (Aβ) plaques are well described in PDD but their contribution in synucleinopathies is still controversial. Objective: To investigate regional [18 F]Florbetapir binding and its relative contribution to cognitive dysfunction in a cohort of PDD patients and to test whether PDD patients with comorbid amyloidopathy have different clinical and neuropsychological characteristics. Methods: 21 PDD patients, 20 with Alzheimer’s disease (AD), and 9 control subjects underwent amyloid positron emission tomography (PET) imaging, neurological, and neuropsychological assessment. Radioligand binding was compared across the groups. …PDD scans were interpreted qualitatively and semiquantitatively and categorized as positive or negative. Annual longitudinal Mini-Mental State Examination (MMSE) of PDD subjects was retrospectively collected in order to relate Aβ burden to the course of cognitive impairment. Results: [18 F]Florbetapir PET imaging was positive in 11 PDD patients (52.38%) using the semi-quantitative method. There were no group differences between PDD subjects with increased cortical [18 F]Florbetapir (+) and those without (–), according to demographic and clinical parameters. PDD+ performed worse on Digit Span Foward and on Rey Auditory Verbal Learning Test delayed recall than the PDD– with a significant negative correlation between global cortical retention and specific memory tests. Aβ load did not correlate with MMSE ratings although PDD+ demonstrated a faster clinical progression of dementia. Conclusions: Significant Aβ deposition is common in PDD patients contributing to memory impairment and driving a faster rate of cognitive decline. Show more

Keywords: Amyloid, dementia, dementia with Lewy bodies, Parkinson’s disease, PET imaging, synucleinopathies

DOI: 10.3233/JAD-190323

Citation: Journal of Alzheimer's Disease, vol. 70, no. 2, pp. 597-609, 2019

Authors: Bauman, Julianna | Gibbons, Laura E. | Moore, Mackenzie | Mukherjee, Shubhabrata | McCurry, Susan M. | McCormick, Wayne | Bowen, James D. | Trittschuh, Emily | Glymour, Maria | Mez, Jesse | Saykin, Andrew J. | Dams-O’Conner, Kristen | Bennett, David A. | Larson, Eric B. | Crane, Paul K. | for the Executive Prominent AD (EPAD) investigators

Article Type: Research Article

Abstract: Background: There is considerable heterogeneity in clinical presentation among people with late-onset Alzheimer’s disease (LOAD). We have categorized people with LOAD into subgroups based on relative impairments across cognitive domains. These 6 groups are people with no relatively impaired domains (AD-No Domains), 4 groups with one relatively impaired domain (AD-Memory, AD-Executive, AD-Language, and AD-Visuospatial), and a group with multiple relatively impaired domains (AD-Multiple Domains). Our previous analysis demonstrated that genetic factors vary across cognitively-defined LOAD groups. Objective: To determine whether risks associated with depression and traumatic brain injury with loss of consciousness (TBI) for cognitively defined LOAD subgroups …are similar. Methods: We used cognitive data at LOAD diagnosis from three prospective cohort studies to determine cognitively-defined subgroups. We compared subgroups in endorsement of items from the Centers for Epidemiological Studies Depression (CES-D) scale and history of TBI. Results: Among 1,505 people with LOAD from the three studies, there were substantial differences across subgroups in total CES-D score, with lower scores (less depression) for people with AD with relative impairments in memory (AD-Memory) compared to those in other groups. Differences were noteworthy for the sleep-related item of the CES-D, as people with AD-Memory were less likely to report restless sleep than people in other groups. There were no differences in TBI history across groups. Conclusions: Differences in risk factor associations across subgroups such as differences in endorsement of depression symptoms and restless sleep provide support for the hypothesis that there are biologically coherent subgroups of AD. Show more

Keywords: Cognition, cognitively-defined Alzheimer’s disease subgroups, depression, psychometrics, restless sleep, traumatic brain injury

DOI: 10.3233/JAD-181212

Citation: Journal of Alzheimer's Disease, vol. 70, no. 2, pp. 611-619, 2019