Regional Hypoperfusion Predicts Decline in Everyday Functioning at Three-Year Follow-Up in Older Adults without Dementia

2020 ◽  
Vol 77 (3) ◽  
pp. 1291-1304
Author(s):  
Danielle L. Sanchez ◽  
Kelsey R. Thomas ◽  
Emily C. Edmonds ◽  
Mark W. Bondi ◽  
Katherine J. Bangen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Cerebral Metabolism ◽  
Functional Decline ◽  
Amyloid Β ◽  
Cognitive Status ◽  
White Matter Hyperintensity ◽  
Everyday Functioning

Background: Increasing evidence indicates that cerebrovascular dysfunction may precede cognitive decline in aging and Alzheimer’s disease (AD). Reduced cerebral blood flow (CBF) is associated with cognitive impairment in older adults. However, less is known regarding the association between CBF and functional decline, and whether CBF predicts functional decline beyond cerebrovascular and metabolic risk factors. Objective: To examine the association between regional CBF and functional decline in nondemented older adults. Method: One hundred sixty-six (N = 166) participants without dementia from the Alzheimer’s Disease Neuroimaging Initiative underwent neuropsychological testing and neuroimaging. Pulsed arterial spin labeling magnetic resonance imaging was acquired to quantify resting CBF. Everyday functioning was measured using the Functional Assessment Questionnaire at baseline and annual follow-up visit across three years. Results: Adjusting for age, education, sex, cognitive status, depression, white matter hyperintensity volume, cerebral metabolism, and reference (precentral) CBF, linear mixed effects models showed that lower resting CBF at baseline in the medial temporal, inferior temporal, and inferior parietal lobe was significantly associated with accelerated decline in everyday functioning. Results were similar after adjusting for conventional AD biomarkers, including cerebrospinal fluid (CSF) amyloid-β (Aβ) and hyperphosphorylated tau (p-tau) and apolipoprotein E (APOE) ɛ4 positivity. Individuals who later converted to dementia had lower resting CBF in the inferior temporal and parietal regions compared to those who did not. Conclusion: Lower resting CBF in AD vulnerable regions including medial temporal, inferior temporal, and inferior parietal lobes predicted faster rates of decline in everyday functioning. CBF has utility as a biomarker in predicting functional declines in everyday life and conversion to dementia.

scholarly journals Automatic Prediction of Cognitive and Functional Decline Can Significantly Decrease the Number of Subjects Required for Clinical Trials in Early Alzheimer’s Disease

2021 ◽  
pp. 1-8
Author(s):  
Neda Shafiee ◽  
Mahsa Dadar ◽  
Simon Ducharme ◽  
D. Louis Collins ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Decline ◽  
Functional Decline ◽  
Amyloid Β ◽  
Cognitive Test ◽  
Disease Heterogeneity ◽  
Early Alzheimer’S Disease

Background: While both cognitive and magnetic resonance imaging (MRI) data has been used to predict progression in Alzheimer’s disease, heterogeneity between patients makes it challenging to predict the rate of cognitive and functional decline for individual subjects. Objective: To investigate prognostic power of MRI-based biomarkers of medial temporal lobe atrophy and macroscopic tissue change to predict cognitive decline in individual patients in clinical trials of early Alzheimer’s disease. Methods: Data used in this study included 312 patients with mild cognitive impairment from the ADNI dataset with baseline MRI, cerebrospinal fluid amyloid-β, cognitive test scores, and a minimum of two-year follow-up information available. We built a prognostic model using baseline cognitive scores and MRI-based features to determine which subjects remain stable and which functionally decline over 2 and 3-year follow-up periods. Results: Combining both sets of features yields 77%accuracy (81%sensitivity and 75%specificity) to predict cognitive decline at 2 years (74%accuracy at 3 years with 75%sensitivity and 73%specificity). When used to select trial participants, this tool yields a 3.8-fold decrease in the required sample size for a 2-year study (2.8-fold decrease for a 3-year study) for a hypothesized 25%treatment effect to reduce cognitive decline. Conclusion: When used in clinical trials for cohort enrichment, this tool could accelerate development of new treatments by significantly increasing statistical power to detect differences in cognitive decline between arms. In addition, detection of future decline can help clinicians improve patient management strategies that will slow or delay symptom progression.

scholarly journals Risk factors for functional decline and institutionalisation among community-dwelling older adults with mild to severe Alzheimer’s disease: one year of follow-up

2006 ◽  
Vol 35 (3) ◽  
pp. 308-310 ◽  
Author(s):  
Maria E. Soto ◽  
Sandrine Andrieu ◽  
Sophie Gillette-Guyonnet ◽  
Christelle Cantet ◽  
Fati Nourhashemi ◽  
...  
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Functional Decline ◽  
Community Dwelling ◽  
One Year ◽  
Community Dwelling Older Adults

scholarly journals Persistent neuropathological effects 14 years following amyloid-β immunization in Alzheimer’s disease

Brain ◽  
2019 ◽  
Vol 142 (7) ◽  
pp. 2113-2126 ◽  
Author(s):  
James A R Nicoll ◽  
George R Buckland ◽  
Charlotte H Harrison ◽  
Anton Page ◽  
Scott Harris ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Active Agent ◽  
Amyloid Β ◽  
Cognitive Status ◽  
Post Mortem ◽  
Plaque Removal ◽  
Topographical Distribution ◽  
Antibody Titres

Abstract We performed a 15-year post-mortem neuropathological follow-up of patients in the first trial of amyloid-β immunotherapy for Alzheimer’s disease. Twenty-two participants of a clinical trial of active amyloid-β42 immunization (AN1792, Elan Pharmaceuticals) or placebo were studied. Comprehensive post-mortem neuropathological assessments were performed from 4 months to 15 years after the trial. We analysed the relationships between the topographical distribution of amyloid-β removal from the cerebral cortex and tau pathology, cerebrovascular territories, plasma anti-AN1792 antibody titres and late cognitive status. Seventeen of 22 (77%) participants had Alzheimer’s neuropathological change, whereas 5 of 22 (23%) had alternative causes for dementia (progressive supranuclear palsy = 1, Lewy body disease = 1, vascular brain injury = 1, and frontotemporal lobar degeneration = 2). Nineteen of the 22 participants had received the active agent, three the placebo. Fourteen of 16 (88%) patients with Alzheimer’s disease receiving the active agent had evidence of plaque removal (very extensive removal = 5, intermediate = 4, very limited = 5, no removal = 2). Of particular note, two Alzheimer’s patients who died 14 years after immunization had only very sparse or no detectable plaques in all regions examined. There was a significant inverse correlation between post-vaccination peripheral blood anti-AN1792 antibody titres and post-mortem plaque scores (ρ = − 0.664, P = 0.005). Cortical foci cleared of plaques contained less tau than did cortex with remaining plaques, but the overall distribution of tangles was extensive (Braak V/VI). In conclusion, patients with Alzheimer’s disease actively immunized against amyloid-β can remain virtually plaque-free for 14 years. The extent of plaque removal is related to the immune response. This long duration of efficacy is important in support of active immunization protocols as therapy for, or potentially prevention of, neurodegeneration-associated protein accumulations. Inclusion of patients without Alzheimer’s disease in Alzheimer’s therapy trials is a problem for assessing the efficacy of treatment. Despite modification of Alzheimer’s pathology, most patients had progressed to severe dementia, notably including the five with very extensive plaque removal, possibly due to continued tau propagation. Neuropathology follow-up of patients in therapeutic trials provides valuable information on the causes of dementia and effects of treatment.

Prospective longitudinal study of depression and anosognosia in Alzheimer's disease

1997 ◽  
Vol 171 (1) ◽  
pp. 47-52 ◽  
Author(s):  
Sergio E. Starkstein ◽  
Erán Chemerinski ◽  
Liliana Sabe ◽  
Gabriela Kuzis ◽  
Gustavo Petracca ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Major Depression ◽  
Cognitive Status ◽  
Initial Evaluation ◽  
Consecutive Series ◽  
Psychiatric Interview ◽  
Prospective Longitudinal Study ◽  
Prospective Longitudinal

BackgroundThe aim was to examine the longitudinal evolution of depression and anosognosia in patients with probable Alzheimer's disease (AD).MethodSixty-two of a consecutive series of 116 AD patients that were examined with a structured psychiatric interview had a follow-up evaluation between one and two years after the initial evaluation.ResultsAt the initial evaluation 19% of the 62 patients had major depression, 34% had dysthymia, and 47% were not depressed. After a mean follow-up of 16 months, 58% of patients with major depression at the initial evaluation were still depressed, whereas only 28% of patients with initial dysthymia and 21% of the non-depressed patients were depressed at follow-up. During the follow-up period, all three groups showed similar declines in cognitive status and activities of daily living. At the initial evaluation, 39% of the patients had anosognosia, and there was a significant increment of anosognosia during the follow-up period.ConclusionsWhile dysthymia in AD is a brief emotional disorder, major depression is a longer-lasting mood change. Anosognosia is another prevalent disorder among AD patients, and increases with the progression of the illness.

scholarly journals Anticholinergics and Benzodiazepines on Cognitive Impairment among Elderly with Alzheimer’s Disease: a One year Follow-Up Study

2019 ◽  
Author(s):  
Rewadee Jenraumjit ◽  
Surarong Chinwong ◽  
Dujrudee Chinwong ◽  
Tipaporn Kanjanarach ◽  
Thanat Kshetradat ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Psychological Symptoms ◽  
Esterase Inhibitors ◽  
One Year ◽  
State Examination ◽  
Harmful Effects

Abstract Objective Age-associated decline in central cholinergic activity makes older adults susceptible to harmful effects of anticholinergics (ACs). Evidence exists of an association between effects of AC medications on cognition. This retrospective cohort study examines how ACs affect cognition among older adults with Alzheimer’s disease (AD) who received acetylcholine esterase inhibitors (AChEIs) over the course of 12 months. Results A total of 133 (80% women, mean age 78.38 years, SD 7.4) were recruited. No difference in sex, age and comorbid diseases was observed between participants who took ACs, Benzodiazepines (BZDs) and AChEIs. The most common prescribed ACs was quetiapine, being used for behavioral and psychological symptoms (BPSD). Multilevel analysis showed that the change of mental state examination scores were significantly predicted in the group using ACs (t (169), -2.52, p = .020) but not with the groups using BZD (t (162), 0.84, p = .440). Evidence showed that older adults with Alzheimer’s disease and exposed to ACs exhibited lower global cognitive scores than those without AC exposure. Using ACs could be a trade-off between controlling BPSD and aggravating cognitive impairment. Highlighting the awareness of the potential anticholinergic effect is important and may be the best policy.

The Trajectory of Cerebrospinal Fluid Growth-Associated Protein 43 in the Alzheimer’s Disease Continuum: A Longitudinal Study

2021 ◽  
pp. 1-12
Author(s):  
Heng Zhang ◽  
Diyang Lyu ◽  
Jianping Jia ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Amyloid Β ◽  
Dementia Patients ◽  
Positron Emission ◽  
Potential Biomarker ◽  
Synaptic Degeneration ◽  
Over Time

Background: Synaptic degeneration has been suggested as an early pathological event that strongly correlates with severity of dementia in Alzheimer’s disease (AD). However, changes in longitudinal cerebrospinal fluid (CSF) growth-associated protein 43 (GAP-43) as a synaptic biomarker in the AD continuum remain unclear. Objective: To assess the trajectory of CSF GAP-43 with AD progression and its association with other AD hallmarks. Methods: CSF GAP-43 was analyzed in 788 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), including 246 cognitively normal (CN) individuals, 415 individuals with mild cognitive impairment (MCI), and 127 with AD dementia based on cognitive assessments. The associations between a multimodal classification scheme with amyloid-β (Aβ), tau, and neurodegeneration, and changes in CSF GAP-43 over time were also analyzed. Results: CSF GAP-43 levels were increased at baseline in MCI and dementia patients, and increased significantly over time in the preclinical (Aβ-positive CN), prodromal (Aβ-positive MCI), and dementia (Aβ-positive dementia) stages of AD. Higher levels of CSF GAP-43 were also associated with higher CSF phosphorylated tau (p-tau) and total tau (t-tau), cerebral amyloid deposition and hypometabolism on positron emission tomography, the hippocampus and middle temporal atrophy, and cognitive performance deterioration at baseline and follow-up. Furthermore, CSF GAP-43 may assist in effectively predicting the probability of dementia onset at 2- or 4-year follow-up. Conclusion: CSF GAP-43 can be used as a potential biomarker associated with synaptic degeneration in subjects with AD; it may also be useful for tracking the disease progression and for monitoring the effects of clinical trials.

scholarly journals Midlife physical activity is associated with lower incidence of vascular dementia but not Alzheimer’s disease

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Oskar Hansson ◽  
Martina Svensson ◽  
Anna-Märta Gustavsson ◽  
Emelie Andersson ◽  
Yiyi Yang ◽  
...  
Keyword(s):  
Physical Activity ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Vascular Dementia ◽  
Lower Incidence ◽  
Amyloid Β ◽  
Synaptic Proteins ◽  
Cancer Study ◽  
Diet And Cancer

Abstract Background Physical activity might reduce the risk of developing dementia. However, it is still unclear whether the protective effect differs depending on the subtype of dementia. We aimed to investigate if midlife physical activity affects the development of vascular dementia (VaD) and Alzheimer’s disease (AD) differently in two large study populations with different designs. Methods Using a prospective observational design, we studied whether long-distance skiers of the Swedish Vasaloppet (n = 197,685) exhibited reduced incidence of VaD or AD compared to matched individuals from the general population (n = 197,684) during 21 years of follow-up (median 10, interquartile range (IQR) 5–15 years). Next, we studied the association between self-reported physical activity, stated twice 5 years apart, and incident VaD and AD in 20,639 participants in the Swedish population-based Malmo Diet and Cancer Study during 18 years of follow-up (median 15, IQR 14–17 years). Finally, we used a mouse model of AD and studied brain levels of amyloid-β, synaptic proteins, and cognitive function following 6 months of voluntary wheel running. Results Vasaloppet skiers (median age 36.0 years [IQR 29.0–46.0], 38% women) had lower incidence of all-cause dementia (adjusted hazard ratio (HR) 0.63, 95% CI 0.52–0.75) and VaD (adjusted HR 0.49, 95% CI 0.33–0.73), but not AD, compared to non-skiers. Further, faster skiers exhibited a reduced incidence of VaD (adjusted HR 0.38, 95% CI 0.16–0.95), but not AD or all-cause dementia compared to slower skiers. In the Malmo Diet and Cancer Study (median age 57.5 years [IQR 51.0–63.8], 60% women), higher physical activity was associated with reduced incidence of VaD (adjusted HR 0.65, 95% CI 0.49-0.87), but not AD nor all-cause dementia. These findings were also independent of APOE-ε4 genotype. In AD mice, voluntary running did not improve memory, amyloid-β, or synaptic proteins. Conclusions Our results indicate that physical activity in midlife is associated with lower incidence of VaD. Using three different study designs, we found no significant association between physical activity and subsequent development of AD.

Cortisol, Amyloid-β, and Reserve Predicts Alzheimer’s Disease Progression for Cognitively Normal Older Adults

2019 ◽  
Vol 70 (2) ◽  
pp. 553-562 ◽  
Author(s):  
Chinedu T. Udeh-Momoh ◽  
Bowen Su ◽  
Stephanie Evans ◽  
Bang Zheng ◽  
Shireen Sindi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Disease Progression ◽  
Amyloid Β ◽  
Cognitively Normal

The Correlations between Postmortem Brain Pathologies and Cognitive Dysfunction in Aging and Alzheimer's Disease

2018 ◽  
Vol 15 (5) ◽  
pp. 462-473 ◽  
Author(s):  
Wen-Ying Qiu ◽  
Qian Yang ◽  
Wanying Zhang ◽  
Naili Wang ◽  
Di Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Brain ◽  
Amyloid Β ◽  
Cognitive Status ◽  
Postmortem Brain ◽  
Braak Stage ◽  
Brain Bank ◽  
General Linear Multivariate Model ◽  
Human Brains

Background: The pathological diagnostic criteria for Alzheimer's disease (AD) updated by the National Institute on Aging-Alzheimer's Association (NIA-AA) in 2012 has been widely adopted, but the clinicopathological relevance remained obscure in Chinese population. Objective: This study aims to investigate the correlations between the antemortem clinical cognitive performances and the postmortem neuropathological changes in the aging and AD brains collected in a human brain bank in China. Method: A total of 52 human brains with antemortem cognitive status information [Everyday Cognition (ECog)] were collected through the willed donation program by CAMS/PUMC Human Brain Bank. Pathological changes were evaluated with the “ABC” score following the guidelines of NIA-AA. The clinicopathological relationship was analyzed with correlation analysis and general linear multivariate model. Results: The general ABC score has a significant correlation with global ECog score (r=0.37, p=0.014) and most of ECog domains. The CERAD score of neuritic plaques (C score) has a significant correlation with global ECog score (r=0.40, p=0.007) and the majority of ECog domains, such as memory (r=0.50, p=0.001), language (r=0.45, p=0.002), visuospatial functions (r=0.31, p=0.040), planning (r=0.35, p=0.021) and organization (r=0.39, p=0.010). The Braak stage of neurofibrillary tangles (NFTs) (B score) has a moderate correlation with memory (r=0.32, p=0.035). The Thal phases of amyloid-β (Aβ) deposits (A score) present no significant correlation with any of ECog domains. Conclusion: In this study, we verified the correlation of postmortem C and B scores, but not the A score with cognition performance in a collection of samples from the Chinese human brain bank.

scholarly journals Visuospatial alpha and gamma oscillations scale with the severity of cognitive dysfunction in patients on the Alzheimer’s disease spectrum

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Alex I. Wiesman ◽  
Daniel L. Murman ◽  
Pamela E. May ◽  
Mikki Schantell ◽  
Sara L. Wolfson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Gamma Oscillations ◽  
Cognitive Status ◽  
Neural Oscillations ◽  
Novel Therapy ◽  
Frequency Responses ◽  
Disease Spectrum ◽  
Visuospatial Processing

Abstract Background Entrainment of neural oscillations in occipital cortices by external rhythmic visual stimuli has been proposed as a novel therapy for patients with Alzheimer’s disease (AD). Despite this increased interest in visual neural oscillations in AD, little is known regarding their role in AD-related cognitive impairment and in particular during visuospatial processing. Methods We used source-imaged magnetoencephalography (MEG) and an established visuospatial processing task to elicit multi-spectral neuronal responses in 35 biomarker-confirmed patients on the AD spectrum and 20 biomarker-negative older adults. Neuronal oscillatory responses were imaged to the level of the cortex, and group classifications and neurocognitive relationships were modeled using logistic and linear regression, respectively. Results Visuospatial neuronal oscillations in the theta, alpha, and gamma ranges significantly predicted the classification of patients on the AD spectrum. Importantly, the direction of these effects differed by response frequency, such that patients on the AD spectrum exhibited weaker alpha-frequency responses in lateral occipital regions, and stronger gamma-frequency responses in the primary visual cortex, as compared to biomarker-negative older adults. In addition, alpha and gamma, but not theta, oscillations robustly predicted cognitive status (i.e., MoCA and MMSE scores), such that patients with neural responses that deviated more from those of healthy older adults exhibited poorer cognitive performance. Conclusions We find that the multi-spectral neural dynamics supporting visuospatial processing differentiate patients on the AD spectrum from cognitively normal, biomarker-negative older adults. Oscillations in the alpha and gamma bands also relate to cognitive status in ways that are informative for emerging clinical interventions.

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