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.

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 P1-414: ASSOCIATION OF BRAIN MICROSTRUCTURE AND AMYLOID-β WITH COGNITIVE DECLINE IN EARLY ALZHEIMER'S DISEASE

2019 ◽  
Vol 15 ◽  
pp. P421-P421
Author(s):  
Emilie T. Reas ◽  
Donald J. Hagler ◽  
Nathan White ◽  
Joshua Kuperman ◽  
Hauke Bartsch ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Amyloid Β ◽  
Brain Microstructure ◽  
Early Alzheimer’S Disease

scholarly journals Amyloid-β misfolding as a plasma biomarker indicates risk for future clinical Alzheimer’s disease in individuals with subjective cognitive decline

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Julia Stockmann ◽  
Inge M. W. Verberk ◽  
Nina Timmesfeld ◽  
Robin Denz ◽  
Brian Budde ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Roc Curve ◽  
External Validation ◽  
Area Under The Curve ◽  
Amyloid Β ◽  
Sensor Technology ◽  
Subjective Cognitive Decline

Abstract Background We evaluated Aβ misfolding in combination with Aβ42/40 ratio as a prognostic tool for future clinical progression to mild cognitive impairment (MCI) or dementia due to Alzheimer’s disease (AD) in individuals with subjective cognitive decline (SCD). Methods Baseline plasma samples (n = 203) from SCD subjects in the SCIENCe project and Amsterdam Dementia Cohort (age 61 ± 9 years; 57% male, mean follow-up time 2.7 years) were analyzed using immuno-infrared-sensor technology. Within 6 years of follow-up, 22 (11%) individuals progressed to MCI or dementia due to AD. Sensor readout values > 1646 cm− 1 reflected normal Aβ folding; readouts at ≤ 1646 cm− 1 reflected low and at < 1644 cm− 1 high misfolding. We used Cox proportional hazard models to quantify Aβ misfolding as a prognostic biomarker for progression to MCI and dementia due to AD. The accuracy of the predicted development of MCI/AD was determined by time-dependent receiver operating characteristic (t-ROC) curve analyses that take individual follow-up and conversion times into account. Statistical models were adjusted for age, sex, and APOEε4 status. Additionally, plasma Aβ42/40 data measured by SIMOA were statistically analyzed and compared. Results All 22 patients who converted to MCI or AD-dementia within 6 years exhibited Aβ misfolding at baseline. Cox analyses revealed a hazard ratio (HR) of 19 (95% confidence interval [CI] 2.2–157.8) for future conversion of SCD subjects with high misfolding and of 11 (95% CI 1.0–110.1) for those with low misfolding. T-ROC curve analyses yielded an area under the curve (AUC) of 0.94 (95% CI 0.86–1.00; 6-year follow-up) for Aβ misfolding in an age, sex, and APOEε4 model. A similar model with plasma Aβ42/40 ratio yielded an AUC of 0.92 (95% CI, 0.82–1.00). The AUC increased to 0.99 (95% CI, 0.99–1.00) after inclusion of both Aβ misfolding and the Aβ42/40 ratio. Conclusions A panel of structure- and concentration-based plasma amyloid biomarkers may predict conversion to clinical MCI and dementia due to AD in cognitively unimpaired subjects. These plasma biomarkers provide a noninvasive and cost-effective alternative for screening early AD pathological changes. Follow-up studies and external validation in larger cohorts are in progress for further validation of our findings.

scholarly journals Predicting Progression & Cognitive Decline in Amyloid-Positive Patients with Alzheimer's Disease

2021 ◽  
Author(s):  
Hákon Valur Dansson ◽  
Lena Stempfle ◽  
Hildur Egilsdóttir ◽  
Alexander Schliep ◽  
Erik Portelius ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Disease Progression ◽  
Test Scores ◽  
Amyloid Β ◽  
Cognitive Test ◽  
Progression Rate ◽  
Specific Level ◽  
Clinical Variables

Abstract BackgroundIn Alzheimer’s disease (AD), amyloid- β (Aβ) peptides aggregate in the brain forming amyloid plaques, which are a key pathological hallmark of the disease. However, plaques may also be present in cognitively unimpaired elderly individuals. Therefore, it is of great value to explain the variance in disease progression among patients with Aβ pathology. MethodsA cohort of n= 2293 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database was selected to study heterogeneity in disease progression for individuals with Aβ plaque pathology. The analysis used baseline clinical variables including demographics, genetic markers and neuropsychological data to predict how the cognitive ability and AD diagnosis of subjects progressed using statistical models and machine learning. Due to the limited prevalence of Aβ pathology, models fit only to Aβ-positive subjects were compared to models fit to an extended cohort including subjects without established Aβ pathology, adjusting for covariate differences between the cohorts. ResultsAβ pathology status was determined based the Aβ 42 /Aβ 40 ratio. The best predictive model of change in cognitive test scores for Aβ-positive subjects at the two-year follow-up achieved an R 2 score of 0.388 while the best model predicting adverse changes in diagnosis achieved a weighted F1 score of 0.791. Conforming to expectations, Aβ-positive subjects declined faster on average than those without Aβ pathology, but the specific level of Aβ plaques was not predictive of progression rate. For the four-year prediction task of cognitive score change, the best model achieved an R 2 score of 0.325 and it was found that fitting models to the extended cohort substantially improved performance. Moreover, using all clinical variables outperformed the best model based only on baseline cognitive test scores which achieved an R 2 score of 0.228. ConclusionOur analysis shows that levels of Aβ plaques are not strong predictors of the rate of cognitive decline in Aβ-positive subjects. Baseline assessments of cognitive function accounts for the majority of variance explained in the prediction of two-year decline but is insufficient for achieving optimal results in longer-term predictions. Predicting changes both in cognitive test scores and in diagnosis provides multiple perspectives of the progression of potential AD subjects.

Amyloid-β Peptides in Plasma and Cognitive Decline After 1 Year Follow-Up in Alzheimer's Disease Patients

2010 ◽  
Vol 21 (4) ◽  
pp. 1263-1269 ◽  
Author(s):  
Christoph Laske ◽  
Kateryna Sopova ◽  
Christos Gkotsis ◽  
Gerhard W. Eschweiler ◽  
Guido Straten ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Amyloid Β

scholarly journals Age, vascular disease, and Alzheimer’s disease pathologies in amyloid negative elderly adults

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Tengfei Guo ◽  
Susan M. Landau ◽  
William J. Jagust ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Fdg Pet ◽  
Amyloid Β ◽  
Hippocampal Volume ◽  
Factors Associated ◽  
Male Sex ◽  
The Relationship

Abstract Background We recently reported that CSF phosphorylated tau (p-Tau181) relative to Aβ40 (CSF p-Tau/Aβ40 ratio) was less noisy and increased associations with Alzheimer’s disease (AD) biomarkers compared to CSF p-Tau181 alone. While elevations of CSF p-Tau/Aβ40 can occur in amyloid-β (Aβ) negative (Aβ-) individuals, the factors associated with these elevations and their role in neurodegeneration and cognitive decline are unknown. We aim to explore factors associated with elevated tau in CSF, and how these elevated tau are related to neurodegeneration and cognitive decline in the absence of Aβ positivity. Methods We examined relationships between CSF p-Tau/Aβ40, and CSF Aβ42/Aβ40, Aβ PET, and white matter hyperintensities (WMH) as well as vascular risk factors in 149 cognitively unimpaired and 52 impaired individuals who were presumably not on the Alzheimer’s disease (AD) pathway due to negative Aβ status on both CSF and PET. Subgroups had 18F-fluorodeoxyglucose (FDG) PET and adjusted hippocampal volume (aHCV), and longitudinal measures of CSF, aHCV, FDG PET, and cognition data, so we examined CSF p-Tau/Aβ40 associations with these measures as well. Results Elevated CSF p-Tau/Aβ40 was associated with older age, male sex, greater WMH, and hypertension as well as a pattern of hippocampal atrophy and temporoparietal hypometabolism characteristic of AD. Lower CSF Aβ42/Aβ40, higher WMH, and hypertension but not age, sex, Aβ PET, APOE-ε4 status, body mass index, smoking, and hyperlipidemia at baseline predicted CSF p-Tau/Aβ40 increases over approximately 5 years of follow-up. The relationship between CSF p-Tau/Aβ40 and subsequent cognitive decline was partially or fully explained by neurodegenerative measurements. Conclusions These data provide surprising clues as to the etiology and significance of tau pathology in the absence of Aβ. It seems likely that, in addition to age, both cerebrovascular disease and subthreshold levels of Aβ are related to this tau accumulation. Crucially, this phenotype of CSF tau elevation in amyloid-negative individuals share features with AD such as a pattern of metabolic decline and regional brain atrophy.

Pharmacogenetics of Angiotensin-Converting Enzyme Inhibitors in Patients with Alzheimer's Disease Dementia

2018 ◽  
Vol 15 (4) ◽  
pp. 386-398 ◽  
Author(s):  
Fabricio Ferreira de Oliveira ◽  
Elizabeth Suchi Chen ◽  
Marilia Cardoso Smith ◽  
Paulo Henrique Ferreira Bertolucci
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Angiotensin Converting Enzyme ◽  
Cognitive Decline ◽  
Enzyme Inhibitors ◽  
Late Onset ◽  
Amyloid Β ◽  
Converting Enzyme ◽  
Converting Enzyme Inhibitors ◽  
Alzheimer’S Disease Dementia

Background: While the angiotensin-converting enzyme degrades amyloid-β, angiotensinconverting enzyme inhibitors (ACEis) may slow cognitive decline by way of cholinergic effects, by increasing brain substance P and boosting the activity of neprilysin, and by modulating glucose homeostasis and augmenting the secretion of adipokines to enhance insulin sensitivity in patients with Alzheimer’s disease dementia (AD). We aimed to investigate whether ACE gene polymorphisms rs1800764 and rs4291 are associated with cognitive and functional change in patients with AD, while also taking APOE haplotypes and anti-hypertensive treatment with ACEis into account for stratification. Methods: Consecutive late-onset AD patients were screened with cognitive tests, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic correlations were estimated for one year, considering APOE and ACE genotypes and haplotypes, and treatment with ACEis. Results: For 193 patients, minor allele frequencies were 0.497 for rs1800764 – C (44.6% heterozygotes) and 0.345 for rs4291 – T (38.9% heterozygotes), both in Hardy-Weinberg equilibrium. Almost 94% of all patients used cholinesterase inhibitors, while 155 (80.3%) had arterial hypertension, and 124 used ACEis. No functional impacts were found regarding any genotypes or pharmacological treatment. Either for carriers of ACE haplotypes that included rs1800764 – T and rs4291 – A, or for APOE4- carriers of rs1800764 – T or rs4291 – T, ACEis slowed cognitive decline independently of blood pressure variations. APOE4+ carriers were not responsive to treatment with ACEis. Conclusion: ACEis may slow cognitive decline for patients with AD, more remarkably for APOE4- carriers of specific ACE genotypes.

scholarly journals 24(S)-Saringosterol Prevents Cognitive Decline in a Mouse Model for Alzheimer’s Disease

Marine Drugs ◽  
2021 ◽  
Vol 19 (4) ◽  
pp. 190
Author(s):  
Nikita Martens ◽  
Melissa Schepers ◽  
Na Zhan ◽  
Frank Leijten ◽  
Gardi Voortman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Cognitive Decline ◽  
Inflammatory Marker ◽  
Amyloid Β ◽  
Liver Fat ◽  
Gas Chromatography Mass Spectrometry ◽  
Memory Decline ◽  
Plaque Load

We recently found that dietary supplementation with the seaweed Sargassum fusiforme, containing the preferential LXRβ-agonist 24(S)-saringosterol, prevented memory decline and reduced amyloid-β (Aβ) deposition in an Alzheimer’s disease (AD) mouse model without inducing hepatic steatosis. Here, we examined the effects of 24(S)-saringosterol as a food additive on cognition and neuropathology in AD mice. Six-month-old male APPswePS1ΔE9 mice and wildtype C57BL/6J littermates received 24(S)-saringosterol (0.5 mg/25 g body weight/day) (APPswePS1ΔE9 n = 20; C57BL/6J n = 19) or vehicle (APPswePS1ΔE9 n = 17; C57BL/6J n = 19) for 10 weeks. Cognition was assessed using object recognition and object location tasks. Sterols were analyzed by gas chromatography/mass spectrometry, Aβ and inflammatory markers by immunohistochemistry, and gene expression by quantitative real-time PCR. Hepatic lipids were quantified after Oil-Red-O staining. Administration of 24(S)-saringosterol prevented cognitive decline in APPswePS1ΔE9 mice without affecting the Aβ plaque load. Moreover, 24(S)-saringosterol prevented the increase in the inflammatory marker Iba1 in the cortex of APPswePS1ΔE9 mice (p < 0.001). Furthermore, 24(S)-saringosterol did not affect the expression of lipid metabolism-related LXR-response genes in the hippocampus nor the hepatic neutral lipid content. Thus, administration of 24(S)-saringosterol prevented cognitive decline in APPswePS1ΔE9 mice independent of effects on Aβ load and without adverse effects on liver fat content. The anti-inflammatory effects of 24(S)-saringosterol may contribute to the prevention of cognitive decline.

Sign in / Sign up

Export Citation Format

Share Document