scholarly journals Cognitive Impairment Precedes and Predicts Functional Impairment in Mild Alzheimer’s Disease

2015 ◽  
Vol 47 (1) ◽  
pp. 205-214 ◽  
Author(s):  
Hong Liu-Seifert ◽  
Eric Siemers ◽  
Karen Price ◽  
Baoguang Han ◽  
Katherine J. Selzler ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Functional Impairment

scholarly journals Impaired spike-gamma coupling of area CA3 fast-spiking interneurons as the earliest functional impairment in the AppNL-G-F mouse model of Alzheimer’s disease

2021 ◽  
Author(s):  
Luis Enrique Arroyo-García ◽  
Arturo G. Isla ◽  
Yuniesky Andrade-Talavera ◽  
Hugo Balleza-Tapia ◽  
Raúl Loera-Valencia ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mouse Model ◽  
Functional Impairment ◽  
Amyloid Β ◽  
Gamma Oscillations ◽  
Gamma Oscillation ◽  
Gamma Rhythm ◽  
Fast Spiking

AbstractIn Alzheimer’s disease (AD) the accumulation of amyloid-β (Aβ) correlates with degradation of cognition-relevant gamma oscillations. The gamma rhythm relies on proper neuronal spike-gamma coupling, specifically of fast-spiking interneurons (FSN). Here we tested the hypothesis that decrease in gamma power and FSN synchrony precede amyloid plaque deposition and cognitive impairment in AppNL-G-F knock-in mice (AppNL-G-F). The aim of the study was to evaluate the amyloidogenic pathology progression in the novel AppNL-G-F mouse model using in vitro electrophysiological network analysis. Using patch clamp of FSNs and pyramidal cells (PCs) with simultaneous gamma oscillation recordings, we compared the activity of the hippocampal network of wild-type mice (WT) and the AppNL-G-F mice at four disease stages (1, 2, 4, and 6 months of age). We found a severe degradation of gamma oscillation power that is independent of, and precedes Aβ plaque formation, and the cognitive impairment reported previously in this animal model. The degradation correlates with increased Aβ1-42 concentration in the brain. Analysis on the cellular level showed an impaired spike-gamma coupling of FSN from 2 months of age that correlates with the degradation of gamma oscillations. From 6 months of age PC firing becomes desynchronized also, correlating with reports in the literature of robust Aβ plaque pathology and cognitive impairment in the AppNL-G-F mice. This study provides evidence that impaired FSN spike-gamma coupling is one of the earliest functional impairment caused by the amyloidogenic pathology progression likely is the main cause for the degradation of gamma oscillations and consequent cognitive impairment. Our data suggests that therapeutic approaches should be aimed at restoring normal FSN spike-gamma coupling and not just removal of Aβ.

F3-02-01: COGNITIVE IMPAIRMENT PRECEDES AND PREDICTS FUNCTIONAL IMPAIRMENT IN MILD ALZHEIMER'S DISEASE

2014 ◽  
Vol 10 ◽  
pp. P203-P203
Author(s):  
Hong Liu-Seifert ◽  
Baoguang Han ◽  
David Henley ◽  
Eric Siemers ◽  
Jeffrey Cummings ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Functional Impairment

ANALYSIS OF THE RELATIONSHIP OF COGNITIVE IMPAIRMENT AND FUNCTIONAL IMPAIRMENT IN MILD ALZHEIMER’S DISEASE IN EXPEDITION 3

2018 ◽  
pp. 1-4
Author(s):  
H. Liu-Seifert ◽  
E. Siemers ◽  
K. Sundell ◽  
M. Mynderse ◽  
J. Cummings ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Functional Impairment ◽  
Functional Decline ◽  
Clinical Trial Data ◽  
Cognitive Outcomes ◽  
Functional Measures ◽  
Functional Scores ◽  
The Relationship

BACKGROUND: Clinical progression of Alzheimer’s disease is characterized by impairment in cognition and function. OBJECTIVE: To assess the relationship between cognitive and functional impairment in mild Alzheimer’s disease. DESIGN: Spearman’s rank correlations between cognitive and functional measures were calculated. Autoregressive cross-lagged panel analyses were used to determine the temporal relationship between cognitive and functional decline. SETTING: Post-hoc analysis of clinical trial data. PARTICIPANTS: Placebo-treated patients with mild Alzheimer’s disease from the Phase 3 solanezumab study EXPEDITION 3. INTERVENTION: Placebo MEASUREMENTS: Cognitive and functional measures were assessed at baseline and at six post-baseline time points through Week 80. RESULTS: Correlation between cognitive and functional measures was 0.41 at baseline and 0.65 at Week 80. Autoregressive cross-lagged panel analysis demonstrated that cognitive impairment preceded and predicted subsequent functional decline, but functional scores did not predict cognitive outcomes. CONCLUSIONS: This study supports the hypothesis that functional impairment predictably follows cognitive decline in mild Alzheimer’s disease dementia.

scholarly journals THE ROLE OF CLINICAL TRIALS IN PRECLINICAL ALZHEIMER’S DISEASE DRUG DEVELOPMENT PROGRAMS

2020 ◽  
pp. 1-3
Author(s):  
J. Cummings
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Impairment ◽  
Functional Impairment ◽  
Amyloid Beta Protein ◽  
Neuropsychological Measures ◽  
Preclinical Phase ◽  
Preclinical Ad ◽  
Positron Emission

Alzheimer’s disease (AD) has a 15-20 year preclinical phase during which the individuals have normal cognition by conventional measures and have state measures of AD pathology including elevated levels of brain amyloid when assessed with positron emission tomography (PET) and abnormally decreased levels cerebrospinal fluid (CSF) amyloid beta-protein (Aß) and increased levels of total tau and hyperphosphorylated tau (p-tau) (1, 2). Recognition of this long-preclinical phase and the presence of biomarker changes affords, the opportunity to plan secondary prevention trials to prevent or delay the onset of cognitive impairment and progression to dementia. The US Food and Drug Administration (FDA) facilitated planning of clinical trials for participants in the preclinical phase of AD by defining two stages of the preclinical period: in stage 1 participants have characteristic pathophysiologic changes of AD but no evidence of clinical impact; in stage 2 participants have characteristic pathophysiologic changes of AD and subtle detectable abnormalities on sensitive neuropsychological measures, but no functional impairment. Stage 3 participants are no longer in the preclinical phase of AD; they have mild cognitive impairment (MCI)/prodromal AD with characteristic pathophysiologic changes of AD, subtle or more apparent detectable abnormalities on sensitive neuropsychological measures, and mild but detectable functional impairment. Stages 4, 5, and 6 describe patients with mild, moderate and severe AD dementia. Biomarker, clinical definitions, and regulatory engagement have set the stage for planning and conduct of trials in preclinical AD.

scholarly journals Relationship of Homocysteine Plasma Levels with Mild Cognitive Impairment, Alzheimer’s Disease, Vascular Dementia, Psychobehavioral, and Functional Complications

2021 ◽  
pp. 1-14
Author(s):  
Michele Lauriola ◽  
Grazia D’Onofrio ◽  
Filomena Ciccone ◽  
Carmela Germano ◽  
Leandro Cascavilla ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Vascular Dementia ◽  
Functional Impairment ◽  
Symptom Severity ◽  
Neuropsychiatric Symptom ◽  
Hemoglobin C ◽  
Impairment Severity

Background: Alzheimer’s disease (AD) may be a vascular disorder with neurodegenerative consequences opening possibility of preventing AD by targeting vascular risk factors including homocysteine. Objective: The study aims were to assess homocysteine distribution in different forms and severity of cognitive impairment (CogI) [mild cognitive impairment (MCI), probable AD (Prob-AD), possible AD (Poss-AD), and vascular dementia (VaD)] and in NoCogI, and to estimate possible association between hyperhomocysteinemia levels with functional deficit severity and psychobehavioral complications. Methods: In total, 929 (M = 366, F = 563; mean age of 72.55±6.24 years) patients were evaluated with cognitive, neuropsychiatric, affective, and functional assessment scales. Homocysteine serum was set on two levels: between 0 and 10μmol/L and >  10μmol/L. For each patient, blood concentration of folate, vitamin B12, hemoglobin, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), cholesterol, triglycerides, and glycemia were measured. Results: CogI patients demonstrated significantly a higher frequency of homocysteine >  10 (p = 0.003), than NoCogI patients. Patients with moderate and severe dementia had a higher frequency of homocysteine >  10 (p <  0.0001), than MCI and mild dementia. Poss-AD and VaD had a higher frequency of homocysteine >  10 (p = 0.003), than Prob-AD patients. Homocysteine >  10 frequency is directly proportional to increased neuropsychiatric symptom severity (p <  0.0001), and functional impairment severity respectively for ADL (p <  0.0001) and IADL (p <  0.0001). Conclusion: Higher homocysteine level seems to be significantly related to cognitive impairment frequency and severity, possible AD and VaD, neuropsychiatric symptom severity, and functional impairment severity.

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