The 12 Years Preceding Mild Cognitive Impairment Due to Alzheimer's Disease: The Temporal Emergence of Cognitive Decline.
ABSTRACT: The identification of the type and sequence of cognitive decline in preclinical mild cognitive impairment (MCI) prior to Alzheimer's disease (AD) is crucial for understanding AD pathogenesis and implementing therapeutic interventions.To model the longitudinal courses of different neuropsychological functions in MCI due to AD.We investigated the prodromal phase of MCI over a 12-year period in 27 initially healthy participants with subsequent MCI preceding AD (NC-MCI) and 60 demographically matched healthy individuals (NC-NC). The longitudinal courses of cognitive performance (verbal and visual episodic memory, semantic memory, executive functioning, constructional praxis, psychomotor speed, language, and informant-based reports) were analyzed with linear mixed effects models.The sequence with which different cognitive functions declined in the NC-MCI relative to the NC-NC group began with verbal memory and savings performance approximately eight years, and verbal episodic learning, visual memory, and semantic memory (animal fluency) circa four years prior to the MCI diagnosis. Executive functioning, psychomotor speed, and informant-based reports of the NC-MCI group declined approximately two years preceding the MCI diagnosis.Measurable neuropsychological deterioration occurs up to approximately eight years preceding MCI due to AD.
Project description:<h4>Background</h4>Fibrillar amyloid deposition preferentially affects the frontal lobes, temporal pole/neocortex, and posterior cingulate by age 65 years in APOE ?4 carriers prior to the diagnosis of mild cognitive impairment (MCI) and Alzheimer disease (AD), but is it impairing frontally mediated neuropsychological performance?<h4>Methods</h4>A total of 71 ?4 homozygotes (HMZ), 194 ?4 heterozygotes (HTZ), and 356 ?4 noncarriers (NC) who did not differ significantly in mean age (56.6 years), years of education (15.6), gender (70% women), or follow-up duration (6.3 years) had neuropsychological testing every 2 years including the Auditory Verbal Learning Test (AVLT) and frontal/executive tasks sensitive to psychomotor speed, working memory, problem solving, and activity. A subset also received the Iowa Gambling Task (IGT). Findings were then tested in a clinical sample of 27 patients with incident MCI and AD.<h4>Results</h4>APOE ?4 carriers had greater acceleration of decline (quadratic effect) than NC on the AVLT (p = 0.04) but not on any frontal test. APOE ?4 HMZ had greater velocity of decline (linear effects) than NC on all mental arithmetic tests: paced auditory serial attention task (PASAT) 3 second (p = 0.01) and 2 second (p = 0.004) versions; and Wechsler Adult Intelligence Scale-Revised arithmetic (p = 0.048). IGT performance did not differ between 12 ?4 HMZ, 27 ?4 HTZ, and 44 NC. Among 27 patients with incident MCI and AD, the PASAT showed progressive decline preceding diagnosis in 50%.<h4>Conclusions</h4>No frontal cognitive effects were as robust as memory decline. APOE ?4 HMZ declined more quickly than NC on mental arithmetic tests related to frontal lobe-mediated working memory ability.
Project description:Episodic memory is typically affected during the course of Alzheimer's disease (AD). Due to the pronounced heterogeneity of functional neuroimaging studies on episodic memory impairments in mild cognitive impairment (MCI) and AD regarding their methodology and findings, we aimed to delineate consistent episodic memory-related brain activation patterns. We performed a systematic, quantitative, coordinate-based whole-brain activation likelihood estimation meta-analysis of 28 functional magnetic resonance imaging (fMRI) studies comprising 292 MCI and 102 AD patients contrasted to 409 age-matched control subjects. We included episodic encoding and/or retrieval phases, investigated the effects of group, verbal or image stimuli and correlated mean Mini-Mental-Status-Examination (MMSE) scores with the modelled activation estimates. MCI patients presented increased right hippocampal activation during memory encoding, decreased activation in the left hippocampus and fusiform gyrus during retrieval tasks, as well as attenuated activation in the right anterior insula/inferior frontal gyrus during verbal retrieval. In AD patients, however, stronger activation within the precuneus during encoding tasks was accompanied by attenuated right hippocampal activation during retrieval tasks. Low cognitive performance (MMSE scores) was associated with stronger activation of the precuneus and reduced activation of the right (para)hippocampus and anterior insula/inferior frontal gyrus. This meta-analysis provides evidence for a specific and probably disease stage-dependent brain activation pattern related to the pathognomonic AD characteristic of episodic memory loss.
Project description:Clinical trials in incipient and clinical Alzheimer disease (AD) often include informant-reported outcomes. Whereas informant reports in AD dementia may be modulated by the nature of participant-informant relationships, whether informant type affects reporting at earlier disease stages is less certain. We sought to determine the effects of participant-informant relationships on informant assessments of quality of life (QOL), functional abilities, and behavioral symptoms in individuals with normal cognition (NC), mild cognitive impairment (MCI), and mild-to-moderate AD dementia.Cross-sectional.Easton Center for Alzheimer Disease Research at the University of California, Los Angeles.A total of 399 individuals who met criteria for NC (N?=?100), MCI [amnestic (N?=?125) and nonamnestic (N?=?61)], and AD (N?=?113). Participants were subdivided into groups based on informant-participant relationships (spouse versus other).We examined informant effects on the Quality of Life-Alzheimer's Disease (QOL-AD) scale, the Functional Activities Questionnaire (FAQ), and the Neuropsychiatric Inventory (NPI).After adjustments for demographic and cognitive factors, spouse informants reported higher participant QOL in the amnestic MCI and AD groups than did other informants. No informant effects were seen on QOL-AD ratings in the nonamnestic MCI or NC groups or on the FAQ or NPI in the MCI and AD groups.Participant-informant relationships may modulate informant responses on subjective measures such as the QOL-AD in both incipient and clinical AD. Clinical trials that use informant measures may need to address these effects.
Project description:<h4>Background and objective</h4>Prior research with patients with mild cognitive impairment (MCI) suggests that visual versus verbal episodic memory test performance may be more sensitive to emergent illness. However, little research has examined visual versus verbal episodic memory performance as related to MCI subtypes.<h4>Research design and methods</h4>Patients were diagnosed with non-MCI, amnestic MCI (aMCI), and combined mixed/dysexecutive MCI (mixed/dys MCI). Visual and verbal episodic memory were assessed with the Brief Visuospatial Memory Test-Revised (BVMT-R) and the 12-word Philadelphia (repeatable) Verbal Learning Test (P[r]VLT), respectively.<h4>Results</h4>BVMT-R and P(r)VLT scores yielded similar between-group patterns of performance. Non-MCI patients scored better than other groups on all parameters. aMCI and mixed/dys MCI did not differ on immediate or delayed free recall. Both delayed BVMT-R and P(r)VLT recognition test performance dissociated all three groups. Logistic regression analyses found that BVMT-R delayed free recall and delayed recognition scores correctly classified more patients with MCI (75.40%) than analogous P(r)VLT scores (66.20%). Visual versus verbal memory within-group analyses found no differences among non-MCI patients; P(r)VLT immediate free recall was worse among aMCI patients, but BVMT-R immediate free recall and delayed recognition were worse among mixed/dys MCI patients.<h4>Discussion and implications</h4>Between-group analyses found convergent patterns of performance such that both tests identified elements of amnesia. However, logistic and within-group analyses found differing performance patterns suggesting that impaired visual episodic memory performance may be specific to emergent illness in mixed/dys MCI. Complementary but divergent neurocognitive networks may underlie visual versus verbal episodic memory performance in some patients with MCI.
Project description:This study (n=161) related morphometric MR imaging, FDG-PET and APOE genotype to memory scores in normal controls (NC), mild cognitive impairment (MCI) and Alzheimer's disease (AD). Stepwise regression analyses focused on morphometric and metabolic characteristics of the episodic memory network: hippocampus, entorhinal, parahippocampal, retrosplenial, posterior cingulate, precuneus, inferior parietal, and lateral orbitofrontal cortices. In NC, hippocampal metabolism predicted learning; entorhinal metabolism predicted recognition; and hippocampal metabolism predicted recall. In MCI, thickness of the entorhinal and precuneus cortices predicted learning, while parahippocampal metabolism predicted recognition. In AD, posterior cingulate cortical thickness predicted learning, while APOE genotype predicted recognition. In the total sample, hippocampal volume and metabolism, cortical thickness of the precuneus, and inferior parietal metabolism predicted learning; hippocampal volume and metabolism, parahippocampal thickness and APOE genotype predicted recognition. Imaging methods appear complementary and differentially sensitive to memory in health and disease. Medial temporal and parietal metabolism and morphometry best explained memory variance. Medial temporal characteristics were related to learning, recall and recognition, while parietal structures only predicted learning.
Project description:Hippocampal subfields have different vulnerability to the degenerative processes related to aging, amnestic mild cognitive impairment (MCI) and Alzheimer's disease (AD), but the temporal evolution in Parkinson's disease (PD) is unknown. The purposes of the current work are to describe regional hippocampal changes over time in a sample of PD patients classified according to their baseline cognitive status and to relate these changes to verbal memory loss. T1-weighted images and verbal memory assessment were obtained at two separate time points (3.8 ± 0.4 years apart) from 28 PD with normal cognition (PD-NC), 16 PD with MCI (PD-MCI) and 21 healthy controls (HCs). FreeSurfer 6.0 automated pipeline was used to segment the hippocampus into 12 bilateral subregions. Memory functions were measured with Rey's Auditory Verbal learning test (RAVLT). We found significant reductions in cornu ammonis 1 (CA1) over time in controls as well as in PD subgroups. Right whole-hippocampal volumes showed time effects in both PD groups but not in controls. PD-NC patients also displayed time effects in the left hippocampal tail and right parasubiculum. Regression analyses showed that specific hippocampal subfield volumes at time 1 predicted almost 60% of the variability in RAVLT delayed-recall score decline. Changes in several hippocampal subregions also showed predictive value for memory loss. In conclusion, CA1 changes in PD were similar to those that occur in normal aging, but PD patients also had more decline in both anterior and posterior hippocampal segments with a more pronounced atrophy of the right hemisphere. Hippocampal segments are better predictors of changes in memory performance than whole-hippocampal volumes.
Project description:BACKGROUND/OBJECTIVES:Obstructive sleep apnea (OSA) has been linked to an increased risk for Alzheimer's disease (AD), but little prospective evidence exists on the effects of OSA treatment in preclinical AD. The objective was to determine if continuous positive airway pressure (CPAP) treatment adherence, controlling for baseline differences, predicts cognitive and everyday function after 1 year in older adults with mild cognitive impairment (MCI) and to determine effect sizes for a larger trial. DESIGN:Quasi-experimental pilot clinical trial with CPAP adherence defined as CPAP use 4 hours or more per night over 1 year. SETTING:Sleep and geriatric clinics and community. PARTICIPANTS:Older adults, aged 55 to 89 years, with an apnea-hypopnea index of 10 or higher participated: (1) MCI, OSA, and CPAP adherent (MCI +CPAP), n = 29; and (2) MCI, OSA, CPAP nonadherent (MCI -CPAP), n = 25. INTERVENTION:CPAP. MEASUREMENTS:The primary cognitive outcome was memory (Hopkins Verbal Learning Test-Revised), and the secondary cognitive outcome was psychomotor/cognitive processing speed (Digit Symbol subtest from the Wechsler Adult Intelligence Scale Substitution Test). Secondary function and progression measures were the Everyday Cognition, Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Scale, and Clinical Dementia Rating. RESULTS:Statistically significant improvements in psychomotor/cognitive processing speed in the MCI +CPAP group vs the MCI -CPAP group were observed at 1 year after adjustment for age, race, and marital status (parameter estimate = 1.68; standard error = 0.47; 95% confidence interval = 0.73-2.62), with a 6-month effect size (ES) of 0.46 and a 1-year ES of 1.25. There were small to moderate ESs for memory (ES 0.20, 6 mo), attention (ES 0.25, 1 y), daytime sleepiness (ES 0.33, 6 mo and ES 0.22, 1 y), and everyday function (ES 0.50, 6 mo) favoring the MCI +CPAP group vs the MCI -CPAP group. CONCLUSION:Controlling for baseline differences, 1 year of CPAP adherence in MCI +OSA significantly improved cognition, compared with a nonadherent control group, and may slow the trajectory of cognitive decline. TRIAL REGISTRATION NUMBER:Memories; NCT01482351; https://clinicaltrials.gov/ct2/show/NCT01482351?cond=MCI+and+OSA&rank=1 J Am Geriatr Soc 67:558-564, 2019.
Project description:BACKGROUND AND PURPOSE:Mild cognitive impairment (MCI) is a condition with diverse clinical outcomes and subgroups. Here we investigated the topographic distribution of tau in vivo using the positron emission tomography (PET) tracer [¹?F]THK5351 in MCI subgroups. METHODS:This study included 96 participants comprising 38 with amnestic MCI (aMCI), 21 with nonamnestic MCI (naMCI), and 37 with normal cognition (NC) who underwent 3.0-T MRI, [¹?F]THK5351 PET, and detailed neuropsychological tests. [¹?F]flutemetamol PET was also performed in 62 participants. The aMCI patients were further divided into three groups: 1) verbal-aMCI, only verbal memory impairment; 2) visual-aMCI, only visual memory impairment; and 3) both-aMCI, both visual and verbal memory impairment. Voxel-wise statistical analysis and region-of-interest -based analyses were performed to evaluate the retention of [¹?F]THK5351 in the MCI subgroups. Subgroup analysis of amyloid-positive and -negative MCI patients was also performed. Correlations between [¹?F]THK5351 retention and different neuropsychological tests were evaluated using statistical parametric mapping analyses. RESULTS:[¹?F]THK5351 retention in the lateral temporal, mesial temporal, parietal, frontal, posterior cingulate cortices and precuneus was significantly greater in aMCI patients than in NC subjects, whereas it did not differ significantly between naMCI and NC participants. [¹?F] THK5351 retention was greater in the both-aMCI group than in the verbal-aMCI and visualaMCI groups, and greater in amyloid-positive than amyloid-negative MCI patients. The cognitive function scores were significantly correlated with cortical [¹?F]THK5351 retention. CONCLUSIONS:[¹?F]THK5351 PET might be useful for identifying distinct topographic patterns of [¹?F]THK5351 retention in subgroups of MCI patients who are at greater risk of the progression to Alzheimer's dementia.
Project description:Transactive response DNA binding protein 43 (TDP-43) is detected in pathological inclusions in many cases of Alzheimer's disease (AD) and mild cognitive impairment (MCI), but its pathological role in AD and MCI remains unknown. Recently, TDP-43 was reported to contribute to pathogenesis in amyotrophic lateral sclerosis through its interaction with p65 nuclear factor ?B (NF-?B) resulting in abnormal hyperactivation of this signaling pathway in motor neurons. Hence, we investigated the interaction of TDP-43 with p65 in the temporal cortex of subjects with a clinical diagnosis of MCI (n = 12) or AD (n = 12) as well as of age-matched controls with no cognitive impairment (NCI, n = 12).Immunoprecipitation and immunofluorescence approaches revealed a robust interaction of TDP-43 with p65 in the nucleus of temporal lobe neurons in four individuals with MCI (named MCI-p). These MCI-p cases exhibited high expression levels of soluble TDP-43, p65, phosphorylated p65 and low expression levels of ?-amyloid 40 when compared to AD or NCI cases. The analysis of cognitive performance tests showed that MCI-p individuals presented intermediate deficits of global cognition and episodic memory between those of AD cases and of NCI cases and MCI cases with no interaction of TDP-43 with p65.From these results, we propose that enhanced NF-?B activation due to TDP-43 and p65 interaction may contribute to neuronal dysfunction in MCI individuals with episodic memory deficits. Accordingly, treatment with inhibitors of NF-?B activation may be considered for MCI individuals with episodic memory deficits.
Project description:Introduction: Memory alterations are common in Parkinson's disease (PD) patients but the mechanisms involved in these deficits remain poorly understood. The study aims to explore the profile of episodic memory deficits in non-demented early PD patients. Methods: We obtained neurological, cognitive and behavioral data from 114 PD patients and 41 healthy controls (HC). PD participants were grouped as normal cognition (PD-NC) and mild cognitive impairment (PD-MCI) according to the Level II criteria of the Movement Disorders Society Task Force (MDS-TF). We evaluate the performance amongst groups on an episodic memory task using the Free and Cued Selective Reminding Test (FCSRT). Additionally, gray matter volume (GMV) voxel based morphometry, and mean diffusivity (MD) analyses were conducted in a subset of patients to explore the structural brain correlates of FCSRT performance. Results: Performance on all subscores of the FCSRT was significantly worse in PD-MCI than in PD-NC and HC. Delayed total recall (DTR) subscore was the best at differentiating PD-NC from PD-MCI. Using crosstabulation, DTR allowed identification of PD-MCI patients with an accuracy of 80%. Delayed free and cued recall was associated with decreased GMV and increased MD in multiple fronto-temporal and parietal areas. Conclusion: Encoding and retrieval deficits are a main characteristic of PD-MCI and are associated with structural damage in temporal, parietal and prefrontal areas.