Longitudinal Cognitive, Electroencephalographic and Morphological Brain Changes in Ageing and Alzheimer's Disease

BackgroundThe natural course of cognitive performance, electrophysiological alterations and brain atrophy in ageing and Alzheimer's disease (AD) has been investigated in numerous studies, but only few attempts have been made to examine the relationship between clinical, electroencephalographic (EEG) and morphological changes with quantitative methods prospectively over longer periods of time.MethodFifty-five patients with clinically diagnosed AD and 66 healthy elderly controls were examined biannually using a cognitive test (CAMCOG), EEG band power and volumetric estimates of brain atrophy.ResultsOn average cognitive performance deteriorated by 28 points on the CAMCOG in the AD group, the alpha/theta ratio decreased by 0.2, and the proportion of intracranial cerebrospinal fluid volume increased by 3.5% during a 2-year period. Similar changes were observed after a second 2-year interval. A multiple regression model demonstrated a significant influence of age on cognition and atrophy and a significant influence of the estimated duration of symptoms on cognition, alpha/theta ratio and brain atrophy at the initial examination. Cognitive performance at the first examination exerted significant effects on the performance and also on brain atrophy at re-examination after 2 or 4 years, whereas the EEG and neuroimaging findings at the previous examination were exclusively related to the corresponding findings at the follow-up examinations. In the control group no significant cognitive, EEG and morphological changes were observed after 2 and 4 years.ConclusionAfter 2 consecutive follow-up periods, we were able to verify significant deteriorations of cognition accompanied by neurophysiological and neuroradiological changes in AD, but not in normal ageing. In clinically diagnosed AD, cognitive performance at the follow-up examination could not be predicted by the previous alpha/theta ratio or by the previous degree of global brain atrophy, whereas the cognitive test score determined not only performance, but also structural findings at follow-up. Performance on cognitive tests appears to be a more sensitive indicator of the degenerative process than EEG band-power and morphological changes in manifest AD. Neuroimaging, neurophysiology and genetic risk markers may be more important for the early differential diagnosis than for the prediction of the course of illness.

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

Journal of Alzheimer s Disease ◽

10.3233/jad-210664 ◽

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.

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Functional (un-)Coupling: Impairment, Compensation, and Future Progression in Alzheimer's Disease

Clinical EEG and Neuroscience ◽

10.1177/15500594211052208 ◽

2021 ◽

pp. 155005942110522

Author(s):

Jochen A. Mosbacher ◽

Markus Waser ◽

Heinrich Garn ◽

Stephan Seiler ◽

Carmina Coronel ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Cognitive Performance ◽

Functional Coupling ◽

General Importance ◽

Coupling Mechanisms ◽

Anterior Posterior

Background: Functional (un-)coupling (task-related change of functional connectivity) between different sites of the brain is a mechanism of general importance for cognitive processes. In Alzheimer's disease (AD), prior research identified diminished cortical connectivity as a hallmark of the disease. However, little is known about the relation between the amount of functional (un-)coupling and cognitive performance and decline in AD. Method: Cognitive performance (based on CERAD-Plus scores) and electroencephalogram (EEG)-based functional (un-)coupling measures (connectivity changes from rest to a Face-Name-Encoding task) were assessed in 135 AD patients (age: M = 73.8 years; SD = 9.0). Of these, 68 patients ( M = 73.9 years; SD = 8.9) participated in a follow-up assessment of their cognitive performance 1.5 years later. Results: The amounts of functional (un-)coupling in left anterior-posterior and homotopic interhemispheric connections in beta1-band were related to cognitive performance at baseline (β = .340; p < .001; β = .274; P = .001, respectively). For both markers, a higher amount of functional coupling was associated with better cognitive performance. Both markers also were significant predictors for cognitive decline. However, while patients with greater functional coupling in left anterior-posterior connections declined less in cognitive performance (β = .329; P = .035) those with greater functional coupling in interhemispheric connections declined more (β = −.402; P = .010). Conclusion: These findings suggest an important role of functional coupling mechanisms in left anterior–posterior and interhemispheric connections in AD. Especially the complex relationship with cognitive decline in AD patients might be an interesting aspect for future studies.

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Synergistic Effects of APOE and CLU May Increase the Risk of Alzheimer’s Disease: Acceleration of Atrophy in the Volumes and Shapes of the Hippocampus and Amygdala

Journal of Alzheimer s Disease ◽

10.3233/jad-201162 ◽

2021 ◽

Vol 80 (3) ◽

pp. 1311-1327

Author(s):

Na An ◽

Yu Fu ◽

Jie Shi ◽

Han-Ning Guo ◽

Zheng-Wu Yang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Morphological Changes ◽

Synergistic Effects ◽

Combined Effects ◽

Individual Effects ◽

The Individual ◽

Neuroimaging Genetics ◽

Surface Based Morphometry

Background: The volume loss of the hippocampus and amygdala in non-demented individuals has been reported to increase the risk of developing Alzheimer’s disease (AD). Many neuroimaging genetics studies mainly focused on the individual effects of APOE and CLU on neuroimaging to understand their neural mechanisms, whereas their synergistic effects have been rarely studied. Objective: To assess whether APOE and CLU have synergetic effects, we investigated the epistatic interaction and combined effects of the two genetic variants on morphological degeneration of hippocampus and amygdala in the non-demented elderly at baseline and 2-year follow-up. Methods: Besides the widely-used volume indicator, the surface-based morphometry method was also adopted in this study to evaluate shape alterations. Results: Our results showed a synergistic effect of homozygosity for the CLU risk allele C in rs11136000 and APOE ɛ4 on the hippocampal and amygdalar volumes during a 2-year follow-up. Moreover, the combined effects of APOE ɛ4 and CLU C were stronger than either of the individual effects in the atrophy progress of the amygdala. Conclusion: These findings indicate that brain morphological changes are caused by more than one gene variant, which may help us to better understand the complex endogenous mechanism of AD.

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045 Associations of Actigraphic Sleep and Circadian Rest/Activity Rhythms with Cognition in the Early Phase of Alzheimer’s Disease

SLEEP ◽

10.1093/sleep/zsab072.044 ◽

2021 ◽

Vol 44 (Supplement_2) ◽

pp. A19-A20

Author(s):

Alfonso Alfini ◽

Marilyn Albert ◽

Andreia Faria ◽

Anja Soldan ◽

Corinne Pettigrew ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Executive Function ◽

Episodic Memory ◽

Cognitive Performance ◽

Cognitive Test ◽

Activity Rhythms ◽

Combining Data ◽

Normal Cognition ◽

Rest Activity

Abstract Introduction Alterations in sleep and circadian rhythms are common in persons with Alzheimer’s disease (AD) dementia, but the nature of such changes in the early phases of AD remains unclear. This study compared sleep and circadian rest/activity rhythms (RARs), measured by standard and novel actigraphic indices, between participants with normal cognition or mild cognitive impairment (MCI), and examined cross-sectional associations between these measures and cognition. Methods Actigraphy data were collected in 179 individuals (mean age=72.6 years, gender=64.8% female) with normal cognition (n=153) or MCI (n=26) from the Biomarkers for Older Controls at Risk of Dementia (BIOCARD) study. Standard sleep parameters (i.e., total sleep time [TST], sleep efficiency [SE], wake after sleep onset [WASO], average wake bout length [WBL]), and standard non-parametric RAR metrics (i.e., relative amplitude [RA], intradaily variability [IV], interdaily stability [IS]) were generated. Functional principal component (fPC) methods were used to generate three novel RAR indices (fPC1, fPC2, fPC3) representing 69% of the total variance. Cognitive test scores were used to generate composite measures reflecting the domains of episodic memory and executive function using factor analysis. Regression models were used to compare sleep and circadian RAR parameters between the diagnostic groups and to evaluate their associations with cognitive performance. Results After adjustment for age, sex, education, and APOE-4 genotype, compared to normal controls, MCI subjects had significantly lower SE, lower RA, and lower scores on the novel RAR measure fPC3, which reflects a later rhythm phase, lower amplitude, and lower activity both at night and early in the day. In analyses combining data from participants with MCI and controls, several standard RAR parameters (e.g., higher RA and IS) and higher fPC3 scores were associated with both better episodic memory and executive function. Additionally, several standard measures (e.g., lower WASO and IV) and lower fPC1 scores (reflecting higher rhythm amplitude and greater activity throughout daytime hours) were linked with better executive function. Conclusion MCI participants have sleep and circadian alterations, which are significantly associated with cognitive performance. A novel RAR measure, fPC3, showed differences in rhythm patterns that extended from the night into the daytime. Support (if any) Funding-support NIA (U19-AG033655, T32-AG027668, R01-AG050507) and AASMF (#223-BS-19).

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The Interplay of Diet Quality and Alzheimer’s Disease Genetic Risk Score in Relation to Cognitive Performance Among Urban African Americans

Nutrients ◽

10.3390/nu11092181 ◽

2019 ◽

Vol 11 (9) ◽

pp. 2181 ◽

Cited By ~ 2

Author(s):

Sharmin Hossain ◽

May A. Beydoun ◽

Marie F Kuczmarski ◽

Salman Tajuddin ◽

Michele K Evans ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Performance ◽

Risk Score ◽

Diet Quality ◽

Genetic Risk ◽

Verbal Fluency ◽

Genetic Risk Score ◽

Healthy Eating Index ◽

Cognitive Test

We examined the interactive associations of poor diet quality and Alzheimer’s Disease (AD) genetic risk with cognitive performance among 304 African American adults (mean age~57 years) from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. In this cross-sectional study, selected participants had complete predictors and covariate data with 13 cognitive test scores as outcomes. Healthy Eating Index-2010 (HEI-2010), Dietary Approaches to Stop Hypertension (DASH), and mean adequacy ratio (MAR) were measured. A genetic risk score for AD in HANDLS (hAlzScore) was computed from 12 selected single nucleotide polymorphisms (SNPs). Our key hypotheses were tested using linear regression models. The hAlzScore was directly associated with poor performance in verbal memory (−0.4 ± 0.2, 0.01) and immediate visual memory (0.4 ± 0.2, 0.03) measured in seconds, in women only. The hAlzScore interacted synergistically with poorer diet quality to determine lower cognitive performance on a test of verbal fluency. Among numerous SNP × diet quality interactions for models of cognitive performance as outcomes, only one passed correction for multiple testing, namely verbal fluency. Our results suggest that improved diet quality can potentially modify performance on cognitive tests of verbal fluency among individuals with higher AD genetic risk.

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Neuropsychiatric, cognitive and brain morphology characteristics of conversion from Mild Cognitive Impairment to Alzheimer’s Disease

10.1101/2021.12.01.21267124 ◽

2021 ◽

Author(s):

Ronat Lucas ◽

Hanganu Alexandru ◽

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Cognitive Performance ◽

Brain Structures ◽

Analysis Of Covariance ◽

Brain Morphology ◽

The Impact

AbstractThe impact of neuropsychiatric symptoms (NPS) on cognitive performance has been extensively reported, and this impact was better defined in the aging population. Yet a potential impact of NPS on brain morphology, cognitive performance and interactions between them in a longitudinal setting, as well as the potential of using these values as prediction of conversion – have remained questionable. We studied 156 participants with mild cognitive impairment (MCI) from the Alzheimer’s Disease Neuroimaging Initiative database who maintained the same level of cognitive performance after a 4-year follow-up and compared them to 119 MCI participants who converted to dementia. Additionally, we assessed the same analysis in 170 healthy controls who remained healthy at follow-up. Compared to 15 controls who converted to MCI. Their neuropsychological, neuropsychiatric, and brain morphology data underwent statistical analyses of 1) baseline comparison between the groups; (2) analysis of covariance model controlling for age, sex, education, and MMSE score, to specify the cognitive performance and brain structures that distinguish the two subgroups, and 3) used the significant ANCOVA variables to construct a binary logistic regression model that generates a probability equation for a given individual to convert to a lower cognitive performance state.Results showed that MCI who converted to AD in comparison to those who did not convert, exhibited a higher NPS prevalence, a lower cognitive performance and a higher number of involved brain structures. Furthermore, agitation, memory and the volumes of inferior temporal, hippocampal and amygdala sizes were significant predictors of MCI to AD conversion.

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THE ASPREE STUDY: DEMENTIA DUE TO ALZHEIMER’S DISEASE OUTCOMES

Innovation in Aging ◽

10.1093/geroni/igz038.2359 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S633-S633

Author(s):

Raj C Shah

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Community Dwelling ◽

Cognitive Test ◽

Secondary Outcome ◽

International Panel ◽

Incident Dementia ◽

Low Dose Aspirin ◽

Dsm Iv

Abstract In the ASPREE clinical trial, aspirin 100mg daily in health older adults did not delay onset of dementia, a pre-specified secondary outcome over a period of 5 years. We examine whether low-dose aspirin versus placebo is related to incident dementia due to Alzheimer’s disease. Older community-dwelling participants free of dementia, physical disability, and conditions requiring aspirin treatment were recruited (n=19,114). Participants were administered a cognitive test battery during follow-up and participants with suspected dementia underwent a more extensive dementia assessment. An expert international panel adjudicated dementia according to DSM-IV criteria, with sub-classification according to NIA-AA criteria. Over a median 4.7 years, 575 participants had a confirmed dementia diagnosis. In analysis of the 41% of cases classified as dementia probably due to Alzheimer’s disease, no difference in the incidence between the treatment arms was found (HR=0.96, 95% CI =0.74, 1.24). Plans for continued assessment of cognition in ASPREE-XT will be presented.

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Apolipoprotein E ɛ4–related effects on cognition are limited to the Alzheimer’s disease spectrum

GeroScience ◽

10.1007/s11357-021-00450-x ◽

2021 ◽

Author(s):

Alberto Fernández ◽

Lucía Vaquero ◽

Ricardo Bajo ◽

Pilar Zuluaga ◽

Michael W. Weiner ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Performance ◽

Strong Support ◽

Positive Sample ◽

Amyloid Pet ◽

Neurodegenerative Process ◽

Disease Spectrum ◽

Healthy Carriers

Abstract Whether the deleterious effects of APOE4 are restricted to the Alzheimer’s disease (AD) spectrum or cause cognitive impairment irrespectively of the development of AD is still a matter of debate, and the focus of this study. Our analyses included APOE4 genotype, neuropsychological variables, amyloid-βeta (Aβ) and Tau markers, FDG-PET values, and hippocampal volumetry data derived from the healthy controls sample of the ADNI database. We formed 4 groups of equal size (n = 30) based on APOE4 carriage and amyloid-PET status. Baseline and follow-up (i.e., 48 months post-baseline) results indicated that Aβ-positivity was the most important factor to explain poorer cognitive performance, while APOE4 only exerted a significant effect in Aβ-positive subjects. Additionally, multiple regression analyses evidenced that, within the Aβ-positive sample, hippocampal volumetry explained most of the variability in cognitive performance for APOE4 carriers. These findings represent a strong support for the so-called preclinical/prodromal hypothesis, which states that the reported differences in cognitive performance between healthy carriers and non-carriers are mainly due to the APOE4’s capability to increase the risk of AD. Moreover, our results reinforce the notion that a synergistic interaction of Aβ and APOE4 elicits a neurodegenerative process in the hippocampus that might be the main cause of impaired cognitive performance.

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Quality, and not Just Quantity, of Education Accounts for Differences in Psychometric Performance between African Americans and White Non-Hispanics with Alzheimer's Disease

Journal of the International Neuropsychological Society ◽

10.1017/s1355617711001688 ◽

2012 ◽

Vol 18 (2) ◽

pp. 277-285 ◽

Cited By ~ 18

Author(s):

Alexander L. Chin ◽

Selam Negash ◽

Sharon Xie ◽

Steven E. Arnold ◽

Roy Hamilton

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

African Americans ◽

Cognitive Performance ◽

Test Performance ◽

Cognitive Test ◽

Quality Of Education ◽

Cognitive Test Performance ◽

Quantity Of Education

AbstractThe effect of race on cognitive test performance in the evaluation of Alzheimer's disease (AD) remains controversial. One factor that may contribute substantially to differences in cognitive test performance in diverse populations is education. The current study examined the extent to which quality of education, even after controlling for formal years of education, accounts for differences in cognitive performance between African Americans and White Non-Hispanics (WNHs). The retrospective cohort included 244 patients diagnosed with AD who self-identified as African Americans (n= 51) or WNHs (n= 193). The Wechsler Test of Adult Reading (WTAR) was used as an estimate of quality of education. In an analysis that controlled for traditional demographics, including age, sex, and years of formal education, African Americans scored significantly lower than WNHs on the Mini-Mental State Examination, as well as on neuropsychological tests of memory, attention, and language. However, after also adjusting for reading level, all previously observed differences were significantly attenuated. The attenuating effect remained even after controlling for disease severity, indicating that reading scores are not confounded by severity of dementia. These findings suggest that quality, and not just quantity, of education needs to be taken into account when assessing cognitive performance in African Americans with AD. (JINS, 2012,18, 277–285)

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Longitudinal Changes in Individual BrainAGE in Healthy Aging, Mild Cognitive Impairment, and Alzheimer’s Disease

GeroPsych ◽

10.1024/1662-9647/a000074 ◽

2012 ◽

Vol 25 (4) ◽

pp. 235-245 ◽

Cited By ~ 64

Author(s):

Katja Franke ◽

Christian Gaser

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Healthy Aging ◽

Brain Aging ◽

Elderly Subjects ◽

Additional Increase ◽

Longitudinal Changes ◽

Novel Method ◽

The Brain

We recently proposed a novel method that aggregates the multidimensional aging pattern across the brain to a single value. This method proved to provide stable and reliable estimates of brain aging – even across different scanners. While investigating longitudinal changes in BrainAGE in about 400 elderly subjects, we discovered that patients with Alzheimer’s disease and subjects who had converted to AD within 3 years showed accelerated brain atrophy by +6 years at baseline. An additional increase in BrainAGE accumulated to a score of about +9 years during follow-up. Accelerated brain aging was related to prospective cognitive decline and disease severity. In conclusion, the BrainAGE framework indicates discrepancies in brain aging and could thus serve as an indicator for cognitive functioning in the future.

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