The interactive effect of demographic and clinical factors on hippocampal volume: A multicohort study on 1958 cognitively normal individuals.

Alzheimer's disease is characterized by hippocampal atrophy. Other factors also influence the hippocampal volume, but their interactive effect has not been investigated before in cognitively healthy individuals. The aim of this study is to evaluate the interactive effect of key demographic and clinical factors on hippocampal volume, in contrast to previous studies frequently investigating these factors in a separate manner. Also, to investigate how comparable the control groups from ADNI, AIBL, and AddNeuroMed are with five population-based cohorts. In this study, 1958 participants were included (100 AddNeuroMed, 226 ADNI, 155 AIBL, 59 BRC, 295 GENIC, 279 BioFiNDER, 398 PIVUS, and 446 SNAC-K). ANOVA and random forest were used for testing between-cohort differences in demographic-clinical variables. Multiple regression was used to study the influence of demographic-clinical variables on hippocampal volume. ANCOVA was used to analyze whether between-cohort differences in demographic-clinical variables explained between-cohort differences in hippocampal volume. Age and global brain atrophy were the most important variables in explaining variability in hippocampal volume. These variables were not only important themselves but also in interaction with gender, education, MMSE, and total intracranial volume. AddNeuroMed, ADNI, and AIBL differed from the population-based cohorts in several demographic-clinical variables that had a significant effect on hippocampal volume. Variability in hippocampal volume in individuals with normal cognition is high. Differences that previously tended to be related to disease mechanisms could also be partly explained by demographic and clinical factors independent from the disease. Furthermore, cognitively normal individuals especially from ADNI and AIBL are not representative of the general population. These findings may have important implications for future research and clinical trials, translating imaging biomarkers to the general population, and validating current diagnostic criteria for Alzheimer's disease and predementia stages.

The block design subtest of the Wechsler adult intelligence scale as a possible non-verbal proxy of cognitive reserve.

Objectives: To investigate the potential of the Block design subtest of the Wechsler Adults Intelligence Scale as a non-verbal proxy of cognitive reserve. Method: A total of 391 cognitively unimpaired participants were included in this study. The association between the Block design subtest and the Information subtest (an established verbal proxy of cognitive reserve) from the WAIS, as well as the association of the two subtests with a Cognitive Reserve Questionnaire (CRQ) were tested. In addition, multiple linear regression models were conducted to investigate the association of the Block design and Information subtests with cognitive performance. The capacity of the Block design subtest to minimize the negative effect of an older age over cognitive performance was also assessed and this effect was compared with that of the Information subtest. The four cognitive domains included were: verbal memory, visual-visuospatial memory, executive-premotor functions and processing speed. Results: The Block design subtest correlated positively with both the Information subtest and the CRQ. A statistically significant association was observed between the Block design subtest and all four cognitive domains. Higher scores in the Block design subtest minimized the negative effect of aging on the cognitive domains of visual-visuospatial memory and executive-premotor functions, in a similar way to the results obtained for the Information subtest. Conclusion: The Block design subtest is significantly correlated with two established proxies of cognitive reserve: it correlates with cognitive performance and high scores in Block design have the capacity to minimize the negative effect of an older age on cognitive performance. Therefore, the results suggest that the corrected Block design subtest could be considered as a non-verbal proxy of cognitive reserve.

The interplay between gray matter and white matter neurodegeneration in subjective cognitive decline.

AIMS: To investigate the interplay between gray matter (GM) and white matter (WM) neurodegeneration in subjective cognitive decline (SCD), including thickness across the whole cortical mantle, hippocampal volume, and integrity across the whole WM. METHODS: We included 225 cognitively unimpaired individuals from a community-based cohort. Subjective cognitive complaints were assessed through 9 questions covering amnestic and non-amnestic cognitive domains. In our cohort, 123 individuals endorsed from one to six subjective cognitive complaints (i.e. they fulfilled the diagnostic criteria for SCD), while 102 individuals reported zero complaints. GM neurodegeneration was assessed through measures of cortical thickness across the whole mantle and hippocampal volume. WM neurodegeneration was assessed through measures of mean diffusivity (MD) across the whole WM skeleton. Mediation analysis and multiple linear regression were conducted to investigate the interplay between the measures of GM and WM neurodegeneration. RESULTS: A higher number of complaints was associated with reduced hippocampal volume, cortical thinning in several frontal and temporal areas and the insula, and higher MD across the WM skeleton, with a tendency to spare the occipital lobe. SCD-related cortical thinning and increased MD were associated with each other and jointly contributed to complaints, but the contribution of cortical thinning to the number of complaints was stronger. CONCLUSIONS: Neurodegeneration processes affecting the GM and WM seem to be associated with each other in SCD and include brain areas other than those typically targeted by Alzheimer's disease. Our findings suggest that SCD may be a sensitive behavioral marker of heterogeneous brain pathologies in individuals recruited from the community.

Subjective Cognitive Decline Below and Above the Age of 60: A Multivariate Study on Neuroimaging, Cognitive, Clinical, and Demographic Measures.

Subjective cognitive complaints in cognitively normal individuals are a relevant predictor of Alzheimer's disease (AD), cerebrovascular disease, and age-related tauopathy. Complaints starting after the age of 60 increase the likelihood of preclinical AD. However, this criterion is arbitrary and current data show that neurodegenerative disorders likely start before that age. Further, data on the role of subjective complaints below the age of 60 in individuals qualifying for subjective cognitive decline (SCD) are lacking. We investigated the association of subjective cognitive complaints with an extensive number of neuroimaging, demographic, clinical, and cognitive measures in individuals fulfilling criteria for SCD below and above the age of 60. Nine complaints were scored in 416 individuals. Complaints were related to a higher load of white matter signal abnormalities, and this association was stronger the more subclinical changes in personality, interest, and drive were reported. In individuals <60 years, complaints were associated with lower global cognitive performance. In individuals ≥60 years, complaints were related to greater global brain atrophy and smaller total intracranial volume, and this association was stronger the more subclinical difficulties in activities of daily living were reported. Also, complaints were associated with increased depressive symptomatology irrespective of age. We conclude that complaints below the age of 60 may be associated with subtle signs of brain pathology. In the community, screening for risk of future cognitive decline should include subjective cognitive complaints, depressive symptomatology, and subclinical reduced cognition (<60 years)/activities of daily living (≥60 years), supported by basic neuroimaging examinations.

Proposal for a hierarchical, multidimensional, and multivariate approach to investigate cognitive aging.

Cognitive aging is highly complex. We applied a data-driven statistical method to investigate aging from a hierarchical, multidimensional, and multivariate approach. Orthogonal partial least squares to latent structures and hierarchical models were applied for the first time in a study of cognitive aging. The association between age and a total of 316 demographic, clinical, cognitive, and neuroimaging measures was simultaneously analyzed in 460 cognitively normal individuals (35-85 years). Age showed a strong association with brain structure, especially with cortical thickness in frontal and parietal association regions. Age also showed a fairly strong association with cognition. Although a strong association of age with executive functions and processing speed was captured as expected, the association of age with visual memory was stronger. Clinical measures were less strongly associated with age. Hierarchical and correlation analyses further showed these associations in a neuroimaging-cognitive-clinical order of importance. We conclude that orthogonal partial least square and hierarchical models are a promising approach to better understand the complexity in cognitive aging.

Cognitive Variability during Middle-Age: Possible Association with Neurodegeneration and Cognitive Reserve.

Objective: Increased variability in cognition with age has been argued as an indication of pathological processes. Focusing on early detection of neurodegenerative disorders, we investigated variability in cognition in healthy middle-aged adults. In order to understand possible determinants of this variability, we also investigated associations with cognitive reserve, neuroimaging markers, subjective memory complaints, depressive symptomatology, and gender. Method: Thirty-one 50 ± 2 years old individuals were investigated as target group and deviation was studied in comparison to a reference younger group of 30 individuals 40 ± 2 years old. Comprehensive neuropsychological and structural imaging protocols were collected. Brain regional volumes and cortical thickness were calculated with FreeSurfer, white matter hyperintensities with CASCADE, and mean diffusivity with FSL. Results: Across-individuals variability showed greater dispersion in lexical access, processing speed, executive functions, and memory. Variability in global cognition correlated with, reduced cortical thickness in the right parietal-temporal-occipital association cortex, and increased mean diffusivity in the cingulum bundle and right inferior fronto-occipital fasciculus. A trend was also observed for the correlation between global cognition and hippocampal volume and female gender. All these associations were influenced by cognitive reserve. No correlations were found with subjective memory complaints, white matter hyperintensities and depressive symptomatology. Across-domains and across-tasks variability was greater in several executive components and cognitive processing speed. Conclusion: Variability in cognition during middle-age is associated with neurodegeneration in the parietal-temporal-occipital association cortex and white matter tracts connecting this to the prefrontal dorsolateral cortex and the hippocampus. Moreover, this effect is influenced by cognitive reserve. Studying variability offers valuable information showing that differences do not occur in the same magnitude and direction across individuals, cognitive domains and tasks. These findings may have important implications for early detection of subtle cognitive impairment and clinical interpretation of deviation from normality.

Different reserve proxies confer overlapping and unique endurance to cortical thinning in healthy middle-aged adults.

AIM: To investigate different proxies of brain and cognitive reserve as potential mediators of the effect of cortical thinning on cognition in healthy middle-aged adults. METHODS: Eighty-two middle-aged individuals were included (mean(SD) age=45.1(3.9)years). Cortical thickness was calculated for multiple brain regions using FreeSurfer. Cognitive measures sensitive to early cognitive decline were selected, including Block Design from the Wechsler Adult Intelligence Scale-III (WAIS-III), Judgment of Line Orientation Test (JLOT), Color Trails Test (CTT), and first learning trial of TAVEC (the Spanish version of the California Verbal Learning Test, CVLT). Brain reserve was operationalized as total intracranial volume (TIV); and cognitive reserve was estimated by means of Years of Education, WAIS-III Vocabulary subtest, WAIS-III Information subtest, and a Cognitive Reserve Questionnaire (CRQ). Mediation effects were investigated with multiple linear regression and bootstrapping analysis. RESULTS: Information and Vocabulary showed the greatest mediation capacity. All the observed mediations were positive indicating that higher levels of reserve attenuate the effect of reduced cortical thickness on cognition. Information, Vocabulary and TIV buffered the effect of frontal thinning on Block Design; Vocabulary and Years of Education buffered the effect of frontal thinning on JLOT; and CRQ buffered the effect of temporal thinning on CTT. CONCLUSION: Higher reserve buffers the effect of cortical thinning on cognition in healthy middle-aged adults. The investigated proxies might be underpinned by slightly different neural networks. Advancing in the understanding of the influences of reserve in healthy middle-aged adults is crucial to facilitate early interventions.

Increased Spontaneous Central Bleeding and Cognition Impairment in APP/PS1 Mice with Poorly Controlled Diabetes Mellitus.

Alzheimer's disease (AD) and vascular dementia (VaD) are the most common causes of dementia, and borderlines are blurred in many cases. Aging remains the main risk factor to suffer dementia; however, epidemiological studies reveal that diabetes may also predispose to suffer AD. In order to further study this relationship, we have induced hypoinsulinemic diabetes to APPswe/PS1dE9 (APP/PS1) mice, a classical model of AD. APP/PS1 mice received streptozotocin (STZ) ip at 18 weeks of age, when AD pathology is not yet established in this animal model. Cognition was evaluated at 26 weeks of age in the Morris water maze and the new object discrimination tests. We observed that STZ-induced episodic and working memory impairment was significantly worsened in APP/PS1 mice. Postmortem assessment included brain atrophy, amyloid-beta and tau pathology, spontaneous bleeding, and increased central inflammation. Interestingly, in APP/PS1-STZ diabetic mice, we detected a shift in Aß soluble/insoluble levels, towards more toxic soluble species. Phospho-tau levels were also increased in APP/PS1-STZ mice, accompanied by an exacerbated inflammatory process, both in the close proximity to senile plaque (SP) and in SP-free areas. The presence of hemorrhages was significantly higher in APP/PS1-STZ mice, and although pericytes and endothelium were only partially affected, it remains possible that blood-brain barrier alterations underlie observed pathological features. Our data support the implication of the diabetic process in AD and VaD, and it is feasible that improving metabolic control could delay observed central pathology.

Cognitive decline before the age of 50 can be detected with sensitive cognitive measures.

BACKGROUND: To define the profile of age-related differences in cognition in healthy middle-aged adults in order to identify the most sensitive measures of early cognitive decline. To study whether these differences precede cognitive decline in the elderly. METHOD: 141 cognitively normal participants (101 middle-aged adults with age 40-50±2; and 40 elderly individuals with age 65±2) were assessed with a comprehensive neuropsychological protocol covering processing speed, attention, executive functions, verbal and visual episodic memory, procedural memory, visuoconstructive, visuoperceptive and visuospatial functions, and language. RESULTS: Age-related differences were detected before the age of 50 in cognitive reaction time, executive control, initial learning in verbal episodic memory, complex visuoconstructive and visuospatial functions, and lexical access. These differences preceded more extensive cognitive decline present at the age of 65. CONCLUSIONS: Our findings suggest subtle executive dysfunction before the age of 50, together with slowing in processing speed later on in the transition to old age. This profile could be explained by changes in the frontal lobe and its connections, starting at middle-age. These findings, together with future research, may be important for the diagnosis, prognosis, and prevention of pathological aging at a very early level.

Cognitive decline is mediated by gray matter changes during middle age.

The present theoretical framework of Alzheimer's disease proposes that pathophysiological changes occur 10-20 years before the diagnosis of dementia. We addressed the question of how age-related changes in gray matter mediate the cognitive performance during middle age. Eighty-two participants (40-50 years, ±2) were assessed with a comprehensive neuropsychological battery covering a broad spectrum of cognitive domains and components. Mediation effects were studied with hierarchical regression and bootstrapping analysis. Results showed that more vulnerable cognitive components were related to executive functioning and in a lesser degree to processing speed. Age-related differences in gray matter mainly involved the frontal lobes. Moreover, age-related differences in visuoconstructive, visuospatial functions, reaction time, and mental flexibility and executive control were mediated by several gray matter regions. It is important to increase the knowledge of the impact of brain changes on cognitive function during middle age. To define the early stages of the aging process may allow early detection of pathologic changes and therapeutic interventions.