Brain Reserve Capacity Research Articles

Dopaminergic mesolimbic structural reserve is positively linked to better outcome after severe stroke.

The concept of brain reserve capacity has emerged in stroke recovery research in recent years. Imaging-based biomarkers of brain health have helped to better understand outcome variability in clinical cohorts. Still, outcome inferences are far from being satisfactory, particularly in patients with severe initial deficits. Neurorehabilitation after stroke is a complex process, comprising adaption and learning processes, which, on their part, are critically influenced by motivational and reward-related cognitive processes. Amongst others, dopaminergic neurotransmission is a key contributor to these mechanisms. The question arises, whether the amount of structural reserve capacity in the dopaminergic system might inform about outcome variability after severe stroke. For this purpose, this study analysed imaging and clinical data of 42 severely impaired acute stroke patients. Brain volumetry was performed within the first 2 weeks after the event using the Computational Anatomy Toolbox CAT12, grey matter volume estimates were collected for seven key areas of the human dopaminergic system along the mesocortical, mesolimbic and nigrostriatal pathways. Ordinal logistic regression models related regional volumes to the functional outcome, operationalized by the modified Rankin Scale, obtained 3-6 months after stroke. Models were adjusted for age, lesion volume and initial impairment. The main finding was that larger volumes of the amygdala and the nucleus accumbens at baseline were positively associated with a more favourable outcome. These data suggest a link between the structural state of mesolimbic key areas contributing to motor learning, motivational and reward-related brain networks and potentially the success of neurorehabilitation. They might also provide novel evidence to reconsider dopaminergic interventions particularly in severely impaired stroke patients to enhance recovery after stroke.

Subcortical volumes and cognition in CADASIL – A pilot study

BackgroundCerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) represents the most common heritable cause of vascular dementia. Subcortical volumes might be proxies of brain reserve capacity and reflective of cognitive function. We explored the impact of subcortical volumes on cognition in CADASIL patients. MethodsWe included 90 patients with pathogenic NOTCH3 variants from the Taiwan Associated Genetic and Nongenetic Small Vessel Disease cohort. They underwent MRI sessions at baseline. The volumes of the putamen, caudate, pallidum, thalamus, cerebellum, cortical gray matter and brain parenchymal fraction (BPF) were calculated by using FreeSurfer. We tested the association of the subcortical volumes, cortical gray matter volume and BPF with scores of the Mini-mental state examination (MMSE), cognitive domains, and the diagnosis of vascular cognitive impairment (VCI) which was defined as MMSE score <24. ResultsThe thalamus and putamen were consistently associated with the MMSE (thalamus adjusted beta per SD decrement -1.41 [95 % CI -2.68–(-0.14)], p = 0.03; R²=0.25; putamen -1.93 [95 % CI -2.99–(-0.86)], p < 0.001; R²=0.36) and VCI (thalamus OR per SD-decrement 3.66 [95 % CI 1.38–9.72], p = 0.009), putamen (OR 3.06 [95 % CI 1.21–7.73], p = 0.02). A larger thalamus volume was also associated with better executive function and visuospatial perception. The cortical gray matter volume and the BPF showed associations with various cognitive outcomes in all analyses. ConclusionAlthough cortical gray matter volume and the BPF still appear to be robust markers of cognitive performance in CADASIL, the volumes of the thalamus and the putamen might also be promising regions of interest for future research.

NCOG-21. TESTING AND VALIDATION OF A DIFFUSE GLIOMA COGNITIVE RESERVE MODEL

Abstract Behavioral and cognitive symptom severity varies widely across patients with glioma because of unknown mechanisms. The concept of cognitive reserve (CR) recognizes that there are individual differences in each person’s brain reserve capacity and this theory accounts for the common disconnection between the degree of brain injury and its symptom manifestations. CR is a fixed variable throughout an individual’s life and works by recruitment of dormant yet redundant neural networks, and by efficient information modulation. New strategies to treat cognitive impairments have been encumbered by a lack of models that accurately reflect human disease. Here, we measure the Cognitive Reserve Index (CRI) in a registry of 450 patients with WHO grade 2-4 glioma. Transient behavioral impairments were induced by anesthetic medications propofol, dexmedetomidine, and remifentanil during standard of clinical care. We administered and analyzed 48 picture naming (PN) and 32 auditory stimulus naming (AN) trials per patient both before and after drug administration with impairments defined as a decline in task performance by more than one standard deviation from the mean. We discovered that the CRI in patients with glioma follows a normal distribution, like the general US population. Next, we found a significant decline in task performance in a subgroup of patients in both PN and AN. Electrode arrays in vivo to record human local field potentials from glioma infiltrated cortex demonstrated electrophysiological biomarkers of cognitive decline. Further elucidation and validation of CR measures in patients may significantly influence the delivery and timing of cancer directed therapies.

A-7 Extending the Quantified Process Approach - Application of Nonlinear Models Toward the Understanding of Neurocognitive Decline Across the Lifespan

Abstract Objective: In this presentation, I will extend the Reliability Theory of Cognitive Decline and examine the emergence of infrequent errors on neurocognitive tests following cognitive decline or brain insult. Data Selection: Unpublished, meta norms (Figure 1), data published by Poreh (2020) (Figure 2), and cognitive/genetic data collected by the National Alzheimer’s Coordinating Center (NACC) will be used to illustrate the validity and utility of the model. Data Synthesis: Nonlinear models will be presented to show how performance on various neuropsychological tests declines across the life span and how the threshold and rate of decline are impacted by education and genetics (Figures 3a and 3b). Next, a new theoretical model will be used to explain how task-specific neurocognitive systems (neural networks) fail. The “time to failure” curve-fitting hazard model (Figure 4) will be used to illustrate how this process occurs and how this method can be applied to the development of age-based norms for such errors on neuropsychological tests. Conclusions: This cohesive empirical model extends on the Quantified Process Approach using cross-sectional and longitudinal neuropsychological data. This model allows clinicians to understand the effect of education on cognition decline (also known as “brain reserve capacity”), genetic predisposition, and heuristic biases regarding cognitive aging.

Structural cerebellar reserve positively influences outcome after severe stroke.

The concept of brain reserve capacity positively influencing the process of recovery after stroke has been continuously developed in recent years. Global measures of brain health have been linked with a favourable outcome. Numerous studies have evidenced that the cerebellum is involved in recovery after stroke. However, it remains an open question whether characteristics of cerebellar anatomy, quantified directly after stroke, might have an impact on subsequent outcome after stroke. Thirty-nine first-ever ischaemic non-cerebellar stroke patients underwent MRI brain imaging early after stroke and longitudinal clinical follow-up. Structural images were used for volumetric analyses of distinct cerebellar regions. Ordinal logistic regression analyses were conducted to associate cerebellar volumes with functional outcome 3-6 months after stroke, operationalized by the modified Rankin Scale. Larger volumes of cerebellar lobules IV, VI, and VIIIB were positively correlated with favourable outcome, independent of the severity of initial impairment, age, and lesion volume (P < 0.01). The total cerebellar volume did not exhibit a significant structure-outcome association. The present study reveals that pre-stroke anatomy of distinct cerebellar lobules involved in motor and cognitive functioning might be linked to outcome after acute non-cerebellar stroke, thereby promoting the emerging concepts of structural brain reserve for recovery processes after stroke.

Are Brain and Cognitive Reserve Shaped by Early Life Circumstances?

When growing older, many people are faced with cognitive deterioration, which may even amount to a form of dementia at some point in time. Although neuropathological signs of dementia disorders can often be demonstrated in brains of patients, the degree to which clinical symptoms are present does mostly not accurately reflect the amount of neuropathology that is present. Sometimes existent pathology even goes without any obvious clinical presentation. An explanation for this phenomenon may be found in the concept of reserve capacity. Reserve capacity refers to the ability of the brain to effectively buffer changes that are associated with normal aging processes and to cope with pathological damage. A larger reserve capacity has been suggested to increase resilience against age-associated cognitive deterioration and dementia disorders. Traditionally, a division has been made between brain reserve, which is based on morphological characteristics of the brain, and cognitive reserve, which is based on functional characteristics of the brain. The present review discusses the premises that brain and cognitive reserve capacity are shaped by prenatal and early postnatal factors. Evidence is accumulating that circumstances during the first 1,000 days of life are of the utmost importance for the lifelong health of an individual. Cognitive deterioration and dementia disorders may also have their origin in early life and a potentially important pathway by which the early environment affects the risk for neurodegenerative diseases is by developmental programming of the reserve capacity of the brain. The basic idea behind developmental programming of brain and cognitive reserve is explained and an overview of studies that support this idea is presented. The review is concluded by a discussion of potential mechanisms, synthesis of the evidence and relevance and future directions in the field of developmental origins of reserve capacity.

Physical exercise is effective for neuropsychiatric symptoms in Alzheimer's disease: a systematic review.

Neuropsychiatric symptoms are disorders frequently seen in Alzheimer's disease. These symptoms contribute to reduction of brain reserve capacity and, in addition, they present unfavorable implications, such as: poor prognosis for the disease, increased functional decline, increased burden on the caregiver and institutionalization. This scenario makes neuropsychiatric symptoms one of the biggest problems in Alzheimer's disease, and gives rise to a need for treatments focused on improving these symptoms. Sow progress in drug trials has led to interest in exploring non-pharmacological measures for improving the neuropsychiatric symptoms of Alzheimer's disease, such as physical exercise. To ascertain the effect of exercise on the neuropsychiatric symptoms of Alzheimer's disease and its implications. This was a systematic review of effective longitudinal research, conducted by searching for articles in the PubMed, Web of Science, CINAHL and Scopus electronic databases, from 2009 to 2019. Studies in which the sample consisted of elderly people aged 65 years old or over with a diagnosis of Alzheimer's disease were included. Initially 334 articles were identified. After exclusions, 21 articles remained to be read in full. From these, five articles fitted the eligibility criteria, and a further two articles were added through manual searches in the references of the articles found. Out of the seven articles analyzed in this review, five studies revealed that physical exercise had a positive effect on the neuropsychiatric symptoms of Alzheimer's disease. This systematic review indicated that physical exercise is a favorable non-pharmacological means for attenuating the neuropsychiatric symptoms of elderly people with Alzheimer's disease, with special attention to aerobic exercises.

The brain cognitive reserve hypothesis: A review with emphasis on the contribution of nuclear medicine neuroimaging techniques.

Neuropathological and clinical evidence indicates that the clinical expression of Alzheimer's disease (AD) occurs as neuropathology exceeds the brain reserve capacity. The brain or cognitive reserve (BCR) hypothesis states that high premorbid intelligence, education, and an active and stimulating lifestyle provide reserve capacity, which acts as a buffer against the cognitive deficits due to accumulating neuropathology. Neuroimaging studies that assessed the BCR hypothesis are critically reviewed with emphasis on study design and statistical analysis. Many studies were performed in the last two decades owing to the increasing availability of positron emission tomography (PET) and PET/computed tomography scanners and to the synthesis of new radiopharmaceuticals, including tracers for amyloid and tau proteins. Studies with different tracers provided complementary consistent results supporting the BCR hypothesis. Many studies were appropriately designed with a measure of reserve, a measure of brain anatomy/function/neuropathology, and a measure of cognitive functions that are necessary. Most of the early studies were performed with PET and [ 18 F]fluorodeoxyglucose, and occasionally with [ 15 O]water, reporting a significant association between higher occupation/education and lower glucose metabolism (blood flow) in associative temporo-parietal cortex in patients with AD and also in patients with MCI, after correcting for the degree in the cognitive impairment. On the contrary, performances on several neuropsychological tests increased with increasing education for participants with elevated [ 11 C]PiB uptake. Studies with the tracers specific for tau protein showed that patients with AD with elevated tau deposits had higher cognitive performances compared with patients with similar levels of tau deposits. BCR in AD is also associated with a preserved cholinergic function. The BCR hypothesis has been validated with methodologically sound study designs and sophisticated neuroimaging techniques using different radiotracers and providing an explanation for neuropathological and clinical observations on patients with AD.

Prefrontal Lobe Brain Reserve Capacity with Resistance to Higher Global Amyloid Load and White Matter Hyperintensity Burden in Mild Stage Alzheimer's Disease.

BackgroundAmyloid deposition and white matter lesions (WMLs) in Alzheimer's disease (AD) are both considered clinically significant while a larger brain volume is thought to provide greater brain reserve (BR) against these pathological effects. This study identified the topography showing BR in patients with mild AD and explored the clinical balances among BR, amyloid, and WMLs burden.MethodsThirty patients with AD were enrolled, and AV-45 positron emission tomography was conducted to measure the regional standardized uptake value ratio (SUVr) in 8 cortical volumes-of- interests (VOIs). The quantitative WMLs burden was measured from magnetic resonance imaging while the normalized VOIs volumes represented BR in this study. The cognitive test represented major clinical correlates.ResultsSignificant correlations between the prefrontal volume and global (r = 0.470, p = 0.024), but not regional (r = 0.264, p = 0.223) AV-45 SUVr were found. AD patients having larger regional volume in the superior- (r = 0.572, p = 0.004), superior medial- (r = 0.443, p = 0.034), and middle-prefrontal (r = 0.448, p = 0.032) regions had higher global AV-45 SUVr. For global WML loads, the prefrontal (r = -0.458, p = 0.019) and hippocampal volume (r = -0.469, p = 0.016) showed significant correlations while the prefrontal (r = -0.417, p = 0.043) or hippocampal volume (r = -0.422, p = 0.04) also predicted better composite memory scores. There were no interactions between amyloid SUVr and WML loads on the prefrontal volume.ConclusionsBR of the prefrontal region might modulate the adverse global pathological burden caused by amyloid deposition. While prefrontal volume positively associated with hippocampal volume, WMLs had an adverse impact on the hippocampal volume that predicts memory performance in mild stage AD.

Compensation in the course of Huntington's disease — More than just a hypothesis?

Compensation in the course of Huntington's disease — More than just a hypothesis?

Chapter 43 - Traumatic brain injury and reserve

The potential role of brain and cognitive reserve in traumatic brain injury (TBI) is reviewed. Brain reserve capacity (BRC) refers to preinjury quantitative measures such as brain size that relate to outcome. Higher BRC implies threshold differences when clinical deficits will become apparent after injury, where those individuals with higher BRC require more pathology to reach that threshold. Cognitive reserve (CR) refers to how flexibly and efficiently the individual makes use of available brain resources. The CR model suggests the brain actively attempts to cope with brain damage by using pre-existing cognitive processing approaches or by enlisting compensatory approaches. Standard proxies for CR include education and IQ although this has expanded to include literacy, occupational attainment, engagement in leisure activities, and the integrity of social networks. Most research on BRC and CR has taken place in aging and degenerative disease but these concepts likely apply to the effects of TBI, especially with regards to recovery. Since high rates of TBI occur in those under age 35, both CR and BRC factors likely relate to how the individual copes with TBI over the lifespan. These factors may be particularly relevant to the relationship of developing dementia in the individual who has sustained a TBI earlier in life.

Functional MRI as a marker of memory network disruption in early Alzheimer's disease

characterized by an anterior-to-posterior gradient of greater-to-lesser degeneration could also be confirmed by several studies of structural integrity using DTI. A discrimination of those patterns, together with the estimation of the actual brain reserve capacity by estimates of structural connectivity, could increase the precision of individual disease course prediction and thus increasing the timeframe for secondary preventive strategies. However, the utility and feasibility of DTI for early AD diagnosis and for the monitoring (or treatment) of the disease needs further evaluation, especially compared to other MR-measures and in the context of larger multicentre approaches.

Are Apathy and Depression Independently Associated with Longitudinal Trajectories of Cortical Atrophy in Mild Cognitive Impairment?

To examine whether depression and apathy are independently associated with longitudinal trajectories of cortical atrophy in the entorhinal cortex compared with frontal subregions previously implicated in late-life mood disturbance. Data from 334 participants classified as having mild cognitive impairment in the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed by using multilevel models for change adjusted for age, global cognitive status, and total intracranial volume at enrollment. Participants in ADNI were recruited from >50 clinical research sites in the United States and Canada. Depression and apathy were identified by informants using the Neuropsychiatric Inventory Questionnaire. Serial magnetic resonance imaging was performed on 1.5-Tesla scanners according to the standardized ADNI-1 protocol on an average of 5 occasions over an average of 30.5 months. Regional cortical thickness values were derived from longitudinal data processing in FreeSurfer version 4.4. Depression was associated with reduced cortical thickness in the entorhinal cortex at baseline and accelerated atrophy in the anterior cingulate cortex. Similar relationships between depression and the orbitofrontal cortex and between apathy and the anterior cingulate cortex were not significant. In mild cognitive impairment, depression signs are a better marker of longitudinal cortical atrophy than apathy. Results are consistent with hypotheses that depression is an early sign of a more aggressive neurodegenerative process or that depression lowers brain reserve capacity, allowing for more rapid progression of Alzheimer disease neuropathology.

Education and Dementia in the Context of the Cognitive Reserve Hypothesis: A Systematic Review with Meta-Analyses and Qualitative Analyses

BackgroundCognitive reserve (CR) or brain reserve capacity explains why individuals with higher IQ, education, or occupational attainment have lower risks of developing dementia, Alzheimer’s disease (AD) or vascular dementia (VaD). The CR hypothesis postulates that CR reduces the prevalence and incidence of AD or VaD. It also hypothesizes that among those who have greater initial cognitive reserve (in contrast to those with less reserve) greater brain pathology occurs before the clinical symptoms of disease becomes manifest. Thus clinical disease onset triggers a faster decline in cognition and function, and increased mortality among those with initial greater cognitive reserve. Disease progression follows distinctly separate pathological and clinical paths. With education as a proxy we use meta-analyses and qualitative analyses to review the evidence for the CR hypothesis.Methodology/Principal FindingsWe searched PubMed, PsycoINFO, EMBASE, HealthStar, and Scopus databases from January 1980 to June 2011 for observational studies with clear criteria for dementia, AD or VaD and education. One hundred and thirty-three articles with a variety of study designs met the inclusion criteria. Prevalence and incidence studies with odds ratios (ORs), relative risks or original data were included in the meta-analyses. Other studies were reviewed qualitatively. The studies covered 437,477 subjects. Prevalence and incidence studies with pooled ORs of 2.61 (95%CI 2.21–3.07) and 1.88 (95%CI 1.51–2.34) respectively, showed low education increased the risk of dementia. Heterogeneity and sensitivity tests confirmed the evidence. Generally, study characteristics had no effect on conclusions. Qualitative analyses also showed the protective effects of higher education on developing dementia and with clinical disease onset hastening a decline in cognition and function, and greater brain pathology.Conclusion/SignificanceThis systematic review and meta-analyses covering a wide range of observational studies and diverse settings provides robust support for the CR hypothesis. The CR hypothesis suggests several avenues for dementia prevention.

Structural and Functional Imaging Correlates of Cognitive and Brain Reserve Hypotheses in Healthy and Pathological Aging

In the field of ageing and dementia, brain- or cognitive reserve refers to the capacity of the brain to manage pathology or age-related changes thereby minimizing clinical manifestations. The brain reserve capacity (BRC) hypothesis argues that this capacity derives from an individual's unique neural profile (e.g., cell count, synaptic connections, brain volume, etc.). Complimentarily, the cognitive reserve (CR) hypothesis emphasizes inter-individual differences in the effective recruitment of neural networks and cognitive processes to compensate for age-related effects or pathology. Despite an abundance of research, there is scarce literature attempting to synthesize the BRC the CR models. In this paper, we will review important aging and dementia studies using structural and functional neuroimaging techniques to investigate and attempt to assimilate both reserve hypotheses. The possibility to conceptualize reserve as reflecting indexes of brain plasticity will be proposed and novel data suggesting an intimate and complex correspondence between active and passive components of reserve will be presented.

White Matter Microstructure in Relation to Education in Aging and Alzheimer's Disease1

The reduced risk of dementia in high-educated individuals has been suggested to reflect brain reserve capacity. In the present study, we determined the association between integrity of white matter microstructure and education separately in twenty-one patients with clinically probable Alzheimer's disease (AD) and 18 healthy elderly subjects. We used fractional anisotropy derived from high-resolution diffusion-tensor weighted imaging at 3 Tesla as an in vivo marker of white matter microstructure. Based on multivariate network analysis, more years of education were associated with reduced white matter integrity of medial temporal lobe areas and association fiber tracts when age, gender, and dementia severity had been controlled for (p < 0.001). In controls, higher education was associated with greater white matter integrity in medial temporal lobe areas and association fiber tracts (p < 0.001). In multiple regression models, education was the main factor accounting for fiber tract integrity even when occupation was taken into account. Reduced fiber tract integrity with higher education at the same level of cognitive impairment in AD patients and higher fiber tract integrity with higher education in similar white matter areas in cognitively healthy controls agrees with the hypothesis that white matter microstructure may contribute to brain reserve capacity in humans.

PL-05-01: Brain reserve: The epidemiological perspective

It has long been recognized that some type of reserve can protect the nervous system from expressing AD pathology as cognitive impairment and dementia. However, little data are available from humans regarding the neurobiologic basis of reserve and the factors that determine the ability of the nervous system to tolerate AD pathology. Data are presented from two, large, longitudinal epidemiologic clinical-pathologic studies, the Religious Orders Study and the Rush Memory and Aging Project, designed to identify risk factors for incident AD and investigate biologic pathways linking risk factors to clinical disease. Incident AD is diagnosed by NINCDS/ADRDA criteria and 19 cognitive function tests are used to summarize global cognition and five domains (episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability). AD pathology was quantified by counts of neuritic plaques, diffuse plaques, and neurfibrillary tangles based on silve stain, amyloid load by image analysis, and tangle density by stereology. The number, age, volume and location of macrospic cerebral infarcts were recored. The number and location of alpha-synuclein positive Lewy bodies were recorded. Data from these studies suggest the existence of three types of brain reserve. First, evidence is presented demonstrating that common co-existing neuropathology (e.g., cerebral infarcts and Lewy bodies) reduce brain reserve capacity and that some risk factors for clinical AD (e.g., diabetes) are related to coexisting pathology rather than to AD pathology. Second, some risk factors for incident AD (e.g., social networks) are not directly related to measures of neuropathology but modify the relation of neuropathology to clinical AD, consistent with neural efficiency or compensation. Finally, some risk factors for incident AD (e.g., psychological distress) are unrelated to measures of neuropathology and work through as yet completely unknown mechanisms to reduce brain reserve. These data suggest a variety of approaches to the prevention of AD including reducing the occurrence of coexisting pathology, identifying factors that allow one to tolerate AD pathology, and using these risk factor clinical disease associations to identify novel targets for therapy.

Cognitive Performance in Long‐Term Abstinent Elderly Alcoholics

To date, there is a wealth of literature describing the deleterious effects of active alcoholism on cognitive function. There is also a growing body of literature on the extent of cognitive recovery that can occur with abstinence. However, there is still a dearth of published findings on cognitive functioning in very long-term abstinence alcoholics, especially in the elderly population. The current study examines 91 elderly abstinent alcoholics (EAA) (49 men and 42 women) with an average age of 67.3 years, abstinent for an average of 14.8 years (range 0.5 to 45 years), and age and gender comparable light/nondrinking controls. The EAA group was divided into 3 subgroups: individuals that attained abstinence before age 50 years, between the ages 50 and 60 years, and after age 60 years. Attention, verbal fluency, abstraction/cognitive flexibility, psychomotor, immediate memory, delayed memory, reaction time, spatial processing, and auditory working memory were assessed. The AMNART and cranium size were used as estimates of brain reserve capacity, and the association of all variables with alcohol use measures was examined. Overall, the EAA groups performed comparably to controls on the assessments of cognitive function. Only the abstinent in group before 50 years of age performed worse than controls, and this was only in the domain of auditory working memory. EAAs had larger craniums than their controls. This effect was strongest for those who drank the longest and had the shortest abstinence. Such individuals also performed better cognitively. Our data showed that elderly alcoholics that drank late into life, but with at least 6 months abstinence can exhibit normal cognitive functioning. Selective survivorship and selection bias probably play a part in these findings. Cognitively healthier alcoholics, with more brain reserve capacity, may be more likely to live into their 60s, 70s, or 80s of age with relatively intact cognition, and to volunteer for studies such as this. Our results do not imply that all elderly alcoholics with long-term abstinence will attain normal cognition.

Mapping the connections between education and dementia

Explanations for the association between educational attainment and the risk of dementia fall into three main categories. It may arise as an artefact of study methods; education may predict broader socioeconomic circumstances and exposures, or education may reflect brain reserve or cognitive capacity that protect against dementia. Data from the Canadian Study of Health and Aging (N = 6646, giving 44,676 person-years of follow-up) are analyzed to test a series of hypotheses reflecting these explanations. Years of education showed a strong association with the risk of dementia (relative risk [RR] 2.1 for those with less than 6 years of education compared to those with 13 or more years; RR = 2.9 among survivors). Possible artefactual factors were detected, but were insufficient to invalidate the association. Adjustments for a range of other socioeconomic indicators, health problems and lifestyle factors reduced, but did not remove, the association. Adjustments for intelligence and for an indicator of lifetime mental activity also appeared to account for some but not all of the association. The conclusion is that there appears to be a real association between educational attainment and the risk of dementia 50 to 60 years later; this influence appears to run through a number of different, and sometimes complementary, pathways.

Brain reserve capacity in frontotemporal dementia: a voxel-based 18F-FDG PET study

The association of the regional cerebral metabolic rate of glucose utilisation (rCMRglc) and years of schooling has been extensively studied in Alzheimer's disease (AD). The results suggest that brain reserve capacity (BRC) allows patients with more years of schooling to cope better with AD pathology. The objective of this study was to provide initial evidence for BRC in frontotemporal dementia (FTD). Twenty-nine patients with FTD and 16 healthy age- and education-matched controls underwent PET imaging of the brain with 18F-fluoro-2-deoxy-glucose. A group comparison of rCMRglc was conducted between patients and controls and the output was saved as region of interest (ROI). A linear regression analysis with education as the independent and rCMRglc as the dependent variable, adjusted for age, gender and total score on the CERAD neuropsychological battery, was conducted in SPM2 over the pre-assigned ROI. Patients showed a reduced rCMRglc in almost the entire prefrontal cortex and the anterior cingulate cortex as compared with controls (p < 0.05 corrected for multiple comparisons). The regression analysis revealed a significant negative association between years of schooling and rCMRglc in the bilateral inferior frontal cortex (p < 0.001, uncorrected for multiple comparisons), which was independent of demographic variables and cognitive performance level. There was a strong negative correlation of rCMRglc and education (r = -0.45). The study provides initial evidence for BRC in FTD. The findings suggest that interindividual differences in educational level affect BRC by partially mediating the relationship between neurodegeneration and the clinical manifestation of FTD.