Diurnal cortisol, neuroinflammation, and neuroimaging visual rating scales in memory clinic patients.

BACKGROUND: Neuroinflammation is a hallmark of the Alzheimer's disease (AD) pathogenic process. Cortisol dysregulation may increase AD risk and is related to brain atrophy. This cross-sectional study aims to examine interactions of cortisol patterns and neuroinflammation markers in their association with neuroimaging correlates. METHOD: 134 participants were recruited from the Karolinska University Hospital memory clinic (Stockholm, Sweden). Four visual rating scales were applied to magnetic resonance imaging or computed tomography scans: medial temporal lobe atrophy (MTA), global cortical atrophy (GCA), white matter lesions (WML), and posterior atrophy. Participants provided saliva samples for assessment of diurnal cortisol patterns, and underwent lumbar punctures for cerebrospinal fluid (CSF) sampling. Three cortisol measures were used: the cortisol awakening response, total daily output, and the ratio of awakening to bedtime levels. Nineteen CSF neuroinflammation markers were categorized into five composite scores: proinflammatory cytokines, other cytokines, angiogenesis markers, vascular injury markers, and glial activation markers. Ordinal logistic regressions were conducted to assess associations between cortisol patterns, neuroinflammation scores, and visual rating scales, and interactions between cortisol patterns and neuroinflammation scores in relation to visual rating scales. RESULT: Higher levels of angiogenesis markers were associated with more severe WML. Some evidence was found for interactions between dysregulated diurnal cortisol patterns and greater neuroinflammation-related biomarkers in relation to more severe GCA and WML. No associations were found between cortisol patterns and visual rating scales. CONCLUSION: This study suggests an interplay between diurnal cortisol patterns and neuroinflammation in relation to brain structure. While this cross-sectional study does not provide information on causality or temporality, these findings suggest that neuroinflammation may be involved in the relationship between HPA-axis functioning and AD.

Effects of daily L-dopa administration on learning and brain structure in older adults undergoing cognitive training: a randomised clinical trial.

Cognitive aging creates major individual and societal burden, motivating search for treatment and preventive care strategies. Behavioural interventions can improve cognitive performance in older age, but effects are small. Basic research has implicated dopaminergic signalling in plasticity. We investigated whether supplementation with the dopamine-precursor L-dopa improves effects of cognitive training on performance. Sixty-three participants for this randomised, parallel-group, double-blind, placebo-controlled trial were recruited via newspaper advertisements. Inclusion criteria were: age of 65-75 years, Mini-Mental State Examination score >25, absence of serious medical conditions. Eligible subjects were randomly allocated to either receive 100/25 mg L-dopa/benserazide (n = 32) or placebo (n = 31) prior to each of twenty cognitive training sessions administered during a four-week period. Participants and staff were blinded to group assignment. Primary outcomes were latent variables of spatial and verbal fluid intelligence. Compared to the placebo group, subjects receiving L-dopa improved less in spatial intelligence (-0.267 SDs; 95%CI [-0.498, -0.036]; p = 0.024). Change in verbal intelligence did not significantly differ between the groups (-0.081 SDs, 95%CI [-0.242, 0.080]; p = 0.323). Subjects receiving L-dopa also progressed slower through the training and the groups displayed differential volumetric changes in the midbrain. No statistically significant differences were found for the secondary cognitive outcomes. Adverse events occurred for 10 (31%) and 7 (23%) participants in the active and control groups, correspondingly. The results speak against early pharmacological interventions in older healthy adults to improve broader cognitive functions by targeting the dopaminergic system and provide no support for learning-enhancing properties of L-dopa supplements in the healthy elderly. The findings warrant closer investigation about the cognitive effects of early dopamine-replacement therapy in neurological disorders. This trial was preregistered at the European Clinical Trial Registry, EudraCT#2016-000891-54 (2016-10-05).

Midlife Work-Related Stress is Associated with Late-Life Gray Matter Volume Atrophy.

BACKGROUND: Work-related stress has been associated with an increased dementia risk. However, less is known about the mechanisms that underlie these associations. OBJECTIVE: The goal is to examine associations between midlife work-related stress and late-life structural brain alterations. METHODS: The Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study participants were randomly selected from independent population-based surveys (mean age 50) in Finland. MRI measurements included gray matter (GM) volume, white matter lesions (WML) and medial temporal atrophy (MTA) (1st re-examination, n = 102); and GM volume, hippocampal volume, WML volume, cortical thickness, and MTA (2nd re-examination, n = 64). Work-related stress comprised a score from two questions administered in midlife. RESULTS: Higher levels of midlife work-related stress were associated with lower GM volume (ß= -0.077, p = 0.033) at the first re-examination, even after adjusting for several confounders. No significant associations were found with MTA, WML, or MRI measurements at the second re-examination. CONCLUSION: Previously shown associations of midlife work-related stress with dementia risk may be at least partly explained by associations with lower GM volume in late-life. The lack of associations at the second re-examination may indicate a critical time window for the effects of midlife work-related stress, and/or selective survival/participation.

Reproducible segmentation of white matter hyperintensities using a new statistical definition.

OBJECTIVES: We present a method based on a proposed statistical definition of white matter hyperintensities (WMH), which can work with any combination of conventional magnetic resonance (MR) sequences without depending on manually delineated samples. MATERIALS AND METHODS: T1-weighted, T2-weighted, FLAIR, and PD sequences acquired at 1.5 Tesla from 119 subjects from the Kings Health Partners-Dementia Case Register (healthy controls, mild cognitive impairment, Alzheimer's disease) were used. The segmentation was performed using a proposed definition for WMH based on the one-tailed Kolmogorov-Smirnov test. RESULTS: The presented method was verified, given all possible combinations of input sequences, against manual segmentations and a high similarity (Dice 0.85-0.91) was observed. Comparing segmentations with different input sequences to one another also yielded a high similarity (Dice 0.83-0.94) that exceeded intra-rater similarity (Dice 0.75-0.91). We compared the results with those of other available methods and showed that the segmentation based on the proposed definition has better accuracy and reproducibility in the test dataset used. CONCLUSION: Overall, the presented definition is shown to produce accurate results with higher reproducibility than manual delineation. This approach can be an alternative to other manual or automatic methods not only because of its accuracy, but also due to its good reproducibility.

Reduced perfusion in white matter lesions in multiple sclerosis.

OBJECTIVE: To investigate dynamic susceptibility contrast (DSC) perfusion weighted imaging (PWI) in white matter lesions (WML) in patients with multiple sclerosis (MS), using automatically generated binary masks of brain tissue. BACKGROUND: WML in MS have in some studies demonstrated perfusion abnormalities compared to normal appearing white matter (NAWM), however perfusion changes in WML in MS have in general not been well documented. METHODS: DSC PWI was performed at 1.5 Tesla in 69 newly diagnosed MS patients. Parametric perfusion maps representing cerebral blood volume (CBV), cerebral blood flow (CBF) and mean transit time (MTT) were obtained. Binary masks of WML, white matter (WM) and grey matter (GM) were automatically generated and co-registered to the perfusion maps. The WML mask was manually edited and modified to correct for errors in the automatic lesion detection. Perfusion parameters were derived both from WML and NAWM using the manually modified WML mask, and using the original non-modified WML mask (with and without GM exclusion mask). Differences in perfusion measures between WML and NAWM were analyzed. RESULTS: CBF was significantly lower (p<0.001) and MTT significantly higher (p<0.001) in WML compared to NAWM. CBV did not show significant difference between WML and NAWM. The non-modified WML mask gave similar results as manually modified WML mask if the GM exclusion mask was used in the analysis. CONCLUSIONS: DSC PWI revealed lower CBF and higher MTT, consistent with reduced perfusion, in WML compared to NAWM in patients with early MS. Automatically generated binary masks are a promising tool in perfusion analysis of WML.

Midlife CAIDE dementia risk score and dementia-related brain changes up to 30 years later on magnetic resonance imaging.

BACKGROUND: CAIDE Dementia Risk Score is a validated tool for estimating 20-year dementia risk in the general population based on a midlife risk profile. OBJECTIVE: To investigate the associations between CAIDE score and dementia-related brain changes up to 30 years later on magnetic resonance imaging (MRI). METHODS: Participants in the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study were derived from random, population-based samples surveyed in 1972, 1977, 1982, or 1987. A first re-examination was conducted in 1998, and a second re-examination in 2005-2008 (total follow-up time up to 30 years). The MRI study population included 112 individuals with MRIs from the first re-examination, and a different group of 69 individuals with MRIs from the second re-examination. MRIs from 1998 were used to determine gray matter volume, and to visually rate white matter hyperintensities (WMH) of presumed vascular origin and medial temporal lobe atrophy (MTA). MRIs from 2005-2008 were used to assess cortical thickness, gray matter and WMH volume, and to visually rate MTA. CAIDE scores were calculated for participants in both re-examinations based on midlife sociodemographic and vascular factors and additionally apolipoprotein E status. RESULTS: Higher midlife CAIDE score was associated with more severe WMH 20 years later: RR (95% CI) was 1.69 (1.15-2.08); and with higher WMH volume (ß 0.27, p = 0.036) and higher MTA score (RR 1.91, 95% CI 1.16-2.34) up to 30 years later. CONCLUSION: CAIDE Dementia Risk Score in midlife was most consistently associated with WMH later in life. A relation with MTA was observed in individuals with longer follow-up time.

Cortical thickness and surface area relate to specific symptoms in early relapsing-remitting multiple sclerosis.

BACKGROUND: Cortical atrophy is common in early relapsing-remitting multiple sclerosis (RRMS). Whether this atrophy is caused by changes in cortical thickness or cortical surface area is not known, nor is their separate contributions to clinical symptoms. OBJECTIVES: To investigate the difference in cortical surface area, thickness and volume between early RRMS patients and healthy controls; and the relationship between these measures and neurological disability, cognitive decline, fatigue and depression. METHODS: RRMS patients (n = 61) underwent magnetic resonance imaging (MRI), neurological and neuropsychological examinations. We estimated cortical surface area, thickness and volume and compared them with matched healthy controls (n = 61). We estimated the correlations between clinical symptoms and cortical measures within the patient group. RESULTS: We found no differences in cortical surface area, but widespread differences in cortical thickness and volume between the groups. Neurological disability was related to regionally smaller cortical thickness and volume. Better verbal memory was related to regionally larger surface area; and better visuo-spatial memory, to regionally larger cortical volume. Higher depression scores and fatigue were associated with regionally smaller cortical surface area and volume. CONCLUSIONS: We found that cortical thickness, but not cortical surface area, is affected in early RRMS. We identified specific structural correlates to the main clinical symptoms in early RRMS.

Shape abnormalities of the caudate nucleus correlate with poorer gait and balance: results from a subset of the LADIS study.

OBJECTIVE: Functional deficits seen in several neurodegenerative disorders have been linked with dysfunction in frontostriatal circuits and with associated shape alterations in striatal structures. The severity of visible white matter hyperintensities (WMHs) on magnetic resonance imaging has been found to correlate with poorer performance on measures of gait and balance. This study aimed to determine whether striatal volume and shape changes were correlated with gait dysfunction. METHODS: Magnetic resonance imaging scans and clinical gait/balance data (scores from the Short Physical Performance Battery [SPPB]) were sourced from 66 subjects in the previously published LADIS trial, performed in nondisabled individuals older than age 65 years with WMHs at study entry. Data were obtained at study entry and at 3-year follow-up. Caudate nuclei and putamina were manually traced using a previously published method and volumes calculated. The relationships between volume and physical performance on the SPPB were investigated with shape analysis using the spherical harmonic shape description toolkit. RESULTS: There was no correlation between the severity of WMHs and striatal volumes. Caudate nuclei volume correlated with performance on the SPPB at baseline but not at follow-up, with subsequent shape analysis showing left caudate changes occurred in areas corresponding to inputs of the dorsolateral prefrontal, premotor, and motor cortex. There was no correlation between putamen volumes and performance on the SPPB. CONCLUSION: Disruption in frontostriatal circuits may play a role in mediating poorer physical performance in individuals with WMHs. Striatal volume and shape changes may be suitable biomarkers for functional changes in this population.

Coronary heart disease and cortical thickness, gray matter and white matter lesion volumes on MRI.

Coronary heart disease (CHD) has been linked with cognitive decline and dementia in several studies. CHD is strongly associated with blood pressure, but it is not clear how blood pressure levels or changes in blood pressure over time affect the relation between CHD and dementia-related pathology. The aim of this study was to investigate relations between CHD and cortical thickness, gray matter volume and white matter lesion (WML) volume on MRI, considering CHD duration and blood pressure levels from midlife to three decades later. The study population included 69 elderly at risk of dementia who participated in the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study. CAIDE participants were examined in midlife, re-examined 21 years later, and then after additionally 7 years (in total up to 30 years follow-up). MRIs from the second re-examination were used to calculate cortical thickness, gray matter and WML volume. CHD diagnoses were obtained from the Finnish Hospital Discharge Register. Linear regression analyses were adjusted for age, sex, follow-up time and scanner type, and additionally total intracranial volume in GM volume analyses. Adding diabetes, cholesterol or smoking to the models did not influence the results. CHD was associated with lower thickness in multiple regions, and lower total gray matter volume, particularly in people with longer disease duration (>10 years). Associations between CHD, cortical thickness and gray matter volume were strongest in people with CHD and hypertension in midlife, and those with CHD and declining blood pressure after midlife. No association was found between CHD and WML volumes. Based on these results, long-term CHD seems to have detrimental effects on brain gray matter tissue, and these effects are influenced by blood pressure levels and their changes over time.

Multiple sclerosis patients lacking oligoclonal bands in the cerebrospinal fluid have less global and regional brain atrophy.

To investigate whether multiple sclerosis (MS) patients with and without cerebrospinal fluid (CSF) oligoclonal immunoglobulin G bands (OCB) differ in brain atrophy. Twenty-eight OCB-negative and thirty-five OCB-positive patients were included. Larger volumes of total CSF and white matter (WM) lesions; smaller gray matter (GM) volume in the basal ganglia, diencephalon, cerebellum, and hippocampus; and smaller WM volume in corpus callosum, periventricular-deep WM, brainstem, and cerebellum, were observed in OCB-positives. OCB-negative patients, known to differ genetically from OCB-positives, are characterized by less global and regional brain atrophy. This finding supports the notion that OCB-negative MS patients may represent a clinically relevant MS subgroup.

Vitamin D in relation to cognitive impairment, cerebrospinal fluid biomarkers, and brain volumes.

BACKGROUND: Low vitamin D status is associated with poorer cognitive function in older adults, but little is known about the potential impact on cerebrospinal fluid (CSF) biomarkers and brain volumes. The objective of this study was to examine the relations between plasma 25-hydroxyvitamin D (25(OH)D) and cognitive impairment, CSF biomarkers of Alzheimer's disease (AD), and structural brain tissue volumes. METHODS: A total of 75 patients (29 with subjective cognitive impairment, 28 with mild cognitive impairment, 18 with AD) referred to the Memory Clinic at Karolinska University Hospital, Huddinge, Sweden were recruited. Plasma 25(OH)D, CSF levels of amyloid ß (Aß(1-42)), total-tau, and phosphorylated tau, and brain tissue volumes have been measured. RESULTS: After adjustment for several potential confounders, the odds ratios (95% confidence interval) for cognitive impairment were as follows: 0.969 (0.948-0.990) per increase of 1 nmol/L of 25(OH)D and 4.19 (1.30-13.52) for 24(OH)D values less than 50 nmol/L compared with values greater than or equal to 50 nmol/L. Adjusting for CSF Aß(1-42) attenuated the 25(OH)D-cognition link. In a multiple linear regression analysis, higher 25(OH)D levels were related to higher concentrations of CSF Aß(1-42) and greater brain volumes (eg, white matter, structures belonging to medial temporal lobe). The associations between 25(OH)D and tau variables were not significant. CONCLUSIONS: This study suggests that vitamin D may be associated with cognitive status, CSF Aß(1-42) levels, and brain tissue volumes.

Executive dysfunction correlates with caudate nucleus atrophy in patients with white matter changes on MRI: a subset of LADIS.

White matter changes (WMC) are common magnetic resonance imaging (MRI) findings, particularly in the elderly. Recent studies such as the Leukoaraiosis and Disability Study (LADIS) have found that WMC relate to adverse outcomes including cognitive impairment, depression, disability, unsteadiness and falls in cross-sectional and follow-up studies. Frontostriatal (or frontosubcortical) brain circuits may serve many of these functions, with the caudate nuclei playing a role in convergence of cognitive functions. This study aimed to determine whether reduced caudate volume relates to cognitive functions (executive functions, memory functions and speed of processing) and WMC. We determined caudate nuclei volumes, through manual tracing, on a subgroup of the LADIS study (n=66) from four centres with baseline and 3-year follow-up MRI scans. Regression analysis was used to assess relationships between caudate volume, cognitive function and WMC. Severity of WMC did not relate to caudate volume. Smaller caudate volumes were significantly associated with poorer executive functioning at baseline and at 3 years, but were not associated with scores of memory or speed of processing. Thus, in patients with WMC, a surrogate of small vessel disease, caudate atrophy relates to the dysexecutive syndrome, supporting the role of caudate as an important part of the frontostriatal circuit.

Changes in vascular factors 28 years from midlife and late-life cortical thickness.

We assessed midlife blood pressure (BP), body mass index, total cholesterol, and their changes over time in relation to cortical thickness on magnetic resonance imaging 28 years later in 63 elderly at risk of dementia. Participants in the population-based Cardiovascular Risk Factors, Aging, and Dementia study were first examined at midlife. A first follow-up was conducted after 21 years, and a second follow-up after an additional 7 years. Magnetic resonance images from the second follow-up were analyzed using algorithms developed at McGill University, Montreal, Canada. Midlife hypertension was related to thinner cortex in several brain areas, including insular, frontal, and temporal cortices. In elderly with thinner insular cortex, there was a continuous decline in systolic BP and an increase in pulse pressure after midlife, while in elderly with thicker insular cortex the decline in systolic BP started at older ages, paralleled by a decline in pulse pressure. No associations were found between body mass index, cholesterol, or apolipoprotein E ε4 allele and cortical thickness in this group of elderly at risk individuals.

Multispectral MRI segmentation of age related white matter changes using a cascade of support vector machines.

White matter changes (WMC) are the focus of intensive research and have been linked to cognitive impairment and depression in the elderly. Cumbersome manual outlining procedures make research on WMC labor intensive and prone to subjective bias. We present a fast, fully automated method for WMC segmentation using a cascade of reduced support vector machines (SVMs) with active learning. Data of 102 subjects was used in this study. Two MRI sequences (T1-weighted and FLAIR) and masks of manually outlined WMC from each subject were used for the image analysis. The segmentation framework comprises pre-processing, classification (training and core segmentation) and post-processing. After pre-processing, the model was trained on two subjects and tested on the remaining 100 subjects. The effectiveness and robustness of the classification was assessed using the receiver operating curve technique. The cascade of SVMs segmentation framework outputted accurate results with high sensitivity (90%) and specificity (99.5%) values, with the manually outlined WMC as reference. An algorithm for the segmentation of WMC is proposed. This is a completely competitive and fast automatic segmentation framework, capable of using different input sequences, without changes or restrictions of the image analysis algorithm.

Grey matter and cognitive patterns in cognitive impaired subjects using CSF biomarker cut-offs.

The aim of this study was to investigate brain tissue volumes, grey matter (GM) distribution, and cognitive performance for cognitively impaired subjects using cerebrospinal fluid (CSF) biomarker cut-offs as grouping criteria. 41 subjects attending the Memory Clinic, Karolinska University Hospital, Huddinge, Sweden, were divided into groups based on normal or abnormal CSF levels of Aß1-42, t-tau, and p-tau181. SIENAX algorithms were employed for brain tissue volumes estimation and voxel-based morphometry (VBM) for mapping the differences in GM patterns. VBM revealed significant lower GM volumes in temporo-parietal, occipital, and prefrontal cortices for those subjects belonging to abnormal CSF t-tau and p-tau181 groups. No differences were found between groups according to CSF Aß1-42 cut-offs. Patients with abnormal CSF p-tau181 showed lower cognitive performance compared to those with normal levels. Patients with abnormal levels of CSF tau (but not Aß1-42) showed an Alzheimer's disease-like pattern for both GM distribution and cognitive profile, compared to those with normal levels. These results support the hypothesis that CSF t-tau or p-tau181 levels may be of direct value for the evaluation of disease severity.

Structural brain changes and cognition in relation to markers of vascular dysfunction.

The aim was to investigate the relationship between blood markers of vascular dysfunction with brain microstructural changes and cognition. Eighty-six participants from the Barcelona-Asymptomatic Intracranial Atherosclerosis (AsIA) neuropsychology study were included. Subjects were 50-65 years old, free from dementia and without history of vascular disease. We assessed correlations of blood levels of inflammatory biomarkers (C-reactive protein [CRP] and resistin) and fibrinolysis inhibitors (plasminogen activator inhibitor-1 [PAI-1] and A-lipoprotein (Lp (a)) with fractional anisotropy (FA) measurements of diffusion tensor images (DTI), regional gray matter (GM) volumes and performance in several cognitive domains. Increasing levels of C-reactive protein and PAI-1 levels were associated with white matter (WM) integrity loss in corticosubcortical pathways and association fibers of frontal and temporal lobes, independently of age, sex and vascular risk factors. PAI-1 was also related to lower speed and visuomotor/coordination. None of the biomarkers were related to gray matter volume changes. Our findings suggest that inflammation and dysregulation of the fibrynolitic system may be involved in the pathological mechanisms underlying the WM damage seen in cerebrovascular disease and subsequent cognitive impairment.

Evolution of global and local grey matter atrophy on serial MRI scans during the progression from MCI to AD.

Mild cognitive impairment (MCI) often represents a prodromal form of dementia, conferring a significantly higher risk of converting to probable Alzheimer's disease (AD). The aim of this study is to characterise the differences of grey matter (GM) distribution and dynamics between progressive and stable MCI subjects during a 2 year period preceding the conversion to AD. We included 48 stable MCI and 12 progressive MCI cases based on the availability of 3 serial scans acquired with approximately 1 year scan interval. For the progressive MCI group, the third scan was acquired at the time of the clinical diagnosis of AD, while the first two scans were acquired approximately 2 and 1 years earlier. For the stable MCI group, the three scans were acquired at approximately 1 year intervals during a period free from significant cognitive decline. We used longitudinal voxel-based morphometry (VBM) for mapping the progression of GM loss over time. For the progressive MCI group, the cross-sectional analysis revealed areas of lower GM volumes in the parahippocampal gyrus, precuneus and posterior cingulate 12 months before the AD diagnosis. For the longitudinal VBM analysis the progressive MCI group revealed increased GM loss in cortical regions belonging to the temporal neocortex, parahippocampal cortex, and cingulate gyrus. The frontal lobe, insula and the cerebellum were also affected. This accelerated atrophy may offer new insights into the understanding of neurodegenerative pathology and the clinical relevance of these changes remains to be verified by subsequent studies.

Diffusion tensor imaging and tract-based spatial statistics in Alzheimer's disease and mild cognitive impairment.

We aimed to explore the changes in fractional anisotropy (FA) in subjects with mild cognitive impairment (MCI) and Alzheimer's disease (AD) by analyzing diffusion tensor imaging (DTI) data using the Tract-Based Spatial Statistics (TBSS). DTI data were collected from 17 AD patients, 27 MCI subjects and 19 healthy controls. Voxel-based analysis with TBSS was used to compare FA among the three groups. Additionally, guided by TBSS findings, a region of interest (ROI)-based analysis along the TBSS skeleton was performed on group-level and the accuracy of the method was assessed by the back-projection of ROIs to the native space FA. Neurofiber tracts with decreased FA included: the parahippocampal white matter, cingulum, uncinate fasciculus, inferior and superior longitudinal fasciculus, corpus callosum, fornix, tracts in brain stem, and cerebellar tracts. Quantitative ROI-analysis further demonstrated the significant decrease on FA values in AD patients relative to controls whereas FA values of MCI patients were found in between the controls and AD patients. We conclude that TBSS is a promising method in examining the degeneration of neurofiber tracts in MCI and AD patients.

Whole brain atrophy rate predicts progression from MCI to Alzheimer's disease.

For both clinical and research reasons, it is essential to identify which mild cognitive impairment (MCI) subjects subsequently progress to Alzheimer's disease (AD). The prediction may be facilitated by accelerated whole brain atrophy exhibited by AD subjects. Iterative principal component analysis (IPCA) was used to characterize whole brain atrophy rates using sequential MRI scans for 102 MCI subjects from the Kuopio University Hospital. We modelled the likelihood of progression to probable AD, and found that each additional percent of annualized whole brain atrophy rate was associated with a higher odds ratio (OR) of progression (OR=1.30, p=0.01, 95% CI=1.05-1.60). Our study demonstrates an association between whole brain atrophy rate and subsequent rate of clinical progression from MCI to AD. These findings suggest that IPCA could be an effective brain-imaging marker of progression to AD and useful tool for the evaluation of disease-modifying treatments.

The effect of midlife physical activity on structural brain changes in the elderly.

Physical activity has been associated with decreased dementia risk in recent studies, but the effects for structural brain changes (i.e. white matter lesions (WML) and/or brain atrophy) have remained unclear. The CAIDE participants were a random population-based sample studied in midlife and re-examined on average 21 years later (n=2000). A subpopulation (n=75; 31 control, 23 MCI, 21 dementia) was MRI scanned at the re-examination. T1-weighted images were used to investigate grey matter (GM) density, and FLAIR-images for WML rating. Persons who actively participated in physical activity at midlife tended to have larger total brain volume (ß 0.12; 95% CI 0.17-1.16, p=0.10) in late-life than sedentary persons even after adjustments. GM volume was larger among the active (ß 0.19; 95% CI 0.07-1.48, p=0.03), whereas the association between midlife physical activity and larger WM volume became non-significant (ß 0.03; 95% CI -0.64 to 0.86, p=0.77) after full adjustments. The differences in the GM density localized mainly in frontal lobes. There was no significant association between midlife physical activity and severe WML later in life after full adjustments (OR 4.20, 95% CI 0.26-69.13, p=0.32).