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1.  White Matter Integrity on DTI, Amyloid Load, and Neurodegeneration in Non-demented Elderly 
JAMA neurology  2014;71(12):1547-1554.
Importance
Pathophysiologic mechanisms leading to loss of white matter (WM) integrity and the temporal positioning of biomarkers of WM integrity relative to the biomarkers of gray matter (GM) neurodegeneration and amyloid load in the course of AD are poorly understood.
Objective
To investigate the effects of Alzheimer’s disease (AD)-related GM neurodegeneration and high β-amyloid on white matter (WM) microstructure in non-demented older adults.
Design
Longitudinal cohort study
Setting
Population-based Mayo Clinic Study of Aging.
Participants
Participants (n=701) with MRI/DTI and PET studies diagnosed as cognitively normal (CN; n=570) or mild cognitive impairment (MCI; n=131) were included. CN and MCI subjects were divided into biomarker-negative, amyloid- positive only, neurodegeneration- positive only, and amyloid plus neurodegeneration-positive groups based on their amyloid load on 11C-Pittsburgh compound-B PET, AD hypometabolic pattern on 18F-fluorodeoxyglucose PET and/or hippocampal atrophy on MRI.
Main Outcome Measure
Fractional anisotrophy (FA) from diffusion tensor imaging (DTI)
Results
No FA alterations were observed in biomarker-negative MCI, and amyloid-positive only CN and MCI groups. Conversely, neurodegeneration-positive only and amyloid plus neurodegeneration- positive CN and MCI groups consistently had decreased FA in the fornix, which correlated with cognitive performance (Rho=0.38; p<0.001). Patients with MCI had more extensive WM involvement than CN subjects, and greatest FA decreases were observed in the amyloid plus neurodegeneration-positive MCI group.
Conclusions and Relevance
High amyloid load does not influence DTI-based measures of WM integrity in the absence of co-existent GM neurodegeneration in non-demented older adults.
doi:10.1001/jamaneurol.2014.1482
PMCID: PMC4810441  PMID: 25347157
Diffusion tensor imaging; mild cognitive impairment; preclinical Alzheimer’s disease
2.  Working memory and language network dysfunction in logopenic aphasia: a task-free fMRI comparison to Alzheimer’s dementia 
Neurobiology of aging  2014;36(3):1245-1252.
We aimed to determine whether network-level functional connectivity differs in two clinical variants of Alzheimer’s disease: logopenic primary progressive aphasia (lvPPA) and dementia of the Alzheimer’s type (DAT). Twenty-four lvPPA subjects with amyloid deposition on PET and task-free fMRI were matched to 24 amyloid-positive DAT subjects and 24 amyloid-negative controls. Independent-component analysis and spatial-temporal dual-regression were used to assess functional connectivity within the language network, left and right working memory networks and ventral default mode network. lvPPA showed reduced connectivity in left temporal language network and inferior parietal and prefrontal regions of the left working memory network compared to controls and DAT. Both groups showed reduced connectivity in parietal regions of the right working memory network compared to controls. Only DAT showed reduced ventral default mode network connectivity compared to controls. Aphasia severity correlated with connectivity in left working memory network within lvPPA. Patterns of network dysfunction differ across these two clinical variants of Alzheimer’s disease, with lvPPA particularly associated with disruptions in the language and left working memory networks.
doi:10.1016/j.neurobiolaging.2014.12.013
PMCID: PMC4346438  PMID: 25592958
Alzheimer’s disease; primary progressive aphasia; language; MRI; functional imaging
3.  Pattern of Brain Atrophy Rates in Autopsy-Confirmed Dementia with Lewy Bodies 
Neurobiology of aging  2014;36(1):452-461.
Dementia with Lewy bodies (DLB) is characterized by preserved whole brain and medial temporal lobe volumes compared to Alzheimer’s disease dementia (AD) on MRI. However, frequently coexistent AD-type pathology may influence the pattern of regional brain atrophy rates in DLB patients. We investigated the pattern and magnitude of the atrophy rates from two serial MRIs in autopsy-confirmed DLB (n=20) and mixed DLB/AD patients (n=22), compared to AD (n=30) and elderly non-demented controls (n=15), followed antemortem. DLB patients without significant AD-type pathology were characterized by lower global and regional rates of atrophy, similar to controls. The mixed DLB/AD patients displayed greater rates in the whole brain, temporo-parietal cortices, hippocampus and amygdala, and ventricle expansion, similar to AD patients. In the DLB and DLB/AD patients, the atrophy rates correlated with Braak neurofibrillary tangle stage, cognitive decline and progression of motor symptoms. Global and regional atrophy rates are associated with AD-type pathology in DLB, and can be used as biomarkers of AD progression in patients with LB pathology.
doi:10.1016/j.neurobiolaging.2014.07.005
PMCID: PMC4268128  PMID: 25128280
autopsy-confirmed dementia with Lewy bodies; Alzheimer’s disease; serial MRI; atrophy rate; Braak neurofibrillary tangle stage; sample size estimate
4.  Dementia with Lewy bodies 
Neurology  2014;83(9):801-809.
Objectives:
To investigate clinical, imaging, and pathologic associations of the cingulate island sign (CIS) in dementia with Lewy bodies (DLB).
Methods:
We retrospectively identified and compared patients with a clinical diagnosis of DLB (n = 39); patients with Alzheimer disease (AD) matched by age, sex, and education (n = 39); and cognitively normal controls (n = 78) who underwent 18F-fluorodeoxyglucose (FDG) and C11 Pittsburgh compound B (PiB)-PET scans. Among these patients, we studied those who came to autopsy and underwent Braak neurofibrillary tangle (NFT) staging (n = 10).
Results:
Patients with a clinical diagnosis of DLB had a higher ratio of posterior cingulate to precuneus plus cuneus metabolism, cingulate island sign (CIS), on FDG-PET than patients with AD (p < 0.001), a finding independent of β-amyloid load on PiB-PET (p = 0.56). Patients with CIS positivity on visual assessment of FDG-PET fit into the group of high- or intermediate-probability DLB pathology and received clinical diagnosis of DLB, not AD. Higher CIS ratio correlated with lower Braak NFT stage (r = −0.96; p < 0.001).
Conclusions:
Our study found that CIS on FDG-PET is not associated with fibrillar β-amyloid deposition but indicates lower Braak NFT stage in patients with DLB. Identifying biomarkers that measure relative contributions of underlying pathologies to dementia is critical as neurotherapeutics move toward targeted treatments.
doi:10.1212/WNL.0000000000000734
PMCID: PMC4155048  PMID: 25056580
5.  Antemortem MRI findings associated with microinfarcts at autopsy 
Neurology  2014;82(22):1951-1958.
Objective:
To determine antemortem MRI findings associated with microinfarcts at autopsy.
Methods:
Patients with microinfarcts (n = 22) and patients without microinfarcts (n = 44) who underwent antemortem MRI were identified from a dementia clinic–based, population–based, and community clinic–based autopsy cohort. The microinfarct and no-microinfarct groups were matched on age at MRI, age at death, sex, APOE status, Mini-Mental State Examination score, and pathologic diagnosis of Alzheimer disease. Brain infarcts were assessed on fluid-attenuated inversion recovery (FLAIR) MRI. White matter hyperintensities on FLAIR MRI and hippocampal volumes on T1-weighted MRI were quantified using automated methods. A subset of subjects with microinfarcts (n = 15) and a matched group of subjects without microinfarcts (n = 15) had serial T1-weighted MRIs and were included in an analysis of global and regional brain atrophy rates using automated methods.
Results:
The presence of cortical (p = 0.03) and subcortical (p = 0.02) infarcts on antemortem MRI was associated with presence of microinfarcts at autopsy. Higher numbers of cortical (p = 0.05) and subcortical (p = 0.03) infarcts on antemortem MRI were also associated with presence of microinfarcts. Presence of microinfarcts was not associated with white matter hyperintensities and cross-sectional hippocampal volume on antemortem MRI. Whole-brain and regional precuneus, motor, and somatosensory atrophy rates were higher in subjects with microinfarcts compared to subjects without microinfarcts.
Conclusions:
Microinfarcts increase brain atrophy rates independent of Alzheimer disease pathology. Association between microinfarct pathology and macroinfarcts on MRI suggests either common risk factors or a shared pathophysiology and potentially common preventive targets.
doi:10.1212/WNL.0000000000000471
PMCID: PMC4105260  PMID: 24793188
6.  Early Alzheimer's Disease Neuropathology Detected by Proton MR Spectroscopy 
The Journal of Neuroscience  2014;34(49):16247-16255.
Proton magnetic resonance spectroscopy (1H-MRS) is sensitive to early neurodegenerative processes associated with Alzheimer's disease (AD). Although 1H-MRS metabolite ratios of N-acetyl aspartate (NAA)/creatine (Cr), NAA/myoinositol (mI), and mI/Cr measured in the posterior cingulate gyrus reveal evidence of disease progression in AD, pathologic underpinnings of the 1H-MRS metabolite changes in AD are unknown. Pathologically diagnosed human cases ranging from no likelihood to high likelihood AD (n = 41, 16 females and 25 males) who underwent antemortem 1H-MRS of the posterior cingulate gyrus at 3 tesla were included in this study. Immunohistochemical evaluation was performed on the posterior cingulate gyrus using antibodies to synaptic vesicles, hyperphosphorylated tau (pTau), neurofibrillary tangle conformational-epitope (cNFT), amyloid-β, astrocytes, and microglia. The slides were digitally analyzed using Aperio software, which allows neuropathologic quantification in the posterior cingulate gray matter. MRS and pathology associations were adjusted for time from scan to death. Significant associations across AD and control subjects were found between reduced synaptic immunoreactivity and both NAA/Cr and NAA/mI in the posterior cingulate gyrus. Higher pTau burden was associated with lower NAA/Cr and NAA/mI. Higher amyloid-β burden was associated with elevated mI/Cr and lower NAA/mI ratios, but not with NAA/Cr. 1H-MRS metabolite levels reveal early neurodegenerative changes associated with AD pathology. Our findings support the hypothesis that a decrease in NAA/Cr is associated with loss of synapses and early pTau pathology, but not with amyloid-β or later accumulation of cNFT pathology in the posterior cingulate gyrus. In addition, elevation of mI/Cr is associated with the occurrence of amyloid-β plaques in AD.
doi:10.1523/JNEUROSCI.2027-14.2014
PMCID: PMC4252542  PMID: 25471565
Alzheimer's disease; digital microscopy; magnetic resonance spectroscopy; neuropathology; posterior cingulate; tau
7.  Association of type 2 diabetes with brain atrophy and cognitive impairment 
Neurology  2014;82(13):1132-1141.
Objective:
We investigated the associations of diabetes and hypertension with imaging biomarkers (markers of neuronal injury and ischemic damage) and with cognition in a population-based cohort without dementia.
Methods:
Participants (n = 1,437, median age 80 years) were evaluated by a nurse and physician and underwent neuropsychological testing. A diagnosis of cognitively normal, mild cognitive impairment (MCI), or dementia was made by an expert panel. Participants underwent MRI to determine cortical and subcortical infarctions, white matter hyperintensity (WMH) volume, hippocampal volume (HV), and whole brain volume (WBV). The medical records were reviewed for diabetes and hypertension in midlife or later.
Results:
Midlife diabetes was associated with subcortical infarctions (odds ratio, 1.85 [95% confidence interval, 1.09–3.15]; p = 0.02), reduced HV (−4% [−7 to −1.0]; p = 0.01), reduced WBV (−2.9% [−4.1 to −1.6]), and prevalent MCI (odds ratio, 2.08; p = 0.01). The association between diabetes and MCI persisted with adjustment for infarctions and WMH volume but was attenuated after adjustment for WBV (1.60 [0.87–2.95]; p = 0.13) and HV (1.82 [1.00–3.32]; p = 0.05). Midlife hypertension was associated with infarctions and WMH volume and was marginally associated with reduced performance in executive function. Effects of late-life onset of diabetes and hypertension were few.
Conclusions:
Midlife onset of diabetes may affect late-life cognition through loss of brain volume. Midlife hypertension may affect executive function through ischemic pathology. Late-life onset of these conditions had fewer effects on brain pathology and cognition.
doi:10.1212/WNL.0000000000000269
PMCID: PMC3966799  PMID: 24647028
8.  Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer’s disease spectrum 
Brain  2015;138(5):1370-1381.
Murray et al. examine the correspondence between Thal amyloid phase, tau pathology and clinical characteristics in a large Alzheimer’s disease autopsy series. They extrapolate their findings to an autopsy cohort for which Pittsburgh compound-B imaging data are available, and evaluate the neuropathological significance of a quantitative amyloid-β imaging cut-off point.
Murray et al. examine the correspondence between Thal amyloid phase, tau pathology and clinical characteristics in a large Alzheimer’s disease autopsy series. They extrapolate their findings to an autopsy cohort for which Pittsburgh compound-B imaging data are available, and evaluate the neuropathological significance of a quantitative amyloid-β imaging cut-off point.
Thal amyloid phase, which describes the pattern of progressive amyloid-β plaque deposition in Alzheimer’s disease, was incorporated into the latest National Institute of Ageing – Alzheimer’s Association neuropathologic assessment guidelines. Amyloid biomarkers (positron emission tomography and cerebrospinal fluid) were included in clinical diagnostic guidelines for Alzheimer’s disease dementia published by the National Institute of Ageing – Alzheimer’s Association and the International Work group. Our first goal was to evaluate the correspondence of Thal amyloid phase to Braak tangle stage and ante-mortem clinical characteristics in a large autopsy cohort. Second, we examined the relevance of Thal amyloid phase in a prospectively-followed autopsied cohort who underwent ante-mortem 11C-Pittsburgh compound B imaging; using the large autopsy cohort to broaden our perspective of 11C-Pittsburgh compound B results. The Mayo Clinic Jacksonville Brain Bank case series (n = 3618) was selected regardless of ante-mortem clinical diagnosis and neuropathologic co-morbidities, and all assigned Thal amyloid phase and Braak tangle stage using thioflavin-S fluorescent microscopy. 11C-Pittsburgh compound B studies from Mayo Clinic Rochester were available for 35 participants scanned within 2 years of death. Cortical 11C-Pittsburgh compound B values were calculated as a standard uptake value ratio normalized to cerebellum grey/white matter. In the high likelihood Alzheimer’s disease brain bank cohort (n = 1375), cases with lower Thal amyloid phases were older at death, had a lower Braak tangle stage, and were less frequently APOE-ε4 positive. Regression modelling in these Alzheimer’s disease cases, showed that Braak tangle stage, but not Thal amyloid phase predicted age at onset, disease duration, and final Mini-Mental State Examination score. In contrast, Thal amyloid phase, but not Braak tangle stage or cerebral amyloid angiopathy predicted 11C-Pittsburgh compound B standard uptake value ratio. In the 35 cases with ante-mortem amyloid imaging, a transition between Thal amyloid phases 1 to 2 seemed to correspond to 11C-Pittsburgh compound B standard uptake value ratio of 1.4, which when using our pipeline is the cut-off point for detection of clear amyloid-positivity regardless of clinical diagnosis. Alzheimer’s disease cases who were older and were APOE-ε4 negative tended to have lower amyloid phases. Although Thal amyloid phase predicted clinical characteristics of Alzheimer’s disease patients, the pre-mortem clinical status was driven by Braak tangle stage. Thal amyloid phase correlated best with 11C-Pittsburgh compound B values, but not Braak tangle stage or cerebral amyloid angiopathy. The 11C-Pittsburgh compound B cut-off point value of 1.4 was approximately equivalent to a Thal amyloid phase of 1–2.
doi:10.1093/brain/awv050
PMCID: PMC4407190  PMID: 25805643
Alzheimer’s disease; neuropathology; Thal amyloid phase; Pittsburgh compound B; Braak tangle stage
9.  Vascular and amyloid pathologies are independent predictors of cognitive decline in normal elderly 
Brain  2015;138(3):761-771.
Vemuri et al. show that amyloid and vascular pathologies are independent processes, and that both are major drivers of cognitive decline in the elderly. Cognitive reserve as measured by educational/occupational level and mid/late-life cognitive activity seems to offset the deleterious effects of both pathologies on cognitive trajectories.
Our primary objective was to investigate a biomarker driven model for the interrelationships between vascular disease pathology, amyloid pathology, and longitudinal cognitive decline in cognitively normal elderly subjects between 70 and 90 years of age. Our secondary objective was to investigate the beneficial effect of cognitive reserve on these interrelationships. We used brain amyloid-β load measured using Pittsburgh compound B positron emission tomography as a marker for amyloid pathology. White matter hyperintensities and brain infarcts were measured using fluid-attenuated inversion recovery magnetic resonance imaging as a marker for vascular pathology. We studied 393 cognitively normal elderly participants in the population-based Mayo Clinic Study of Aging who had a baseline 3 T fluid-attenuated inversion recovery magnetic resonance imaging assessment, Pittsburgh compound B positron emission tomography scan, baseline cognitive assessment, lifestyle measures, and at least one additional clinical follow-up. We classified subjects as being on the amyloid pathway if they had a global cortical amyloid-β load of ≥1.5 standard uptake value ratio and those on the vascular pathway if they had a brain infarct and/or white matter hyperintensities load ≥1.11% of total intracranial volume (which corresponds to the top 25% of white matter hyperintensities in an independent non-demented sample). We used a global cognitive z-score as a measure of cognition. We found no evidence that the presence or absence of vascular pathology influenced the presence or absence of amyloid pathology and vice versa, suggesting that the two processes seem to be independent. Baseline cognitive performance was lower in older individuals, in males, those with lower education/occupation, and those on the amyloid pathway. The rate of cognitive decline was higher in older individuals (P < 0.001) and those with amyloid (P = 0.0003) or vascular (P = 0.0037) pathologies. In those subjects with both vascular and amyloid pathologies, the effect of both pathologies on cognition was additive and not synergistic. For a 79-year-old subject, the predicted annual rate of global z-score decline was −0.02 if on neither pathway, −0.07 if on the vascular pathway, −0.08 if on the amyloid pathway and −0.13 if on both pathways. The main conclusions of this study were: (i) amyloid and vascular pathologies seem to be at least partly independent processes that both affect longitudinal cognitive trajectories adversely and are major drivers of cognitive decline in the elderly; and (ii) cognitive reserve seems to offset the deleterious effect of both pathologies on the cognitive trajectories.
doi:10.1093/brain/awu393
PMCID: PMC4339775  PMID: 25595145
ageing; cognitive neurology; neuroimaging; neuro protective strategies
10.  Association of Lifetime Intellectual Enrichment with Cognitive Decline in the Older Population 
JAMA neurology  2014;71(8):1017-1024.
IMPORTANCE
Intellectual lifestyle enrichment throughout life is increasingly viewed as a protective strategy against commonly observed cognitive decline in the elderly.
OBJECTIVE
To investigate the association of lifetime intellectual enrichment with baseline cognitive performance and rate of cognitive decline in a non-demented elderly population and to estimate difference (in years) associated with lifetime intellectual enrichment to the onset of cognitive impairment.
DESIGN, SETTING, PARTICIPANTS
Prospective analysis of subjects enrolled in the Mayo Clinic Study of Aging (MCSA), a longitudinal population-based study of cognitive aging in Olmsted County, Minnesota. We studied 1995 non-demented (1718 cognitively normal, 277 MCI) participants in MCSA who completed intellectual lifestyle measures at baseline and underwent at least one follow-up visit.
MAIN OUTCOMES AND MEASURES
We studied the effect of lifetime intellectual enrichment by separating the variables into two non-overlapping principal components: education/occupation-score and mid/late-life cognitive activity measure based on self-report questionnaires. A global cognitive Z-score served as our summary cognition measure. We used linear mixed-effects models to investigate the associations of demographic and intellectual enrichment measures with global cognitive Z-score trajectories.
RESULTS
Baseline cognitive performance was lower in older subjects and in those with lower education/occupation, lower mid/late-life cognitive activity, apolipoprotein E4 (APOE) genotype, and in men. The interaction between the two intellectual enrichment measures was significant such that the beneficial effect of mid/late-life cognitive activity on baseline cognitive performance was reduced with increasing education/occupation. Only baseline age, mid/late-life cognitive activity, and APOE4 genotype were significantly associated with longitudinal change in cognitive performance from baseline. For APOE4 carriers with high lifetime intellectual enrichment (75th percentile of both education/occupation and mid/late-life cognitive activity), the onset of cognitive impairment was about 8.7 years later compared with low lifetime intellectual enrichment (25th percentile of both education/occupation and mid/late-life cognitive activity) in an 80 year old subject.
CONCLUSIONS AND RELEVANCE
Higher levels of education/occupation were associated with higher levels of cognition. Higher levels of mid/late-life leisure activity were also associated with higher levels of cognition, but the slope of this relationship slightly increased over time. Lifetime intellectual enrichment might delay the onset of cognitive impairment and be used as a successful preventive intervention to reduce the impending dementia epidemic.
doi:10.1001/jamaneurol.2014.963
PMCID: PMC4266551  PMID: 25054282
11.  MRI and pathology of REM sleep behavior disorder in dementia with Lewy bodies 
Neurology  2013;81(19):1681-1689.
Objective:
To determine structural MRI and digital microscopic characteristics of REM sleep behavior disorder in individuals with low-, intermediate-, and high-likelihood dementia with Lewy bodies (DLB) at autopsy.
Methods:
Patients with autopsy-confirmed low-, intermediate-, and high-likelihood DLB, according to the probability statement recommended by the third report of the DLB Consortium, and antemortem MRI, were identified (n = 75). The clinical history was assessed for presence (n = 35) and absence (n = 40) of probable REM sleep behavior disorder (pRBD), and patients' antemortem MRIs were compared using voxel-based morphometry. Pathologic burdens of phospho-tau, β-amyloid, and α-synuclein were measured in regions associated with early neuropathologic involvement, the hippocampus and amygdala.
Results:
pRBD was present in 21 patients (60%) with high-likelihood, 12 patients (34%) with intermediate-likelihood, and 2 patients (6%) with low-likelihood DLB. Patients with pRBD were younger, more likely to be male (p ≤ 0.001), and had a more frequent neuropathologic diagnosis of diffuse (neocortical) Lewy body disease. In the hippocampus and amygdala, phospho-tau and β-amyloid burden were lower in patients with pRBD compared with those without pRBD (p < 0.01). α-Synuclein burden did not differ in the hippocampus, but trended in the amygdala. Patients without pRBD had greater atrophy of temporoparietal cortices, hippocampus, and amygdala (p < 0.001) than those with pRBD; atrophy of the hippocampus (p = 0.005) and amygdala (p = 0.02) were associated with greater phospho-tau burdens in these regions.
Conclusion:
Presence of pRBD is associated with a higher likelihood of DLB and less severe Alzheimer-related pathology in the medial temporal lobes, whereas absence of pRBD is characterized by Alzheimer-like atrophy patterns on MRI and increased phospho-tau burden.
doi:10.1212/01.wnl.0000435299.57153.f0
PMCID: PMC3812105  PMID: 24107861
12.  Improved DTI registration allows voxel-based analysis that outperforms Tract-Based Spatial Statistics 
NeuroImage  2014;94:65-78.
Tract-Based Spatial Statistics (TBSS) is a popular software pipeline to coregister sets of diffusion tensor Fractional Anisotropy (FA) images for performing voxel-wise comparisons. It is primarily defined by its skeleton projection step intended to reduce effects of local misregistration. A white matter “skeleton” is computed by morphological thinning of the inter-subject mean FA, and then all voxels are projected to the nearest location on this skeleton. Here we investigate several enhancements to the TBSS pipeline based on recent advances in registration for other modalities, principally based on groupwise registration with the ANTS-SyN algorithm. We validate these enhancements using simulation experiments with synthetically-modified images. When used with these enhancements, we discover that TBSS's skeleton projection step actually reduces algorithm accuracy, as the improved registration leaves fewer errors to warrant correction, and the effects of this projection's compromises become stronger than those of its benefits. In our experiments, our proposed pipeline without skeleton projection is more sensitive for detecting true changes and has greater specificity in resisting false positives from misregistration. We also present comparative results of the proposed and traditional methods, both with and without the skeleton projection step, on three real-life datasets: two comparing differing populations of Alzheimer's disease patients to matched controls, and one comparing progressive supranuclear palsy patients to matched controls. The proposed pipeline produces more plausible results according to each disease's pathophysiology.
doi:10.1016/j.neuroimage.2014.03.026
PMCID: PMC4137565  PMID: 24650605
DTI; Fractional Anisotropy; Voxel-based analysis; VBM; TBSS; Registration
13.  MRI and MRS predictors of mild cognitive impairment in a population-based sample 
Neurology  2013;81(2):126-133.
Objective:
To investigate MRI and proton magnetic resonance spectroscopy (MRS) predictors of mild cognitive impairment (MCI) in cognitively normal older adults.
Methods:
Subjects were cognitively normal older adults (n = 1,156) who participated in the population-based Mayo Clinic Study of Aging MRI/MRS study from August 2005 to December 2010 and had at least one annual clinical follow-up. Single-voxel MRS was performed from the posterior cingulate gyri, and hippocampal volumes and white matter hyperintensity volumes were quantified using automated methods. Brain infarcts were assessed on MRI. Cox proportional hazards regression, with age as the time scale, was used to assess the effect of MRI and MRS markers on the risk of progression from cognitively normal to MCI. Linear mixed-effects models were used to assess the effect of MRI and MRS markers on cognitive decline.
Results:
After a median follow-up of 2.8 years, 214 participants had progressed to MCI or dementia (estimated incidence rate = 6.1% per year; 95% confidence interval = 5.3%–7.0%). In univariable modeling, hippocampal volume, white matter hyperintensity volume, and N-acetylaspartate/myo-inositol were significant predictors of MCI in cognitively normal older adults. In multivariable modeling, only decreased hippocampal volume and N-acetylaspartate/myo-inositol were independent predictors of MCI. These MRI/MRS predictors of MCI as well as infarcts were associated with cognitive decline (p < 0.05).
Conclusion:
Quantitative MRI and MRS markers predict progression to MCI and cognitive decline in cognitively normal older adults. MRS may contribute to the assessment of preclinical dementia pathologies by capturing neurodegenerative changes that are not detected by hippocampal volumetry.
doi:10.1212/WNL.0b013e31829a3329
PMCID: PMC3770173  PMID: 23761624
14.  Effect of Lifestyle Activities on AD Biomarkers and Cognition 
Annals of neurology  2012;72(5):730-738.
Objectives
To investigate the effect of intellectual and physical activity on biomarkers of Alzheimer’s disease (AD) pathophysiology and cognition in a non-demented elderly population. The biomarkers evaluated were brain Aβ-amyloid load via PIB-PET, neuronal dysfunction via FDG-PET and neurodegeneration via Structural-MRI.
Methods
We studied 515 non-demented (428 cognitively normal and 87 MCI) participants in the population based Mayo Clinic Study of Aging who completed a 3T MRI, PET scans, APOE genotype, had lifestyle activity measures and cognition data available. The imaging measures computed were global PiB-PET uptake; global FDG-PET and MRI based hippocampal volume. We consolidated activity variables into lifetime intellectual, current intellectual and current physical activities. We used a global cognitive Z-score as a measure of cognition. We applied two independent methods – partial correlation analysis adjusted for age and gender and path analysis using structural equations to evaluate the associations between lifestyle activities, imaging biomarkers and global cognition.
Results
None of the lifestyle variables correlated with the biomarkers and the path associations between lifestyle variables and biomarkers were not significant (p>0.05). On the other hand, all the biomarkers were correlated with global cognitive Z-score (p<0.05) and the path associations between (lifetime and current) intellectual activities and global Z-score were significant (p<0.01).
Interpretation
Intellectual and physical activity lifestyle factors were not associated with AD biomarkers but intellectual lifestyle factors explained variability in the cognitive performance in this non-demented population. This study provides evidence that lifestyle activities may delay the onset of dementia but do not significantly influence the expression of AD pathophysiology.
doi:10.1002/ana.23665
PMCID: PMC3539211  PMID: 23280791
Alzheimer’s disease; Imaging biomarkers; Lifestyle Activities
15.  Multimodality Imaging Characteristics of Dementia with Lewy Bodies 
Neurobiology of Aging  2011;33(9):2091-2105.
Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia after Alzheimer's disease (AD). Our objective was to determine whether the 11C–Pittsburgh Compound-B (PiB) retention and regional hypometabolism on PET and regional cortical atrophy on MRI are complementary in characterizing patients with DLB and differentiating them from AD. We studied age, gender and education matched patients with a clinical diagnosis of DLB (n=21), AD (n=21), and cognitively normal subjects (n=42). Hippocampal atrophy, global cortical PiB retention and occipital lobe metabolism in combination distinguished DLB from AD better than any of the measurements alone (area under the receiver operating characteristic=0.98).Five of the DLB and AD patients who underwent autopsy were distinguished through multimodality imaging. These data demonstrate that MRI and PiB PET contribute to characterizing the distinct pathological mechanisms in patients with AD compared to DLB. Occipital and posterior parietotemporal lobe hypometabolism is a distinguishing feature of DLB and this regional hypometabolic pattern is independent of the amyloid pathology.
doi:10.1016/j.neurobiolaging.2011.09.024
PMCID: PMC3288845  PMID: 22018896
Dementia with Lewy bodies; MRI; PET; FDG; PiB; Alzheimer's disease
16.  Focal atrophy on MRI and neuropathologic classification of dementia with Lewy bodies 
Neurology  2012;79(6):553-560.
Objective:
To determine the association between the focal atrophy measures on antemortem MRI and postmortem neuropathologic classification of dementia with Lewy bodies (DLB) using the Third Report of the DLB Consortium criteria.
Methods:
We retrospectively identified 56 subjects who underwent antemortem MRI and had Lewy body (LB) pathology at autopsy. Subjects were pathologically classified as high (n = 25), intermediate (n = 22), and low likelihood DLB (n = 9) according to the Third Report of the DLB Consortium criteria. We included 2 additional pathologic comparison groups without LBs: one with low likelihood Alzheimer disease (AD) (control; n = 27) and one with high likelihood AD (n = 33). The associations between MRI-based volumetric measurements and the pathologic classification of DLB were tested with analysis of covariance by adjusting for age, sex, and MRI-to-death interval.
Results:
Antemortem hippocampal and amygdalar volumes increased from low to intermediate to high likelihood DLB (p < 0.001, trend test). Smaller hippocampal and amygdalar volumes were associated with higher Braak neurofibrillary tangle stage (p < 0.001). Antemortem dorsal mesopontine gray matter (GM) atrophy was found in those with high likelihood DLB compared with normal control subjects (p = 0.004) and those with AD (p = 0.01). Dorsal mesopontine GM volume decreased from low to intermediate to high likelihood DLB (p = 0.01, trend test).
Conclusion:
Antemortem hippocampal and amygdalar volumes increase and dorsal mesopontine GM volumes decrease in patients with low to high likelihood DLB according to the Third Report of the DLB Consortium criteria. Patients with high likelihood DLB typically have normal hippocampal volumes but have atrophy in the dorsal mesopontine GM nuclei.
doi:10.1212/WNL.0b013e31826357a5
PMCID: PMC3413765  PMID: 22843258
17.  Imaging and acetylcholinesterase inhibitor response in dementia with Lewy bodies 
Brain  2012;135(8):2470-2477.
Acetylcholinesterase inhibitors are commonly used to treat patients with dementia with Lewy bodies. Hippocampal atrophy on magnetic resonance imaging and amyloid-β load on positron emission tomography are associated with the Alzheimer’s disease-related pathology in patients with dementia with Lewy bodies. To date, few studies have investigated imaging markers that predict treatment response in patients with dementia with Lewy bodies. Our objective was to determine whether imaging markers of Alzheimer’s disease-related pathology such as hippocampal volume, brain amyloid-β load on 11C Pittsburgh compound B positron emission tomography predict treatment response to acetylcholinesterase inhibitors in patients with dementia with Lewy bodies. We performed a retrospective analysis on consecutive treatment-naive patients with dementia with Lewy bodies (n = 54) from the Mayo Clinic Alzheimer’s Disease Research Centre who subsequently received acetylcholinesterase inhibitors and underwent magnetic resonance imaging with hippocampal volumetry. Baseline and follow-up assessments were obtained with the Mattis Dementia Rating Scale. Subjects were divided into three groups (reliable improvement, stable or reliable decline) using Dementia Rating Scale reliable change indices determined previously. Associations between hippocampal volumes and treatment response were tested with analysis of covariance adjusting for baseline Dementia Rating Scale, age, gender, magnetic resonance field strength and Dementia Rating Scale interval. Seven subjects underwent 11C Pittsburgh compound B imaging within 12 weeks of magnetic resonance imaging. Global cortical 11C Pittsburgh compound B retention (scaled to cerebellar retention) was calculated in these patients. Using a conservative psychometric method of assessing treatment response, there were 12 patients with reliable decline, 29 stable cases and 13 patients with reliable improvement. The improvers had significantly larger hippocampi than those that declined (P = 0.02) and the stable (P = 0.04) group. An exploratory analysis demonstrated larger grey matter volumes in the temporal and parietal lobes in improvers compared with those who declined (P < 0.05). The two patients who had a positive 11C Pittsburgh compound B positron emission tomography scan declined and those who had a negative 11C Pittsburgh compound B positron emission tomography scan improved or were stable after treatment. Patients with dementia with Lewy bodies who do not have the imaging features of coexistent Alzheimer’s disease-related pathology are more likely to cognitively improve with acetylcholinesterase inhibitor treatment.
doi:10.1093/brain/aws173
PMCID: PMC3407425  PMID: 22810436
dementia with Lewy bodies; acetylcholinesterase inhibitors; MRI; PiB; PET; amyloid
18.  Temporoparietal atrophy: a marker of AD pathology independent of clinical diagnosis 
Neurobiology of aging  2009;32(9):1531-1541.
Alzheimer's disease (AD) can present with non-amnestic clinical syndromes. We investigated whether there is an imaging signature of AD pathology in these atypical subjects. We identified 14 subjects that had pathological AD, a non-amnestic presentation (i.e. atypical AD), and MRI. These subjects were matched to 14 with clinical and pathological AD (i.e. typical AD), 14 with the same non-amnestic presentations with frontotemporal lobar degeneration (FTLD) pathology, and 20 controls. Voxel-based morphometry and region-of-interest (ROI) analysis were used to assess patterns of grey matter loss. Loss was observed in the temporoparietal cortex in both typical and atypical AD, and showed significantly greater loss than FTLD. However, the medial temporal lobes were more severely affected in typical AD and FTLD compared to atypical AD. A ratio of hippocampal and temporoparietal volumes provided excellent discrimination of atypical AD from FTLD subjects. Temporoparietal atrophy may therefore provide a useful marker of the presence of AD pathology even in subjects with atypical clinical presentations, especially in the context of relative sparing of the hippocampus.
doi:10.1016/j.neurobiolaging.2009.10.012
PMCID: PMC2888989  PMID: 19914744
Alzheimer's disease; pathology; voxel-based morphometry; atypical presentation; frontotemporal lobar degeneration; temporoparietal cortex; hippocampus
19.  Effect of APOE ε4 Status on Intrinsic Network Connectivity in Cognitively Normal Elderly 
Archives of Neurology  2011;68(9):1131-1136.
Objective
To examine default mode and salience network functional connectivity as a function of APOE ε4 status in a group of cognitively normal age, gender and education-matched older adults.
Design
Case-control study.
Setting
Community-based sample
Subjects
Fifty-six cognitively normal APOE ε4 carriers and 56 age, gender and education-matched cognitively normal APOE ε4 non-carriers.
Main Outcome Measure
Alterations in in-phase default mode and salience network connectivity in APOE ε4 carriers compared to APOE ε4 non-carriers ranging from 63 to 91 years of age.
Results
A posterior cingulate seed revealed decreased in-phase connectivity in regions of the posterior default mode network that included the left inferior parietal lobe, left middle temporal gyrus, and bilateral anterior temporal lobes in the ε4 carriers relative to APOE ε4 non-carriers. An anterior cingulate seed showed greater in-phase connectivity in the salience network, including the cingulate gyrus, medial prefrontal cortex, bilateral insular cortex, striatum, and thalamus in APOE ε4 carriers vs. non-carriers. There were no group-wise differences in brain anatomy.
Conclusions
We found reductions in posterior default mode network connectivity but increased salience network connectivity in elderly cognitively normal APOE ε4 carriers relative to APOE ε4 non-carriers at rest. The observation of functional alterations in connectivity in the absence of structural changes between APOE e4 carriers and non-carriers suggests that alterations in connectivity may have the potential to serve as an early biomarker.
doi:10.1001/archneurol.2011.108
PMCID: PMC3392960  PMID: 21555604
20.  Non-Stationarity in the “Resting Brain’s” Modular Architecture 
PLoS ONE  2012;7(6):e39731.
Task-free functional magnetic resonance imaging (TF-fMRI) has great potential for advancing the understanding and treatment of neurologic illness. However, as with all measures of neural activity, variability is a hallmark of intrinsic connectivity networks (ICNs) identified by TF-fMRI. This variability has hampered efforts to define a robust metric of connectivity suitable as a biomarker for neurologic illness. We hypothesized that some of this variability rather than representing noise in the measurement process, is related to a fundamental feature of connectivity within ICNs, which is their non-stationary nature. To test this hypothesis, we used a large (n = 892) population-based sample of older subjects to construct a well characterized atlas of 68 functional regions, which were categorized based on independent component analysis network of origin, anatomical locations, and a functional meta-analysis. These regions were then used to construct dynamic graphical representations of brain connectivity within a sliding time window for each subject. This allowed us to demonstrate the non-stationary nature of the brain’s modular organization and assign each region to a “meta-modular” group. Using this grouping, we then compared dwell time in strong sub-network configurations of the default mode network (DMN) between 28 subjects with Alzheimer’s dementia and 56 cognitively normal elderly subjects matched 1∶2 on age, gender, and education. We found that differences in connectivity we and others have previously observed in Alzheimer’s disease can be explained by differences in dwell time in DMN sub-network configurations, rather than steady state connectivity magnitude. DMN dwell time in specific modular configurations may also underlie the TF-fMRI findings that have been described in mild cognitive impairment and cognitively normal subjects who are at risk for Alzheimer’s dementia.
doi:10.1371/journal.pone.0039731
PMCID: PMC3386248  PMID: 22761880
21.  Antemortem Differential Diagnosis of Dementia Pathology using Structural MRI: Differential-STAND 
NeuroImage  2010;55(2):522-531.
The common neurodegenerative pathologies underlying dementia are Alzheimer’s disease (AD), Lewy body disease (LBD) and Frontotemporal lobar degeneration (FTLD). Our aim was to identify patterns of atrophy unique to each of these diseases using antemortem structural-MRI scans of pathologically-confirmed dementia cases and build an MRI-based differential diagnosis system. Our approach of creating atrophy maps using structural-MRI and applying them for classification of new incoming patients is labeled Differential-STAND (Differential-diagnosis based on STructural Abnormality in NeuroDegeneration). Pathologically-confirmed subjects with a single dementing pathologic diagnosis who had an MRI at the time of clinical diagnosis of dementia were identified: 48 AD, 20 LBD, 47 FTLD-TDP (pathology-confirmed FTLD with TDP-43). Gray matter density in 91 regions-of-interest was measured in each subject and adjusted for head-size and age using a database of 120 cognitively normal elderly. The atrophy patterns in each dementia type when compared to pathologically-confirmed controls mirrored known disease-specific anatomic patterns: AD-temporoparietal association cortices and medial temporal lobe; FTLD-TDP-frontal and temporal lobes and LBD-bilateral amygdalae, dorsal midbrain and inferior temporal lobes. Differential-STAND based classification of each case was done based on a mixture model generated using bisecting k-means clustering of the information from the MRI scans. Leave-one-out classification showed reasonable performance compared to the autopsy gold-standard and clinical diagnosis: AD (sensitivity:90.7%; specificity:84 %), LBD (sensitivity:78.6%; specificity:98.8%) and FTLD-TDP (sensitivity:84.4%; specificity:93.8%). The proposed approach establishes a direct a priori relationship between specific topographic patterns on MRI and “gold standard” of pathology which can then be used to predict underlying dementia pathology in new incoming patients.
doi:10.1016/j.neuroimage.2010.12.073
PMCID: PMC3039279  PMID: 21195775
MRI; Alzheimer’s disease; Lewy body disease; Frontotemporal lobar degeneration
22.  Untreated Type 2 Diabetes and Its Complications Are Associated With Subcortical Infarctions 
Diabetes Care  2010;34(1):184-186.
OBJECTIVE
To investigate the association of type 2 diabetes with subcortical infarctions.
RESEARCH DESIGN AND METHODS
We investigated this association in subjects with type 2 diabetes (case subjects; n = 93) and without type 2 diabetes (control subjects; n = 186), matched by age, sex, and years of education. Participants were a subset of the Mayo Clinic Study of Aging (median age 79 years) who had undergone magnetic resonance imaging.
RESULTS
The frequency of subcortical infarctions was 39% in case subjects and 29% in control subjects (odds ratio 1.59 [95% CI 0.91–2.75]). The association was stronger in case subjects without treatment (2.60 [1.11–6.08]) and in case subjects with diabetes-related complications (1.96 [1.02–3.74]) compared with control subjects.
CONCLUSIONS
These findings suggest that untreated type 2 diabetes and type 2 diabetes with complications are associated with subcortical infarctions.
doi:10.2337/dc10-0602
PMCID: PMC3005470  PMID: 20980413
23.  Cognitive reserve and Alzheimer's disease biomarkers are independent determinants of cognition 
Brain  2011;134(5):1479-1492.
The objective of this study was to investigate how a measure of educational and occupational attainment, a component of cognitive reserve, modifies the relationship between biomarkers of pathology and cognition in Alzheimer's disease. The biomarkers evaluated quantified neurodegeneration via atrophy on magnetic resonance images, neuronal injury via cerebral spinal fluid t-tau, brain amyloid-β load via cerebral spinal fluid amyloid-β1–42 and vascular disease via white matter hyperintensities on T2/proton density magnetic resonance images. We included 109 cognitively normal subjects, 192 amnestic patients with mild cognitive impairment and 98 patients with Alzheimer's disease, from the Alzheimer's Disease Neuroimaging Initiative study, who had undergone baseline lumbar puncture and magnetic resonance imaging. We combined patients with mild cognitive impairment and Alzheimer's disease in a group labelled ‘cognitively impaired’ subjects. Structural Abnormality Index scores, which reflect the degree of Alzheimer's disease-like anatomic features on magnetic resonance images, were computed for each subject. We assessed Alzheimer's Disease Assessment Scale (cognitive behaviour section) and mini-mental state examination scores as measures of general cognition and Auditory–Verbal Learning Test delayed recall, Boston naming and Trails B scores as measures of specific domains in both groups of subjects. The number of errors on the American National Adult Reading Test was used as a measure of environmental enrichment provided by educational and occupational attainment, a component of cognitive reserve. We found that in cognitively normal subjects, none of the biomarkers correlated with the measures of cognition, whereas American National Adult Reading Test scores were significantly correlated with Boston naming and mini-mental state examination results. In cognitively impaired subjects, the American National Adult Reading Test and all biomarkers of neuronal pathology and amyloid load were independently correlated with all cognitive measures. Exceptions to this general conclusion were absence of correlation between cerebral spinal fluid amyloid-β1–42 and Boston naming and Trails B. In contrast, white matter hyperintensities were only correlated with Boston naming and Trails B results in the cognitively impaired. When all subjects were included in a flexible ordinal regression model that allowed for non-linear effects and interactions, we found that the American National Adult Reading Test had an independent additive association such that better performance was associated with better cognitive performance across the biomarker distribution. Our main conclusions included: (i) that in cognitively normal subjects, the variability in cognitive performance is explained partly by the American National Adult Reading Test and not by biomarkers of Alzheimer's disease pathology; (ii) in cognitively impaired subjects, the American National Adult Reading Test, biomarkers of neuronal pathology (structural magnetic resonance imaging and cerebral spinal fluid t-tau) and amyloid load (cerebral spinal fluid amyloid-β1–42) all independently explain variability in general cognitive performance; and (iii) that the association between cognition and the American National Adult Reading Test was found to be additive rather than to interact with biomarkers of Alzheimer's disease pathology.
doi:10.1093/brain/awr049
PMCID: PMC3097887  PMID: 21478184
Alzheimer's disease; mild cognitive impairment; CSF biomarkers; MRI; cognitive reserve
24.  Distinct anatomical subtypes of the behavioural variant of frontotemporal dementia: a cluster analysis study 
Brain  2009;132(11):2932-2946.
The behavioural variant of frontotemporal dementia is a progressive neurodegenerative syndrome characterized by changes in personality and behaviour. It is typically associated with frontal lobe atrophy, although patterns of atrophy are heterogeneous. The objective of this study was to examine case-by-case variability in patterns of grey matter atrophy in subjects with the behavioural variant of frontotemporal dementia and to investigate whether behavioural variant of frontotemporal dementia can be divided into distinct anatomical subtypes. Sixty-six subjects that fulfilled clinical criteria for a diagnosis of the behavioural variant of frontotemporal dementia with a volumetric magnetic resonance imaging scan were identified. Grey matter volumes were obtained for 26 regions of interest, covering frontal, temporal and parietal lobes, striatum, insula and supplemental motor area, using the automated anatomical labelling atlas. Regional volumes were divided by total grey matter volume. A hierarchical agglomerative cluster analysis using Ward's clustering linkage method was performed to cluster the behavioural variant of frontotemporal dementia subjects into different anatomical clusters. Voxel-based morphometry was used to assess patterns of grey matter loss in each identified cluster of subjects compared to an age and gender-matched control group at P < 0.05 (family-wise error corrected). We identified four potentially useful clusters with distinct patterns of grey matter loss, which we posit represent anatomical subtypes of the behavioural variant of frontotemporal dementia. Two of these subtypes were associated with temporal lobe volume loss, with one subtype showing loss restricted to temporal lobe regions (temporal-dominant subtype) and the other showing grey matter loss in the temporal lobes as well as frontal and parietal lobes (temporofrontoparietal subtype). Another two subtypes were characterized by a large amount of frontal lobe volume loss, with one subtype showing grey matter loss in the frontal lobes as well as loss of the temporal lobes (frontotemporal subtype) and the other subtype showing loss relatively restricted to the frontal lobes (frontal-dominant subtype). These four subtypes differed on clinical measures of executive function, episodic memory and confrontation naming. There were also associations between the four subtypes and genetic or pathological diagnoses which were obtained in 48% of the cohort. The clusters did not differ in behavioural severity as measured by the Neuropsychiatric Inventory; supporting the original classification of the behavioural variant of frontotemporal dementia in these subjects. Our findings suggest behavioural variant of frontotemporal dementia can therefore be subdivided into four different anatomical subtypes.
doi:10.1093/brain/awp232
PMCID: PMC2768663  PMID: 19762452
behavioural variant frontotemporal dementia; atrophy; cluster analysis; voxel-based morphometry
25.  3D Maps from Multiple MRI Illustrate Changing Atrophy Patterns as Subjects Progress from MCI to AD 
Brain : a journal of neurology  2007;130(Pt 7):1777-1786.
Summary
Mild cognitive impairment (MCI), particularly the amnestic subtype (aMCI), is considered as a transitional stage between normal aging and a diagnosis of clinically probable Alzheimer's disease (AD). The aMCI construct is particularly useful as it provides an opportunity to assess a clinical stage which in most subjects represents prodromal AD. The aim of this study was to assess the progression of cerebral atrophy over multiple serial MRI during the period from aMCI to conversion to AD. Thirty-three subjects were selected that fulfilled clinical criteria for aMCI and had three serial MRI scans: the first scan approximately three years before conversion to AD, the second scan approximately one year before conversion, and the third scan at the time of conversion from aMCI to AD. A group of 33 healthy controls were age and gender-matched to the study cohort. Voxel-based morphometry (VBM) was used to assess patterns of grey matter atrophy in the aMCI subjects at each time-point compared to the control group. Customized templates and prior probability maps were used to avoid normalization and segmentation bias. The pattern of grey matter loss in the aMCI subject scans that were three years before conversion was focused primarily on the medial temporal lobes, including the amygdala, anterior hippocampus and entorhinal cortex, with some additional involvement of the fusiform gyrus, compared to controls. The extent and magnitude of the cerebral atrophy further progressed by the time the subjects were one year before conversion. At this point atrophy in the temporal lobes spread to include the middle temporal gyrus, and extended into more posterior regions of the temporal lobe to include the entire extent of the hippocampus. The parietal lobe also started to become involved. By the time the subjects had converted to a clinical diagnosis of AD the pattern of grey matter atrophy had become still more widespread with more severe involvement of the medial temporal lobes and the temporoparietal association cortices and, for the first time, substantial involvement of the frontal lobes. This pattern of progression fits well with the Braak and Braak neurofibrillary pathological staging scheme in AD. It suggests that the earliest changes occur in the anterior medial temporal lobe and fusiform gyrus, and that these changes occur at least three years before conversion to AD. These results also suggest that 3-dimensional patterns of grey matter atrophy may help to predict the time to conversion in subjects with aMCI.
doi:10.1093/brain/awm112
PMCID: PMC2752411  PMID: 17533169
Alzheimer's disease; mild cognitive impairment; longitudinal; magnetic resonance imaging; voxel-based morphometry

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