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1.  Midbrain atrophy is not a biomarker of PSP pathology 
Background
Midbrain atrophy is a characteristic feature of progressive supranuclear palsy (PSP), although it is unclear whether it is associated with the PSP syndrome (PSPS) or PSP pathology. We aimed to determine whether midbrain atrophy is a useful biomarker of PSP pathology, or whether it is only associated with typical PSPS.
Methods
We identified all autopsy-confirmed subjects with the PSP clinical phenotype (i.e. PSPS) or PSP pathology and a volumetric MRI. Of 24 subjects with PSP pathology, 11 had a clinical diagnosis of PSPS (PSP-PSPS), and 13 had a non-PSPS clinical diagnosis (PSP-other). Three subjects had PSPS and corticobasal degeneration pathology (CBD-PSPS). Healthy control and disease control groups (i.e. a group without PSPS or PSP pathology) and a group with CBD pathology and corticobasal syndrome (CBD-CBS) were selected. Midbrain area was measured in all subjects.
Results
Midbrain area was reduced in each group with clinical PSPS (with and without PSP pathology). The group with PSP pathology and non-PSPS clinical syndromes did not show reduced midbrain area. Midbrain area was smaller in the subjects with PSPS compared to those without PSPS (p<0.0001), with an area under the receiver-operator-curve of 0.99 (0.88,0.99). A midbrain area cut-point of 92 mm2 provided optimum sensitivity (93%) and specificity (89%) for differentiation.
Conclusion
Midbrain atrophy is associated with the clinical presentation of PSPS, but not with the pathological diagnosis of PSP in the absence of the PSPS clinical syndrome. This finding has important implications for the utility of midbrain measurements as diagnostic biomarkers for PSP pathology.
doi:10.1111/ene.12212
PMCID: PMC3773014  PMID: 23746093
Progressive supranuclear palsy; tau; neuropathology; MRI; midbrain
2.  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
3.  Brain Injury Biomarkers Are Not Dependent on β-amyloid in Normal Elderly 
Annals of neurology  2013;73(4):472-480.
Background
The new criteria for preclinical Alzheimer’s Disease (AD) proposed 3 stages: abnormal levels of β-amyloid (stage 1); stage 1 plus evidence of brain injury (stage 2); and stage 2 plus subtle cognitive changes (stage 3). However, a large group of subjects with normal β-amyloid biomarkers have evidence of brain injury; we labeled them as “suspected non-Alzheimer pathway” (sNAP) group. The characteristics of the sNAP group are poorly understood.
Methods
Using the preclinical AD classification, 430 cognitively normal subjects from the Mayo Clinic Study of Aging who underwent brain MR, 18fluorodeoxyglucose (FDG) and Pittsburgh compound B (PiB) positron emission tomography (PET) were evaluated with FDG PET regional volumetrics, MR regional brain volumetrics, white matter hyperintensity (WMH) volume and number of infarcts. We examined cross-sectional associations across AD preclinical stages, those with all biomarkers normal, and the sNAP group.
Results
The sNAP group had a lower proportion (14%) with APOE ε4 genotype than the preclinical AD stages 2 + 3. The sNAP group did not show any group differences compared to stages 2 + 3 of the preclinical AD group on measures of FDG PET regional hypometabolism, MR regional brain volume loss, cerebrovascular imaging lesions, vascular risk factors, imaging changes associated with α-synucleinopathy or physical findings of parkinsonism.
Conclusions
Cognitively normal persons with brain injury biomarker abnormalities, with or without abnormal levels of β-amyloid, were indistinguishable on a variety of imaging markers, clinical features and risk factors. The initial appearance of brain injury biomarkers that occurs in cognitively normal persons with preclinical AD may not depend on β-amyloidosis.
doi:10.1002/ana.23816
PMCID: PMC3660408  PMID: 23424032
Alzheimer’s disease; PET imaging; MR imaging; Epidemiology
4.  Brain β-amyloid load approaches a plateau 
Neurology  2013;80(10):890-896.
Objective:
To model the temporal trajectory of β-amyloid accumulation using serial amyloid PET imaging.
Methods:
Participants, aged 70–92 years, were enrolled in either the Mayo Clinic Study of Aging (n = 246) or the Mayo Alzheimer's Disease Research Center (n = 14). All underwent 2 or more serial amyloid PET examinations. There were 205 participants classified as cognitively normal and 55 as cognitively impaired (47 mild cognitive impairment and 8 Alzheimer dementia). We measured baseline amyloid PET-relative standardized uptake values (SUVR) and, for each participant, estimated a slope representing their annual amyloid accumulation rate. We then fit regression models to predict the rate of amyloid accumulation given baseline amyloid SUVR, and evaluated age, sex, clinical group, and APOE as covariates. Finally, we integrated the amyloid accumulation rate vs baseline amyloid PET SUVR association to an amyloid PET SUVR vs time association.
Results:
Rates of amyloid accumulation were low at low baseline SUVR. Rates increased to a maximum at baseline SUVR around 2.0, above which rates declined—reaching zero at baseline SUVR above 2.7. The rate of amyloid accumulation as a function of baseline SUVR had an inverted U shape. Integration produced a sigmoid curve relating amyloid PET SUVR to time. The average estimated time required to travel from an SUVR of 1.5–2.5 is approximately 15 years.
Conclusion:
This roughly 15-year interval where the slope of the amyloid SUVR vs time curve is greatest and roughly linear represents a large therapeutic window for secondary preventive interventions.
doi:10.1212/WNL.0b013e3182840bbe
PMCID: PMC3653215  PMID: 23446680
5.  Selective Worsening of Brain Injury Biomarker Abnormalities in Cognitively Normal Elderly with β-amyloidosis 
JAMA neurology  2013;70(8):10.1001/jamaneurol.2013.182.
Importance
The appearance of β-amyloidosis and brain injury biomarkers in cognitively normal (CN) persons is thought to define risk for the future development of cognitive impairment due to Alzheimer’s disease (AD), but their interaction is poorly understood.
Objective
To test the hypothesis that the joint presence of β-amyloidosis and brain injury biomarkers would lead to more rapid neurodegeneration.
Design
Longitudinal Cohort Study
Setting
Population-based Mayo Clinic Study of Aging.
Participants
191 CN persons (median age 77, range 71–93) in the Mayo Clinic Study of Aging who underwent MR, FDG PET and PiB PET imaging at least twice 15 months apart. Subjects were grouped according to the recommendations of the NIA-AA Preclinical AD criteria, based on the presence of β-amyloidosis, defined as a PiB PET SUVr >1.5, alone (Stage 1) or with brain injury (stage 2+3), defined as hippocampal atrophy or FDG hypometabolism. We also studied a group of MCI (n=17) and dementia (n=9) patients from the Mayo Clinic Study of Aging or the Mayo Alzheimer Center with similar follow-up times who had had comparable imaging and who all had PiB PET SUVr >1.5.
Main Outcome Measures
Rate of change of cortical volume on volumetric MR scans and rate of change of glucose metabolism on FDG PET scans.
Results
There were 25 CN subjects with both high PiB retention and low hippocampal volume or FDG hypometabolism at baseline (Preclinical AD stages 2+3). On follow-up scans, the Preclinical AD stages 2+3 subjects had greater loss of medial temporal lobe volume and greater glucose hypometabolism in the medial temporal lobe compared to other CN groups. The changes were similar to the cognitively impaired participants. Extra-temporal regions did not show similar changes.
Conclusions
Higher rates of medial temporal neurodegeneration occurred in CN individuals who, on their initial scans, had abnormal levels of both β-amyloid and brain injury biomarkers.
doi:10.1001/jamaneurol.2013.182
PMCID: PMC3884555  PMID: 23797806
Alzheimer’s disease; PET imaging; MR imaging; Epidemiology
6.  Indicators of amyloid burden in a population-based study of cognitively normal elderly 
Neurology  2012;79(15):1570-1577.
Objectives:
Secondary prevention trials in subjects with preclinical Alzheimer disease may require documentation of brain amyloidosis. The identification of inexpensive and noninvasive screening variables that can identify individuals who have significant amyloid accumulation would reduce screening costs.
Methods:
A total of 483 cognitively normal (CN) individuals, aged 70–92 years, from the population-based Mayo Clinic Study of Aging, underwent Pittsburgh compound B (PiB)–PET imaging. Logistic regression determined whether age, sex, APOE genotype, family history, or cognitive performance was associated with odds of a PiB retention ratio >1.4 and >1.5. Area under the receiver operating characteristic curve (AUROC) evaluated the discrimination between PiB-positive and -negative subjects. For each characteristic, we determined the number needed to screen in each age group (70–79 and 80–89) to identify 100 participants with PiB >1.4 or >1.5.
Results:
A total of 211 (44%) individuals had PiB >1.4 and 151 (31%) >1.5. In univariate and multivariate models, discrimination was modest (AUROC ∼0.6–0.7). Multivariately, age and APOE best predicted odds of PiB >1.4 and >1.5. Subjective memory complaints were similar to cognitive test performance in predicting PiB >1.5. Indicators of PiB positivity varied with age. Screening APOE ε4 carriers alone reduced the number needed to screen to enroll 100 subjects with PIB >1.5 by 48% in persons aged 70–79 and 33% in those aged 80–89.
Conclusions:
Age and APOE genotype are useful predictors of the likelihood of significant amyloid accumulation, but discrimination is modest. Nonetheless, these results suggest that inexpensive and noninvasive measures could significantly reduce the number of CN individuals needed to screen to enroll a given number of amyloid-positive subjects.
doi:10.1212/WNL.0b013e31826e2696
PMCID: PMC3475629  PMID: 22972644
7.  Neuroimaging correlates of pathologically-defined atypical Alzheimer’s disease 
Lancet neurology  2012;11(10):868-877.
Background
Atypical variants of Alzheimer’s disease (AD) have been pathologically defined based on the distribution of neurofibrillary tangles; hippocampal sparing (HpSp) AD shows minimal involvement of the hippocampus and limbic predominant (LP) AD shows neurofibrillary tangles restricted to the medial temporal lobe. We aimed to determine whether MRI patterns of atrophy differ across HpSp AD, LP AD and typical AD, and whether imaging could be a useful predictor of pathological subtype during life.
Methods
In this case-control study, we identified 177 patients who had been prospectively followed in the Mayo Clinic Alzheimer’s Disease Research Center, were demented during life, had AD pathology at autopsy (Braak stage ≥ IV, intermediate-high probability AD) and an antemortem MRI. Cases were assigned to one of three pathological subtypes (HpSp n=19, typical n=125, or LP AD n=33) based on neurofibrillary tangle counts and their ratio in association cortices to hippocampus, without reference to neuronal loss. Voxel-based morphometry and atlas-based parcellation were used to compare patterns of grey matter loss across groups, and to controls.
Findings
The severity of medial temporal and cortical grey matter atrophy differed across subtypes. The most severe medial temporal atrophy was observed in LP AD, followed by typical AD, and then HpSp AD. Conversely, the most severe cortical atrophy was observed in HpSp AD, followed by typical AD, and then LP AD. A ratio of hippocampal-to-cortical volume provided the best discrimination across all three AD subtypes. The majority of typical AD (98/125;78%) and LP AD (31/33;94%) subjects, but only 8/19 (42%) of the HpSp AD subjects, presented with a dominant amnestic syndrome.
Interpretation
Patterns of atrophy on MRI differ across the pathological subtypes of AD, suggesting that MR regional volumetrics reliably track the distribution of neurofibrillary tangle pathology and can predict pathological subtype during life.
Funding
US National Institutes of Health (National Institute on Aging)
doi:10.1016/S1474-4422(12)70200-4
PMCID: PMC3490201  PMID: 22951070
8.  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
9.  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
10.  Comparison of imaging biomarkers in ADNI versus the Mayo Clinic Study of Aging 
Archives of neurology  2012;69(5):614-622.
Objective
To determine whether MRI measurements observed in the Alzheimer's Disease Neuroimaging Initiative (ADNI; convenience-sample) differ from those observed in the Mayo Clinic Study of Aging (MCSA; population-based sample).
Design
Comparison of two samples.
Setting
59 recruiting sites for the ADNI in US/Canada, and the MCSA, a population-based cohort in Olmsted County, MN.
Patients
Cognitively normal (CN) subjects and amnestic mild cognitive impairment (aMCI) subjects were selected from the ADNI convenience cohort and MCSA population-based cohort. Two samples were selected; the first was a simple random sample of subjects from both cohorts in the same age range, and the second applied matching for age, sex, education, apolipoprotein E genotype, and Mini-Mental State Examination.
Main outcome measures
Baseline hippocampal volumes and annual percent decline in hippocampal volume.
Results
In the population-based sample, MCSA subjects were older, less educated, performed worse on MMSE, and less often had family history of AD than ADNI subjects. Baseline hippocampal volumes were larger in ADNI compared to MCSA CN subjects in the random sample, although no differences were observed after matching. Rates of decline in hippocampal volume were greater in ADNI compared to MCSA for both CN and aMCI, even after matching.
Conclusions
Rates of decline in hippocampal volume suggest that ADNI subjects have more aggressive brain pathology than MCSA subjects, and hence may not be representative of the general population. These findings have implications for treatment trials that employ ADNI-like recruitment mechanisms and for studies validating new diagnostic criteria for AD in its various stages.
doi:10.1001/archneurol.2011.3029
PMCID: PMC3569033  PMID: 22782510
11.  Shapes of the Trajectories of Five Major Biomarkers of Alzheimer’s Disease 
Archives of neurology  2012;69(7):856-867.
Objective
To characterize the shape of the trajectories of Alzheimer’s Disease (AD) biomarkers as a function of MMSE.
Design
Longitudinal registries from the Mayo Clinic and the Alzheimer’s Disease Neuroimaging Initiative (ADNI).
Patients
Two different samples (n=343 and n=598) were created that spanned the cognitive spectrum from normal to AD dementia. Subgroup analyses were performed in members of both cohorts (n=243 and n=328) who were amyloid positive at baseline.
Main Outcome Measures
The shape of biomarker trajectories as a function of MMSE, adjusted for age, was modeled and described as baseline (cross-sectional) and within-subject longitudinal effects. Biomarkers evaluated were cerebro spinal fluid (CSF) Aβ42 and tau; amyloid and fluoro deoxyglucose position emission tomography (PET) imaging, and structural magnetic resonance imaging (MRI).
Results
Baseline biomarker values generally worsened (i.e., non-zero slope) with lower baseline MMSE. Baseline hippocampal volume, amyloid PET and FDG PET values plateaued (i.e., non-linear slope) with lower MMSE in one or more analyses. Longitudinally, within-subject rates of biomarker change were associated with worsening MMSE. Non-constant within-subject rates (deceleration) of biomarker change were found in only one model.
Conclusions
Biomarker trajectory shapes by MMSE were complex and were affected by interactions with age and APOE status. Non-linearity was found in several baseline effects models. Non-constant within-subject rates of biomarker change were found in only one model, likely due to limited within-subject longitudinal follow up. Creating reliable models that describe the full trajectories of AD biomarkers will require significant additional longitudinal data in individual participants.
doi:10.1001/archneurol.2011.3405
PMCID: PMC3595157  PMID: 22409939
Alzheimer’s disease biomarkers; Magnetic Resonance Imaging; cerebro spinal fluid; amyloid PET imaging; FDG PET imaging
12.  An Operational Approach to NIA-AA Criteria for Preclinical Alzheimer’s Disease 
Annals of neurology  2012;71(6):765-775.
Objective
A workgroup commissioned by the Alzheimer’s Association (AA) and the National Institute on Aging (NIA) recently published research criteria for preclinical Alzheimer’s disease (AD). We performed a preliminary assessment of these guidelines.
Methods
We employed Pittsburgh compound B positron emission tomography (PET) imaging as our biomarker of cerebral amyloidosis and 18fluorodeoxyglucose PET imaging and hippocampal volume as biomarkers of neurodegeneration. A group of 42 clinically diagnosed AD subjects was used to create imaging biomarker cut-points. A group of 450 cognitively normal (CN) subjects from a population based sample was used to develop cognitive cut-points and to assess population frequencies of the different preclinical AD stages using different cut-point criteria.
Results
The new criteria subdivide the preclinical phase of AD into stages 1–3. To classify our CN subjects, two additional categories were needed. Stage 0 denotes subjects with normal AD biomarkers and no evidence of subtle cognitive impairment. Suspected Non-AD Pathophysiology (SNAP) denotes subjects with normal amyloid PET imaging, but abnormal neurodegeneration biomarker studies. At fixed cut-points corresponding to 90% sensitivity for diagnosing AD and the 10th percentile of CN cognitive scores, 43% of our sample was classified as stage 0; 16% stage 1; 12 % stage 2; 3% stage 3; and 23% SNAP.
Interpretation
This cross-sectional evaluation of the NIA-AA criteria for preclinical AD indicates that the 1–3 staging criteria coupled with stage 0 and SNAP categories classify 97% of CN subjects from a population-based sample, leaving just 3% unclassified. Future longitudinal validation of the criteria will be important.
doi:10.1002/ana.22628
PMCID: PMC3586223  PMID: 22488240
13.  Does amyloid deposition produce a specific atrophic signature in cognitively normal subjects?☆ 
NeuroImage : Clinical  2013;2:249-257.
The objective of our study was to evaluate whether cognitively normal (CN) elderly participants showing elevated cortical beta-amyloid (Aβ) deposition have a consistent neuroanatomical signature of brain atrophy that may characterize preclinical Alzheimer's disease (AD). 115 CN participants who were Aβ-positive (CN +) by amyloid PET imaging; 115 CN participants who were Aβ-negative (CN −); and 88 Aβ-positive mild cognitive impairment or AD participants (MCI/AD +) were identified. Cortical thickness (FreeSurfer) and gray matter volume (SPM5) were measured for 28 regions-of-interest (ROIs) across the brain and compared across groups. ROIs that best discriminated CN − from CN + differed for FreeSurfer cortical thickness and SPM5 gray matter volume. Group-wise discrimination was poor with a high degree of uncertainty in terms of the rank ordering of ROIs. In contrast, both techniques showed strong and consistent findings comparing MCI/AD + to both CN − and CN + groups, with entorhinal cortex, middle and inferior temporal lobe, inferior parietal lobe, and hippocampus providing the best discrimination for both techniques. Concordance across techniques was higher for the CN − and CN + versus MCI/AD + comparisons, compared to the CN − versus CN + comparison. The weak and inconsistent nature of the findings across technique in this study cast doubt on the existence of a reliable neuroanatomical signature of preclinical AD in elderly PiB-positive CN participants.
Highlights
► We measured atrophy in cognitively normal subjects with amyloid deposition (CN +). ► Findings in CN + subjects were weak and disconcordant across Freesurfer and SPM5. ► Concordance across techniques was higher when assessing Alzheimer disease subjects. ► Evidence for a neuroanatomical signature of preclinical AD in CN + subjects is weak.
doi:10.1016/j.nicl.2013.01.006
PMCID: PMC3778266  PMID: 24179779
Amyloid; Preclinical; Alzheimer's disease; Freesurfer; Voxel-based morphometry; Cognitively normal
14.  Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics 
Brain  2012;135(3):794-806.
A major recent discovery was the identification of an expansion of a non-coding GGGGCC hexanucleotide repeat in the C9ORF72 gene in patients with frontotemporal dementia and amyotrophic lateral sclerosis. Mutations in two other genes are known to account for familial frontotemporal dementia: microtubule-associated protein tau and progranulin. Although imaging features have been previously reported in subjects with mutations in tau and progranulin, no imaging features have been published in C9ORF72. Furthermore, it remains unknown whether there are differences in atrophy patterns across these mutations, and whether regional differences could help differentiate C9ORF72 from the other two mutations at the single-subject level. We aimed to determine the regional pattern of brain atrophy associated with the C9ORF72 gene mutation, and to determine which regions best differentiate C9ORF72 from subjects with mutations in tau and progranulin, and from sporadic frontotemporal dementia. A total of 76 subjects, including 56 with a clinical diagnosis of behavioural variant frontotemporal dementia and a mutation in one of these genes (19 with C9ORF72 mutations, 25 with tau mutations and 12 with progranulin mutations) and 20 sporadic subjects with behavioural variant frontotemporal dementia (including 50% with amyotrophic lateral sclerosis), with magnetic resonance imaging were included in this study. Voxel-based morphometry was used to assess and compare patterns of grey matter atrophy. Atlas-based parcellation was performed utilizing the automated anatomical labelling atlas and Statistical Parametric Mapping software to compute volumes of 37 regions of interest. Hemispheric asymmetry was calculated. Penalized multinomial logistic regression was utilized to create a prediction model to discriminate among groups using regional volumes and asymmetry score. Principal component analysis assessed for variance within groups. C9ORF72 was associated with symmetric atrophy predominantly involving dorsolateral, medial and orbitofrontal lobes, with additional loss in anterior temporal lobes, parietal lobes, occipital lobes and cerebellum. In contrast, striking anteromedial temporal atrophy was associated with tau mutations and temporoparietal atrophy was associated with progranulin mutations. The sporadic group was associated with frontal and anterior temporal atrophy. A conservative penalized multinomial logistic regression model identified 14 variables that could accurately classify subjects, including frontal, temporal, parietal, occipital and cerebellum volume. The principal component analysis revealed similar degrees of heterogeneity within all disease groups. Patterns of atrophy therefore differed across subjects with C9ORF72, tau and progranulin mutations and sporadic frontotemporal dementia. Our analysis suggested that imaging has the potential to be useful to help differentiate C9ORF72 from these other groups at the single-subject level.
doi:10.1093/brain/aws001
PMCID: PMC3286334  PMID: 22366795
frontotemporal dementia; magnetic resonance imaging; C9ORF72; tau; progranulin
15.  Predicting functional decline in behavioural variant frontotemporal dementia 
Brain  2011;134(2):432-448.
Behavioural variant frontotemporal dementia is characterized by a change in comportment. It is associated with considerable functional decline over the course of the illness albeit with sometimes dramatic variability among patients. It is unknown whether any baseline features, or combination of features, could predict rate of functional decline in behavioural variant frontotemporal dementia. The aim of this study was to investigate the effects of different baseline clinical, neuropsychological, neuropsychiatric, genetic and anatomic predictors on the rate of functional decline as measured by the Clinical Dementia Rating Sum of Boxes scale. We identified 86 subjects with behavioural variant frontotemporal dementia that had multiple serial Clinical Dementia Rating Sum of Boxes assessments (mean 4, range 2–18). Atlas-based parcellation was used to generate volumes for specific regions of interest at baseline. Volumes were utilized to classify subjects into different anatomical subtypes using the advanced statistical technique of cluster analysis and were assessed as predictor variables. Composite scores were generated for the neuropsychological domains of executive, language, memory and visuospatial function. Behaviours from the brief questionnaire form of the Neuropsychiatric Inventory were assessed. Linear mixed-effects regression modelling was used to determine which baseline features predict rate of future functional decline. Rates of functional decline differed across the anatomical subtypes of behavioural variant frontotemporal dementia, with faster rates observed in the frontal dominant and frontotemporal subtypes. In addition, subjects with poorer performance on neuropsychological tests of executive, language and visuospatial function, less disinhibition, agitation/aggression and night-time behaviours at presentation, and smaller medial, lateral and orbital frontal lobe volumes showed faster rates of decline. In many instances, the effect of the predictor variables observed across all subjects was also preserved within anatomical subtypes. Furthermore, some of the predictor variables improved our prediction of rate of functional decline after anatomical subtype was taken into account. In particular, age at onset was a highly significant predictor but only after adjusting for subtype. We also found that although some predictor variables, for example gender, Mini-Mental State Examination score, and apathy/indifference, did not affect the rate of functional decline; these variables were associated with the actual Clinical Dementia Rating Sum of Boxes score estimated for any given time-point. These findings suggest that in behavioural variant frontotemporal dementia, rate of functional decline is driven by the combination of anatomical pattern of atrophy, age at onset, and neuropsychiatric characteristics of the subject at baseline.
doi:10.1093/brain/awq348
PMCID: PMC3030765  PMID: 21252111
frontotemporal dementia; behaviour; functional decline; brain volumes; mixed effects models
16.  Time-to-event Voxel Based Techniques to Assess Regional Atrophy Associated with MCI Risk of Progression to AD 
NeuroImage  2010;54(2):985-991.
Objective
When using imaging to predict time to progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD), time-to-event statistical methods account for varying lengths of follow-up times among subjects whereas two-sample t-tests in voxel-based morphometry (VBM) do not. Our objectives were to apply a time-to-event voxel-based analytic method to identify regions on MRI where atrophy is associated with significantly increased risk of future progression to AD in subjects with MCI and to compare it to traditional voxel-level patterns obtained by applying two-sample methods. We also compared the power required to detect an association using time-to-event methods versus two-sample approaches.
Methods
Subjects with MCI at baseline were followed prospectively. The event of interest was clinical diagnosis of AD. Cox proportional hazards models adjusted for age, sex, and education were used to estimate the relative hazard of progression from MCI to AD based on rank-transformed voxel-level gray matter density (GMD) estimates.
Results
The greatest risk of progression to AD was associated with atrophy of the medial temporal lobes. Patients ranked at the 25th percentile of GMD in these regions had more than a doubling of risk of progression to AD at a given time-point compared to patients at the 75th percentile. Power calculations showed the time-to-event approach to be more efficient than the traditional two-sample approach.
Conclusions
We present a new voxel-based analytic method that incorporates time-to-event statistical methods. In the context of a progressive disease like AD, time-to-event VBM seems more appropriate and powerful than traditional two-sample methods.
doi:10.1016/j.neuroimage.2010.09.004
PMCID: PMC2997139  PMID: 20832487
Alzheimer Disease; mild cognitive impairment; magnetic resonance imaging; Cox proportional hazards model
17.  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
18.  Effects of age on the glucose metabolic changes in mild cognitive impairment 
Background and Purpose
Decreased glucose metabolism in the temporal and parietal lobes on [18F]fluorodeoxyglucose (FDG) PET is recognized as an early imaging marker for the Alzheimer’s disease (AD) pathology. Our objective was to investigate the effects of age on FDG PET findings in aMCI.
Methods
25 patients with aMCI at 55–86 years of age (median = 73), and 25 age and gender matched cognitively normal (CN) subjects underwent FDG PET. SPM5 was used to compare the FDG uptake in aMCI-old (>73 years) and aMCI-young (>73 years) patients to CN subjects. The findings in the aMCI-old patients were independently validated in a separate cohort of 10 aMCI and 13 CN subjects older than 73 years of age.
Results
The pattern of decreased glucose metabolism and gray matter atrophy in the medial temporal, posterior cingulate, precuneus, lateral parietal and temporal lobes in aMCI-young subjects was consistent with the typical pattern observed in AD. The pattern of glucose metabolic changes in aMCI-old subjects was different, predominantly involving the frontal lobes and the left parietal lobe. Gray matter atrophy in aMCI-old subjects was less pronounced than the aMCI-young subjects involving the hippocampus and the basal forebrain in both hemispheres
Conclusion
Pathological heterogeneity may be underlying the absence of AD-like glucose metabolic changes in older compared to younger aMCI patients. This may be an important consideration for the clinical use of temporoparietal hypometabolism on FDG PET as a marker for early diagnosis of AD in aMCI.
doi:10.3174/ajnr.A2070
PMCID: PMC2890033  PMID: 20299441
19.  DWI PREDICTS FUTURE PROGRESSION TO ALZHEIMER’S DISEASE IN AMNESTIC MILD COGNITIVE IMPAIRMENT 
Neurology  2005;64(5):902-904.
This study tests if measures of hippocampal water diffusivity at baseline can predict future progression to Alzheimer’s Disease (AD) in amnestic mild cognitive impairment (aMCI). Higher baseline hippocampal diffusivity was associated with a greater hazard of progression to AD in aMCI (p=0.002). MR diffusion weighted imaging (DWI) may help identify patients with aMCI who will progress to AD as well or better than structural MRI measures of hippocampal atrophy.
doi:10.1212/01.WNL.0000153076.46126.E9
PMCID: PMC2771335  PMID: 15753434
20.  1H MR SPECTROSCOPY IN COMMON DEMENTIAS 
Neurology  2004;63(8):1393-1398.
Objective
To determine the 1H MR spectroscopic (MRS) findings and inter-group differences among common dementias: Alzheimer's disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration (FTLD).
Methods
We consecutively recruited 206 normal elderly, 121 patients with AD, 41 with FTLD, 20 with DLB, and 8 with VaD. We evaluated the 1H MRS metabolite ratio changes in common dementias with respect to normal, and also differences among the common dementias.
Results
N-acetylaspartate/Creatine (NAA/Cr) was lower than normal in patients with AD, FTLD, and VaD. Myo-inositol (mI)/Cr was higher than normal in patients with AD and FTLD. Choline (Cho)/Cr was higher than normal in patients with, AD, FTLD, and DLB. There were no metabolite differences between patients with AD and FTLD, nor between patients with DLB and VaD. NAA /Cr was lower in patients with AD and FTLD than DLB. MI /Cr was higher in patients with AD and FTLD than VaD. MI /Cr was also higher in patients with FTLD than DLB.
Conclusions
NAA/Cr levels are decreased in dementias that are characterized by neuron loss such as AD, FTLD, and VaD. MI/Cr levels are elevated in dementias that are pathologically characterized by gliosis such as AD and FTLD. Cho/Cr levels are elevated in dementias that are characterized by a profound cholinergic deficit such as AD and DLB.
PMCID: PMC2766798  PMID: 15505154
21.  Longitudinal 1H MRS changes in mild cognitive impairment and Alzheimer’s disease 
Neurobiology of aging  2006;28(9):1330-1339.
Magnetic Resonance (MR)- based volume measurements of atrophy are potential markers of disease progression in patients with amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD). Longitudinal changes in 1H MR spectroscopy (1H MRS) metabolite markers have not been characterized in aMCI subjects. Our objective was to determine the longitudinal 1H MRS metabolite changes in patients with aMCI, and AD, and to compare 1H MRS metabolite ratios and ventricular volumes in tracking clinical disease progression in AD. The neuronal integrity marker N-acetylaspartate/Creatine ratio declined in aMCI and AD patients compared to cognitively normal elderly. The changein 1H MRS metabolite ratios correlated with clinical progression about as strongly as the rate of ventricular expansion, suggesting that 1H MRS metabolite ratios may be useful markers for the progression of AD. Choline/Creatine ratio declined in stable aMCI, compared to converter aMCI patients and cognitively normal elderly, which may be related to a compensatory mechanism in aMCI patients who did not to progress to AD.
doi:10.1016/j.neurobiolaging.2006.06.018
PMCID: PMC2766807  PMID: 16860440
1H MR spectroscopy; 1H MRS; imaging; Alzheimer’s disease; mild cognitive impairment; serial; longitudinal; N-acetylaspartate; choline
22.  Hippocampal Volumes, Proton Magnetic Resonance Spectroscopy Metabolites, and Cerebrovascular Disease in Mild Cognitive Impairment Subtypes 
Archives of neurology  2008;65(12):1621-1628.
Background
Although a majority of patients with amnestic mild cognitive impairment (aMCI) progress to Alzheimer disease, the natural history of nonamnestic MCI (naMCI) is less clear. Noninvasive imaging surrogates for underlying pathological findings in MCI would be clinically useful for identifying patients who may benefit from disease-specific treatments at the prodromal stage of dementia.
Objective
To determine the characteristic magnetic resonance imaging (MRI) and proton MR spectroscopy (1H MRS) profiles of MCI subtypes.
Design
Case-control study.
Setting
Community-based sample at a tertiary referral center.
Patients
Ninety-one patients with single-domain aMCI, 32 patients with multiple-domain aMCI, 20 patients with single- or multiple-domain naMCI, and 100 cognitively normal elderly subjects frequency-matched by age and sex.
Main Outcome Measures
Posterior cingulate gyrus 1H MRS metabolite ratios, hippocampal volumes, and cerebrovascular disease on MRI.
Results
Patients with single-domain aMCI were characterized by small hippocampal volumes and elevated ratios of myo-inositol to creatine levels. Patients with naMCI on average had normal hippocampal volumes and 1H MRS metabolite ratios, but a greater proportion (3 of 20 patients [15%]) had cortical infarctions compared with patients with single-domain aMCI (6 of 91 [7%]). For characterization of MCI subtypes, 1H MRS and structural MRI findings were complementary.
Conclusions
The MRI and 1H MRS findings in singledomain aMCI are consistent with a pattern similar to that of Alzheimer disease. Absence of this pattern on average in patients with naMCI suggests that cerebrovascular disease and other neurodegenerative diseases may be contributing to the cognitive impairment in many individuals with naMCI.
doi:10.1001/archneur.65.12.1621
PMCID: PMC2743393  PMID: 19064749
23.  Alzheimer Disease: Postmortem Neuropathologic Correlates of Antemortem 1H MR Spectroscopy Metabolite Measurements 
Radiology  2008;248(1):210-220.
Purpose
To determine the neuropathologic correlates of antemortem hydrogen 1 (1H) magnetic resonance (MR) spectroscopy metabolite measurements in subjects with Alzheimer disease (AD)-type pathology.
Materials and Methods
This study was approved by the institutional review board and was compliant with HIPAA regulations. Informed consent was obtained from each subject. The authors identified 54 subjects who underwent antemortem 1H MR spectroscopy and were clinically healthy or had AD-type pathology with low to high likelihood of AD according to National Institute on Aging–Reagan neuropathologic criteria at autopsy. They investigated the associations between 1H MR spectroscopy metabolite measurements and Braak neurofibrillary tangle stage (Braak stage), neuritic plaque score, and AD likelihood, with adjustments for subject age, subject sex, and time between 1H MR spectroscopy and death.
Results
Decreases in N-acetylaspartate–to-creatine ratio, an index of neuronal integrity, and increases in myo-inositol–to-creatine ratio were associated with higher Braak stage, higher neuritic plaque score, and greater likelihood of AD. The N-acetylaspartate–to–myo-inositol ratio proved to be the strongest predictor of the pathologic likelihood of AD. The strongest association observed was that between N-acetylaspartate–to–myo-inositol ratio and Braak stage (RN2 = 0.47, P < .001).
Conclusion
Antemortem 1H MR spectroscopy metabolite changes correlated with AD-type pathology seen at autopsy. The study findings validated 1H MR spectroscopy metabolite measurements against the neuropathologic criteria for AD, and when combined with prior longitudinal 1H MR spectroscopy findings, indicate that these measurements could be used as biomarkers for disease progression in clinical trials.
doi:10.1148/radiol.2481071590
PMCID: PMC2735577  PMID: 18566174
24.  Beta-amyloid burden is not associated with rates of brain atrophy 
Annals of neurology  2008;63(2):204-212.
Objective
To test the hypothesis that beta-amyloid (Aβ) burden is associated with rates of brain atrophy.
Methods
Forty-five subjects who had been prospectively studied, died, and had an autopsy diagnosis of low, intermediate, or high probability of Alzheimer's disease that had two volumetric head MRI scans were identified. Compact, as well as total (compact + diffuse) Aβ burden was measured using a computerized image analyzer with software program to detect the proportion of grey matter occupied by Aβ. Visual ratings of Aβ burden were also performed. The boundary-shift integral (BSI) was used to calculate change over time in whole brain and ventricular volume. All BSI results were annualized by adjusting for scan interval. Demographics, cognitive measures, clinical diagnoses, apolipoprotein E genotype, neurofibrillary tangle pathology, and vascular lesion burden were determined.
Results
There was no correlation between compact or total Aβ burden, or visual Aβ ratings, and rates of brain loss or ventricular expansion in all subjects. However, significant correlations were observed between rates of brain loss and age, Braak stage, and change over time in cognitive measures. These features also correlated with rates of ventricular expansion. The rates of brain loss and ventricular expansion were greater in demented compared to non-demented subjects.
Interpretation
These findings suggest that rate of brain volume loss is not determined by the amount of insoluble Aβ in the grey matter.
doi:10.1002/ana.21223
PMCID: PMC2735194  PMID: 17894374
25.  Atrophy Rates Accelerate in Amnestic Mild Cognitive Impairment 
Neurology  2007;70(19 Pt 2):1740-1752.
Background
We tested if rates of brain atrophy accelerate in individuals with amnestic mild cognitive impairment (aMCI) as they progress to typical late onset Alzheimer's Disease (AD). We included comparisons to aMCI subjects who did not progress (labeled aMCI-S) and also to cognitively normal elderly subjects (CN).
Methods
We studied 46 aMCI subjects who progressed to AD (labeled aMCI-P), 46 CN, and 23 aMCI-S. All subjects must have had three or more serial MRI scans. Rates of brain shrinkage and ventricular expansion were measured across all available serial MRI scans in each subject. Change in volumes relative to the point at which subjects progressed to a clinical diagnosis of AD (the index date) was modeled in aMCI-P. Change in volumes relative to age was modeled in all three clinical groups.
Results
In aMCI-P the change in pre to post index rate (i.e. acceleration) of ventricular expansion was 1.7 cm3/yr, and acceleration in brain shrinkage was 5.3 cm3/yr. Brain volume declined and ventricular volume increased in all three groups with age. Volume changes decelerated with increasing age in aMCI-P, and to a lesser extent aMCI-S, but were linear in the matched CN. Among all aMCI subjects, rates of atrophy were greater in apolipoprotein E ε4 carriers than non-carriers.
Conclusions
Rates of atrophy accelerate as individuals progress from aMCI to typical late onset AD. Rates of atrophy are greater in younger than older aMCI-P and aMCI-S subjects. We did not find that atrophy rates varied with age in 70 – 90 year old CN subjects.
doi:10.1212/01.wnl.0000281688.77598.35
PMCID: PMC2734477  PMID: 18032747

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