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1.  TDP-43 in Alzheimer’s disease is not associated with clinical FTLD or Parkinsonism 
Journal of neurology  2014;261(7):1344-1348.
Widespread deposition of TAR DNA-binding protein of 43 kDa (TDP-43), a major protein inclusion commonly found in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) can also be seen in a subset of cases with Alzheimer’s disease (AD). Some of these AD cases have TDP-43 immunoreactivity in basal ganglia (BG) and substantia nigra (SN), regions that when affected can be associated with parkinsonian signs or symptoms, or even features suggestive of frontotemporal dementia. Here, we examined the presence of clinical features of FTLD, parkinsonian signs and symptoms, and BG atrophy on MRI, in 51 pathologically confirmed AD cases (Braak neurofibrillary tangle stage IV–VI) with widespread TDP-43 deposition, with and without BG and SN involvement. All 51 cases had presented with progressive cognitive impairment with prominent memory deficits. None of the patients demonstrated early behavioral disinhibition, apathy, loss of empathy, stereotyped behavior, hyperorality, and/or executive deficits. Furthermore, TDP-43 deposition in BG or SN had no significant association with tremor (p = 0.80), rigidity (p = 0.19), bradykinesia (p = 0.19), and gait/postural instability (p = 0.39). Volumes of the BG structures were not associated with TDP-43 deposition in the BG. The present study demonstrates that TDP-43 deposition in pathologically confirmed AD cases is not associated with a clinical manifestation suggestive of FTLD, or parkinsonian features.
PMCID: PMC4101047  PMID: 24760339
TDP-43; Alzheimer’s disease; Frontotemporal dementia; Parkinsonism
2.  TDP-43 is a key player in the clinical features associated with Alzheimer’s disease 
Acta neuropathologica  2014;127(6):811-824.
The aim of this study was to determine whether the TAR DNA-binding protein of 43kDa (TDP-43) independently has any effect on the clinical and neuroimaging features typically ascribed to Alzheimer’s disease (AD) pathology, and whether TDP-43 pathology could help shed light on the phenomenon of resilient cognition in AD. Three-hundred forty-two subjects pathologically diagnosed with AD were screened for the presence, burden and distribution of TDP-43. All had been classified as cognitively impaired or normal, prior to death. Atlas-based parcellation and voxel-based morphometry were used to assess regional atrophy on MRI. Regression models controlling for age at death, apolipoprotein ε4 and other AD-related pathologies were utilized to explore associations between TDP-43 and cognition or brain atrophy, stratified by Braak stage. Additionally, we determined whether the effects of TDP-43 were mediated by hippocampal sclerosis. One-hundred ninety-five (57%) cases were TDP-positive. After accounting for age, apolipoprotein ε4, and other pathologies, TDP-43 had a strong effect on cognition, memory loss, and medial temporal atrophy in AD. These effects were not mediated by hippocampal sclerosis. TDP-positive subjects were 10× more likely to be cognitively impaired at death compared to TDP-negative subjects. Greater cognitive impairment and medial temporal atrophy were associated with greater TDP-43 burden and more extensive TDP-43 distribution. TDP-43 is an important factor in the manifestation of the clinico-imaging features of AD. TDP-43 also appears to be able to overpower what has been termed resilient brain aging. TDP-43 therefore should be considered a potential therapeutic target for the treatment of AD.
PMCID: PMC4172544  PMID: 24659241
TDP-43; Alzheimer disease; resilience; APOE ε4; Braak stage; MRI
3.  Midbrain atrophy is not a biomarker of PSP pathology 
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.
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.
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.
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.
PMCID: PMC3773014  PMID: 23746093
Progressive supranuclear palsy; tau; neuropathology; MRI; midbrain
4.  Frontal asymmetry in behavioral variant FTD: clinicoimaging & pathogenetic correlates 
Neurobiology of aging  2012;34(2):636-639.
We aimed to assess associations between clinical, imaging, pathological and genetic features and frontal lobe asymmetry in behavioral variant frontotemporal dementia (bvFTD). Volumes of the left and right dorsolateral, medial and orbital frontal lobes were measured in 80 bvFTD subjects and subjects were classified into three groups according to the degree of asymmetry (asymmetric left, asymmetric right, symmetric) using cluster analysis. The majority of subjects were symmetric (65%), with 20% asymmetric left and 15% asymmetric right. There were no clinical differences across groups, although there was a trend for greater behavioral dyscontrol in right asymmetric compared to left asymmetric subjects. More widespread atrophy involving the parietal lobe was observed in the symmetric group. Genetic features differed across groups with symmetric frontal lobes associated with C9ORF72 and tau mutations, while asymmetric frontal lobes were associated with progranulin mutations. These findings therefore suggest that neuroanatomical patterns of frontal lobe atrophy in bvFTD are influenced by specific gene mutations.
PMCID: PMC3404265  PMID: 22502999
Frontotemporal dementia; frontal lobes; MRI; asymmetry; microtubule associated protein tau; progranulin; C9ORF72; pathology
5.  Corticospinal tract degeneration associated with TDP-43 type C pathology and semantic dementia 
Brain  2013;136(2):455-470.
Four subtypes of frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions have been described (types A–D). Of these four subtypes, motor neuron disease is more commonly associated with type B pathology, but has also been reported with type A pathology. We have noted, however, the unusual occurrence of cases of type C pathology having corticospinal tract degeneration. We aimed to assess the severity of corticospinal tract degeneration in a large cohort of cases with type C (n = 31). Pathological analysis included semi-quantitation of myelin loss of fibres of the corticospinal tract and associated macrophage burden, as well as axonal loss, at the level of the medullary pyramids. We also assessed for motor cortex degeneration and fibre loss of the medial lemniscus/olivocerebellar tract. All cases were subdivided into three groups based on the degree of corticospinal tract degeneration: (i) no corticospinal tract degeneration; (ii) equivocal corticospinal tract degeneration; and (iii) moderate to very severe corticospinal tract degeneration. Clinical, genetic, pathological and imaging comparisons were performed across groups. Eight cases had no corticospinal tract degeneration, and 14 cases had equivocal to mild corticospinal tract degeneration. Nine cases, however, had moderate to very severe corticospinal tract degeneration with myelin and axonal loss. In these nine cases, there was degeneration of the motor cortex without lower motor neuron degeneration or involvement of other brainstem tracts. These cases most commonly presented as semantic dementia, and they had longer disease duration (mean: 15.3 years) compared with the other two groups (10.8 and 9.9 years; P = 0.03). After adjusting for disease duration, severity of corticospinal tract degeneration remained significantly different across groups. Only one case, without corticospinal tract degeneration, was found to have a hexanucleotide repeat expansion in the C9ORF72 gene. All three groups were associated with anterior temporal lobe atrophy on MRI; however, the cases with moderate to severe corticospinal tract degeneration showed right-sided temporal lobe asymmetry and greater involvement of the right temporal lobe and superior motor cortices than the other groups. In contrast, the cases with no or equivocal corticospinal tract degeneration were more likely to show left-sided temporal lobe asymmetry. For comparison, the corticospinal tract was assessed in 86 type A and B cases, and only two cases showed evidence of corticospinal tract degeneration without lower motor neuron degeneration. These findings confirm that there exists a unique association between frontotemporal lobar degeneration with type C pathology and corticospinal tract degeneration, with this entity showing a predilection to involve the right temporal lobe.
PMCID: PMC3572926  PMID: 23358603
TDP-43 type C; corticospinal tract; MRI; semantic dementia; right temporal lobe
6.  Neuroimaging correlates of pathologically-defined atypical Alzheimer’s disease 
Lancet neurology  2012;11(10):868-877.
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.
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.
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.
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.
US National Institutes of Health (National Institute on Aging)
PMCID: PMC3490201  PMID: 22951070
7.  Comparison of imaging biomarkers in ADNI versus the Mayo Clinic Study of Aging 
Archives of neurology  2012;69(5):614-622.
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).
Comparison of two samples.
59 recruiting sites for the ADNI in US/Canada, and the MCSA, a population-based cohort in Olmsted County, MN.
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.
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.
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.
PMCID: PMC3569033  PMID: 22782510
8.  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.
► 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.
PMCID: PMC3778266  PMID: 24179779
Amyloid; Preclinical; Alzheimer's disease; Freesurfer; Voxel-based morphometry; Cognitively normal
9.  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.
PMCID: PMC2888989  PMID: 19914744
Alzheimer's disease; pathology; voxel-based morphometry; atypical presentation; frontotemporal lobar degeneration; temporoparietal cortex; hippocampus
10.  Imaging signatures of molecular pathology in behavioral variant frontotemporal dementia 
Journal of Molecular Neuroscience  2011;45(3):372-378.
Pathology underlying behavioral variant frontotemporal dementia (bvFTD) is heterogeneous, with the most common pathologies being Pick’s disease (PiD), corticobasal degeneration (CBD), and FTLD-TDP type 1. Clinical features are unhelpful in differentiating these pathologies. We aimed to determine whether imaging atrophy patterns differ across these pathologies in bvFTD subjects. We identified 15 bvFTD subjects that had volumetric MRI during life and autopsy: five with PiD, five CBD and five FTLD-TDP type 1. Voxel-based morphometry was used to assess atrophy patterns in each bvFTD group compared to 20 age and gender-matched controls. All three pathological groups showed grey matter loss in frontal lobes, although specific patterns of atrophy differed across groups: PiD showed widespread loss in frontal lobes with additional involvement of anterior temporal lobes; CBD showed subtle patterns of loss involving posterior lateral and medial superior frontal lobe; FTLD-TDP type 1 showed widespread loss in frontal, temporal and parietal lobes. Greater parietal loss was observed in FTLD-TDP type 1 compared to both other groups, and greater anterior temporal and medial frontal loss was observed in PiD compared to CBD. Imaging patterns of atrophy in bvFTD vary according to pathological diagnosis and may therefore be helpful in predicting these pathologies in bvFTD.
PMCID: PMC3401589  PMID: 21556732
Frontotemporal dementia; behavioral variant; Pick’s disease; corticobasal degeneration; TDP-43; atrophy; voxel-based morphometry; MRI
11.  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.
PMCID: PMC3039279  PMID: 21195775
MRI; Alzheimer’s disease; Lewy body disease; Frontotemporal lobar degeneration
12.  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.
PMCID: PMC3286334  PMID: 22366795
frontotemporal dementia; magnetic resonance imaging; C9ORF72; tau; progranulin
13.  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.
PMCID: PMC3030765  PMID: 21252111
frontotemporal dementia; behaviour; functional decline; brain volumes; mixed effects models
14.  Anatomical Differences between CBS-Corticobasal degeneration and CBS-Alzheimer’s Disease 
We compare patterns of grey matter loss on MRI in subjects presenting as corticobasal syndrome (CBS) with Alzheimer disease pathology (CBS-AD) to those presenting as CBS with corticobasal degeneration pathology (CBS-CBD). Voxel-based morphometry was used to compare patterns of grey matter loss in pathologically confirmed CBS-AD subjects (n=5) and CBS-CBD subjects (n=6) to a group of normal controls (n=20), and to each other. Atlas based parcellation using the automated anatomic labeling atlas was also utilized in a region-of-interest analysis to account for laterality. The CBS-AD subjects were younger at the time of scan compared to CBS-CBD subjects (median: 60 years vs 69; P=0.04). After adjusting for age at time of MRI scan, the CBS-AD subjects showed loss in posterior frontal, temporal, and superior and inferior parietal lobes, while CBS-CBD showed more focal loss predominantly in the posterior frontal lobes, compared to controls. In both CBS-AD and CBS-CBD groups there was basal ganglia volume loss, yet relative sparing of hippocampi. On direct comparisons between the two subject groups, CBS-AD showed greater loss in both temporal and inferior parietal cortices than CBS-CBD. No regions showed greater loss in the CBS-CBD group compared to the CBS-AD group. These findings persisted when laterality was taken into account. In subjects presenting with CBS, prominent temporoparietal, especially posterior temporal and inferior parietal, atrophy may be a clue to the presence of underlying AD pathology.
PMCID: PMC2921765  PMID: 20629131
Voxel based morphometry; Alzheimer’s disease; Corticobasal syndrome; Corticobasal degeneration; Region-of-Interest
15.  Caudate atrophy on MRI is a characteristic feature of FTLD-FUS 
Background and Purpose
Frontotemporal lobar degeneration (FTLD) can be subdivided into those in which the abnormal protein is tau (FTLD-TAU), the TAR DNA binding protein 43 (FTLD-TDP) and the fused in sarcoma protein (FTLD-FUS). We have observed severe caudate atrophy at autopsy in FTLD-FUS, and hence we aimed to determine whether caudate atrophy on MRI is a feature that can distinguish FTLD-FUS from FTLD-TDP and FTLD-TAU.
From a cohort of 207 cases of FTLD we identified all cases of FTLD-FUS that had a volumetric antemortem head MRI (n=3). Caudate and frontal lobe volumes were measured in all three cases using atlas based parcellation and SPM5, and were compared to 10 randomly selected cases of FTLD-TDP and 10 randomly selected cases of FTLD-TAU. Total grey matter volumes were also calculated for all cases.
The FTLD-FUS cases had significantly smaller caudate volumes (p=0.02) yet similar frontal lobe grey matter volumes (p=0.12) compared to FTLD-TDP and FTLD-TAU. Caudate volumes when corrected for total grey matter volume (p=0.01) or frontal lobe grey matter volume (p=0.01) were significantly smaller in FTLD-FUS than FTLD-TDP and FTLD-TAU, and showed no overlap with the other two groups.
Caudate atrophy on MRI appears to be significantly greater in FTLD-FUS compared with FTLD-TDP and FTLD-TAU suggesting that severe caudate atrophy may be a useful clinical feature to predict FTLD-FUS pathology.
PMCID: PMC2989679  PMID: 20236174
TDP-43; FTLD-TAU; FTLD-FUS; atlas based parcellation; caudate atrophy
16.  Antemortem MRI based Structural Abnormality Index (STAND)-Scores Correlate with Postmortem Braak Neurofibrillary Tangle Stage 
NeuroImage  2008;42(2):559-567.
The clinical diagnosis of Alzheimer Disease (AD) does not exactly match the pathological findings at autopsy in every subject. Therefore, in-vivo imaging measures, such as Magnetic Resonance Imaging (MRI) that measure anatomical variations in each brain due to atrophy, would be clinically useful independent supplementary measures of pathology. We have developed an algorithm that extracts atrophy information from individual patient’s 3D MRI scans and assigns a STructural Abnormality iNDex (STAND)-score to the scan based on the degree of atrophy in comparison to patterns extracted from a large library of clinically well characterized AD and CN (cognitively normal) subject’s MRI scans. STAND-scores can be adjusted for demographics to give adjusted-STAND (aSTAND)-scores which are typically > 0 for subjects with abnormal brains. Since histopathological findings are considered to represent the “ground truth”, our objective was to assess the sensitivity of aSTAND-scores to pathological AD staging. This was done by comparing antemortem MRI based aSTAND-scores with post mortem grading of disease severity in 101 subjects who had both antemortem MRI and postmortem Braak neurofibrillary tangle (NFT) staging. We found a rank correlation of 0.62 (p<0.0001) between Braak NFT stage and aSTAND-scores. The results show that optimally extracted information from MRI scans such as STAND-scores accurately capture disease severity and can be used as an independent approximate surrogate marker for in-vivo pathological staging as well as for early identification of AD in individual subjects.
PMCID: PMC3097053  PMID: 18572417
Alzheimer Disease; neurofibrillary tangles; amnestic mild cognitive impairment; Braak NFT stage; magnetic resonance imaging
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.
PMCID: PMC2768663  PMID: 19762452
behavioural variant frontotemporal dementia; atrophy; cluster analysis; voxel-based morphometry
18.  Symmetric corticobasal degeneration (S-CBD) 
Parkinsonism & related disorders  2009;16(3):208-214.
Corticobasal degeneration (CBD) is a neurodegenerative disease characterized pathologically by neuronal loss, gliosis and tau deposition in neocortex, basal ganglia and brainstem. Typical clinical presentation is known as corticobasal syndrome (CBS) and involves the core features of progressive asymmetric rigidity and apraxia, accompanied by other signs of cortical and extrapyramidal dysfunction. Asymmetry is also emphasized on neuroimaging.
To describe a series of cases of CBD with symmetric clinical features and to compare clinical and imaging features of these symmetric CBD cases (S-CBD) to typical cases of CBS with CBD pathology.
All cases of pathologically confirmed CBD from the Mayo Clinic Rochester database were identified. Clinical records were reviewed and quantitative volumetric analysis of symmetric atrophy on head MRI using atlas based parcellation was performed. Subjects were classified as S-CBD if no differences had been observed between right- and left-sided cortical or extrapyramidal signs or symptoms. S-CBD cases were compared to 10 randomly selected typical CBS cases.
Five cases (2 female) met criteria for S-CBD. None had limb dystonia, myoclonus, apraxia or alien limb phenomena. S-CBD cases had significantly less asymmetric atrophy when compared with CBS cases (p=0.009); they were also younger at onset (median 61 versus 66 years, p<0.05) and death (67 versus 73 years, p<0.05). Family history was present in 40% of S-CBD cases.
CBD can have a symmetric presentation, clinically and radiologically, in which typical features of CBS, such as limb apraxia, myoclonus, dystonia and alien limb phenomenon, may be absent.
PMCID: PMC2941264  PMID: 20018548
Corticobasal degeneration; Corticobasal syndrome; Symmetric CBD; Atlas Based Parcellation; Pathology
19.  Abnormal TDP-43 immunoreactivity in AD modifies clinicopathological and radiological phenotype 
Neurology  2008;70(19 Pt 2):1850-1857.
TAR DNA-binding protein 43 (TDP-43) is one of the major disease proteins in frontotemporal lobar degeneration with ubiquitin immunoreactivity. Approximately 1/4 of subjects with pathologically confirmed Alzheimer's disease (AD) have abnormal TDP-43 (abTDP-43) immunoreactivity. The aim of this study was to determine if subjects with pathologically confirmed AD and abTDP-43 immunoreactivity have distinct clinical, neuropsychological, imaging or pathological features compared to subjects with AD without abTDP-43 immunoreactivity.
Eighty-four subjects were identified that had a pathological diagnosis of AD, neuropsychometric testing, and volumetric MRI. Immunohistochemistry for TDP-43 was performed on sections of hippocampus and medial temporal lobe, and positive cases were classified into one of three types. Neuropsychometric data was collated and compared in subjects with and without abTDP-43 immunoreactivity. Voxel-based morphometry was used to assess patterns of gray matter atrophy in subjects with and without abTDP-43 immunoreactivity compared to age and gender matched controls.
Twenty-nine (34%) of the 84 AD subjects had abTDP-43 immunoreactivity. Those with abTDP-43 immunoreactivity were older at onset and death, and performed worse on the Clinical Dementia Rating scale, Mini-Mental State Examination and Boston Naming Test than subjects without abTDP-43 immunoreactivity. Subjects with and without abTDP-43 immunoreactivity had medial temporal and temporoparietal gray matter loss compared to controls; however, those with abTDP-43 immunoreactivity showed greater hippocampal atrophy. Multivariate logistic regression adjusting for age at death demonstrated that hippocampal sclerosis was the only pathological predictor of abTDP-43 immunoreactivity.
The presence of abTDP-43 immunoreactivity is associated with a modified AD clinicopathological and radiological phenotype.
PMCID: PMC2779031  PMID: 18401022
20.  Voxel-based morphometry in frontotemporal lobar degeneration with ubiquitin-positive inclusions with and without progranulin mutations 
Archives of neurology  2007;64(3):371-376.
Mutations in the progranulin gene (PGRN) have recently been identified as a cause of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) in some families.
To determine whether there is a difference in the patterns of atrophy in cases with FTLD-U with and without a mutation in PGRN.
Case control study
Brain bank of a tertiary care medical center
All subjects that had screened positive for mutations in PGRN and had a volumetric MRI were identified (n=8, PGRN (+)). Subjects were then matched by clinical diagnosis to a group of eight subjects with a pathological diagnosis of FTLD-U that had screened negative for mutations in PGRN (PGRN (−)). All subjects were then age and gender-matched to a control subject.
Main outcome Measures
Voxel-based morphometry was used to assess the patterns of grey matter atrophy in the PGRN (+) and (−) groups compared to controls, and compared to each other.
The PGRN (+) group showed a widespread and severe pattern of grey matter loss predominantly affecting the frontal, temporal and parietal lobes. In comparison, the PGRN (−) group showed a less severe pattern of loss restricted mainly to the temporal and frontal lobes. On direct comparison the PGRN (+) group showed greater loss in the frontal and parietal lobes compared to the PGRN (−) group.
This study suggests that PGRN mutations may be associated with a specific and severe pattern of cerebral atrophy in subjects with FTLD-U.
PMCID: PMC2752412  PMID: 17353379
Frontotemporal dementia; Voxel-based morphometry; Ubiquitin; Dentate; Progranulin
21.  Progressive aphasia secondary to Alzheimer disease pathology: A clinicopathologic and MRI study 
Neurology  2008;70(1):25-34.
The pathology causing progressive aphasia is typically a variant of frontotemporal lobar degeneration, especially with ubiquitin-positive-inclusions (FTLD-U). Less commonly the underlying pathology is Alzheimer disease (AD).
To compare clinicopathological and MRI features of subjects with progressive aphasia and AD pathology, to subjects with aphasia and FTLD-U pathology, and subjects with typical AD.
We identified 5 subjects with aphasia and AD pathology and 5 with aphasia and FTLD-U pathology with an MRI from a total of 216 aphasia subjects. Ten subjects with typical AD clinical features and AD pathology were also identified. All subjects with AD pathology underwent pathological re-analysis with TDP-43 immunohistochemistry. Voxel-based morphometry (VBM) was used to assess patterns of grey matter atrophy in the aphasia cases with AD pathology, aphasia cases with FTLD-U, and typical AD cases with AD pathology, compared to a normal control group.
All aphasic subjects had fluent speech output. However, those with AD pathology had better processing speed than those with FTLD-U pathology. Immunohistochemistry with TDP-43 antibodies was negative. VBM revealed grey matter atrophy predominantly in the temporoparietal cortices with notable sparing of the hippocampus in the aphasia with AD subjects. In comparison, the aphasic subjects with FTLD-U showed sparing of the parietal lobe. Typical AD subjects showed temporoparietal and hippocampal atrophy.
A temporoparietal pattern of atrophy on MRI in patients with progressive fluent aphasia and relatively preserved processing speed is suggestive of underlying AD pathology rather than FTLD-U.
PMCID: PMC2749307  PMID: 18166704
Primary progressive aphasia; Progressive non-fluent aphasia; Logopenic progressive aphasia; frontotemporal lobar degeneration with ubiquitin-only-immunoreactive changes; Voxel based morphometry
22.  Visual Hallucinations in Posterior Cortical Atrophy 
Archives of neurology  2006;63(10):1427-1432.
To compare clinical and imaging features of patients with posterior cortical atrophy (PCA) with and without well-formed visual hallucinations.
Tertiary care medical center
Fifty-nine patients fulfilling criteria for PCA were retrospectively identified, and divided into two groups based on the presence (N=13) and absence (N=46) of visual hallucinations. Both groups were then compared statistically for clinical differences, as well as with voxel-based morphometry (VBM) for imaging differences.
In PCA patients with hallucinations, parkinsonism and rapid eye movement sleep behavior disorder occurred more frequently (p<0.0001), as did myoclonic jerks (p=0.0002). VBM analysis showed greater atrophy in a network of structures, including the primary visual cortex, lentiform nuclei, thalamus, basal forebrain and midbrain in the patients with hallucinations.
Hallucinations in patients with PCA are associated with parkinsonism, rapid eye movement sleep behavior disorder, and myoclonic jerks. The results from the VBM analysis suggest that hallucinations in PCA cannot be exclusively attributed to atrophy of the posterior association cortices and may involve a circuit of thalamocortical connections.
PMCID: PMC2748870  PMID: 17030659
Parkinsonism; Thalamus; Myoclonic jerks; REM sleep; Voxel based morphometry
23.  Clinicopathologic and Imaging Correlates of Progressive Aphasia and Apraxia of Speech 
Brain : a journal of neurology  2006;129(Pt 6):1385-1398.
Apraxia of speech (AOS) is a motor speech disorder characterized by slow speaking rate, abnormal prosody and distorted sound substitutions, additions, repetitions and prolongations, sometimes accompanied by groping and trial-and error articulatory movements. Although AOS is frequently subsumed under the heading of aphasia, and indeed most often co-occurs with aphasia, it can be the predominant or even the sole manifestation of a degenerative neurologic disease. In this study we determined whether the clinical classifications of aphasia and AOS correlated with pathological diagnoses and specific biochemical and anatomical structural abnormalities. Seventeen cases with initial diagnoses of a degenerative aphasia or AOS were reclassified independently by two speech-language pathologists — blinded to pathologic and biochemical findings - into one of five operationally defined categories of aphasia and AOS. Pathological diagnoses in the 17 cases were progressive supranuclear palsy in six, corticobasal degeneration in five, frontotemporal lobar degeneration with ubiquitin-only-immunoreactive changes in five, and Pick’s disease in one. Voxel-based morphometry and SPECT were completed, blinded to the clinical diagnoses, and clinico-imaging and clinico-pathological associations were then sought. Interjudge clinical classification reliability was 87% (κ =0.8) for all evaluations. Eleven cases had evidence of AOS, of which all (100%) had a pathological diagnosis characterized by underlying tau biochemistry, while five of the other six cases without AOS did not have tau biochemistry (p=0.001). A majority of the 17 cases had more than one yearly evaluation, demonstrating the evolution of the speech and language syndromes, as well as motor signs. Voxel-based morphometry revealed the premotor and supplemental motor cortices to be the main cortical regions associated with AOS, while the anterior peri-sylvian region was associated with non-fluent aphasia. Refining the classification of the degenerative aphasias and AOS may be necessary to improve our understanding of the relationships among behavioral, pathological, and imaging correlations.
PMCID: PMC2748312  PMID: 16613895
Premotor cortex; supplementary motor cortex; progressive supranuclear palsy; apraxia of speech; aphasia
24.  MRI correlates of protein deposition and disease severity in postmortem frontotemporal lobar degeneration 
Neuro-degenerative diseases  2009;6(3):106-117.
Frontotemporal lobar degeneration (FTLD) can be classified based on the presence of the microtubule associated protein tau and the TAR DNA binding protein-43 (TDP-43). Future treatments will likely target these proteins; therefore it is important to identify biomarkers to help predict protein biochemistry.
To determine whether there is an MRI signature pattern of tau or TDP-43 using a large cohort of FTLD subjects and to investigate how patterns of atrophy change according to disease severity using a large autopsy-confirmed cohort of FTLD subjects.
Patterns of grey matter loss were assessed using voxel-based morphometry in 37 tau-positive and 44 TDP-43 positive subjects compared to 35 age and gender-matched controls, and compared to each other. Comparisons were also repeated in behavioral variant frontotemporal dementia (bvFTD) subjects (n=15 tau-positive and n=30 TDP-43 positive). Patterns of atrophy were also assessed according to performance on the clinical dementia rating (CDR) scale and mini-mental state examination (MMSE).
The tau-positive and TDP-43 positive groups showed patterns of frontotemporal grey matter loss compared to controls with no differences observed between the groups, for all subjects and for bvFTD subjects. Patterns of grey matter loss increased in a graded manner by CDR and MMSE with loss in the frontal lobes, insula and hippocampus in mild subjects, spreading to the temporal and parietal cortices and striatum in more advanced disease.
There is no signature pattern of atrophy for tau or TDP-43; however patterns of atrophy in FTLD progress with measures of clinical disease severity.
PMCID: PMC2745704  PMID: 19299900
frontotemporal lobar degeneration; autopsy; tau; TAR DNA binding protein-43; voxel-based morphometry; Clinical Dementia Rating Scale; Mini-Mental State Examination
25.  Hippocampal Volumes, Proton Magnetic Resonance Spectroscopy Metabolites, and Cerebrovascular Disease in Mild Cognitive Impairment Subtypes 
Archives of neurology  2008;65(12):1621-1628.
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.
To determine the characteristic magnetic resonance imaging (MRI) and proton MR spectroscopy (1H MRS) profiles of MCI subtypes.
Case-control study.
Community-based sample at a tertiary referral center.
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.
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.
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.
PMCID: PMC2743393  PMID: 19064749

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