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1.  Microbleeds in the logopenic variant of primary progressive aphasia 
Background
Microbleeds have been associated with Alzheimer’s disease (AD), although it is unclear whether they occur in atypical presentations of AD, such as the logopenic variant of primary progressive aphasia (lvPPA). We aimed to assess the presence and clinical correlates of microbleeds in lvPPA.
Methods
Thirteen lvPPA subjects underwent 3T T2*-weighted and fluid-attenuated inversion recovery MRI and Pittsburgh Compound B (PiB) PET imaging. Microbleeds were identified on manual review and assigned a regional location. Total and regional white matter hyperintensity (WMH) burden was measured.
Results
Microbleeds were observed in four lvPPA subjects (31%); most common in frontal lobe. Subjects with microbleeds were older, more likely female, and had a greater burden of WMH than those without microbleeds. The regional distribution of microbleeds did not match the regional distribution of WMH. All cases were PiB-positive.
Conclusions
Microbleeds occur in approximately 1/3 subjects with lvPPA, with older women at the highest risk.
doi:10.1016/j.jalz.2013.01.006
PMCID: PMC3706560  PMID: 23562427
Logopenic variant of primary progressive aphasia; Alzheimer’s disease; microbleeds; white matter hyperintensities
2.  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
3.  Distinct regional anatomic and functional correlates of neurodegenerative apraxia of speech and aphasia: an MRI and FDG-PET study 
Brain and language  2013;125(3):245-252.
Progressive apraxia of speech (AOS) can result from neurodegenerative disease and can occur in isolation or in the presence of agrammatic aphasia. We aimed to determine the neuroanatomical and metabolic correlates of progressive AOS and aphasia. Thirty-six prospectively recruited subjects with progressive AOS or agrammatic aphasia, or both, underwent the Western Aphasia Battery (WAB) and Token Test to assess aphasia, an AOS rating scale (ASRS), 3T MRI and 18-F fluorodeoxyglucose (FDG) PET. Correlations between clinical measures and imaging were assessed. The only region that correlated to ASRS was left superior premotor volume. In contrast, WAB and Token Test correlated with hypometabolism and volume of a network of left hemisphere regions, including pars triangularis, pars opercularis, pars orbitalis, middle frontal gyrus, superior temporal gyrus, precentral gyrus and inferior parietal lobe. Progressive agrammatic aphasia and AOS have non-overlapping regional correlations, suggesting that these are dissociable clinical features that have different neuroanatomical underpinnings.
doi:10.1016/j.bandl.2013.02.005
PMCID: PMC3660445  PMID: 23542727
apraxia of speech; aphasia; atrophy; Broca’s area; premotor cortex; hypometabolism
4.  Neuroimaging comparison of Primary Progressive Apraxia of Speech & Progressive Supranuclear Palsy 
Background
Primary progressive apraxia of speech, a motor speech disorder of planning and programming is a tauopathy that has overlapping histological features with progressive supranuclear palsy. We aimed to compare, for the first time, atrophy patterns, as well as white matter tract degeneration, between these two syndromes.
Methods
Sixteen primary progressive apraxia of speech subjects were age and gender-matched to 16 progressive supranuclear palsy subjects and 20 controls. All subjects were prospectively recruited, underwent neurological and speech evaluations, and 3.0 Tesla magnetic resonance imaging. Grey and white matter atrophy was assessed using voxel-based morphometry and atlas-based parcellation, and white matter tract degeneration was assessed using diffusion tensor imaging.
Results
All progressive supranuclear palsy subjects had typical occulomotor/gait impairments but none had speech apraxia. Both syndromes showed grey matter loss in supplementary motor area, white matter loss in posterior frontal lobes and degeneration of the body of the corpus callosum. While lateral grey matter loss was focal, involving superior premotor cortex, in primary progressive apraxia of speech, loss was less focal extending into prefrontal cortex in progressive supranuclear palsy. Caudate volume loss and tract degeneration of superior cerebellar peduncles was also observed in progressive supranuclear palsy. Interestingly, area of the midbrain was reduced in both syndromes compared to controls, although this was greater in progressive supranuclear palsy.
Discussion
Although neuroanatomical differences were identified between these distinctive clinical syndromes, substantial overlap was also observed, including midbrain atrophy, suggesting these two syndromes may have common pathophysiological underpinnings.
doi:10.1111/ene.12004
PMCID: PMC3556348  PMID: 23078273
Progressive supranuclear palsy; apraxia of speech; voxel-based morphometry; diffusion tensor imaging; midbrain
5.  Elevated occipital β-amyloid deposition is associated with widespread cognitive impairment in logopenic progressive aphasia 
Background
Most subjects with logopenic primary progressive aphasia (lvPPA) have beta-amyloid (Aβ) deposition on Pittsburgh Compound B PET (PiB-PET), usually affecting prefrontal and temporoparietal cortices, with less occipital involvement.
Objectives
To assess clinical and imaging features in lvPPA subjects with unusual topographic patterns of Aβ deposition with highest uptake in occipital lobe.
Methods
Thirty-three lvPPA subjects with Aβ deposition on PiB-PET were included in this case-control study. Line-plots of regional PiB uptake were created, including frontal, temporal, parietal and occipital regions, for each subject. Subjects in which the line sloped downwards in occipital lobe (lvPPA-low), representing low uptake, were separated from those where the line sloped upwards in occipital lobe (lvPPA-high), representing unusually high occipital uptake compared to other regions. Clinical variables, atrophy on MRI, hypometabolism on F18-fluorodeoxyglucose PET, and presence and distribution of microbleeds and white matter hyperintensities (WMH) were assessed.
Results
Seventeen subjects (52%) were classified as lvPPA-high. Mean occipital PiB uptake in lvPPA-high was higher than all other regions, and higher than all regions in lvPPA-low. The lvPPA-high subjects performed more poorly on cognitive testing, including executive and visuospatial testing, but the two groups did not differ in aphasia severity. Proportion of microbleeds and WMH was higher in lvPPA-high than lvPPA-low. Parietal hypometabolism was greater in lvPPA-high than lvPPA-low.
Conclusions
Unusually high occipital Aβ deposition is associated with widespread cognitive impairment and different imaging findings in lvPPA. These findings help explain clinical heterogeneity in lvPPA, and suggest that Aβ influences severity of overall cognitive impairment but not aphasia.
doi:10.1136/jnnp-2013-305628
PMCID: PMC3920541  PMID: 23946416
6.  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.
doi:10.1016/j.neurobiolaging.2012.03.009
PMCID: PMC3404265  PMID: 22502999
Frontotemporal dementia; frontal lobes; MRI; asymmetry; microtubule associated protein tau; progranulin; C9ORF72; pathology
7.  Recent Advances in the Imaging of Frontotemporal Dementia 
Neuroimaging has played an important role in the characterization of the frontotemporal dementia (FTD) syndromes, demonstrating neurodegenerative signatures that can aid in the differentiation of FTD from other neurodegenerative disorders. Recent advances have been driven largely by the refinement of the clinical syndromes that underlie FTD, and by the discovery of new genetic and pathological features associated with FTD. Many new imaging techniques and modalities are also now available that allow the assessment of other aspects of brain structure and function, such as diffusion tensor imaging and resting state functional MRI. Studies have utilized these recent techniques, as well as traditional volumetric MRI, to provide further insight into disease progression across the many clinical, genetic and pathological variants of FTD. Importantly, neuroimaging signatures have been identified that will improve the clinician’s ability to predict underlying genetic and pathological features, and hence ultimately improve patient diagnosis.
doi:10.1007/s11910-012-0317-0
PMCID: PMC3492940  PMID: 23015371
Magnetic Resonance Imaging; Diffusion Tensor Imaging; Resting-state functional MRI; behavioral variant frontotemporal dementia; semantic dementia; agrammatic; apraxia of speech; C9ORF72 hexanucleotide repeat; progranulin; tau; TDP-43; fused in Sarcoma; atrophy; white matter tracts; functional connectivity
8.  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
9.  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
10.  Amyloid Burden Correlates with Cognitive Decline in Alzheimer’s Disease Presenting with Aphasia 
Background
A subset of patients with Alzheimer’s disease (AD) present with early and prominent language deficits. It is unclear whether the burden of underlying β-amyloid pathology is associated with language or general cognitive impairment in these subjects.
Methods
Here, we assess the relationship between cortical β-amyloid burden on [11C]Pittsburgh compound B (PiB) PET and performance on the Montreal Cognitive Assessment (MoCA), the Wechsler Memory Scale-Third Edition (WMS-III), the Boston Naming Test (BNT), and the Western Aphasia Battery (WAB) using regression and correlation analyses in subjects presenting with aphasia that showed β-amyloid deposition on PiB PET.
Results
The global PiB ratio was inversely correlated with MoCA (p = 0.02) and the WMS-III Visual Reproduction (VR) subtest (VR I, p = 0.02; VR II, p = 0.04). However, the correlations between PiB ratio, BNT (p = 0.13), WAB aphasia quotient (p = 0.11), and WAB repetition scores (p = 0.34) were not significant.
Conclusion
This study demonstrates that an increased cortical β-amyloid burden is associated with cognitive impairment, but not language deficits, in AD subjects presenting with aphasia. The results suggest that β-amyloid deposition may partly contribute to impaired cognition in such patients while language dysfunction may be influenced by other pathologic mechanisms, perhaps downstream pathways of β-amyloid deposition.
doi:10.1111/ene.12331
PMCID: PMC4057296  PMID: 24330306
Dementia; Aphasia; PET; Beta-amyloid; PiB
11.  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.
doi:10.1007/s00415-014-7352-5
PMCID: PMC4101047  PMID: 24760339
TDP-43; Alzheimer’s disease; Frontotemporal dementia; Parkinsonism
12.  Disrupted thalamocortical connectivity in PSP: a resting state fMRI, DTI, VBM study 
Parkinsonism & related disorders  2011;17(8):599-605.
Progressive supranuclear palsy (PSP) is associated with pathological changes along the dentatorubrothalamic tract and in premotor cortex. We aimed to assess whether functional neural connectivity is disrupted along this pathway in PSP, and to determine how functional changes relate to changes in structure and diffusion. Eighteen probable PSP subjects and 18 controls had resting-state (task-free) fMRI, diffusion tensor imaging and structural MRI. Functional connectivity was assessed between thalamus and the rest of the brain, and within the basal ganglia, salience and default mode networks (DMN). Patterns of atrophy were assessed using voxel-based morphometry, and patterns of white matter tract degeneration were assessed using tract-based spatial statistics. Reduced in-phase functional connectivity was observed between the thalamus and premotor cortex including supplemental motor area (SMA), striatum, thalamus and cerebellum in PSP. Reduced connectivity in premotor cortex, striatum and thalamus were observed in the basal ganglia network and DMN, with subcortical salience network reductions. Tract degeneration was observed between cerebellum and thalamus and in superior longitudinal fasciculus, with grey matter loss in frontal lobe, premotor cortex, SMA and caudate. SMA functional connectivity correlated with SMA volume and measures of cognitive and motor dysfunction, while thalamic connectivity correlated with degeneration of superior cerebellar peduncles. PSP is therefore associated with disrupted thalamocortical connectivity that is associated with degeneration of the dentatorubrothalamic tract and the presence of cortical atrophy.
doi:10.1016/j.parkreldis.2011.05.013
PMCID: PMC3168952  PMID: 21665514
Resting state fMRI; functional connectivity; white matter tracts; atrophy; dentatorubrothalamic tract
13.  Rates of brain atrophy and clinical decline over 6 and 12-month intervals in PSP: determining sample size for treatment trials 
Parkinsonism & related disorders  2011;18(3):252-256.
Imaging biomarkers are useful outcome measures in treatment trials. We compared sample size estimates for future treatment trials performed over 6 or 12-months in progressive supranuclear palsy using both imaging and clinical measures. We recruited 16 probable progressive supranuclear palsy patients that underwent baseline, 6 and 12 month brain scans, and 16 age-matched controls with serial scans. Disease severity was measured at each time-point using the progressive supranuclear palsy rating scale. Rates of ventricular expansion and rates of atrophy of the whole brain, superior frontal lobe, thalamus, caudate and midbrain were calculated. Rates of atrophy and clinical decline were used to calculate sample sizes required to power placebo-controlled treatment trials over 6 and 12-months. Rates of whole brain, thalamus and midbrain atrophy, and ventricular expansion, were increased over 6 and 12-months in progressive supranuclear palsy compared to controls. The progressive supranuclear palsy rating scale increased by 9 points over 6-months, and 18 points over 12-months. The smallest sample size estimates for treatment trials over 6-months were achieved using rate of midbrain atrophy, followed by rate of whole brain atrophy and ventricular expansion. Sample size estimates were further reduced over 12-month intervals. Sample size estimates for the progressive supranuclear palsy rating scale were worse than imaging measures over 6-months, but comparable over 12-months. Atrophy and clinical decline can be detected over 6-months in progressive supranuclear palsy. Sample size estimates suggest that treatment trials could be performed over this interval, with rate of midbrain atrophy providing the best outcome measure.
doi:10.1016/j.parkreldis.2011.10.013
PMCID: PMC3399183  PMID: 22079523
Progressive supranuclear palsy; atrophy; midbrain; power calculations; short interval
14.  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.
doi:10.1007/s00401-014-1269-z
PMCID: PMC4172544  PMID: 24659241
TDP-43; Alzheimer disease; resilience; APOE ε4; Braak stage; MRI
15.  Nonverbal oral apraxia in primary progressive aphasia and apraxia of speech 
Neurology  2014;82(19):1729-1735.
Objective:
The goal of this study was to explore the prevalence of nonverbal oral apraxia (NVOA), its association with other forms of apraxia, and associated imaging findings in patients with primary progressive aphasia (PPA) and progressive apraxia of speech (PAOS).
Methods:
Patients with a degenerative speech or language disorder were prospectively recruited and diagnosed with a subtype of PPA or with PAOS. All patients had comprehensive speech and language examinations. Voxel-based morphometry was performed to determine whether atrophy of a specific region correlated with the presence of NVOA.
Results:
Eighty-nine patients were identified, of which 34 had PAOS, 9 had agrammatic PPA, 41 had logopenic aphasia, and 5 had semantic dementia. NVOA was very common among patients with PAOS but was found in patients with PPA as well. Several patients exhibited only one of NVOA or apraxia of speech. Among patients with apraxia of speech, the severity of the apraxia of speech was predictive of NVOA, whereas ideomotor apraxia severity was predictive of the presence of NVOA in those without apraxia of speech. Bilateral atrophy of the prefrontal cortex anterior to the premotor area and supplementary motor area was associated with NVOA.
Conclusions:
Apraxia of speech, NVOA, and ideomotor apraxia are at least partially separable disorders. The association of NVOA and apraxia of speech likely results from the proximity of the area reported here and the premotor area, which has been implicated in apraxia of speech. The association of ideomotor apraxia and NVOA among patients without apraxia of speech could represent disruption of modules shared by nonverbal oral movements and limb movements.
doi:10.1212/WNL.0000000000000412
PMCID: PMC4032207  PMID: 24727315
16.  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
17.  Clinical, FDG and amyloid PET imaging in posterior cortical atrophy 
Journal of Neurology  2015;262(6):1483-1492.
The purpose of this study was to identify the clinical, [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) and amyloid-PET findings in a large cohort of posterior cortical atrophy (PCA) patients, to examine the neural correlates of the classic features of PCA, and to better understand the features associated with early PCA. We prospectively recruited 25 patients who presented to the Mayo Clinic between March 2013 and August 2014 and met diagnostic criteria for PCA. All patients underwent a standardized set of tests and amyloid imaging with [11C] Pittsburg compound B (PiB). Seventeen (68 %) underwent FDG-PET scanning. We divided the cohort at the median disease duration of 4 years in order to assess clinical and FDG-PET correlates of early PCA (n = 13). The most common clinical features were simultanagnosia (92 %), dysgraphia (68 %), poly-mini-myoclonus (64 %) and oculomotor apraxia (56.5 %). On FDG-PET, hypometabolism was observed bilaterally in the lateral and medial parietal and occipital lobes. Simultanagnosia was associated with hypometabolism in the right occipital lobe and posterior cingulum, optic ataxia with hypometabolism in left occipital lobe, and oculomotor apraxia with hypometabolism in the left parietal lobe and posterior cingulate gyrus. All 25 PCA patients were amyloid positive. Simultanagnosia was the only feature present in 85 % of early PCA patients. The syndrome of PCA is associated with posterior hemisphere hypometabolism and with amyloid deposition. Many of the classic features of PCA show associated focal, but not widespread, areas of involvement of these posterior hemispheric regions. Simultanagnosia appears to be the most common and hence sensitive feature of early PCA.
doi:10.1007/s00415-015-7732-5
PMCID: PMC4469094  PMID: 25862483
PCA; FDG-PET; Cerebral hypometabolism; Clinical findings; Early PCA
18.  Quantitative application of the primary progressive aphasia consensus criteria 
Neurology  2014;82(13):1119-1126.
Objective:
To determine how well the consensus criteria could classify subjects with primary progressive aphasia (PPA) using a quantitative speech and language battery that matches the test descriptions provided by the consensus criteria.
Methods:
A total of 105 participants with a neurodegenerative speech and language disorder were prospectively recruited and underwent neurologic, neuropsychological, and speech and language testing and MRI in this case-control study. Twenty-one participants with apraxia of speech without aphasia served as controls. Select tests from the speech and language battery were chosen for application of consensus criteria and cutoffs were employed to determine syndromic classification. Hierarchical cluster analysis was used to examine participants who could not be classified.
Results:
Of the 84 participants, 58 (69%) could be classified as agrammatic (27%), semantic (7%), or logopenic (35%) variants of PPA. The remaining 31% of participants could not be classified. Of the unclassifiable participants, 2 clusters were identified. The speech and language profile of the first cluster resembled mild logopenic PPA and the second cluster semantic PPA. Gray matter patterns of loss of these 2 clusters of unclassified participants also resembled mild logopenic and semantic variants.
Conclusions:
Quantitative application of consensus PPA criteria yields the 3 syndromic variants but leaves a large proportion unclassified. Therefore, the current consensus criteria need to be modified in order to improve sensitivity.
doi:10.1212/WNL.0000000000000261
PMCID: PMC3966800  PMID: 24598709
19.  Staging TDP-43 pathology in Alzheimer’s disease 
Acta neuropathologica  2013;127(3):441-450.
TDP-43 immunoreactivity occurs in 19–57% of Alzheimer’s disease (AD) cases. Two patterns of TDP-43 deposition in AD have been described involving hippocampus (Limbic) or hippocampus and neocortex (Diffuse), although focal amygdala involvement has been observed. In 195 AD cases with TDP-43, we investigated regional TDP-43 immunoreactivity with the aim of developing a TDP-43 in AD staging scheme. TDP-43 immunoreactivity was assessed in amygdala, entorhinal cortex, subiculum, hippocampal dentate gyrus, occipitotemporal, inferior temporal and frontal cortices, and basal ganglia. Clinical, neuroimaging, genetic and pathological characteristics were assessed across stages. Five stages were identified: stage I showed scant-sparse TDP-43 in the amygdala only (17%); stage II showed moderate-frequent amygdala TDP-43 with spread into entorhinal and subiculum (25%); stage III showed further spread into dentate gyrus and occipitotemporal cortex (31%); stage IV showed further spread into inferior temporal cortex (20%); and stage V showed involvement of frontal cortex and basal ganglia (7%). Cognition and medial temporal volumes differed across all stages and progression across stages correlated with worsening cognition and medial temporal volume loss. Compared to 147 AD patients without TDP-43, only the Boston Naming Test showed abnormalities in stage I. The findings demonstrate that TDP-43 deposition in AD progresses in a stereotypic manner that can be divided into five distinct topographic stages which are supported by correlations with clinical and neuroimaging features. Given these findings, we recommend sequential regional TDP-43 screening in AD beginning with the amygdala.
doi:10.1007/s00401-013-1211-9
PMCID: PMC3944799  PMID: 24240737
Alzheimer disease; TDP-43; amygdala; TDP-43 type; staging; MRI
20.  Clinical and imaging characterization of progressive spastic dysarthria 
Objective
To describe speech, neurological and imaging characteristics of a series of patients presenting with progressive spastic dysarthria (PSD) as the first and predominant sign of a presumed neurodegenerative disease.
Methods
Participants were 25 patients with spastic dysarthria as the only or predominant speech disorder. Clinical features, pattern of MRI volume loss on voxel-based morphometry, and pattern of hypometabolism with F18-Fluorodeoxyglucose (FDG-PET) scan are described.
Results
All patients demonstrated speech characteristics consistent with spastic dysarthria, including strained voice quality, slow speaking rate, monopitch and monoloudness, and slow and regular speech alternating motion rates. Eight patients did not have additional neurological findings on examination. Pseudobulbar affect, upper motor neuron pattern limb weakness, spasticity, Hoffman sign and positive Babinski reflexes were noted in some of the remaining patients. Twenty-three patients had electromyographic assessment and none had diffuse motor neuron disease or met El Escorial criteria for ALS. Voxel-based morphometry revealed striking bilateral white matter volume loss, , affecting the motor cortex (BA 4), including the frontoparietal operculum (BA 43) with extension into the middle cerebral peduncle. FDG-PET showed subtle hypometabolism affecting the premotor and motor cortices in some patients, particularly in those who had a disease duration longer than two years.
Conclusions
We have characterized a neurodegenerative disorder that begins focally with spastic dysarthria due to involvement of the motor and premotor cortex and descending corticospinal and corticobulbar pathways. We propose the descriptive label “progressive spastic dysarthria” to best capture the dominant presenting feature of the syndrome.
doi:10.1111/ene.12271
PMCID: PMC3945960  PMID: 24053325
dysarthria; neuromuscular disease; MRI; PET
21.  Progranulin-associated PiB-negative logopenic primary progressive aphasia 
Journal of neurology  2014;261(3):604-614.
The logopenic variant of primary progressive aphasia (lvPPA) strongly associates with Alzheimer’s disease, but can also associate with frontotemporal lobar degeneration. We aimed to assess the frequency of lvPPA in patients with speech and language disorders without β-amyloid deposition, and to perform detailed neuroimaging and genetic testing in such lvPPA patients. Seventy-six patients with a neurodegenerative speech and language disorder and Pittsburgh compound B (PiB) PET imaging demonstrating no β-amyloid deposition were analyzed. Six lvPPA patients (8 %) were identified. All six underwent progranulin (GRN) gene testing. Structural abnormality index maps and Cortex ID analysis were utilized to assess individual patterns of grey matter atrophy on MRI and hypometabolism on 18-F fluorodeoxyglucose (FDG) PET. Statistical parametric mapping was used to perform MRI and FDG-PET group comparisons between those with (GRN-positive) and without (GRN-negative) progranulin mutations. All six lvPPA patients showed left temporoparietal atrophy and hypometabolism. Three patients (50 %) were GRN-positive. Speech, language, and neurological and neuropsychological profiles did not differ between GRN-positive and negative patients, although GRN-positive patients had family histories, were on average 8 years younger, and had lower PiB-PET ratios. All six patients showed similar patterns of atrophy and hypometabolism, although, as a group, GRN-positive patients had more severe abnormalities, particularly in anteromedial temporal lobes. Logopenic PPA accounts for a small minority of neurodegenerative speech and language disorders not associated with β-amyloid deposition. Identification of such patients, however, should prompt testing for GRN mutations, since GRN-positive patients do not have distinctive features, yet account for 50 % of this patient population.
doi:10.1007/s00415-014-7243-9
PMCID: PMC3961471  PMID: 24449064
Progranulin; Logopenic; Primary progressive aphasia; β-amyloid; MRI; FDG-PET
22.  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
23.  Accurate automatic estimation of total intracranial volume: A nuisance variable with less nuisance 
Neuroimage  2015;104:366-372.
Total intracranial volume (TIV/ICV) is an important covariate for volumetric analyses of the brain and brain regions, especially in the study of neurodegenerative diseases, where it can provide a proxy of maximum pre-morbid brain volume. The gold-standard method is manual delineation of brain scans, but this requires careful work by trained operators. We evaluated Statistical Parametric Mapping 12 (SPM12) automated segmentation for TIV measurement in place of manual segmentation and also compared it with SPM8 and FreeSurfer 5.3.0. For T1-weighted MRI acquired from 288 participants in a multi-centre clinical trial in Alzheimer's disease we find a high correlation between SPM12 TIV and manual TIV (R2 = 0.940, 95% Confidence Interval (0.924, 0.953)), with a small mean difference (SPM12 40.4 ± 35.4 ml lower than manual, amounting to 2.8% of the overall mean TIV in the study). The correlation with manual measurements (the key aspect when using TIV as a covariate) for SPM12 was significantly higher (p < 0.001) than for either SPM8 (R2 = 0.577 CI (0.500, 0.644)) or FreeSurfer (R2 = 0.801 CI (0.744, 0.843)). These results suggest that SPM12 TIV estimates are an acceptable substitute for labour-intensive manual estimates even in the challenging context of multiple centres and the presence of neurodegenerative pathology. We also briefly discuss some aspects of the statistical modelling approaches to adjust for TIV.
Graphical abstract
Highlights
•288 T1 MRI from multiple scanners were manually segmented for intracranial volume.•We compare SPM12 with the current methods of estimating intracranial volume.•SPM12 shows a very high correlation with manual measures and little bias.•Newer automated volume measures are more accurate controls for head size variation.
doi:10.1016/j.neuroimage.2014.09.034
PMCID: PMC4265726  PMID: 25255942
Intracranial volume; Statistical Parametric Mapping; SPM; Freesurfer; Evaluation; Alzheimer's disease; TIV; ICV
24.  Aphasia with left occipitotemporal hypometabolism: A novel presentation of posterior cortical atrophy? 
Alzheimer’s disease is a common neurodegenerative disease often characterized by initial episodic memory loss. Atypical focal cortical presentations have been described, including the logopenic variant of primary progressive aphasia (lvPPA) which presents with language impairment, and posterior cortical atrophy (PCA) which presents with prominent visuospatial deficits. Both lvPPA and PCA are characterized by specific patterns of hypometabolism: left temporoparietal in lvPPA and bilateral parietoccipital in PCA. However, not every patient fits neatly into these categories. We retrospectively identified two patients with progressive aphasia and visuospatial deficits from a speech and language based disorders study. The patients were further characterized by MRI, fluorodeoxyglucose F18 and Pittsburgh Compound B (PiB) positron emission tomography. Two women, ages 62 and 69, presented with a history of a few years of progressive aphasia characterized by fluent output with normal grammar and syntax, anomia without loss of word meaning, and relatively spared repetition. They demonstrated striking deficits in visuospatial function for which they were lacking insight. Prominent hypometabolism was noted in the left occipitotemporal region and diffuse retention of PiB was noted. Posterior cortical atrophy may present focally with left occipitotemporal metabolism characterized clinically with a progressive fluent aphasia and prominent ventral visuospatial deficits with loss of insight.
doi:10.1016/j.jocn.2013.01.002
PMCID: PMC4217166  PMID: 23850398
Alzheimer dementia; Aphasia; Functional Neuroimaging; Neuropsychology; Visual agnosia
25.  Quantitative neurofibrillary tangle density and brain volumetric MRI analyses in Alzheimer’s disease presenting as logopenic progressive aphasia 
Brain and language  2013;127(2):10.1016/j.bandl.2013.02.003.
Neurofibrillary tangles (NFTs) are one of the key histological lesions of Alzheimer’s disease (AD) and are associated with brain atrophy. We assessed regional NFT density in 30 patients with AD, 10 of which presented as the logopenic variant of primary progressive aphasia (lvPPA) and 20 that presented as dementia of the Alzheimer’s type (DAT). Regional grey matter volumes were measured using antemortem MRI. NFT density was significantly higher in left temporoparietal cortices in lvPPA compared to DAT, with no differences observed in hippocampus. There was a trend for the ratio of temporoparietal-to-hippocampal NFT density to be higher in lvPPA. The imaging findings mirrored the pathological findings, with smaller left temporoparietal volumes observed in lvPPA compared to DAT, and no differences observed in hippocampal volume. This study demonstrates that lvPPA is associated with a phenomenon of enhanced temporoparietal neurodegeneration, a finding that improves our understanding of the biological basis of lvPPA.
doi:10.1016/j.bandl.2013.02.003
PMCID: PMC3840097  PMID: 23541297
Primary progressive aphasia; Logopenic variant of primary progressive aphasia; Alzheimer’s disease; Neurofibrillary tangles; Hippocampus; MRI; Apolipoprotein E; TDP-43; Voxel-based morphometry; Alzheimer’s dementia

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