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1.  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
•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.
PMCID: PMC4265726  PMID: 25255942
Intracranial volume; Statistical Parametric Mapping; SPM; Freesurfer; Evaluation; Alzheimer's disease; TIV; ICV
2.  Microbleeds in the logopenic variant of primary progressive aphasia 
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.
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.
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.
Microbleeds occur in approximately 1/3 subjects with lvPPA, with older women at the highest risk.
PMCID: PMC3706560  PMID: 23562427
Logopenic variant of primary progressive aphasia; Alzheimer’s disease; microbleeds; white matter hyperintensities
3.  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.
PMCID: PMC4217166  PMID: 23850398
Alzheimer dementia; Aphasia; Functional Neuroimaging; Neuropsychology; Visual agnosia
4.  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.
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
5.  Identification of an atypical variant of logopenic progressive aphasia 
Brain and language  2013;127(2):10.1016/j.bandl.2013.02.007.
The purpose of this study was to examine the association between aphasia severity and neurocognitive function, disease duration and temporoparietal atrophy in 21 individuals with the logopenic variant of primary progressive aphasia (lvPPA). We found significant correlations between aphasia severity and neurocognitive severity as well as temporoparietal atrophy; but not disease duration. Cluster analysis identified three variants of lvPPA: (1) subjects with mild aphasia and short disease duration (mild typical lvPPA); (2) subjects with mild aphasia and long disease duration (mild atypical lvPPA); and, (3) subjects with severe aphasia and relatively long disease duration (severe typical lvPPA). All three variants showed temporoparietal atrophy, with the mild atypical group showing the least atrophy despite the longest disease duration. The mild atypical group also showed mild neuropsychological impairment. The subjects with mild aphasia and neuropsychological impairment despite long disease duration may represent a slowly progressive variant of lvPPA.
PMCID: PMC3725183  PMID: 23566690
Primary progressive aphasia; Logopenic aphasia; Neurocognitive impairment; Temporoparietal atrophy; Voxel-based morphometry
6.  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
7.  Improved DTI registration allows voxel-based analysis that outperforms Tract-Based Spatial Statistics 
NeuroImage  2014;94:65-78.
Tract-Based Spatial Statistics (TBSS) is a popular software pipeline to coregister sets of diffusion tensor Fractional Anisotropy (FA) images for performing voxel-wise comparisons. It is primarily defined by its skeleton projection step intended to reduce effects of local misregistration. A white matter “skeleton” is computed by morphological thinning of the inter-subject mean FA, and then all voxels are projected to the nearest location on this skeleton. Here we investigate several enhancements to the TBSS pipeline based on recent advances in registration for other modalities, principally based on groupwise registration with the ANTS-SyN algorithm. We validate these enhancements using simulation experiments with synthetically-modified images. When used with these enhancements, we discover that TBSS's skeleton projection step actually reduces algorithm accuracy, as the improved registration leaves fewer errors to warrant correction, and the effects of this projection's compromises become stronger than those of its benefits. In our experiments, our proposed pipeline without skeleton projection is more sensitive for detecting true changes and has greater specificity in resisting false positives from misregistration. We also present comparative results of the proposed and traditional methods, both with and without the skeleton projection step, on three real-life datasets: two comparing differing populations of Alzheimer's disease patients to matched controls, and one comparing progressive supranuclear palsy patients to matched controls. The proposed pipeline produces more plausible results according to each disease's pathophysiology.
PMCID: PMC4137565  PMID: 24650605
DTI; Fractional Anisotropy; Voxel-based analysis; VBM; TBSS; Registration
8.  Syndromes dominated by apraxia of speech show distinct characteristics from agrammatic PPA 
Neurology  2013;81(4):337-345.
We assessed whether clinical and imaging features of subjects with apraxia of speech (AOS) more severe than aphasia (dominant AOS) are more similar to agrammatic primary progressive aphasia (agPPA) or to primary progressive AOS (PPAOS).
Sixty-seven subjects (PPAOS = 18, dominant AOS = 10, agPPA = 9, age-matched controls = 30) who all had volumetric MRI, diffusion tensor imaging, F18-fluorodeoxyglucose and C11-labeled Pittsburgh compound B (PiB)-PET scanning, as well as neurologic and speech and language assessments, were included in this case-control study. AOS was classified as either type 1, predominated by sound distortions and distorted sound substitutions, or type 2, predominated by syllabically segmented prosodic speech patterns.
The dominant AOS subjects most often had AOS type 2, similar to PPAOS. In contrast, agPPA subjects most often had type 1 (p = 0.01). Both dominant AOS and PPAOS showed focal imaging abnormalities in premotor cortex, whereas agPPA showed widespread involvement affecting premotor, prefrontal, temporal and parietal lobes, caudate, and insula. Only the dominant AOS and PPAOS groups showed midbrain atrophy compared with controls. No differences were observed in PiB binding across all 3 groups, with the majority being PiB negative.
These results suggest that dominant AOS is more similar to PPAOS than agPPA, with dominant AOS and PPAOS exhibiting a clinically distinguishable subtype of progressive AOS compared with agPPA.
PMCID: PMC3772832  PMID: 23803320
9.  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.
PMCID: PMC3660445  PMID: 23542727
apraxia of speech; aphasia; atrophy; Broca’s area; premotor cortex; hypometabolism
10.  Ideomotor Apraxia in Agrammatic and Logopenic Variants of Primary Progressive Aphasia 
Journal of neurology  2013;260(6):1594-1600.
There are few studies examining praxis in subjects with primary progressive aphasia. The aim of this study was to examine the pattern and severity of ideomotor apraxia in subjects with logopenic and agrammatic variants of primary progressive aphasia and to determine if the presence of ideomotor apraxia correlated with specific neuroanatomical structural abnormalities. Subjects with primary progressive aphasia were prospectively recruited and classified according to published criteria. Using the apraxia subtest of the Western Aphasia Battery, pattern and severity of ideomotor apraxia was examined in all subjects diagnosed with agrammatic and logopenic variants of primary progressive aphasia. The study included 47 subjects, 21 diagnosed with agrammatic variant of primary progressive aphasia and 26 with logopenic variant primary progressive aphasia. Subjects with agrammatic aphasia were older at onset than the logopenic variant (67.2 versus 61.7 years, p=0.02), but there was no difference in illness duration prior to evaluation. Those with logopenic aphasia showed more cognitive impairment on the Mini-Mental Status Examination (agrammatic=26.7/30, logopenic=22/30, p=0.002), and a trend for more severe language impairment as measured by Western Aphasia Battery-Aphasia Quotient (agrammatic=82.3, logopenic=75.2, p=0.11). Strong correlations were found between Western Aphasia Battery-Aphasia Quotient and total apraxia, instrumental apraxia, and complex apraxia, while average correlation were seen with upper limb apraxia and modest correlation with facial apraxia. After adjusting for age, mental status performance, and Western Aphasia Battery-Aphasia Quotient score, those with agrammatic aphasia had a higher degree of total apraxia (p=0.004), facial apraxia (p=0.03), instrumental apraxia (p=0.0006), and complex apraxia (p=0.0006) than those with logopenic aphasia. The agrammatic variant of primary progressive aphasia was associated with greater praxis deficits but less cognitive impairment than the logopenic variant. The presence of ideomotor apraxia was associated with grey matter loss in the left lateral premotor cortex with extension into the motor cortex. These findings suggest that although some affected areas in the agrammatic and logopenic variants of primary progressive aphasia overlap, there exists an area that is more affected in the agrammatic variant than the logopenic variant that accounts for the greater association of agrammatic aphasia with apraxia.
PMCID: PMC3676701  PMID: 23358624
Primary progressive aphasia; Agrammatic; Logopenic; Apraxia; Ideomotor; Cortical atrophy
11.  Neuroimaging comparison of Primary Progressive Apraxia of Speech & Progressive Supranuclear Palsy 
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.
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.
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.
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.
PMCID: PMC3556348  PMID: 23078273
Progressive supranuclear palsy; apraxia of speech; voxel-based morphometry; diffusion tensor imaging; midbrain
12.  Occupational differences between Alzheimer’s and aphasic dementias: implication for teachers 
We aimed to determine if there is an association between teaching and the development of progressive speech and language disorders (SLDs). Occupation was compared between 100 patients with a progressive SLD, 404 Alzheimer’s dementia patients, and the 2008 US census. In SLDs the most common occupation was teacher (22%), versus 8% in Alzheimer’s dementia. The odds ratio of being a teacher in SLDs compared to Alzheimer’s dementia was 3.4 (95% CI=1.87, 6.17). No differences were observed in the frequency of other occupations. The frequency of teachers was higher in SLDs compared to the US census; odds ratio of 6.9 (95% CI=4.3, 11.1). Farming, forestry and fishing occupations were more frequent in SLDs compared to the US census. We identified an association between progressive SLDs and the occupation of teaching. Since teaching is a communication demanding occupation, teachers may be more sensitive to the development of speech and language impairments.
PMCID: PMC3920458  PMID: 23838322
Alzheimer’s; dementia; aphasia; teacher; occupation
13.  Elevated occipital β-amyloid deposition is associated with widespread cognitive impairment in logopenic progressive aphasia 
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.
To assess clinical and imaging features in lvPPA subjects with unusual topographic patterns of Aβ deposition with highest uptake in occipital lobe.
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.
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.
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.
PMCID: PMC3920541  PMID: 23946416
14.  The protective role of brain size in Alzheimer disease 
Expert review of neurotherapeutics  2010;10(12):1799-1801.
Evaluation of: Perneczky R, Wagenpfeil S, Lunetta KL, et al. Head circumference, atrophy, and cognition: Implications for brain reserve in Alzheimer disease. Neurology 2010; 75: 137-142.
The brain reserve hypothesis suggests that larger brain size is associated with a greater ability to tolerate pathological damage before showing any cognitive decline. This theory has been used to explain why many patients with Alzheimer’s disease (AD) pathology are cognitively normal before death. The literature concerning the brain reserve hypothesis is however mixed with evidence both for and against this theory. Perneczky and colleagues tested the theory by assessing whether premorbid brain size, measured using head circumference, alters the relationship between brain atrophy and cognitive decline in 270 AD patients. They found that head circumference was associated with a reduced impact of atrophy on cognitive performance. Hence, for a given degree of atrophy, cognitive performance was better in patients with larger head circumference. These findings therefore support the brain reserve hypothesis. This evaluation will discuss the brain reserve concept and potential limitations and significance of this study.
PMCID: PMC3920660  PMID: 21091311
brain reserve; Alzheimer disease; head circumference; cognition; atrophy
15.  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
16.  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
17.  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.
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
18.  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
19.  Voxel-based morphometry in patients with obsessive-compulsive behaviors in behavioral variant frontotemporal dementia 
European Journal of Neurology  2012;19(6):911-917.
Obsessions and compulsive (OC) behaviors are a frequent feature of behavioral variant frontotemporal dementia (bvFTD), but their structural correlates have not been definitively established.
Patients with bvFTD presenting to the Mayo Clinic Alzheimer’s Disease Research Center were recruited. Each patient’s caregiver was given the Yale-Brown Obsessive-Compulsive scale (YBOCS) to document the type and presence of OC behaviors and to rate their severity. All subjects underwent a standardized MRI which was evaluated using VBM. 17 patients with bvFTD were recruited and 11 were included in the study and compared to 11 age and gender matched controls. Six were excluded for lack of MRI at time of survey or a pre-existing neurodegenerative condition.
Nine of the 11 reported OC behaviors, with the most frequent compulsions being checking, hoarding, ordering/arranging, repeating rituals, and cleaning. In the VBM analysis, total YBOCS score correlated with grey matter loss in the bilateral globus pallidus, left putamen, and in the lateral temporal lobe, particularly the left middle and inferior temporal gyri (p<0.001 uncorrected for multiple comparisons).
Obsessive-compulsive behaviors were frequent among these patients. The correlation with basal ganglia atrophy may point to involvement of frontal subcortical neuronal networks. Left lateral temporal lobe volume loss likely reflects the number of MAPT mutation patients included but also provides additional data implicating temporal lobe involvement in OC behaviors.
PMCID: PMC3351534  PMID: 22284815
Frontotemporal dementia; magnetic resonance imaging; obsessive behavior; compulsive behavior
20.  Primary Lateral Sclerosis as Progressive Supranuclear Palsy: Diagnosis by Diffusion Tensor Imaging 
Movement Disorders  2012;27(7):903-906.
Evaluating the integrity of white matter tracts with diffusion tensor imaging may differentiate primary lateral sclerosis from progressive supranuclear palsy.
Thirty-three prospectively recruited subjects had standardized evaluations and diffusion tensor imaging: 3 with primary lateral sclerosis who presented with features suggestive of progressive supranuclear palsy, 10 with probable or definite progressive supranuclear palsy, and 20 matched controls. We compared fractional anisotropy of the corticospinal tract, superior cerebellar peduncle and body of the corpus callosum between groups.
Both the primary lateral sclerosis and progressive supranuclear palsy subjects showed reduced fractional anisotropy in superior cerebellar peduncles and body of the corpus callosum compared to controls, but only primary lateral sclerosis subjects showed reductions in the corticospinal tracts. A ratio of corticospinal tract/superior cerebellar peduncle best distinguished the disorders (p<0.02).
The corticospinal tract/superior cerebellar peduncle ratio is a marker to differentiate primary lateral sclerosis from progressive supranuclear palsy.
PMCID: PMC3383380  PMID: 22517038
Progressive supranuclear palsy; primary lateral sclerosis; motor neuron disease; diffusion tensor imaging
21.  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
22.  FDG PET and MRI in Logopenic Primary Progressive Aphasia versus Dementia of the Alzheimer’s Type 
PLoS ONE  2013;8(4):e62471.
The logopenic variant of primary progressive aphasia is an atypical clinical variant of Alzheimer’s disease which is typically characterized by left temporoparietal atrophy on magnetic resonance imaging and hypometabolism on F-18 fluorodeoxyglucose positron emission tomography. We aimed to characterize and compare patterns of atrophy and hypometabolism in logopenic primary progressive aphasia, and determine which brain regions and imaging modality best differentiates logopenic primary progressive aphasia from typical dementia of the Alzheimer’s type.
A total of 27 logopenic primary progressive aphasia subjects underwent fluorodeoxyglucose positron emission tomography and volumetric magnetic resonance imaging. These subjects were matched to 27 controls and 27 subjects with dementia of the Alzheimer’s type. Patterns of atrophy and hypometabolism were assessed at the voxel and region-level using Statistical Parametric Mapping. Penalized logistic regression analysis was used to determine what combinations of regions best discriminate between groups.
Atrophy and hypometabolism was observed in lateral temporoparietal and medial parietal lobes, left greater than right, and left frontal lobe in the logopenic group. The logopenic group showed greater left inferior, middle and superior lateral temporal atrophy (inferior p = 0.02; middle p = 0.007, superior p = 0.002) and hypometabolism (inferior p = 0.006, middle p = 0.002, superior p = 0.001), and less right medial temporal atrophy (p = 0.02) and hypometabolism (p<0.001), and right posterior cingulate hypometabolism (p<0.001) than dementia of the Alzheimer’s type. An age-adjusted penalized logistic model incorporating atrophy and hypometabolism achieved excellent discrimination (area under the receiver operator characteristic curve = 0.89) between logopenic and dementia of the Alzheimer’s type subjects, with optimal discrimination achieved using right medial temporal and posterior cingulate hypometabolism, left inferior, middle and superior temporal hypometabolism, and left superior temporal volume.
Patterns of atrophy and hypometabolism both differ between logopenic primary progressive aphasia and dementia of the Alzheimer’s type and both modalities provide excellent discrimination between groups.
PMCID: PMC3633885  PMID: 23626825
23.  Characterization of a Family With c9FTD/ALS Associated With the GGGGCC Repeat Expansion in C9ORF72 
Archives of neurology  2012;69(9):1164-1169.
The hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene was recently discovered as the pathogenic mechanism underlying many families with frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) linked to chromosome 9 (c9FTD/ALS). We report the clinical, neuropsychological, and neuroimaging findings of a family with the C9ORF72 mutation and clinical diagnoses bridging the FTD, parkinsonism and ALS spectrum.
To characterize the antemortem characteristics of a family with c9FTD/ALS associated with the GGGGCC repeat expansion in C9ORF72
Clinical series.
Tertiary care academic medical center.
The members of the family affected by the mutation with features of FTD and/or ALS.
Main Outcome Measures
Clinical, neuropsychological, and neuroimaging assessments.
All three examined subjects had the hexanucleotide expansion detected in C9ORF72. All had personality/behavioral changes early in the course of the disease. One case had levodopa-unresponsive parkinsonism, and one had ALS. MRI showed symmetric bilateral frontal, temporal, insular and cingulate atrophy.
This report highlights the clinical and neuroimaging characteristics of a family with c9FTD/ALS. Further studies are needed to better understand the phenotypical variability and the clinico-neuroimaging-neuropathologic correlations.
PMCID: PMC3625860  PMID: 22637471
24.  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
Our objective was to document the clinical and imaging features of Othello's syndrome (delusional jealousy).
The study design was a retrospective case series of 105 patients with Othello's syndrome that were identified by using the Electronic Medical Record system of Mayo Clinic.
The average age at onset of Othello's syndrome was 68 (25–94) years with 61.9% of patients being male. Othello's syndrome was most commonly associated with a neurological disorder (73/105) compared with psychiatric disorders (32/105). Of the patients with a neurological disorder, 76.7% had a neurodegenerative disorder. Seven of eight patients with a structural lesion associated with Othello's syndrome had right frontal lobe pathology. Voxel-based morphometry showed greater grey matter loss predominantly in the dorsolateral frontal lobes in the neurodegenerative patients with Othello's compared to matched patients with neurodegenerative disorders without Othello's syndrome. Treatment success was notable for patients with dopamine agonist induced Othello's syndrome in which all six patients had improvement in symptoms following decrease in medication.
This study demonstrates that Othello's syndrome occurs most frequently with neurological disorders. This delusion appears to be associated with dysfunction of the frontal lobes, especially right frontal lobe.
PMCID: PMC3144984  PMID: 21518145
Othello's Syndrome; Right frontal lobe; Delusions; Dementia

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