K. A. Josephs

Clinicopathologic analysis of frontotemporal and corticobasal degenerations and PSP

Objective: To examine the relationship between early clinical features, pathologies, and biochemistry of the frontotemporal lobar degenerations (FTLDs), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Methods: The authors conducted pathologic reexamination with the most recent immunohistochemistry of all cases diagnosed with FTLD, PSP, and CBD between 1970 and 2004. The authors also reviewed the early clinical features for clinical diagnosis and application of published research criteria. Results: Of 127 cases analyzed, 57 had a pathologic diagnosis of FTLD, 49 PSP, and 21 CBD. Of these, 38 were clinically reclassified as frontal variant frontotemporal dementia (FTD), 13 as progressive non-fluent aphasia (PNFA), 21 as CBD-like, 33 as PSP-like, and 13 with frontotemporal dementia with coexisting motor neuron disease (FTD-MND). The authors were unable to classify nine cases. All cases of FTD-MND were tau-negative and had pathologic evidence of motor neuron degeneration. All cases classified as PSP-like or CBD-like had tau-positive pathology. Of the 13 cases with PNFA, PSP and CBD accounted for almost 70% of the cases, while FTD was almost equally divided between tau-positive and tau-negative diseases. Conclusion: Frontotemporal lobar degeneration, corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP) have overlapping clinical features. The prediction of tau-positive pathology from a CBD or PSP-like presentation is good, while the frontotemporal dementia (FTD)-motor neuron disease syndrome almost certainly predicts motor neuron degeneration. Surprisingly, PSP and CBD accounted for most cases classified as progressive non-fluent aphasia. Frontal variant FTD is an unpredictable disease in terms of its biochemistry.

MRI correlates of neurofibrillary tangle pathology at autopsy: A voxel-based morphometry study

Background: Neurofibrillary tangles (NFTs), composed of hyperphosphorylated tau proteins, are one of the pathologic hallmarks of Alzheimer disease (AD). We aimed to determine whether patterns of gray matter atrophy from antemortem MRI correlate with Braak staging of NFT pathology. Methods: Eighty-three subjects with Braak stage III through VI, a pathologic diagnosis of low- to high-probability AD, and MRI within 4 years of death were identified. Voxel-based morphometry assessed gray matter atrophy in each Braak stage compared with 20 pathologic control subjects (Braak stages 0 through II). Results: In pairwise comparisons with Braak stages 0 through II, a graded response was observed across Braak stages V and VI, with more severe and widespread loss identified at Braak stage VI. No regions of loss were identified in Braak stage III or IV compared with Braak stages 0 through II. The lack of findings in Braak stages III and IV could be because Braak stage is based on the presence of any NFT pathology regardless of severity. Actual NFT burden may vary by Braak stage. Therefore, tau burden was assessed in subjects with Braak stages 0 through IV. Those with high tau burden showed greater gray matter loss in medial and lateral temporal lobes than those with low tau burden. Conclusions: Patterns of gray matter loss are associated with neurofibrillary tangle (NFT) pathology, specifically with NFT burden at Braak stages III and IV and with Braak stage itself at higher stages. This validates three-dimensional patterns of atrophy on MRI as an approximate in vivo surrogate indicator of the full brain topographic representation of the neurodegenerative aspect of Alzheimer disease pathology.

Gray and white matter water diffusion in the syndromic variants of frontotemporal dementia

Objective: To use diffusion tensor imaging (DTI) to assess gray matter and white matter tract diffusion in behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SMD), and progressive nonfluent aphasia (PNFA). Methods: This was a case-control study where 16 subjects with bvFTD, 7 with PNFA, and 4 with SMD were identified and matched by age and gender to 19 controls. All subjects had 3-T head MRI with a DTI sequence with diffusion encoding in 21 directions. Gray matter mean diffusivity (MD) was assessed using a region-of-interest (ROI) and voxel-level approach, and voxel-based morphometry was used to assess patterns of gray matter loss. White matter tract diffusivity (fractional anisotropy and radial diffusivity) was assessed by placing ROIs on tracts of interest. Results: In bvFTD, increased gray matter MD and gray matter loss were identified bilaterally throughout frontal and temporal lobes, with abnormal diffusivity observed in white matter tracts that connect to these regions. In SMD, gray matter loss and increased MD were identified predominantly in the left temporal lobe, with tract abnormalities observed in the inferior longitudinal fasciculus and uncinate fasciculus. In PNFA, gray matter loss and increased MD were observed in left inferior frontal lobe, insula, and supplemental motor area, with tract abnormalities observed in the superior longitudinal fasciculus. Conclusions: The diffusivity of gray matter is increased in regions that are atrophic in frontotemporal dementia, suggesting disruption of the cytoarchitecture of remaining tissue. Furthermore, damage was identified in white matter tracts that interconnect these regions, supporting the hypothesis that these diseases involve different and specific brain networks.

Imaging correlates of pathology in corticobasal syndrome

Background: Corticobasal syndrome (CBS) can be associated with different underlying pathologies that are difficult to predict based on clinical presentation. The aim of this study was to determine whether patterns of atrophy on imaging could be useful to help predict underlying pathology in CBS. Methods: This was a case-control study of 24 patients with CBS who had undergone MRI during life and came to autopsy. Pathologic diagnoses included frontotemporal lobar degeneration (FTLD) with TDP-43 immunoreactivity in 5 (CBS-TDP), Alzheimer disease (AD) in 6 (CBS-AD), corticobasal degeneration in 7 (CBS-CBD), and progressive supranuclear palsy in 6 (CBS-PSP). Voxel-based morphometry and atlas-based parcellation were used to assess atrophy across the CBS groups and compared to 24 age- and gender-matched controls. Results: All CBS pathologic groups showed gray matter loss in premotor cortices, supplemental motor area, and insula on imaging. However, CBS-TDP and CBS-AD showed more widespread patterns of loss, with frontotemporal loss observed in CBS-TDP and temporoparietal loss observed in CBS-AD. CBS-TDP showed significantly greater loss in prefrontal cortex than the other groups, whereas CBS-AD showed significantly greater loss in parietal lobe than the other groups. The focus of loss was similar in CBS-CBD and CBS-PSP, although more severe in CBS-CBD. Conclusions: Imaging patterns of atrophy in CBS vary according to pathologic diagnosis. Widespread atrophy points toward a pathologic diagnosis of FTLD-TDP or AD, with frontotemporal loss suggesting FTLD-TDP and temporoparietal loss suggesting AD. On the contrary, more focal atrophy predominantly involving the premotor and supplemental motor area suggests CBD or PSP pathology.

α-Synuclein pathology in the spinal cords of neurologically asymptomatic aged individuals

The authors assessed the frequency of spinal cord α-synuclein pathology in neurologically asymptomatic individuals older than 60 years of age (N = 106). Using α-synuclein immunohistochemistry, nine cases (8%) had incidental Lewy neurites in the intermediolateral column and at least some α-synuclein pathology in the dorsal motor nucleus of the vagus, locus ceruleus, and central raphe nucleus. Sparse α-synuclein pathology was also detected in the substantia nigra, basal forebrain, amygdala, or cortex in all but two cases.

Atrophy of superior cerebellar peduncle in progressive supranuclear palsy.

Background: Pathologic changes in the superior cerebellar peduncles (SCP) are common in progressive supranuclear palsy (PSP), but atrophy of the SCP has never been systematically studied. Objective: To investigate the SCP width in PSP cases and controls with morphometric methods. Methods: The mean width of the SCP in transverse sections of the pons at the level of trigeminal nerve was determined in 48 PSP cases (29 men, 19 women; mean age 72.5 ± 8.2 years) and 29 age-matched control subjects, many with neurodegenerative disorders that can be clinically mistaken for PSP. As the origin of the SCP is the cerebellar dentate nucleus, correlations were sought between SCP atrophy and severity of grumose degeneration in the dentate nucleus. Results: The average width of the SCP was less in PSP (range 0.09 to 0.24 cm) than in controls (range 0.21 to 0.43 cm; Mann–Whitney U test, p < 0.001), including control cases that had been clinically misdiagnosed as PSP (range 0.26 to 0.41 cm). Severity of SCP atrophy normalized by brain weight correlated with disease duration (Spearman rank order correlation, r = 0.367, p = 0.028), suggesting that SCP atrophy is a relatively early feature of PSP. No correlation was found between grumose degeneration and SCP width. Conclusions: SCP atrophy is common in PSP and correlates with disease duration. Given that measurements of the SCP are within the resolution of MRI, it remains to be determined if SCP atrophy can be used as a diagnostic marker of PSP.

Voxel-based morphometry patterns of atrophy in FTLD with mutations in MAPT or PGRN

Objective: To compare patterns of gray matter loss in subjects with mutations in the progranulin (PGRN) gene to subjects with mutations in the microtubule-associated protein tau (MAPT) gene. Methods: We identified all subjects seen at the Mayo Clinic, Rochester, MN, who had screened positive for mutations in PGRN or MAPT and had a head MRI. Twelve cases with mutations in the PGRN gene were matched by time from disease onset to scan to 12 subjects with mutations in the MAPT gene. Voxel-based morphometry was used to assess patterns of gray matter loss in the PGRN and MAPT groups compared to a control cohort, and compared to each other. MAPT subjects were younger than the PGRN subjects; therefore, each group was also compared to a specific age-matched control group. Results: Both PGRN and MAPT groups showed gray matter loss in frontal, temporal, and parietal lobes compared to controls, although loss was predominantly identified in posterior temporal and parietal lobes in PGRN and anteromedial temporal lobes in MAPT. The MAPT group had greater loss compared to healthy subjects of the same age than the PGRN subjects when compared to healthy subjects of the same age. The MAPT subjects showed greater gray matter loss in the medial temporal lobes, insula, and putamen than the PGRN subjects. Conclusion: These results increase understanding of the biology of these disorders and suggest that patterns of atrophy on MRI may be useful to aid in the differentiation of groups of PGRN and MAPT mutation carriers.

Pathologically confirmed corticobasal degeneration presenting with visuospatial dysfunction

Corticobasal degeneration (CBD) typically manifests as progressive asymmetric rigidity and apraxia, although other non-motor presentations have been reported. We report two patients with pathologically diagnosed CBD who presented with prominent visuospatial dysfunction. The pathological changes were maximal in the visual association cortices, but absent in 31 cases of pathologically proven CBD with more typical antemortem features. Underlying CBD should be considered in the differential diagnosis of patients with findings reflecting posterior cerebral dysfunction.

Altered functional connectivity in asymptomatic MAPT subjects A comparison to bvFTD

Objective: To determine whether functional connectivity is altered in subjects with mutations in the microtubule associated protein tau (MAPT) gene who were asymptomatic but were destined to develop dementia, and to compare these findings to those in subjects with behavioral variant frontotemporal dementia (bvFTD). Methods: In this case-control study, we identified 8 asymptomatic subjects with mutations in MAPT and 8 controls who screened negative for mutations in MAPT. Twenty-one subjects with a clinical diagnosis of bvFTD were also identified and matched to 21 controls. All subjects had resting-state fMRI. In-phase functional connectivity was assessed between a precuneus seed in the default mode network (DMN) and a fronto-insular cortex seed in the salience network, and the rest of the brain. Atlas-based parcellation was used to assess functional connectivity and gray matter volume across specific regions of interest. Results: The asymptomatic MAPT subjects and subjects with bvFTD showed altered functional connectivity in the DMN, with reduced in-phase connectivity in lateral temporal lobes and medial prefrontal cortex, compared to controls. Increased in-phase connectivity was also observed in both groups in the medial parietal lobe. Only the bvFTD group showed altered functional connectivity in the salience network, with reduced connectivity in the fronto-insular cortex and anterior cingulate. Gray matter loss was observed across temporal, frontal, and parietal regions in bvFTD, but not in the asymptomatic MAPT subjects. Conclusions: Functional connectivity in the DMN is altered in MAPT subjects before the occurrence of both atrophy and clinical symptoms, suggesting that changes in functional connectivity are early features of the disease.

Does TDP-43 type confer a distinct pattern of atrophy in frontotemporal lobar degeneration?

Objective: To determine whether TDP-43 type is associated with distinct patterns of brain atrophy on MRI in subjects with pathologically confirmed frontotemporal lobar degeneration (FTLD). Methods: In this case-control study, we identified all subjects with a pathologic diagnosis of FTLD with TDP-43 immunoreactive inclusions (FTLD-TDP) and at least one volumetric head MRI scan (n = 42). In each case we applied published criteria for subclassification of FTLD-TDP into FTLD-TDP types 1–3. Voxel-based morphometry was used to compare subjects with each of the different FTLD-TDP types to age- and gender-matched normal controls (n = 30). We also assessed different pathologic and genetic variants within, and across, the different types. Results: Twenty-two subjects were classified as FTLD-TDP type 1, 9 as type 2, and 11 as type 3. We identified different patterns of atrophy across the types with type 1 showing frontotemporal and parietal atrophy, type 2 predominantly anterior temporal lobe atrophy, and type 3 predominantly posterior frontal atrophy. Within the FTLD-TDP type 1 group, those with a progranulin mutation had significantly more lateral temporal lobe atrophy than those without. All type 2 subjects were diagnosed with semantic dementia. Subjects with a pathologic diagnosis of FTLD with motor neuron degeneration had a similar pattern of atrophy, regardless of whether they were type 1 or type 3. Conclusions: Although there are different patterns of atrophy across the different FTLD-TDP types, it appears that genetic and pathologic factors may also affect the patterns of atrophy.