Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype

Mackenzie, Ian R.; Baborie, Atik; Pickering‐Brown, Stuart; Plessis, Daniel du; Jaros, Evelyn; Perry, Robert H.; Neary, David; Snowden, Julie S.; Mann, David

doi:10.1007/s00401-006-0138-9

Cited by 297 publications

(363 citation statements)

References 31 publications

(68 reference statements)

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“…Sparse granular TDP-43 neuronal cytoplasmic inclusions were also present in the neurons of the dentate fascia. These findings would be consistent with frontotemporal lobar degeneration type 1 [9,27].…”

Section: Neuropathological Findingssupporting

confidence: 82%

Clinical, neuropathological and genotypic variability in SNCA A53T familial Parkinson’s disease

et al. 2008

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Individuals with familial Parkinson's disease (PD) due to a monogenic defect can show considerable clinical and neuropathological variability. To identify factors underlying this variability, histopathological analysis was performed in two clinically different A53T α-synuclein heterozygotes from Family H, a multigenerational α-synuclein A53T kindred. To determine whether additional genetic factors could contribute to phenotypic variability, Family H and another multigenerational A53T kindred were analyzed for parkin polymorphisms. We identified a previously described variant in parkin exon 4 associated with increased PD risk (S167N). The two A53T heterozygotes had markedly different neuropathology and different parkin genotypes: A N167 homozygote had early onset rapidly progressive disease, early dementia, myoclonus and sleep disorder, while a S167 homozygote had late onset, slowly progressive disease and late dementia. Both had brainstem, cortical, and intraneuritic Lewy bodies (LB). The N167 individual had widespread cortical neurofibrillary degeneration, while the S167 individual had only medial temporal lobe neurofibrillary degeneration. The N167 individual had severe neuronal loss in CA2 associated with Lewy neurites (LN), while the S167 individual had severe neuronal loss in CA1 associated with TDP-43 immunoreactive neuronal inclusions. These findings implicate TDP-43 in the pathology of familial PD and suggest that parkin may act as a modifier of the A53T α-synuclein phenotype of familial PD. Furthermore, they suggest a mechanism by which a rare genetic variant that is associated with a minor increase of PD risk in the heterozygous state may, in the homozygous state, exacerbate a disease phenotype associated with a highly penetrant dominant allele.

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Section: Neuropathological Findingssupporting

confidence: 82%

Clinical, neuropathological and genotypic variability in SNCA A53T familial Parkinson’s disease

et al. 2008

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“…3,4 Using the Mackenzie et al 4 scheme, which correlates with clinical diagnosis, FTLD-TDP type 1 is characterized by neuronal cytoplasmic inclusions (NCI) and short dystrophic neurites in superficial cortex, type 2 by long thin dystrophic neurites in superficial and deep cortex, and type 3…”

Section: Discussionmentioning

confidence: 99%

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

Whitwell

Jack²,

Parisi³

et al. 2010

Neurology

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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 ϭ 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 ϭ 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. Recent evidence demonstrates that FTLD-TDP can be subdivided, based on the morphologic appearances, and distribution of TDP-43 immunoreactive inclusions.3,4 Using the Mackenzie et al. 4 scheme, which correlates with clinical diagnosis, FTLD-TDP type 1 is characterized by neuronal cytoplasmic inclusions (NCI) and short dystrophic neurites in superficial cortex, type 2 by long thin dystrophic neurites in superficial and deep cortex, and type 3

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“…These cases have a complex neuropathology comprising NCI, NII, GI, and DN. Four pathological subtypes of FTLD-TDP have been proposed [37,114,150] based on the type and regional distribution of the various types of inclusion. Hence, type 1 cases (Mackenzie-type 2) are characterized by long DN in superficial cortical laminae with few or no NCI or NII, type 2 (Mackenzietype 3) by numerous NCI in superficial and deep cortical laminae with infrequent DN and sparse or no NII, type 3 (Mackenzie-type 1) by pathology predominantly affecting the superficial cortical laminae with numerous NCI, DN and varying numbers of NII, and type 4 by numerous NII, and infrequent NCI and DN especially in neocortical areas.…”

Section: Example 2: Investigation Of Subtypes Of Ftld-tdpmentioning

confidence: 99%

Can neurodegenerative disease be defined by four ‘primary determinants’: anatomy, cells, molecules, and morphology?

Armstrong

2016

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A b s t r a c t , the anatomical pathways affected by the disease ('anatomy'), the cell populations affected ('cells'), the molecular pathology of 'signature' pathological lesions ('molecules'), and the morphological types of neurodegeneration ('morphology'). This review first discusses the limitations of existing classificatory systems and second provides evidence that the four primary determinants could be used as axes to define all cases of neurodegenerative disease.To illustrate the methodology, the primary determinants were applied to the study of a group of closely related tauopathy cases and to heterogeneity within frontotemporal lobar degeneration with .

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Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype

Cited by 297 publications

References 31 publications

Clinical, neuropathological and genotypic variability in SNCA A53T familial Parkinson’s disease

Clinical, neuropathological and genotypic variability in SNCA A53T familial Parkinson’s disease

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

Can neurodegenerative disease be defined by four ‘primary determinants’: anatomy, cells, molecules, and morphology?

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