Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Whitwell JL

PROVIDER: S-EPMC3013590 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Publications

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

Whitwell J L JL Jack C R CR Parisi J E JE Senjem M L ML Knopman D S DS Boeve B F BF Rademakers R R Baker M M Petersen R C RC Dickson D W DW Josephs K A KA

Neurology 20101201 24

<h4>Objective</h4>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).<h4>Methods</h4>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 ...[more]

PMID: 21172844

Similar Datasets

Project description:TAR-DNA binding protein-43 (TDP-43) proteinopathy is seen in multiple brain diseases. A standardized terminology was recommended recently for common age-related TDP-43 proteinopathy: limbic-predominant, age-related TDP-43 encephalopathy (LATE) and the underlying neuropathological changes, LATE-NC. LATE-NC may be co-morbid with Alzheimer's disease neuropathological changes (ADNC). However, there currently are ill-defined diagnostic classification issues among LATE-NC, ADNC, and frontotemporal lobar degeneration with TDP-43 (FTLD-TDP). A practical challenge is that different autopsy cohorts are composed of disparate groups of research volunteers: hospital- and clinic-based cohorts are enriched for FTLD-TDP cases, whereas community-based cohorts have more LATE-NC cases. Neuropathological methods also differ across laboratories. Here, we combined both cases and neuropathologists' diagnoses from two research centres-University of Pennsylvania and University of Kentucky. The study was designed to compare neuropathological findings between FTLD-TDP and pathologically severe LATE-NC. First, cases were selected from the University of Pennsylvania with pathological diagnoses of either FTLD-TDP (n = 33) or severe LATE-NC (mostly stage 3) with co-morbid ADNC (n = 30). Sections from these University of Pennsylvania cases were cut from amygdala, anterior cingulate, superior/mid-temporal, and middle frontal gyrus. These sections were stained for phospho-TDP-43 immunohistochemically and evaluated independently by two University of Kentucky neuropathologists blinded to case data. A simple set of criteria hypothesized to differentiate FTLD-TDP from LATE-NC was generated based on density of TDP-43 immunoreactive neuronal cytoplasmic inclusions in the neocortical regions. Criteria-based sensitivity and specificity of differentiating severe LATE-NC from FTLD-TDP cases with blind evaluation was ∼90%. Another proposed neuropathological feature related to TDP-43 proteinopathy in aged individuals is 'Alpha' versus 'Beta' in amygdala. Alpha and Beta status was diagnosed by neuropathologists from both universities (n = 5 raters). There was poor inter-rater reliability of Alpha/Beta classification (mean κ = 0.31). We next tested a separate cohort of cases from University of Kentucky with either FTLD-TDP (n = 8) or with relatively 'pure' severe LATE-NC (lacking intermediate or severe ADNC; n = 14). The simple criteria were applied by neuropathologists blinded to the prior diagnoses at University of Pennsylvania. Again, the criteria for differentiating LATE-NC from FTLD-TDP was effective, with sensitivity and specificity ∼90%. If more representative cases from each cohort (including less severe TDP-43 proteinopathy) had been included, the overall accuracy for identifying LATE-NC was estimated at >98% for both cohorts. Also across both cohorts, cases with FTLD-TDP died younger than those with LATE-NC (P < 0.0001). We conclude that in most cases, severe LATE-NC and FTLD-TDP can be differentiated by applying simple neuropathological criteria.

Dataset Information

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

Objective

Methods

Results

Conclusions

Publications

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

Similar Datasets

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