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Clinical and neuroanatomical signatures of tissue pathology in frontotemporal lobar degeneration.

ABSTRACT: Relating clinical symptoms to neuroanatomical profiles of brain damage and ultimately to tissue pathology is a key challenge in the field of neurodegenerative disease and particularly relevant to the heterogeneous disorders that comprise the frontotemporal lobar degeneration spectrum. Here we present a retrospective analysis of clinical, neuropsychological and neuroimaging (volumetric and voxel-based morphometric) features in a pathologically ascertained cohort of 95 cases of frontotemporal lobar degeneration classified according to contemporary neuropathological criteria. Forty-eight cases (51%) had TDP-43 pathology, 42 (44%) had tau pathology and five (5%) had fused-in-sarcoma pathology. Certain relatively specific clinicopathological associations were identified. Semantic dementia was predominantly associated with TDP-43 type C pathology; frontotemporal dementia and motoneuron disease with TDP-43 type B pathology; young-onset behavioural variant frontotemporal dementia with FUS pathology; and the progressive supranuclear palsy syndrome with progressive supranuclear palsy pathology. Progressive non-fluent aphasia was most commonly associated with tau pathology. However, the most common clinical syndrome (behavioural variant frontotemporal dementia) was pathologically heterogeneous; while pathologically proven Pick's disease and corticobasal degeneration were clinically heterogeneous, and TDP-43 type A pathology was associated with similar clinical features in cases with and without progranulin mutations. Volumetric magnetic resonance imaging, voxel-based morphometry and cluster analyses of the pathological groups here suggested a neuroanatomical framework underpinning this clinical and pathological diversity. Frontotemporal lobar degeneration-associated pathologies segregated based on their cerebral atrophy profiles, according to the following scheme: asymmetric, relatively localized (predominantly temporal lobe) atrophy (TDP-43 type C); relatively symmetric, relatively localized (predominantly temporal lobe) atrophy (microtubule-associated protein tau mutations); strongly asymmetric, distributed atrophy (Pick's disease); relatively symmetric, predominantly extratemporal atrophy (corticobasal degeneration, fused-in-sarcoma pathology). TDP-43 type A pathology was associated with substantial individual variation; however, within this group progranulin mutations were associated with strongly asymmetric, distributed hemispheric atrophy. We interpret the findings in terms of emerging network models of neurodegenerative disease: the neuroanatomical specificity of particular frontotemporal lobar degeneration pathologies may depend on an interaction of disease-specific and network-specific factors.

SUBMITTER: Rohrer JD

PROVIDER: S-EPMC3170537 | biostudies-other | 2011 Sep

REPOSITORIES: biostudies-other

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Clinical and neuroanatomical signatures of tissue pathology in frontotemporal lobar degeneration.

Rohrer Jonathan D JD Lashley Tammaryn T Schott Jonathan M JM Warren Jane E JE Mead Simon S Isaacs Adrian M AM Beck Jonathan J Hardy John J de Silva Rohan R Warrington Elizabeth E Troakes Claire C Al-Sarraj Safa S King Andrew A Borroni Barbara B Clarkson Matthew J MJ Ourselin Sebastien S Holton Janice L JL Fox Nick C NC Revesz Tamas T Rossor Martin N MN Warren Jason D JD

Brain : a journal of neurology 20110901 Pt 9

Relating clinical symptoms to neuroanatomical profiles of brain damage and ultimately to tissue pathology is a key challenge in the field of neurodegenerative disease and particularly relevant to the heterogeneous disorders that comprise the frontotemporal lobar degeneration spectrum. Here we present a retrospective analysis of clinical, neuropsychological and neuroimaging (volumetric and voxel-based morphometric) features in a pathologically ascertained cohort of 95 cases of frontotemporal loba ...[more]

PMID: 21908872

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Project description:The disruption of brain networks is characteristic of neurodegenerative dementias. However, it is controversial whether changes in connectivity reflect only the functional anatomy of disease, with selective vulnerability of brain networks, or the specific neurophysiological consequences of different neuropathologies within brain networks. We proposed that the oscillatory dynamics of cortical circuits reflect the tuning of local neural interactions, such that different pathologies are selective in their impact on the frequency spectrum of oscillations, whereas clinical syndromes reflect the anatomical distribution of pathology and physiological change. To test this hypothesis, we used magnetoencephalography from five patient groups, representing dissociated pathological subtypes and distributions across frontal, parietal and temporal lobes: amnestic Alzheimer's disease, posterior cortical atrophy, and three syndromes associated with frontotemporal lobar degeneration. We measured effective connectivity with graph theory-based measures of local efficiency, using partial directed coherence between sensors. As expected, each disease caused large-scale changes of neurophysiological brain networks, with reductions in local efficiency compared to controls. Critically however, the frequency range of altered connectivity was consistent across clinical syndromes that shared a likely underlying pathology, whilst the localization of changes differed between clinical syndromes. Multivariate pattern analysis of the frequency-specific topographies of local efficiency separated the disorders from each other and from controls (accuracy 62% to 100%, according to the groups' differences in likely pathology and clinical syndrome). The data indicate that magnetoencephalography has the potential to reveal specific changes in neurophysiology resulting from neurodegenerative disease. Our findings confirm that while clinical syndromes have characteristic anatomical patterns of abnormal connectivity that may be identified with other methods like structural brain imaging, the different mechanisms of neurodegeneration also cause characteristic spectral signatures of physiological coupling that are not accessible with structural imaging nor confounded by the neurovascular signalling of functional MRI. We suggest that these spectral characteristics of altered connectivity are the result of differential disruption of neuronal microstructure and synaptic physiology by Alzheimer's disease versus frontotemporal lobar degeneration.

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Clinical and neuroanatomical signatures of tissue pathology in frontotemporal lobar degeneration.

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Clinical and neuroanatomical signatures of tissue pathology in frontotemporal lobar degeneration.

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