Histopathological changes underlying frontotemporal lobar degeneration with clinicopathological correlation

Abstract

We have investigated the pathological correlates of dementia in the brains from a consecutive series of 70 patients dying with a clinical diagnosis of frontotemporal lobar degeneration (FTLD). Clinical misdiagnosis rate was low with only 3 patients (4%) failing to show pathological changes consistent with this diagnosis; 1 patient had Alzheimer's disease and 2 had cerebrovascular disease (CVD). In the remaining 67 patients, the most common underlying histological cause was ubiquitin pathology with 24 (36%) cases so affected. In these, ubiquitin-positive inclusions were present in the cerebral cortex as small, rounded or crescent-shaped structures within the cytoplasm of neurones of layer II, together with coiled or curvilinear bodies within neurites, and in the hippocampus as small, solid and more spherical-shaped inclusion bodies within the cytoplasm of dentate gyrus granule cells. In one patient, "cat's eye" or "lentiform" intranuclear ubiquitin inclusions were also present. The second most common histological type was dementia lacking distinctive histology (DLDH), in which neither tau nor ubiquitin inclusions were present, with 16 cases (24%) being affected. Pick-type histology was seen in 14 cases (21%) and tau histological changes associated with frontotemporal dementia (FTD) linked to chromosome 17 (FTDP-17) were present in 11 cases (16%). One case (1%) showed an unusual tau pathology that could not be allocated to any of the other tau groups. Only 1 case (1%) had neuronal intermediate filament inclusion dementia. No cases with ubiquitinated, valosin-containing protein-immunoreactive intranuclear inclusion bodies of the type seen in inclusion body myopathy with Paget's disease of bone and frontotemporal dementia were seen. Clinicopathological correlation showed that any of these histological subtypes can be associated with FTD. However, for FTD with motor neurone disease (FTD+MND), semantic dementia or primary progressive aphasia (PA), the histological profile was either ubiquitin type or DLDH type; Pick-type histology was seen in only 1 case of PA. None of these latter three clinical subtypes was associated with a mutation in tau gene and FTDP-17 type of tau pathology. All cases of progressive apraxia were associated with Pick-type histology. Present data therefore indicate that, although ubiquitin pathology is the most common histological form associated with FTLD, this pathology is not tightly linked with, nor is pathologically diagnostic for, any particular clinical form of the disease, including FTD+MND.

Argyrophilic thorny astrocyte clusters in association with Alzheimer’s disease pathology in possible primary progressive aphasia

“…Neuropathological examination of autopsied cases or of brain biopsies have shown that PPA is most commonly associated with diVerent forms of frontotemporal lobar degeneration (FTLD) [5], including FTLD with Pick bodies [14,20,31,66], corticobasal degeneration (CBD) [9,22,39], FTLD with motor neuron disease-type inclusions or ubiquitin-only inclusions (FTLD-U) [34,60], and dementia lacking distinctive histopathology [7,15,35,44,57,59,61], although the latter diagnosis, always questionable, cannot even be considered in the absence of ubiquitin immunostains.…”

Concomitant TAR-DNA-Binding Protein 43 Pathology Is Present in Alzheimer Disease and Corticobasal Degeneration but Not in Other Tauopathies

“…Ubiquitin-positive, tau-, and α-synucleinnegative inclusions found predominantly in neurons in the dentate gyrus and frontotemporal cortex are the characteristic lesions in the most common neuropathologic subtype of FTLD, that is, FTLD with ubiquitin-positive inclusions (FTLD-U) (2)(3)(4). The TAR-DNA-binding protein 43 (TDP-43) has recently been identified as a major disease protein in the ubiquitinated inclusions in FTLD-U and amyotrophic lateral sclerosis (ALS) (5).…”

Patterns of Microglial Cell Activation in Alzheimer Disease and Frontotemporal Lobar Degeneration

“…Whereas AD pathology is characterized by extracellular amyloid beta (Aβ) plaques and intracellular aggregates of aberrantly phosphorylated tau protein, i.e., neurofibrillary tangles (NFT), the pathology of FTLD is more heterogeneous. Approximately half of the cases are defined by the presence of tau-immunoreactive changes (NFT-like structures, Pick bodies, or glial inclusions) [6], and have been designated as FTLD-tau [7]. Most of the remaining cases of FTLD are associated with the presence of various combinations of immunoreactive TDP43 neuronal cytoplasmatic inclusions, dystrophic neurites, and neuronal intranuclear inclusions [6], and such cases have been designated as FTLD-TDP [7].…”