Grossly, the brains of FTD patients are characterized mainly by circumscribed atrophy of the frontal and temporal lobes, hence the pathological designation frontotemporal lobar degeneration (FTLD), and neuronal loss and gliosis are apparent about microscopic examination of affected regions.6,7 Immunohistochemistry reveals the presence of abnormal proteinaceous inclusion bodies in some of the remaining neurons in affected areas of most FTD HQ-415 brains. and the immunostaining properties of the novel mAbs generated here suggest that FTLD-U is definitely pathologically he-terogeneous. Recognition of the disease proteins identified by these mAbs will further advance understanding of molecular substrates of FTLD-U neurodegenerative pathways. Frontotemporal dementia (FTD) is the second most common cause of neurodegenerative dementia in those under the age of 65, after Alzheimers disease (AD).1,2 Clinical presentations of FTD include several behavioral variants of FTD, in which patients encounter profound changes in personality and interpersonal function, as well as language disorders of expression and comprehension, known as progressive aphasia and semantic dementia, respectively.3 Engine manifestations, including signs and symptoms of engine neuron disease (MND) or parkinsonism, also occur with FTD.4,5 The diagnostic gold standard for FTD remains neuropathological examination of the brain. Grossly, the brains of FTD individuals are characterized mainly by circumscribed atrophy of the frontal and temporal lobes, hence the pathological designation frontotemporal lobar degeneration (FTLD), and neuronal loss and gliosis are apparent on microscopic examination of affected areas.6,7 Immunohistochemistry reveals the presence of abnormal proteinaceous inclusion bodies in some of the remaining neurons in affected areas of most FTD brains. Pathological categories of FTD defined by immunohistochemistry include instances without detectable inclusions (ie, dementia lacking distinctive histology), instances with tau-positive inclusions as exemplified by Picks disease (PiD), corticobasal degeneration, progressive supranuclear palsy, and neurofibrillary tangle dementia, instances with neurofilament-positive inclusions (neuronal intermediate filament inclusion disease), and instances with ubiquitin-positive, tau and -synuclein-negative inclusions, known as FTLD with ubiquitin-positive inclusions, or FTLD-U.6 Recent studies suggest that FTLD-U is the most common neuropathological subtype of FTD.8C12 Although most FTLD-U instances are sporadic, several family members exhibiting autosomal dominant inheritance patterns of FTLD-U neuropathology have been linked to chromosomes 9 and 17.13C17 No genetic mutations on chromosomes 9 and HQ-415 17 responsible for the disease in these family members, however, have been found to day, and the molecular pathogenesis underlying FTLD-U remains unknown. In the present study, examination of ubiquitin-immunostained sections from 36 postmortem-confirmed FTLD-U instances was performed to MPO gain insights into the pathological basis of FTLD-U. Three patterns of FTLD-U pathology were delineated based on the morphological characteristics and cortical distribution of ubiquitin-positive inclusions in these cases. To test the hypothesis that FTLD-U is definitely pathologically heterogeneous, novel monoclonal antibodies (mAbs) were generated using immunogens consisting of high molecular mass (Mr > 250 kd) insoluble material from cortical gray matter of two FTLD-U instances with different patterns of ubiquitin-positive pathology. The selective staining of pathological inclusions by these novel mAbs in subsets of FTLD-U instances HQ-415 corresponded to different patterns of ubiquitin-positive pathology, therefore suggesting that there may be multiple pathways of neurodegeneration leading to FTLD-U. Materials and Methods Mind Cells Collection and Neuropathological Assessment Frozen mind cells and fixed, paraffin-embedded cells blocks were from the Center for Neurodegenerative Disease Study brain bank in the University or college of Pennsylvania School of Medicine, Philadelphia, PA, and from the Center for Neuropathology and Prion Study mind standard bank in the University or college of Munich, Munich, Germany. Diagnostic assessment of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U), PiD, AD, dementia with Lewy body (DLB), and neuropathologically normal (NL) instances was performed by a trained neuropathologist in accordance with published recommendations.6,18,19 Although there are no.