No abstract

Objective-Frontotemporal lobar degeneration (FTLD) is characterized by impairments in social, behavioral, and/or language function, but postmortem studies indicate that multiple neuropathological entities lead to FTLD. This study assessed whether specific clinical features predict the underlying pathology.Methods-A clinicopathological correlation was performed on 90 consecutive patients with a pathological diagnosis of frontotemporal dementia and was compared with an additional 24 cases accrued during the same time period with a clinical diagnosis of FTLD, but with pathology not typically associated with frontotemporal dementia.Results-Postmortem examination showed multiple pathologies including tauopathies (46%), FTLD with ubiquitin-positive inclusions (29%), and Alzheimer's disease (17%). The pathological groups manifested some distinct demographic, clinical, and neuropsychological features, although these attributes showed only a statistical association with the underlying pathology. FTLD with ubiquitin-positive inclusions was more likely to present with both social and language dysfunction, and motor neuron disease was more likely to emerge in these patients. Tauopathies were more commonly associated with an extrapyramidal disorder. Alzheimer's disease was associated with relatively greater deficits in memory and executive function.Interpretation-Clinical and neuropsychological features contribute to delineating the spectrum of pathology underlying a patient diagnosed with FTLD, but biomarkers are needed that, together with the clinical phenotype, can predict the underlying neuropathology.Frontotemporal lobar degeneration (FTLD) is characterized clinically by progressive changes in social, behavioral, and/or language function. 1-3 In the frontal or social/dysexecutive variant Address correspondence to Dr Grossman, Department of Neurology, University of Pennsylvania School of Medicine, 3600 Spruce Street, 3 West Gates, Philadelphia, PA 19104-4283. E-mail: mgrossma@mail.med.upenn NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript of FTLD, there is an early change in social comportment and personality often associated with disinhibition, apathy, and lack of insight. In contrast, the aphasic variant of FTLD is further classified as either progressive nonfluent aphasia, characterized by effortful speech and phonemic errors, 4 or semantic dementia, manifested by severe problems with naming and understanding word and object meaning. 5 In both the social/dysexecutive and aphasic variants, there is relative preservation of memory, especially in early stages. In addition, some patients with FTLD manifest a motor disorder such as parkinsonism or motor neuron disease (MND). 6,7Multiple neuropathological abnormalities are associated with FTLD, 3,8 and this pathological heterogeneity is reflected in a recent classification scheme from an frontotemporal dementia (FTD) work group that was the first to incorporate both immunohistochemical and biochemical data in the diagnostic algorithm (Fig 1...

For more than a decade, researchers have refined criteria for the diagnosis of dementia with Lewy bodies (DLB) and at the same time have recognized that cognitive impairment and dementia occur commonly in patients with Parkinson disease (PD). This article addresses the relationship between DLB, PD, and PD with dementia (PDD). The authors agreed to endorse "Lewy body disorders" as the umbrella term for PD, PDD, and DLB, to promote the continued practical use of these three clinical terms, and to encourage efforts at drug discovery that target the mechanisms of neurodegeneration shared by these disorders of alpha-synuclein metabolism. We concluded that the differing temporal sequence of symptoms and clinical features of PDD and DLB justify distinguishing these disorders. However, a single Lewy body disorder model was deemed more useful for studying disease pathogenesis because abnormal neuronal alpha-synuclein inclusions are the defining pathologic process common to both PDD and DLB. There was consensus that improved understanding of the pathobiology of alpha-synuclein should be a major focus of efforts to develop new disease-modifying therapies for these disorders. The group agreed on four important priorities: 1) continued communication between experts who specialize in PDD or DLB; 2) initiation of prospective validation studies with autopsy confirmation of DLB and PDD; 3) development of practical biomarkers for alpha-synuclein pathologies; 4) accelerated efforts to find more effective treatments for these diseases.

The clinical diagnosis of corticobasal degeneration should depend on a specific pattern of impaired cognition as well as an extrapyramidal motor disorder, reflecting the neuroanatomic distribution of disease in frontal and parietal cortices and the basal ganglia.

Pedigrees from 269 patients with frontotemporal lobar degeneration (FTLD), including frontotemporal dementia (FTD), FTD with ALS (FTD/ALS), progressive nonfluent aphasia, semantic dementia (SD), corticobasal degeneration, and progressive supranuclear palsy were analyzed to determine the degree of heritability of these disorders. FTD/ALS was the most and SD the least heritable subtype. FTLD syndromes appear to have different etiologies and recurrence risks.