Frontotemporal dementia: Clinicopathological correlations

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...

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

“…An additional challenge in clinical practice is the differential diagnosis of dementia. Noteworthy, up to 30% of FTLD cases are misdiagnosed with other disorders, especially AD 55. Several studies have shown that ratios with AD CSF biomarkers (i.e., pTau/A β 42 or tTau/A β 42) can discriminate FTLD from AD with performances over 80% 38, 56.…”

“…Thus, it would be also relevant to analyze the performance of the revealed models in cases at more advance stages of the disease. In addition, the lack of autopsy confirmation in some of the selected cases (i.e., those with clinical syndromes highly predictive of FTLD‐Tau and FTLD‐TDP) may have led to the inclusion of cases with AD copathology55 influencing the resulting diagnostic performances. However, inclusion of cases with potential AD comorbidity may provide also a more heterogeneous scenario that better resembles clinical practice.…”

Individual patient diagnosis of AD and FTD via high-dimensional pattern classification of MRI

“…Moreover, it would be beneficial to derive diagnostic tools based on MRI, instead of FDG-PET. In general, only 75 to 85% of patients who fulfill neuropathological criteria for one of the frontotemporal neurodegenerative dementing illnesses will have had a diagnosis of FTD prior to death (Knopman, Boeve et al 2005;Forman, Farmer et al 2006) The proportion of patients with a clinical diagnosis of FTD whose diagnosis is confirmed at autopsy may be even lower (Varma, Adams et al 2002).…”

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

“…Frontotemporal lobar degeneration (FTLD; MIM] 600274) represents the second most common dementia subtype in patients younger than 65 years [McKhann et al, 2001;Forman et al, 2006a]. Clinically, three subclasses can be distinguished: frontal variant FTD (fvFTD or FTD), progressive nonfluent aphasia (PNFA), and semantic dementia (SD).…”