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How to differentiate frontotemporal from Alzheimer's dementia? Recent developments in molecular genetics and neuropathology

Frontotemporal dementia is a major cause of non-Alzheimer dementia (AD). Frontotemporal lobar degeneration (FTLD) is used here as an umbrella term for both clinical and neuropathological entities starting before age of 65 years. FTLD differs clinically from AD because memory loss is rarely an early symptom. Instead, the dementia of FTLD is usually denoted by behavioral and language difficulties, although clinical and cognitive features of FTLD may overlap with AD. Aphasia may be prominent, either fluent or nonfluent. Clinical FTLD is associated with a variety of different neuropathological entities, which share common feature of preferential degeneration of the frontal and temporal lobes. Whereas, in the past, most attention focused on FTLD pathology associated with tau-positive inclusions and microtubule associated protein tau gene (MAPT) mutations (tauopathies), there has recently been greater attention paid to non-tau, ubiquitin positive inclusions (FTLD-U) or non-tauopathies. It is now recognized that FTLD-U is the most common pathology associated with clinical FTLD. Clinically, cases with FTLD-U may additionally present with or without motor neuron disease and parkinsonism. Majority of familial cases of FTLD-U have mutations in the progranulin (PRGN) gene. Some families of FTLD-U with PGRN mutation (hereditary dysphasic disinhibition dementia 1 and 2) are characterized, besides behavior and language difficulties, by additional memory loss and AD-type pathology. Recently, the ubiquitinated pathological protein in FTLD-U has been identified as TAR DNA binding protein (TDP 43) and found in an increasing number of neurodegenerative diseases, including AD. The overlap between FTLD-U and AD is important since as many as 20% of AD cases show some FTLD-U type TDP-43 pathology. Recent developments have helped to clarify the relationship between different types of FTLD and related conditions. Understanding and differentiating between FTLD and AD is very important for the diagnosis when new diagnostic test and therapeutics are becoming realized.

Alzheimer's disease; frontotemporal lobar degeneration; clinical and psychometric distincion; TDP-43; PGRN mutation

Special Issue on Neuroscience