Clinical Spectrum of Tauopathies

Abstract

Tauopathies are both clinical and pathological heterogeneous disorders characterized by neuronal and/or glial accumulation of misfolded tau protein. It is now well understood that every pathologic tauopathy may present with various clinical phenotypes based on the primary site of involvement and the spread and distribution of the pathology in the nervous system making clinicopathological correlation more and more challenging. The clinical spectrum of tauopathies includes syndromes with a strong association with an underlying primary tauopathy, including Richardson syndrome (RS), corticobasal syndrome (CBS), non-fluent agrammatic primary progressive aphasia (nfaPPA)/apraxia of speech, pure akinesia with gait freezing (PAGF), and behavioral variant frontotemporal dementia (bvFTD), or weak association with an underlying primary tauopathy, including Parkinsonian syndrome, late-onset cerebellar ataxia, primary lateral sclerosis, semantic variant PPA (svPPA), and amnestic syndrome. Here, we discuss clinical syndromes associated with various primary tauopathies and their distinguishing clinical features and new biomarkers becoming available to improve in vivo diagnosis. Although the typical phenotypic clinical presentations lead us to suspect specific underlying pathologies, it is still challenging to differentiate pathology accurately based on clinical findings due to large phenotypic overlaps. Larger pathology-confirmed studies to validate the use of different biomarkers and prospective longitudinal cohorts evaluating detailed clinical, biofluid, and imaging protocols in subjects presenting with heterogenous phenotypes reflecting a variety of suspected underlying pathologies are fundamental for a better understanding of the clinicopathological correlations.

Keywords: clinical; corticobasal; frontotemporal dementia; movement; neurodegenerative; primary progressive aphasia; progressive supranuclear palsy; tauopathy.

Figure 1

Clinicopathological correlation in tauopathies spectrum. Pathologic diagnoses are shown on the left and clinical syndromes on the right. Degree to which various pathologies contribute to a specific clinical phenotype is estimated based on available pathology-confirmed studies, including: PSP (–23); CBD (–27); AD (–31); PiD (32); LBD (33); GGT (34); TDP (–37); AGD (38); and PART (15, 39, 40). AD, Alzheimer's disease; AGD, argyrophilic grain disease; CBD, corticobasal degeneration; CBS corticobasal syndrome; FTD-MND, frontotemporal dementia-motor neuron disease; GGT, globular glial tauopathy; LBD, Lewy body disease; LOCA, late onset cerebellar ataxia; lvPPA logopenic variant primary progressive aphasia; MND, motor neuron disease; nfaPPA, non-fluent agrammatic primary progressive aphasia; PAGF, progressive akinesia and gait freezing; PART, primary age-related tauopathy; PCA, posterior cortical atrophy; PiD, Pick's disease; PSP, progressive supranuclear palsy; svPPA, semantic variant primary progressive aphasia; TDP, transactive response DNA binding protein 43 kDa pathology.