Primary Progressive Aphasia
Abstract & Commentary
By Cary Gunther, MD, and Michael Lin, MD
Dr. Gunther completed neurology and psychiatry residency training at New York Presbyterian Hospital/Weill Cornell Medical Center. Dr. Lin is Associate Professor of Neurology and Neuroscience, Weill Medical College, Cornell University. Drs. Gunther and Lin report no financial relationships to this field of study.
Synopsis: Several recent studies examine the contributions of imaging, biomarkers, and neuropsychological testing to a refined understanding of the syndromes collectively known as primary progressive aphasia.
Sources: Gunawardena D, Ash S, et al. Why are patients with progressive nonfluent aphasia nonfluent? Neurology 2010; 75: 588-594. Hu W, McMillan C, et al. Multimodal predictors for Alzheimer's disease in nonfluent primary progressive aphasia. Neurology 2010; 75: 595-602. Rohrer J, Rossor M, et al. Syndromes of nonfluent primary progressive aphasia: A clinical and neurolinguistic analysis. Neurology 2010; 75: 603-610.
Three studies recently published in neurology explore the complexities of primary progressive aphasia (PPA). Initially characterized by M.-Marsel Mesulam, PPA includes at least three clinical disorders in which language skills deteriorate years in advance of other significant cognitive decline. Primary nonfluent aphasia (PNFA) includes grammatical errors and loss of fluency; logopenic progressive aphasia (LPA) is characterized by halting speech; and semantic variant PPA (SV) is notable for retained fluency but impaired comprehension.
Gunawardena et al investigated the basis of nonfluent speech in PNFA. The authors asked which aspects of language dysfunction seen in PNFA could be contributing to reduced language speed. They collected speech samples and neuropsychological assessments of language and executive functioning from 16 PNFA patients and compared these to 12 individuals with behavioral variant frontotemporal dementia (bvFTD) and 13 controls. They found that executive dysfunction predicted speed of speech in bvFTD, but only measures of agrammatism predicted speed of speech in PNFA, pointing to a different underlying mechanism for slow speech. The authors also examined atrophy patterns in these patients and observed that reductions in cortical thickness in the left inferior frontal and anterior-superior temporal regions in PNFA patients correlated with slowness of speech, and overlapping areas of thinning correlated with agrammatism.
The group led by Hu et al attempted to determine the relative contributions of clinical features, formal neuropsychological evaluation, and quantitative neuroimaging to identify Alzheimer's disease as the neuropathology underlying LPA and PNFA. Working with 19 patients with each of these two clinically defined syndromes, they observed that 63% of patients with LPA and 32% of those with PNFA had CSF or autopsy results consistent with underlying Alzheimer pathology. Combining neuropsychological testing with MRI measurements of atrophy yielded 90% specificity for CSF or autopsy diagnosis of Alzheimer pathology, while using both clinical features and neuropsychological testing resulted in 100% sensitivity. Most importantly, they determined that no single methodology was sufficient to reliably predict Alzheimer pathology or biomarkers.
In the third study, Rohrer et al sought to correlate specific features of speech seen in PPA with underlying pathophysiology. They subdivided 24 nonfluent PPA patients by presence or absence of apraxia of speech (AOS), defined as difficulty with planning and sequencing of speech sounds, and agrammatism. When both symptoms were present, parkinsonism was more likely, and the clinical syndrome most closely resembled PNFA. Cases with AOS but without agrammatism were postulated to represent a less advanced version of PNFA, though patients were not followed longitudinally. In cases with only agrammatism, three of three patients carried mutations in the progranulin gene. When neither agrammatism nor AOS was present, CSF Abeta/Tau ratios were consistent with Alzheimer pathology; moreover, these patients demonstrated episodic memory impairment. Both of the latter groups were clinically more similar to LPA.
Commentary
A common thread in these studies is the demonstration that PPA is a heterogeneous syndrome. The rarity of PPA routinely limits the power of studies. In the Gunawardena study, liberal criteria for diagnosis were used, including some patients with features of corticobasal degeneration. Eventually, PPA patients will progress and have cognitive functions other than language affected, making recruitment of patients with isolated aphasia difficult.
The use of quantitative MRI techniques is highlighted in these studies, suggesting the need for further use and validation of neuroimaging techniques such as cerebral amyloid imaging and diffusion tensor imaging. Such approaches may shed additional light on the structural and functional compromise of brain regions in progressive language disorders. These studies also emphasize the connection between dysfunction of specific cerebral areas and neuropsychological testing results, yielding greater reliability from formal testing than from clinical phenomenology alone, even within what appears to be a well- defined clinical syndrome.
Finally, these investigations underscore the need for more autopsy data, as well as wider availability of sensitive and specific biomarkers for neurodegenerative diseases. In the study by Hu, only two patients from each group had neuropathology results available. In the work by Rohrman, although the intent was to evaluate pathophysiology, the investigators relied on biomarkers and genetic testing exclusively. Accurate surrogates for neuropathology will be even more important as disease- modifying treatments are developed.
Several recent studies examine the contributions of imaging, biomarkers, and neuropsychological testing to a refined understanding of the syndromes collectively known as primary progressive aphasia.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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