Association Between the Prevalence of Learning Disabilities and Primary Progressive Aphasia

Primary progressive aphasia (PPA) is a syndrome that arises when the language-dominant (usually left) hemisphere is selectively targeted by a neurodegenerative disease. The underlying neuropathology can be either frontotemporal lobar degeneration (FTLD) or an atypical form of Alzheimer disease (AD).¹ The factors that make the language network selectively susceptible to these neurodegenerative diseases remain unknown. One potential clue emerged from our previous report, which showed a history of learning disability (LD), including developmental dyslexia, to be significantly higher in patients with PPA (n = 108) and their first-degree relatives than in cognitively healthy control individuals (n = 353), as well as dementia of the Alzheimer type (n = 154) or the behavioral variant of frontotemporal dementia (n = 84).²

The prevalence of LD in logopenic PPA (PPA-L) was reported to be approximately twice the rate expected in the general population.³ Logopenic PPA is the subtype most commonly caused by AD, raising the possibility that LD becomes a particularly prominent susceptibility factor for the atypical aphasic manifestation of AD. In our initial report, clinical subtype was not considered and autopsies were not available. The current follow-up study examined 66 consecutive autopsies of patients with PPA to determine whether the presence of LD in either patients or their first-degree family members was associated with a specific aphasia subtype or pathology. In this group, 58 patients with PPA had sufficient information on the status of LD and were included in analyses. Twenty of these were part of our previous report.²

Consensus criteria were used for the diagnosis and subtyping of PPA⁴ and for the pathological diagnoses of AD and FTLD.^5,6 Participants were recruited from Northwestern University’s Alzheimer Disease Center and/or the PPA Research Program. Written informed consent was obtained from each participant. The Northwestern University institutional review board approved this study. The LD status was specifically queried during the clinical interview of patients and families and recorded in the medical record.

Fifty percent of the cases (29 of 58 patients) had either a personal or family history of LD. This is even higher than the 37% prevalence in our original report but the difference was not statistically significant (P = .10, Fisher exact test). Demographics did not differ between the groups with and without a history of LD (Table).

The LD prevalence in PPA with AD (52%) was nearly identical to that in PPA with FTLD (48%). There were too few cases for separate analyses of FTLD subtypes. The incidence in PPA-L (41%) was no greater than that of the nonlogopenic patients (56%). Although the numbers were low, LD prevalence in agrammatic PPA (53%) did not seem to be higher than in nonagrammatic patients (49%).

This set of 58 autopsies yielded an LD prevalence that was at least as high as that in our original study. The prevalence was higher than reported by Miller et al,³ probably because we also included incidence in first-degree relatives and were more inclusive in defining LD. Our findings are consistent with the report by Miller et al³ of a high LD prevalence in PPA-L. However, we did not find that LD was preferentially associated with AD vs FTLD pathology or with PPA-L vs other PPA variants. If LD does turn out to be a susceptibility marker for PPA, at least in some patients, it would seem to be exerting its influence regardless of the underlying pathology or aphasia type. Larger cohorts and greater specification of the LD history will help to refine and amplify these associations.

Corresponding Author: Emily J. Rogalski, PhD, Northwestern University, Cognitive Neurology and Alzheimer’s Disease Center (CNADC), 320 E Superior St, Searle Bldg, 11th Floor, Chicago, IL 60611 (erogalski@gmail.com).

Author Contributions: Dr Rogalski had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Rogalski, Weintraub, Mesulam.

Acquisition, analysis, or interpretation of data: Rogalski, Rademaker, Wieneke, Bigio, Mesulam.

Drafting of the manuscript: Rogalski, Rademaker, Mesulam.

Critical revision of the manuscript for important intellectual content: Rogalski, Wieneke, Bigio, Weintraub, Mesulam.

Statistical analysis: Rogalski, Rademaker, Mesulam.

Obtained funding: Mesulam.

Administrative, technical, or material support: Rogalski, Wieneke.

Study supervision: Weintraub.

Conflict of Interest Disclosures: None reported.

Funding/Support: This project was supported by grant DC008552 from the National Institute on Deafness and Communication Disorders; grant AG13854 (Alzheimer Disease Core Center) from the National Institute on Aging; and grant NS075075 from the National Institute of Neurological Disorders and Stroke.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.