ORIGINAL CONTRIBUTION Quantitative Template for Subtyping Primary Progressive Aphasia Marsel Mesulam, MD; Christina Wieneke, BA; Emily Rogalski, PhD; Derin Cobia, PhD; Cynthia Thompson, PhD; Sandra Weintraub, PhD Background: The syndrome of primary progressive Fourth Edition) classified all 16 patients in concor- aphasia (PPA) is diagnosed when a gradual failure of word dance with a clinical diagnosis that had been made be- usage or comprehension emerges as the principal fea- fore the administration of quantitative tests. All 3 PPA ture of a neurodegenerative disease. subtypes had distinctly asymmetrical atrophy of the left perisylvian language network. Each subtype also had dis- Objective: To provide a quantitative algorithm for clas- tinctive peak atrophy sites: PPA-G in the inferior frontal sifying PPA into agrammatic (PPA-G), semantic (PPA-S), gyrus (Broca area), PPA-S in the anterior temporal lobe, and logopenic (PPA-L) variants, each of which is known and PPA-L in Brodmann area 37. to have a different probability of association with Alzhei- mer disease vs frontotemporal lobar degeneration. Conclusions: Once an accurate root diagnosis of PPA is made, subtyping can be quantitatively guided using a Design: Prospective study. 2-dimensional template based on orthogonal tasks of Setting: University medical center. grammatical competence and word comprehension. Al- though the choice of tasks and the precise cutoff levels Patients: Sixteen consecutively enrolled patients with may need to be adjusted to fit linguistic and educational PPA who underwent neuropsychological testing and mag- backgrounds, these 16 patients demonstrate the feasi- netic resonance imaging recruited nationally in the United bility of using a simple algorithm for clinicoanatomical States as part of a longitudinal study. classification in PPA. Prospective studies will show whether this subtyping can improve clinical prediction Results: A 2-dimensional template that reflects perfor- of the underlying neuropathologic condition. mance on tests of syntax (Northwestern Anagram Test) and lexical semantics (Peabody Picture Vocabulary Test— Arch Neurol. 2009;66(12):1545-1551 HE CLASSIFICATION OF PRI- is particularly important for early-onset de- mary progressive aphasia mentias, in which the concordance be- (PPA) into subtypes has tween clinical predictions and postmor- acquired new relevance in tem confirmation can be quite low. light of postmortem series Although numerous studies1,3-5 have de- Tand in vivo amyloid imaging showing that scribed clinical and neuropsychological individual variants have different likeli- characteristics of PPA subtypes, few have hoods of being caused by Alzheimer dis- included an unselected prospective co- ease (AD) vs frontotemporal lobar de- hort investigated using a unified battery generation (FTLD). The most frequent of easily administered tests specifically cho- associations have been reported between sen to probe the defining features of the the agrammatic variant (PPA-G) and FTLD subtypes. with tauopathy (FTLD-T), the semantic This study describes an empirically es- variant (PPA-S) and FTLD with ubiquitin/ tablished 2-dimensional quantitative tem- TAR-DNA binding protein 43 proteinopa- plate derived from performance on tests of thy (FTLD-TDP), and the logopenic vari- syntax and lexical semantics that success- ant (PPA-L) and AD.1-3 fully classified 16 consecutively investi- In the absence of definitive in vivo bio- gated patients with PPA. The biological va- markers for these diseases, the reliable clas- lidity of the resultant classification was Author Affiliations: Cognitive sification of PPA assumes considerable rel- supported by the presence of distinctive ana- Neurology and Alzheimer’s evance for increasing the accuracy with tomical patterns of peak cortical atrophy in Disease Center, Northwestern which the nature of the underlying patho- each variant. Whether this classification also University, Chicago, Illinois. logic abnormality can be predicted. This corresponds to differential neuropatho- (REPRINTED) ARCH NEUROL / VOL 66 (NO. 12), DEC 2009 WWW.ARCHNEUROL.COM 1545 ©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/04/2021 Table 1. Characteristics of the 16 Study Patientsa WAB % Correct Patient No./ Aphasia Word-Word % Correct % Correct % Correct % BDAE WAB Sex/Age at Symptom Quotient Association PPVT-4 NAT BNT Fluency Repetition Testing, y Education, y Handednessb Duration, y (100) (16) (36) (10) (60) (7) (100) Agrammatic PPA Variant 1/M/62 20 ϩ80 5.0 82.3 100.0 100.0 50 98.3 42.9 80 2/M/59 12 ϩ95 3.0 79.9 100.0 94.4 40 81.7 57.1 78 3/F/61 18 ϩ100 5.0 75.3 100.0 100.0 50 88.3 42.9 88 4/F/56 14 ϩ100 2.0 65.4 100.0 83.3 10 81.7 14.3 42 Semantic PPA Variant 5/F/53 16 ϩ100 3.0 65.9 50.0 22.2 60 6.7 100.0 74 6/M/63 18 ϩ100 5.5 88.2 93.8 47.2 100 23.3 100.0 97 7/F/54 12 ϩ100 3.0 83.2 75.0 27.8 100 10.0 100.0 91 8/F/64 16 ϩ100 7.5 80.6 62.5 38.9 100 8.3 100.0 88 9/F/56 18 ϩ100 2.5 75.5 75.0 38.9 100 5.0 100.0 85 Logopenic PPA Variant 10/M/69 15 ϩ100 2.5 92.0 100.0 97.2 90 98.3 71.4 90 11/M/63 18 ϩ100 2.5 97.1 100.0 100.0 100 96.7 100.0 89 12/M/58 16 ϩ100 2.0 86.9 100.0 97.2 90 90.0 100.0 90 13/F/65 13 ϩ100 5.0 78.6 100.0 83.3 70 83.3 71.4 88 14/F/75 16 ϩ100 2.5 97.2 100.0 97.2 100 88.3 100.0 90 15/M/64 18 ϩ90 2.0 93.2 100.0 100.0 70 98.3 85.7 89 16/M/48 16 ϩ80 6.0 83.2 100.0 100.0 100 98.3 71.4 90 Abbreviations: BDAE, Boston Diagnostic Aphasia Examination; BNT, Boston Naming Test; NAT, Northwestern Anagram Test; PPA, primary progressive aphasia; PPVT-4, Peabody Picture Vocabulary Test—Fourth Edition; WAB, Western Aphasia Battery. a Numbers in parentheses indicate the highest possible raw scores. b A“ϩ” score in the Edinburgh inventory indicates the degree of right-handedness. logic processes remains to be determined by prospective SINGLE-WORD COMPREHENSION studies. Word comprehension (lexical semantics) is commonly tested by asking the patient to match a word to a picture. The auditory METHODS word comprehension subtest of the WAB was too easy. We, there- fore, opted to use the PPVT-412 and selected a subset of 36 mod- Recruitment occurred in the context of a National Institutes erately difficult items (items 157-192). Each item requires the of Health–funded project that brought patients from through- patient to match a word representing an object, action, or at- out the United States to Northwestern University for a 3-day tribute to 1 of 4 picture choices. Because performance on the intensive research program. All of the patients who fulfilled the PPVT-4 could potentially be confounded by problems of pic- criteria for PPA, who could complete the 5 key diagnostic tests, ture recognition, its face validity as a measure of word compre- and who had a magnetic resonance image suitable for quanti- hension was further established by comparing scores with those tative morphometric analysis were included. Only images ob- on a word-word association task in which patients decided which tained within a few days of neuropsychological testing were used. of 2 pairs contained semantically matching words (eg, horse- The root diagnosis of PPA was made on the basis of a progres- saddle vs horse-slippers). Only patients with PPA-S with the low- sive language disturbance (ie, aphasia) that is initially the most est PPVT-4 scores showed less than 100% performance on the salient feature of the clinical picture (ie, primary) and that is caused word-word association task (Table 1). However, the impair- by neurodegeneration (ie, is progressive).6-8 The presence of an ment on this task was milder than that on the PPVT-4. In the aphasia was established by aphasia quotients derived from admin- future, a more difficult form of the word-word association task istration of the Western Aphasia Battery (WAB).9 All of the pa- could be substituted for the PPVT-4 to eliminate potential in- tients were right-handed, as determined using the Edinburgh in- terference from picture-recognition deficits. ventory10; 8 were men and 8 were women (Table 1). Duration of disease at the time of testing varied from 2.0 to 7.5 years. The progressive nature of the deficits and the fact that the language SYNTAX IN THE CONSTRUCTION disorder was the chief problem during the initial few years of the OF SENTENCES disease were documented by the history obtained from the patient, from medical records, and from at least 1 additional informant who Syntax, a major component of grammar, regulates the proper or- lived in the same household.11 All of the patients had received a dering of words into sentences. Its assessment is challenging. The descriptive diagnosis of PPA-G, PPA-L, or PPA-S based on an ini- WAB, for example, has no subtest for assessing syntax. In tradi- tial office evaluation (Table 2), and before administration of the tional aphasiology, fluency and phrase length have been used as quantitative tests, by clinicians with extensive experience with this surrogates for grammatical competence. However, it becomes dif- disease (M.M. and S.W.). Five language tests provided the basis ficult to decide whether apparent agrammatism in a dysfluent pa- for the quantitative classification: the Peabody Picture Vocabu- tient represents an economy of expression, consequences of dys- lary Test—Fourth Edition (PPVT-4), the Northwestern Anagram arthria, or a true insensitivity to rules of syntax.