Features of Patients With Nonfluent/Agrammatic Primary Progressive Aphasia With Underlying Progressive Supranuclear Palsy Pathology or Corticobasal Degeneration | Dementia and Cognitive Impairment | JAMA Neurology | JAMA Network
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Figure 1.  Cross-sectional Voxel-Based Morphometry at Presentation of Nonfluent/Agrammatic Primary Progressive Aphasia
Cross-sectional Voxel-Based Morphometry at Presentation of Nonfluent/Agrammatic Primary Progressive Aphasia

T maps depicted at a P < .001 uncorrected threshold for better visualization of differences and similarities between groups. A 3-group analysis of variance was conducted for progressive supranuclear palsy (PSP; n = 5), corticobasal degeneration (CBD; n = 9), and control individuals (n = 80) using 4 covariates (age, scanner type, total intracranial volume, and sex). The color bar indicates t values (min = 0, max = 6). Images are in neurological view (left = left).

Figure 2.  Longitudinal Voxel-Based Morphometry of Nonfluent/Agrammatic Primary Progressive Aphasia
Longitudinal Voxel-Based Morphometry of Nonfluent/Agrammatic Primary Progressive Aphasia

T maps depicted at a P < .001 uncorrected threshold for better visualization of differences and similarities between groups. A 3-group analysis of variance was conducted for progressive supranuclear palsy (PSP; n = 5), corticobasal degeneration (CBD; n = 5), and control individuals (n = 42) using 4 covariates (age, scanner type, total intracranial volume, and sex). The color bar indicates t values (min = 0, max = 6). Images are in neurological view (left = left).

Table 1.  Demographic and Cognitive Data of Patients With nfvPPA-PSP and nfvPPA-CBD and Control Individuals at Initial Visita
Demographic and Cognitive Data of Patients With nfvPPA-PSP and nfvPPA-CBD and Control Individuals at Initial Visita
Table 2.  Cognitive Data at Baseline and 1-Year Follow-up Evaluationa
Cognitive Data at Baseline and 1-Year Follow-up Evaluationa
Table 3.  Neurological Symptoms and Signs at Presentation, 1-Year Follow-up, and Follow-up Closest to Time of Deatha
Neurological Symptoms and Signs at Presentation, 1-Year Follow-up, and Follow-up Closest to Time of Deatha
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Original Investigation
June 2016

Features of Patients With Nonfluent/Agrammatic Primary Progressive Aphasia With Underlying Progressive Supranuclear Palsy Pathology or Corticobasal Degeneration

Author Affiliations
  • 1Department of Neurology, Memory Aging Center, University of California, San Francisco
  • 2Department of Medicine, Autonomous University of Barcelona, Bellaterra, Barcelona, Spain
  • 3Department of Communication Sciences and Disorders, Temple University, Philadelphia, Pennsylvania
  • 4Department of Speech, Language, and Hearing Sciences, University of Arizona, Tucson
  • 5Department of Communication Sciences and Disorders, University of Texas, Austin
  • 6Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 7Department of Pathology, University of California, San Francisco
JAMA Neurol. 2016;73(6):733-742. doi:10.1001/jamaneurol.2016.0412
Abstract

Importance  We provide novel evidence of specific clinical and neuroimaging features that may help for the in vivo prediction of underlying pathology in patients with nonfluent/agrammatic primary progressive aphasia (nfvPPA) and progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD) proved by autopsy.

Objective  To characterize the neurological, cognitive, and neuroimaging features of patients with nfvPPA—in whom either PSP or CBD was eventually confirmed at autopsy—at initial presentation and at 1-year follow-up.

Design, Setting, and Participants  A prospective longitudinal clinical-pathological study was conducted in a tertiary research clinic that specialized in cognitive disorders. Fourteen patients were evaluated between January 2002 and December 2014. Inclusion criteria for the study were a clinical diagnosis of nfvPPA; the availability of speech, language, and cognitive testing for at least 1 evaluation; magnetic resonance imaging within 6 months of initial evaluation; and a postmortem pathological diagnosis of PSP or CBD. Ten matched healthy control participants were also included.

Main Outcomes and Measures  Clinical, cognitive, and neuroimaging longitudinal data were analyzed to characterize the whole nfvPPA–4-repeat–tau group and identify differences between nfvPPA-PSP and nfvPPA-CBD both at presentation and longitudinally.

Results  Patient groups did not differ significantly in age, sex, or handedness (nfvPPA-PSP group: median [interquartile range (IQR)] age, 74 [67-76] years; 1 of 5 male [20%]; 1 of 5 left-handed [20%]; and nfvPPA-CBD group: mean [IQR] age, 65 [54-81] years; 3 of 9 male [33%]; 0 left-handed). Motor speech impairment and left frontal white matter atrophy were the most prominent common features. At presentation, dysarthria (Motor Speech Examination median [IQR] score: nfvPPA-PSP, 4 [2-7]; nfvPPA-CBD, 0 [0-4]; P = .02), depression (Geriatric Depression Scale median [IQR] score: nfvPPA-PSP, 19 [3-28]; nfvPPA-CBD, 4 [0-16]; P = .04), and relatively selective white matter atrophy were typical of the nfvPPA-PSP group, while greater gray matter atrophy and a trend toward greater sentence comprehension deficits (median [IQR] sentence comprehension correct: nfvPPA-PSP, 98% [80-100]; nfvPPA-CBD, 81% [65-98]; P = .08) were found in the nfvPPA-CBD group. At follow-up after 1 year, we observed no significant differences in any speech or language measures. Furthermore, atrophy in patients with PSP progressed within the subcortical/brainstem motor system generating greater oculomotors deficits and swallowing difficulty; atrophy in patients with CBD spread anteriorly in prefrontal regions consistent with their greater working memory impairment and development of behavioral symptoms.

Conclusions and Relevance  In patients presenting with nfvPPA, presence of early severe dysarthria, relatively selective white matter atrophy at presentation, and a greater rate of change in the brainstem measured by longitudinal imaging may be useful for differentiating underlying PSP from CBD pathology during life.

Introduction

The nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA) is a clinical syndrome strongly linked to underlying frontotemporal lobar degeneration (FTLD) pathology.1,2 Most cases are caused by abnormal aggregation of the microtubule-associated protein tau (FTLD-tau), while most of the remaining cases are associated with the transactive response DNA-binding protein 43-kD inclusions, usually type A.2 The FTLD-tau cases are caused by either 4-repeat (4R) tauopathies, such as progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD), or Pick disease, a 3-repeat tauopathy.

Motor speech (apraxia of speech [AOS] and dysarthria) and grammar impairment along with predominant left posterior frontal lobe and insular atrophy are well-established features of clinically defined nfvPPA.3-5 However, prospectively collected speech, language, and neuroimaging data in pathologically confirmed cohorts are scarce, and to our knowledge, no longitudinal neuroimaging study of pathologically confirmed nfvPPA has been conducted. Consequently, it is not known whether different types of FTLD-tau presenting as nfvPPA can be distinguished by early clinical and neuroimaging features or by their longitudinal trajectories. The small number of clinicopathological studies in nfvPPA1,6-11 show that 2 4R tauopathies, CBD and PSP, are the most common causes of nfvPPA, making the identification of early clinical and neuroimaging biomarkers associated with these pathologies a matter of great interest. Despite significant clinical and pathological overlap, PSP and CBD are considered 2 distinct diseases presenting specific pathological lesions, biochemical features, and cellular and network vulnerabilities.12,13 Also, recent evidence suggests that CBD and PSP may be associated with distinct tau strains, which may require different therapies.14 While it is possible that both diseases might respond to the same 4R-tau–targeted therapy, the ability to differentiate these 2 syndromes at early stages when molecule-specific disease-modifying drugs are most likely to be effective may prove to be critical for successful treatment. Furthermore, the ability to prognosticate future clinical symptoms holds great value for patients and caregivers.

The purpose of this study was to characterize the early features and longitudinal trajectories of neurological, cognitive, and neuroimaging impairment in patients with sporadic nfvPPA and autopsy-confirmed PSP or CBD pathology.

Box Section Ref ID

Key Points

  • Question What are the early cross-sectional and longitudinal features of nonfluent/agrammatic primary progressive aphasia (nfvPPA) with underlying corticobasal degeneration (CBD) or progressive supranuclear palsy (PSP) pathology?

  • Findings In this clinical-pathological study that included 14 patients with nfvPPA and 10 matched healthy control participants, those with nfvPPA-PSP presented significantly more dysarthria and depression and less gray matter atrophy than those with nfvPPA-CBD. Atrophy in PSP progressed within the subcortical/brainstem, whereas atrophy spread anteriorly in prefrontal regions in CBD.

  • Meaning In nfvPPA, the presence of early severe dysarthria, relatively selective white matter atrophy at presentation, and greater rate of change in the brainstem may be useful for differentiating underlying PSP from CBD pathology during life.

Methods
Patients

Patients were evaluated at the University of California, San Francisco, Memory and Aging Center as part of a prospective, longitudinal research study between January 2002 and December 2014. Inclusion criteria for the study were a clinical diagnosis of nfvPPA according to current criteria5; the availability of speech, language, and cognitive testing for at least 1 evaluation; magnetic resonance imaging (MRI) within 6 months of initial evaluation; and a postmortem pathological diagnosis of FTLD–4R-tau. This resulted in a cohort of 15 patients: 5 with pathologically confirmed PSP, 9 with CBD, and 1 with an unclassifiable 4R tauopathy. Tau immunohistochemistry demonstrated evidence of globose tangles and tufted astrocytes15 in all patients with PSP and astrocytic plaques16 and threadlike inclusions in all patients with CBD. Genetic screening results for mutations in microtubule-associated protein tau and progranulin genes were negative in all participants. Because our primary objective was to characterize and contrast features of nfvPPA-PSP and nfvPPA-CBD, the unclassifiable case of 4R tauopathy was excluded. Patients were followed up for a mean (SD) of 2.9 (1.6) years.

We recruited healthy control participants (n = 10) from the San Francisco community. Control individuals were matched for age, sex, and scanner type and had a Clinical Dementia Rating Scale sum of boxes score of 0, a normal neurologic examination, and no cognitive symptoms. In all, there were 3 groups of participants: 5 patients with nfvPPA-PSP, 9 with nfvPPA-CBD, and 10 matched healthy controls. All participants provided written informed consent, and the University of California, San Francisco, Human Research Committee approved the study.

Clinical and Cognitive Data

All patients received a standardized clinical evaluation and neuropsychological and speech and language batteries at initial visit and follow-up as described in previous reports.17-21 Speech production, motor speech, and grammatical processing were of particular interest in nfvPPA and were considered in detail by reviewing videotaped evaluations.22 A detailed description of the speech and language evaluation is included in the supplementary material (eMethods 1 in the Supplement).

The presence of clinical symptoms and neurological signs were compared between groups at presentation (PSP, n = 5; CBD, n = 9), at 1-year follow-up (PSP, n = 5; CBD, n = 6), and at follow-up closest to time of death (PSP, n = 4; CBD, n = 5) using the χ2 test. The criteria used for the syndromic diagnosis of probable PSP and CBD were published previously23 and are included in the supplementary material (eMethods 2 in the Supplement). We compared cognitive test scores between patients with nfvPPA-PSP (n = 5) and nfvPPA-CBD (n = 9) and a subset of control individuals (n = 10) at initial evaluation and at 1-year follow-up (PSP, n = 4; CBD, n = 7). Mann-Whitney U and Kruskal-Wallis tests were used for 2- and 3-group comparisons, respectively. For analysis of longitudinal cognitive data, we performed a paired Wilcoxon test to compare performance at initial evaluation and follow-up within each group.

Neuroimaging

All patients and control individuals underwent whole-brain structural MRI using either a 1.5T Magnetom VISION System (Siemens Healthcare GmbH),3 Siemens Magnetom Trio, A Tim System 3T (Siemens Healthcare GmbH),24 or Bruker MedSpec 4T (Bruker Corporation/Siemens Healthcare GmbH)25 scanner.

Patients

We compared the nfvPPA-PSP (n = 5) and nfvPPA-CBD (n = 9) groups with each other and with healthy control individuals (n = 80). Only patients with 2 MRI scans performed in consecutive years and on the same scanner were included in the longitudinal analysis (5 with nfvPPA-PSP, 5 with nfvPPA-CBD, and 42 control individuals).

Voxel-Based Morphometry Analysis

Image processing was performed using the unified segmentation procedure, DARTEL toolbox, and Pairwise Longitudinal Registration toolbox26 implemented in SPM12 (Wellcome Trust for Neuroimaging) according to standard procedures described elsewhere.27,28 Whole-brain analyses of differences in gray matter (GM), white matter (WM), and annual rate of volume change were investigated using an analysis of variance test across groups, including age, sex, total intracranial volume, and scanner type as nuisance variables. For the Figures, we depicted t maps at a P < .001 uncorrected threshold for better visualization of differences and similarities between groups. Statistical Parametric Mapping Anatomy toolbox version 2.0 (Wellcome Trust Centre for Neuroimaging)29 was used to report GM coordinates (eTable 1 and eTable 2 in the Supplement). Also see eMethods 3 and eTable 3 in the Supplement for a region-of-interest analysis.

Neuropathology

Autopsies were performed at the University of California, San Francisco (n = 14); the University of Pennsylvania (n = 3); and the Vancouver General Hospital (n = 1). Pathological diagnoses were based on consensus guidelines for FTLD30 following standard procedures described previously.17,31

Results
Demographic Data

Age at symptom onset and age at initial evaluation did not differ significantly between patients with PSP and CBD (Table 1). However, 4 of 5 patients with PSP and only 2 of 9 with CBD presented after the age of 65 years. There was a trend in patients with PSP toward longer survival following onset of first symptom (P = .06).

General Cognitive and Language Data
At Initial Evaluation

Results of general cognition (Mini-Mental State Examination scale), memory, and executive function tests were significantly worse in patients with nfvPPA–4R-tau compared with control individuals (Table 1). Speech and language measures showed impairment in motor speech, verbal fluency, naming, and sentence comprehension.

Patients with nfvPPA-PSP had significantly greater depression than those with nfvPPA-CBD, and only patients with nfvPPA-CBD were significantly worse than control individuals in a test of working memory (digits backward). All 14 patients showed AOS. Mixed hypokinetic and spastic dysarthria was present and rated as more severe than AOS in all patients with nfvPPA-PSP. Dysarthria was present in only 4 of 9 patients with CBD. Dysarthria was significantly more severe in patients with nfvPPA-PSP. Only those with nfvPPA-CBD were significantly worse than control individuals in both measures of sentence comprehension, and these patients showed a trend for lower scores compared with those with nfvPPA-PSP. No significant differences were found when directly comparing patient groups in the measures derived from the recorded speech sample. However, both groups scored significantly worse than control individuals in words per minute, distortions per 100 words, proportion of syntactical errors, and proportion of words in sentences. Only patients with nfvPPA-CBD produced significantly fewer narrative words than control individuals.

At 1-Year Follow-up

In patients with nfvPPA–4R-tau, Mini-Mental State Examination scale scores showed significant decline, while visuospatial and visual memory tests were still not significantly impaired compared with control individuals (Table 2). Digits backward remained impaired but did not decline significantly. All speech and language measures declined significantly except phonemic fluency, sequential commands, and dysarthria (which only showed a trend toward significant decline).

At follow-up, cross-sectional comparisons did not show significant differences between patient groups in any cognitive measure. Accordingly, patients with nfvPPA-CBD showed higher dysarthria scores, and those with nfvPPA-PSP performed worse on grammar comprehension than before. However, longitudinal changes in these measures were not significant. In patients with nfvPPA-CBD, longitudinal analysis showed significant decline in Mini-Mental State Examination scale score, AOS, speech fluency, and auditory word recognition (although patients continued to be relatively preserved in this single-word comprehension task, as they missed only 1 of 60 items). Patients with nfvPPA-PSP showed significant decline in semantic fluency only. Both groups showed a trend toward significant decline in grammar comprehension.

Neurological Symptoms and Signs at Initial and Follow-up Evaluations

At presentation, all patients reported difficulty with speech production as their initial and main symptom as well as the primary cause of impaired daily function (Table 3). A significantly greater proportion of patients with nfvPPA-PSP reported a sensation of reduced balance and the presence of at least 2 falls in the previous year. A significantly greater proportion of these patients also showed buccofacial apraxia and mild axial rigidity in the neurological examination. At 1-year follow-up, more patients with nfvPPA-PSP experienced some swallowing difficulties and showed slower or lower amplitude of vertical than horizontal eye movements on neurologic examination. Patients with nfvPPA-CBD showed a trend for greater impulsive and obsessive-compulsive behaviors, which were present in both groups at follow-up.

Cross-sectional Neuroimaging Analysis at Initial Evaluation
Gray Matter

Atrophy in patients with nfvPPA–4R-tau showed primarily in a left posterior frontal insular–basal ganglia and superior medial frontal network (Figure 1). The most significant atrophy peaks were located in left precentral, middle, and inferior frontal gyri; left medial supplemental motor area (SMA); left putamen; and left insula.

Patients with nfvPPA-CBD showed significant GM atrophy compared with control individuals in all regions mentioned here, while those with nfvPPA-PSP only showed small areas of significant GM atrophy in left SMA, precentral and middle frontal gyri, and right cerebellum. Direct group comparison showed greater GM atrophy in patients with nfvPPA-CBD, primarily in the left insula and putamen.

White Matter

Extensive left frontal involvement predominantly affecting the WM between the striatum, premotor, and prefrontal regions was seen in nfvPPA–4R-tau. Other smaller areas of significant atrophy were found in mid–corpus callosum, underlying right premotor cortex, and in the midbrain-diencephalic junction.

Both pathological groups showed predominant WM atrophy beneath the left precentral gyrus and SMA and less significant atrophy in the mid–corpus callosum, right frontal, and left midbrain-diencephalic regions. As shown in Figure 2, atrophy extended considerably more anteriorly for patients with nfvPPA-CBD, affecting WM underlying left frontal middle and inferior gyri. The relative proportion of GM to WM damage was strikingly different between patient groups, with more WM than GM atrophy in patients with PSP. Direct comparison of patient groups showed small regions of greater left prefrontal WM atrophy in those with nfvPPA-CBD.

Longitudinal Neuroimaging Analysis
Gray Matter

The area that showed the greatest annual rate of change in patients with nfvPPA–4R-tau included the left precentral, middle frontal, and inferior frontal cortex (Figure 2). A homotopic area in the right hemisphere showed the second greatest rate of change, followed by contiguous regions of bilateral SMA and middle cingulate cortex.

Both patient groups displayed significant longitudinal atrophy compared with control individuals in left precentral gyrus and SMA. Patients with nfvPPA-PSP showed more areas of significant GM longitudinal change, including bilateral precentral, dorsal midbrain, and right cerebellar regions. Patients with nfvPPA-CBD showed significant change in more anterior parts of left prefrontal cortex. Direct comparison did not reveal any significant differences.

White Matter

The area showing the greatest rate of change in nfvPPA–4R-tau included the left premotor region and extended anteriorly beneath the prefrontal cortex and downwards through the corona radiata, posterior limb of the internal capsule, midbrain-diencephalic junction, left cerebral peduncle, and pons. Another less significant area of contraction was located in right frontal WM.

Patients with nfvPPA-CBD only showed significant longitudinal atrophy in 1 WM cluster underlying the left precentral and middle frontal gyri, which extended further anterior than in those with nfvPPA-PSP. In patients with nfvPPA-PSP, the greatest rate of annual change included WM in the left half of the midbrain and pons and extended bilaterally into the cerebellar peduncles. Large areas of significant WM change were also visible underlying left and right precentral gyri. Direct comparison did not reveal any significant differences.

Discussion

This study analyzed cross-sectional and longitudinal clinical, cognitive, and neuroimaging data in a cohort of prospectively evaluated patients with nfvPPA found to have CBD or PSP at autopsy. The most common pathological subtype in our cohort was CBD. Although the 2 groups showed major similarities, with AOS and left posterior frontal GM and WM involvement being the most salient, common features, our results highlight specific characteristics that might help predict the presentation of PSP in patients with nfvPPA. In particular, the presence of severe dysarthria and greater WM than GM atrophy at presentation and the appearance of adverse brainstem anatomical and clinical signs at follow-up were typical of PSP.

It has been known for a decade that AOS and agrammatism are the most typical features of the clinical presentation of nfvPPA.3,4 In recent years, the term primary progressive apraxia of speech has been used when AOS is the main feature and no apparent agrammatism is detected.32 In our experience, it is often difficult to judge whether grammar production is spared in patients with severe output difficulties. In our cohort, all patients were diagnosed by a speech pathologist as having AOS, while grammatical difficulties were variable and sometimes only detected in written language or at follow-up. Thirteen of 14 of our patients could have been classified as having greater motor speech than grammatical deficits, but patients with nfvPPA-PSP had significantly more dysarthria and buccofacial apraxia at presentation. In contrast, patients with nfvPPA-CBD were significantly worse than control individuals in sentence comprehension while those with nfvPPA-PSP were not. In the direct comparison between patient groups, the difference in sentence comprehension was only a trend (P ≤ .10). A recent clinicopathological study6 in patients with nfvPPA suggested PSP was more likely when AOS dominated the syndrome, whereas CBD was more likely when AOS and aphasia were equal. In our cohort, the presence of dysarthria together with AOS was responsible for greater motor speech deficits than grammar deficits in patients with PSP. Dysarthria has previously been reported in pathologically confirmed PSP cases presenting as both primary progressive aphasia6 and Richardson syndrome.33 The early predominance of motor speech deficits in both patients with PSP and with CBD supports a potential role as an outcome measure if one were to test a tau-directed therapeutic in this population. However, more quantitative and reliable measures of AOS and dysarthria are needed for adequate assessment of change in these areas.

Consistent with their clinical presentation, patients with CBD and PSP showed atrophy that overlapped in left SMA and precentral regions, important components in the motor speech production network.21,34,35 These results are consistent with previous reports of cross-sectional neuroimaging in clinically3,36,37 and pathologically6,10,17,38 confirmed cases of nfvPPA. Our finding of early predominance of WM over GM atrophy in patients with PSP is also in accordance with previous neuroimaging17,38 and quantitative pathology33 studies and may explain why dysarthria was more severe than AOS in patients with PSP. In patients with CBD, the atrophy extended further into the left frontal GM and WM, providing a substrate for their significantly impaired working memory and grammar comprehension compared with control individuals.20,39 Early, severe WM damage has been proposed as typical of FTLD-tau pathology presenting as nfvPPA.9 Our current results refine this association, suggesting that early predominant WM vs GM atrophy should be considered as a possible neuroimaging biomarker of PSP pathology but always in the context of a multidomain approach considering clinical, molecular, genetic, and neuroimaging features.

Analyzing prospectively collected longitudinal data in patients with pathologically confirmed nfvPPA was a unique opportunity of this study. Only patients with PSP showed highly significant GM and WM longitudinal changes in the midbrain, particularly at the level of the cerebral and cerebellar peduncles, presumably affecting the corticospinal tract, pontine-crossing fibers, and other afferent and efferent cerebellar fibers. Accordingly, patients with nfvPPA-PSP developed mild ocular and axial motor abnormalities. In contrast, patients with nfvPPA-CBD showed greater longitudinal changes in prefrontal anterior, medial, and lateral GM and WM, corresponding with their greater longitudinal decline in speech fluency and development of behavioral symptoms. Rohrer et al36 also found more prominent midbrain atrophy but less marked perisylvian atrophy in cases of nfvPPA that developed a typical PSP clinical syndrome compared with cases that did not, although this study did not include longitudinal imaging or pathological data. Greater presence of behavioral symptoms in cases of CBD pathology was also reported in a recent study33 that compared cases of CBD vs PSP presenting as Richardson syndrome. Similar to other longitudinal clinical-pathological reports,40,41 CBD syndrome was more common than Richardson syndrome at later visits. Our results might be relevant for prognoses in nfvPPA because significant initial dysarthria at presentation may indicate considerable subcortical disease and imminent swallowing and balance problems. This study also suggests that differential longitudinal neuroimaging changes in GM and WM may be a sensitive biomarker of disease-specific patterns of progression.42

There were some limitations in this study. Despite being the largest cohort of prospectively studied and pathologically confirmed patients with nfvPPA that has been reported, to our knowledge, this study was necessarily based on a relatively small sample, which limited generalization of results and entailed low-powered statistical analyses. To address this issue and help with the interpretation of results, we included individual patient cognitive data in the supplementary material (eTable 4 and eTable 5 in the Supplement). We also performed a region-of-interest analysis to address the concern that the larger sample size of patients with nfvPPA-CBD was driving the finding of more extensive atrophy in nfvPPA-CBD presentation. The region-of-interest analysis supported the voxel-based morphometry findings and is included in the supplementary material (eTable 3 in the Supplement). Combining MRIs from 3 different scanners is also not ideal, although we controlled for this by matching control individuals and including it as a nuisance variable in the voxel-based morphometry analysis. Finally, diffusion tensor imaging combined with tractography would have been the optimal technique to investigate WM damage in specific tracts. However, voxel-based morphometry was able to show important differences between groups that were consistent with a recent diffusion tensor imaging tractography study35 in the same clinical population that included 4 (2 with PSP and 2 with CBD) of the same patients.

Conclusions

In vivo prediction of the pathology underlying the nfvPPA syndrome is becoming an increasingly important endeavor as future molecule-specific treatments are developed. Our results indicate a promising role for the combination of early cross-sectional and longitudinal clinical and neuroimaging features in the in vivo differentiation between nfvPPA-PSP and nfvPPA-CBD.

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Article Information

Corresponding Author: Maria Luisa Gorno-Tempini, MD, PhD, University of California, San Francisco, Memory and Aging Center, Sandler Neurosciences Center, 675 Nelson Rising Lane, Ste 190, San Francisco, CA 94143 (marilu@memory.ucsf.edu).

Accepted for Publication: February 4, 2016.

Correction: This article was corrected on August 1, 2016, to add a missing author affiliation.

Published Online: April 25, 2016. doi:10.1001/jamaneurol.2016.0412.

Author Contributions: Dr Santos 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: Santos, Rosen, Boxer, Miller, Gorno-Tempini.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Santos, Mandelli, Hubbard, Meese, Rosenberg, Pakvasa, Rosen, Boxer, Miller, Gorno-Tempini.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Santos, Mandelli, Binney, Hubbard, Attygalle, Rosen, Gorno-Tempini.

Obtained funding: Rosen, Boxer, Seeley, Gorno-Tempini.

Administrative, technical, or material support: Santos, Mandelli, Binney, Ogar, Henry, Meese, Rosenberg, Pakvasa, Trojanowski, Rosen, Boxer, Seeley.

Study supervision: Rosen, Boxer, Miller, Seeley, Gorno-Tempini.

Conflict of Interest Disclosures: Dr Boxer is funded by grants R01 AG038791 and U54NS092089 from the National Institutes of Health (NIH). Dr Seeley is funded by the John Douglas French Alzheimer Disease Foundation, Consortium for Frontotemporal Dementia Research, James S. McDonnell Foundation, Larry Hillblom Foundation; has received support for travel by the Alzheimer’s Association; and has received payment for lectures by the Alzheimer’s Association, American Academy of Neurology, and Novartis Korea. Dr Miller serves as board member on the John Douglas French Alzheimer Foundation and Larry L. Hillblom Foundation; serves as a consultant for TauRx Ltd, Allon Therapeutics, Siemens, Bristol-Myers Squibb, the Tau Consortium, and the Consortium for Frontotemporal Research; has received institutional support from Novartis; and is funded by a grant from the state of California. No other disclosures were reported.

Funding/Support: This work was supported by grants R01 NS050915, P01 AG019724, P50 AG023501, K24 AG045333-01, R01 AG032306, U54NS092089, and R01 AG038791 from the National Institute of Neurological Disorders and Stroke of the NIH; grant DHS 04-35516 from the State of California; grant 09-11410 DHS/ADP/ARCC from the Alzheimer Disease Research Center of California; the Larry L. Hillblom Foundation; the Koret Family Foundation; the Consortium for Frontotemporal Dementia Research; the McBean Family Foundation; and the Alfonso Martin Escudero Foundation. Dr Wilson is funded by grant R01 DC013270 from the NIH. Dr Rosen is funded by grants K24 AG045333 and R01 AG032306 from the NIH. Dr Seeley is funded by grant P50 AG1657303 from the NIH. Dr Miller is funded by grants P50AG023501, P01AG019724, and P50 AG1657303 from the NIH. Dr Gorno-Tempini is funded by grant NINDS R01 NS050915 from the NIH.

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

Additional Contributions: We thank the patients and their families for their dedication to the research, Ian Mackenzie, MD (Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver General Hospital), for assistance with one of the autopsies, and John Kornak, PhD (Department of Epidemiology and Biostatistics, University of California, San Francisco), for assistance in the neuroimaging analysis. Mr Mackenzie and Dr Kornak were not compensated for their contributions.

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