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

ABSTRACT: 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.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.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.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.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.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.

SUBMITTER: Santos-Santos MA

PROVIDER: S-EPMC4924620 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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

Santos-Santos Miguel A MA Mandelli Maria Luisa ML Binney Richard J RJ Ogar Jennifer J Wilson Stephen M SM Henry Maya L ML Hubbard H Isabel HI Meese Minerva M Attygalle Suneth S Rosenberg Lynne L Pakvasa Mikhail M Trojanowski John Q JQ Grinberg Lea T LT Rosen Howie H Boxer Adam L AL Miller Bruce L BL Seeley William W WW Gorno-Tempini Maria Luisa ML

JAMA neurology 20160601 6

<h4>Importance</h4>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.<h4>Objective</h4>To characterize the neurological, cognitive, and neuroimaging features of patients with nfvPPA-in whom either PSP or CBD was eventually confirmed at autopsy ...[more]

PMID: 27111692

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Project description:Corticobasal degeneration (CBD) is a clinically heterogeneous tauopathy, which has overlapping clinicopathologic and genetic characteristics with progressive supranuclear palsy (PSP). This study aimed to elucidate whether transactive response DNA-binding protein of 43 kDa (TDP-43) pathology contributes to clinicopathologic heterogeneity of CBD. Paraffin-embedded sections of the midbrain, pons, subthalamic nucleus, and basal forebrain from 187 autopsy-confirmed CBD cases were screened with immunohistochemistry for phospho-TDP-43. In cases with TDP-43 pathology, additional brain regions (i.e., precentral, cingulate, and superior frontal gyri, hippocampus, medulla, and cerebellum) were immunostained. Hierarchical clustering analysis was performed based on the topographical distribution and severity of TDP-43 pathology, and clinicopathologic and genetic features were compared between the clusters. TDP-43 pathology was observed in 45% of CBD cases, most frequently in midbrain tegmentum (80% of TDP-43-positive cases), followed by subthalamic nucleus (69%). TDP-43-positive CBD was divided into TDP-limited (52%) and TDP-severe (48%) by hierarchical clustering analysis. TDP-severe patients were more likely to have been diagnosed clinically as PSP compared to TDP-limited and TDP-negative patients (80 vs 32 vs 30%, P < 0.001). The presence of downward gaze palsy was the strongest factor for the antemortem diagnosis of PSP, and severe TDP-43 pathology in the midbrain tectum was strongly associated with downward gaze palsy. In addition, tau burden in the olivopontocerebellar system was significantly greater in TDP-positive than TDP-negative CBD. Genetic analyses revealed that MAPT H1/H1 genotype frequency was significantly lower in TDP-severe than in TDP-negative and TDP-limited CBD (65 vs 89 vs 91%, P < 0.001). The homozygous minor allele frequencies in GRN rs5848 and TMEM106B rs3173615 were not significantly different between the three groups. In conclusion, the present study indicates that CBD with severe TDP-43 pathology is a distinct clinicopathologic subtype of CBD, characterized by PSP-like clinical presentations, severe tau pathology in the olivopontocerebellar system, and low frequency of MAPT H1 haplotype.

Project description:ImportanceDespite being characterized as a disorder of language production, nonfluent/agrammatic variant primary progressive aphasia (nfvPPA) is frequently associated with auditory symptoms. However, to our knowledge, peripheral auditory function has not been defined in this condition.ObjectiveTo assess peripheral hearing function in individuals with nfvPPA compared with healthy older individuals and patients with Alzheimer disease (AD).Design, setting, and participantsThis cross-sectional single-center study was conducted at the Dementia Research Centre of University College London between August 2015 and July 2018. A consecutive cohort of patients with nfvPPA and patients with AD were compared with healthy control participants. No participant had substantial otological or cerebrovascular disease; all eligible patients fulfilling diagnostic criteria and able to comply with audiometry were included.Main outcomes and measuresWe measured mean threshold sound levels required to detect pure tones at frequencies of 500, 1000, 2000, 4000, and 6000 Hz in the left and right ears separately; these were used to generate better-ear mean and worse-ear mean composite hearing threshold scores and interaural difference scores for each participant. All analyses were adjusted for participant age.ResultsWe studied 19 patients with nfvPPA (9 female; mean [SD] age, 70.3 [9.0] years), 20 patients with AD (9 female; mean [SD] age, 69.4 [8.1] years) and 34 control participants (15 female; mean [SD] age, 66.7 [6.3] years). The patients with nfvPPA had significantly higher scores than control participants on better-ear mean scores (patients with nfvPPA: mean [SD], 36.3 [9.4] decibels [dB]; control participants: 28.9 [7.3] dB; age-adjusted difference, 5.7 [95% CI, 1.4-10.0] dB; P = .01) and worse-ear mean scores (patients with nfvPPA: 42.2 [11.5] dB; control participants: 31.7 [8.1] dB; age-adjusted difference, 8.5 [95% CI, 3.6-13.4] dB; P = .001). The patients with nfvPPA also had significantly higher better-ear mean scores than patients with AD (patients with AD: mean [SD] 31.1 [7.5] dB; age-adjusted difference, 4.8 [95% CI, 0.0-9.6] dB; P = .048) and worse-ear mean scores (patients with AD: mean [SD], 33.8 [8.2] dB; age-adjusted difference, 7.8 [95% CI, 2.4-13.2] dB; P = .005). The difference scores (worse-ear mean minus better-ear mean) were significantly higher in the patients with nfvPPA (mean [SD], 5.9 [5.2] dB) than control participants (mean [SD], 2.8 [2.2] dB; age-adjusted difference, 2.8 [95% CI, 0.9-4.7] dB; P = .004) and patients with AD (mean [SD], 2.8 [2.1] dB; age-adjusted difference, 3.0 [95% CI, 0.9-5.1] dB; P = .005).Conclusions and relevanceIn this study, patients with nfvPPA performed worse on pure-tone audiometry than healthy older individuals or patients with AD, and the difference was not attributable to age or general disease factors. Cases of nfvPPA were additionally associated with increased functional interaural audiometric asymmetry. These findings suggest conjoint peripheral afferent and more central regulatory auditory dysfunction in individuals with nfvPPA.

Dataset Information

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

Publications

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

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