Typical and atypical pathology in primary progressive aphasia variants.
ABSTRACT: To characterize in vivo signatures of pathological diagnosis in a large cohort of patients with primary progressive aphasia (PPA) variants defined by current diagnostic classification.Extensive clinical, cognitive, neuroimaging, and neuropathological data were collected from 69 patients with sporadic PPA, divided into 29 semantic (svPPA), 25 nonfluent (nfvPPA), 11 logopenic (lvPPA), and 4 mixed PPA. Patterns of gray matter (GM) and white matter (WM) atrophy at presentation were assessed and tested as predictors of pathological diagnosis using support vector machine (SVM) algorithms.A clinical diagnosis of PPA was associated with frontotemporal lobar degeneration (FTLD) with transactive response DNA-binding protein (TDP) inclusions in 40.5%, FTLD-tau in 40.5%, and Alzheimer disease (AD) pathology in 19% of cases. Each variant was associated with 1 typical pathology; 24 of 29 (83%) svPPA showed FTLD-TDP type C, 22 of 25 (88%) nfvPPA showed FTLD-tau, and all 11 lvPPA had AD. Within FTLD-tau, 4R-tau pathology was commonly associated with nfvPPA, whereas Pick disease was observed in a minority of subjects across all variants except for lvPPA. Compared with pathologically typical cases, svPPA-tau showed significant extrapyramidal signs, greater executive impairment, and severe striatal and frontal GM and WM atrophy. nfvPPA-TDP patients lacked general motor symptoms or significant WM atrophy. Combining GM and WM volumes, SVM analysis showed 92.7% accuracy to distinguish FTLD-tau and FTLD-TDP pathologies across variants.Each PPA clinical variant is associated with a typical and most frequent cognitive, neuroimaging, and neuropathological profile. Specific clinical and early anatomical features may suggest rare and atypical pathological diagnosis in vivo. Ann Neurol 2017;81:430-443.
Project description:To identify early cognitive and neuroimaging features of sporadic nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA) caused by frontotemporal lobar degeneration (FTLD) subtypes.We prospectively collected clinical, neuroimaging, and neuropathologic data in 11 patients with sporadic nfvPPA with FTLD-tau (nfvPPA-tau, n = 9) or FTLD-transactive response DNA binding protein pathology of 43 kD type A (nfvPPA-TDP, n = 2). We analyzed patterns of cognitive and gray matter (GM) and white matter (WM) atrophy at presentation in the whole group and in each pathologic subtype separately. We also considered longitudinal clinical data.At first evaluation, regardless of pathologic FTLD subtype, apraxia of speech (AOS) was the most common cognitive feature and atrophy involved the left posterior frontal lobe. Each pathologic subtype showed few distinctive features. At presentation, patients with nfvPPA-tau presented with mild to moderate AOS, mixed dysarthria with prominent hypokinetic features, clear agrammatism, and atrophy in the GM of the left posterior frontal regions and in left frontal WM. While speech and language deficits were prominent early, within 3 years of symptom onset, all patients with nfvPPA-tau developed significant extrapyramidal motor signs. At presentation, patients with nfvPPA-TDP had severe AOS, dysarthria with spastic features, mild agrammatism, and atrophy in left posterior frontal GM only. Selective mutism occurred early, when general neurologic examination only showed mild decrease in finger dexterity in the right hand.Clinical features in sporadic nfvPPA caused by FTLD subtypes relate to neurodegeneration of GM and WM in frontal motor speech and language networks. We propose that early WM atrophy in nfvPPA is suggestive of FTLD-tau pathology while early selective GM loss might be indicative of FTLD-TDP.
Project description:OBJECTIVE:To estimate the prevalence of amyloid positivity, defined by positron emission tomography (PET)/cerebrospinal fluid (CSF) biomarkers and/or neuropathological examination, in primary progressive aphasia (PPA) variants. METHODS:We conducted a meta-analysis with individual participant data from 1,251 patients diagnosed with PPA (including logopenic [lvPPA, n?=?443], nonfluent [nfvPPA, n?=?333], semantic [svPPA, n?=?401], and mixed/unclassifiable [n?=?74] variants of PPA) from 36 centers, with a measure of amyloid-? pathology (CSF [n?=?600], PET [n?=?366], and/or autopsy [n?=?378]) available. The estimated prevalence of amyloid positivity according to PPA variant, age, and apolipoprotein E (ApoE) ?4 status was determined using generalized estimating equation models. RESULTS:Amyloid-? positivity was more prevalent in lvPPA (86%) than in nfvPPA (20%) or svPPA (16%; p?<?0.001). Prevalence of amyloid-? positivity increased with age in nfvPPA (from 10% at age 50 years to 27% at age 80 years, p?<?0.01) and svPPA (from 6% at age 50 years to 32% at age 80 years, p?<?0.001), but not in lvPPA (p?=?0.94). Across PPA variants, ApoE ?4 carriers were more often amyloid-? positive (58.0%) than noncarriers (35.0%, p?<?0.001). Autopsy data revealed Alzheimer disease pathology as the most common pathologic diagnosis in lvPPA (76%), frontotemporal lobar degeneration-TDP-43 in svPPA (80%), and frontotemporal lobar degeneration-TDP-43/tau in nfvPPA (64%). INTERPRETATION:This study shows that the current PPA classification system helps to predict underlying pathology across different cohorts and clinical settings, and suggests that age and ApoE genotype should be considered when interpreting amyloid-? biomarkers in PPA patients. Ann Neurol 2018;84:737-748.
Project description:<h4>Introduction</h4>The Frontotemporal Lobar Degeneration Module (FTLD-MOD) includes a neuropsychological battery designed to assess the clinical features of FTLD, although much is unknown about its utility. We investigated FTLD-MOD and Uniform Data Set 3.0 (UDS) language tests for differential diagnosis and disease monitoring.<h4>Methods</h4>Linear regressions compared baseline performances in 1655 National Alzheimer's Coordinating Center participants (behavioral variant frontotemporal dementia (bvFTD, n = 612), semantic variant primary progressive aphasia (svPPA, n = 168), non-fluent/agrammatic variant PPA (nfvPPA, n = 168), logopenic variant PPA (lvPPA, n = 109), and controls (n = 581)). Sample sizes to detect treatment effects were estimated using longitudinal data.<h4>Results</h4>Among PPAs, the FTLD-MOD language tasks and UDS Multilingual Naming Test accurately discriminated svPPA. Number Span Forward best discriminated lvPPA; Phonemic:Semantic Fluency ratio was excellent for nfvPPA classification. UDS fluency and naming measures required the smallest sample size to detect meaningful change.<h4>Discussion</h4>The FTLD-MOD and UDS differentiated among PPA subtypes. UDS 3.0 measures performed best for longitudinal monitoring.
Project description:Digital pathology is increasingly prominent in neurodegenerative disease research, but variability in immunohistochemical staining intensity between staining batches prevents large-scale comparative studies. Here we provide a statistically rigorous method to account for staining batch effects in a large sample of brain tissue with frontotemporal lobar degeneration with tau inclusions (FTLD-Tau, N = 39) or TDP-43 inclusions (FTLD-TDP, N = 53). We analyzed the relationship between duplicate measurements of digital pathology, i.e., percent area occupied by pathology (%AO) for grey matter (GM) and white matter (WM), from two distinct staining batches. We found a significant difference in duplicate measurements from distinct staining batches in FTLD-Tau (mean difference: GM = 1.13 ± 0.44, WM = 1.28 ± 0.56; p < 0.001) and FTLD-TDP (GM = 0.95 ± 0.66, WM = 0.90 ± 0.77; p < 0.001), and these measurements were linearly related (R-squared [Rsq]: FTLD-Tau GM = 0.92, WM = 0.92; FTLD-TDP GM = 0.75, WM = 0.78; p < 0.001 all). We therefore used linear regression to transform %AO from distinct staining batches into equivalent values. Using a train-test set design, we examined transformation prerequisites (i.e., Rsq) from linear-modeling in training sets, and we applied equivalence factors (i.e., beta, intercept) to independent testing sets to determine transformation outcomes (i.e., intraclass correlation coefficient [ICC]). First, random iterations (×100) of linear regression showed that smaller training sets (N = 12-24), feasible for prospective use, have acceptable transformation prerequisites (mean Rsq: FTLD-Tau ?0.9; FTLD-TDP ?0.7). When cross-validated on independent complementary testing sets, in FTLD-Tau, N = 12 training sets resulted in 100% of GM and WM transformations with optimal transformation outcomes (ICC ? 0.8), while in FTLD-TDP N = 24 training sets resulted in optimal ICC in testing sets (GM = 72%, WM = 98%). We therefore propose training sets of N = 12 in FTLD-Tau and N = 24 in FTLD-TDP for prospective transformations. Finally, the transformation enabled us to significantly reduce batch-related difference in duplicate measurements in FTLD-Tau (GM/WM: p < 0.001 both) and FTLD-TDP (GM/WM: p < 0.001 both), and to decrease the necessary sample size estimated in a power analysis in FTLD-Tau (GM:-40%; WM: -34%) and FTLD-TDP (GM: -20%; WM: -30%). Finally, we tested generalizability of our approach using a second, open-source, image analysis platform and found similar results. We concluded that a small sample of tissue stained in duplicate can be used to account for pre-analytical variability such as staining batch effects, thereby improving methods for future studies.
Project description:Frontotemporal lobar degeneration (FTLD) is most commonly associated with TAR-DNA binding protein (TDP-43) or tau pathology at autopsy, but there are no in vivo biomarkers reliably discriminating between sporadic cases. As disease-modifying treatments emerge, it is critical to accurately identify underlying pathology in living patients so that they can be entered into appropriate etiology-directed clinical trials. Patients with tau inclusions (FTLD-TAU) appear to have relatively greater white matter (WM) disease at autopsy than those patients with TDP-43 (FTLD-TDP). In this paper, we investigate the ability of white matter (WM) imaging to help discriminate between FTLD-TAU and FTLD-TDP during life using diffusion tensor imaging (DTI).Patients with autopsy-confirmed disease or a genetic mutation consistent with FTLD-TDP or FTLD-TAU underwent multimodal T1 volumetric MRI and diffusion weighted imaging scans. We quantified cortical thickness in GM and fractional anisotropy (FA) in WM. We performed Eigenanatomy, a statistically robust dimensionality reduction algorithm, and used leave-one-out cross-validation to predict underlying pathology. Neuropathological assessment of GM and WM disease burden was performed in the autopsy-cases to confirm our findings of an ante-mortem GM and WM dissociation in the neuroimaging cohort.ROC curve analyses evaluated classification accuracy in individual patients and revealed 96% sensitivity and 100% specificity for WM analyses. FTLD-TAU had significantly more WM degeneration and inclusion severity at autopsy relative to FTLD-TDP.These neuroimaging and neuropathological investigations provide converging evidence for greater WM burden associated with FTLD-TAU, and emphasise the role of WM neuroimaging for in vivo discrimination between FTLD-TAU and FTLD-TDP.
Project description:BACKGROUND AND PURPOSE:There are three distinct subtypes of primary progressive aphasia (PPA): the nonfluent/agrammatic variant (nfvPPA), the semantic variant (svPPA), and the logopenic variant (lvPPA). We sought to characterize the pattern of [¹⁸F]-THK5351 retention across all three subtypes and determine the topography of [¹⁸F]-THK5351 retention correlated with each neurolinguistic score. METHODS:We enrolled 50 participants, comprising 13 PPA patients (3 nfvPPA, 5 svPPA, and 5 lvPPA) and 37 subjects with normal cognition (NC) who underwent 3.0-tesla magnetic resonance imaging, [¹⁸F]-THK5351 positron-emission tomography scans, and detailed neuropsychological tests. The PPA patients additionally participated in extensive neurolinguistic tests. Voxel-wise and region-of-interest-based analyses were performed to analyze [¹⁸F]-THK5351 retention. RESULTS:The nfvPPA patients exhibited higher [¹⁸F]-THK5351 retention in the the left inferior frontal and precentral gyri. In svPPA patients, [¹⁸F]-THK5351 retention was elevated in the anteroinferior and lateral temporal cortices compared to the NC group (left>right). The lvPPA patients exhibited predominant [¹⁸F]-THK5351 retention in the inferior parietal, lateral temporal, and dorsolateral prefrontal cortices, and the precuneus (left>right). [¹⁸F]-THK5351 retention in the left inferior frontal area was associated with lower fluency scores. Comprehension was correlated with [¹⁸F]-THK5351 retention in the left temporal cortices. Repetition was associated with [¹⁸F]-THK5351 retention in the left inferior parietal and posterior temporal areas, while naming difficulty was correlated with retention in the left fusiform and temporal cortices. CONCLUSIONS:The pattern of [¹⁸F]-THK5351 retention was well matched with clinical and radiological findings for each PPA subtype, in agreement with the anatomical and functional location of each language domain.
Project description:Objective: Behavioral variant frontotemporal dementia (bvFTD), is commonly considered the cognitive presentation of the frontotemporal dementia-motor neuron disease (FTD-MND) spectrum disorder. We evaluated the prevalence of primary progressive aphasia in a series of pathologically confirmed cases of FTD-MND spectrum. Methods: Pathologically confirmed cases of frontotemporal lobar degeneration-motor neuron disease (FTLD-MND) were obtained from the UCSF brain bank. Cases were analyzed for presence of language impairment via retrospective chart review of research visits that include neurologic exam, in-depth cognitive testing and magnetic resonance imaging (MRI) imaging. Forty one cases were included. Thirty two were diagnosed with FTD-MND, while nine cases were diagnosed as MND-only from clinical evaluation. Results: Ten FTLD-MND cases (31%) presented with prominent or isolated language involvement consistent with a diagnosis of primary progressive aphasia (PPA), which we called progressive aphasia with motor neuron disease (PA-MND). Of these, three cases that mirrored the non-fluent variant of PPA (nfvPPA) were named nfvPA-MND. The imaging pattern of these nfvPA-MND showed atrophy strictly confined to the frontal and anterior temporal language cortical areas. Another group of seven cases that resembled patients with the semantic variant PPA (svPPA) were named svPA-MND. The group of svPPA-MND on imaging analysis showed selective atrophy of the temporal lobe and orbitofrontal cortex. Conclusions: Language impairment was a frequent phenotype of FTD-MND associated with focal atrophy patterns within the language networks. This data suggest patients with FTD-MND can present quite often with language phenotype of nfvPPA and svPPA, as opposed to exclusive bvFTD symptoms.
Project description:OBJECTIVE:To identify overlapping and unique grey (GM) and white matter (WM) signatures within the frontotemporal lobar degeneration (FTLD) continuum, and discriminate likely FTLD-TAU and FTLD-TDP patients using structural and diffusion tensor (DT) magnetic resonance imaging (MRI). METHODS:T1-weighted and DT MRI were collected from 121 subjects: 35 motor neuron disease (MND), 14 behavioral variant of frontotemporal dementia, 12 semantic and 11 nonfluent primary progressive aphasia, 21 progressive supranuclear palsy syndrome patients, and 28 healthy controls. Patterns of GM atrophy were established using voxel-based morphometry. Tract-based spatial statistics was used to perform a WM voxelwise analysis of mean diffusivity and fractional anisotropy. RESULTS:In all clinical FTLD phenotypes, the pattern of WM damage was more distributed than that of GM atrophy. All patient groups, with the exception of MND cases with a pure motor syndrome, shared a focal GM atrophy centered around the dorsolateral and medial frontal cortex and a largely overlapping pattern of WM damage involving the genu and body of the corpus callosum and ventral frontotemporal and dorsal frontoparietal WM pathways. Surrounding this common area, phenotype (symptom)-specific GM and WM regions of damage were found in each group. CONCLUSIONS:In the FTLD spectrum, WM disruption is more severe than GM damage. Frontal cortex and WM pathways represent the common target of neurodegeneration in these conditions. The topographic pattern of damage supports a "prion-like" protein propagation through WM connections as underlying mechanism of the stereotyped progression of FTLD.
Project description:OBJECTIVES:To test the ability of the Northwestern Anagram Test-Italian (NAT-I) to distinguish between the non-fluent/agrammatic (nfv-) and phonological/logopenic (lv-) variants of primary progressive aphasia (PPA), and to determine the relationship between NAT-I variables and brain integrity in PPA patients. METHODS:13 nfvPPA and 8 lvPPA patients underwent the 44-item-version of NAT-I and brain MRI. The NAT-I was also administered to six patients with the semantic variant (sv) PPA to sample performance in cases with no grammatical deficits. Performances were recorded and compared between patient groups. Receiver Operating Characteristic curve analysis assessed the ability of NAT-I to discriminate nfvPPA and lvPPA. The correlation between anatomical changes and NAT-I variables were assessed. A shortened (22-item)-version of NAT-I was also tested for classification ability. RESULTS:Participants with NfvPPA performed more poorly than lvPPA patients on canonical and non-canonical sentences. NAT-I non-canonical sentence and total scores achieved the highest diagnostic accuracy in discriminating the two patient groups (area under the curve: .93 and .91, respectively). SvPPA participants showed performances similar to lvPPA. NAT-I variables correlated with the integrity of the left inferior frontal gyrus and the body of the corpus callosum. The NAT-I 22-item-version total and non-canonical sentences scores reached diagnostic accuracy comparable to the full version. CONCLUSIONS:The NAT-I, in particular the measure of non-canonical syntax, is an effective tool for distinguishing nfvPPA and lvPPA patients and correlated with the integrity of crucial brain regions implicated in syntactic processing. The 22-item-brief version of NAT-I is suitable for clinical practice and research.
Project description:To relate fractional anisotropy (FA) changes associated with the semantic and logopenic variants of primary progressive aphasia (PPA) to measures of lexical retrieval.We collected neuropsychological testing, volumetric magnetic resonance imaging, and diffusion-weighted imaging on semantic variant PPA (svPPA) (n?=?11) and logopenic variant PPA (lvPPA) (n?=?13) patients diagnosed using published criteria. We also acquired neuroimaging data on a group of demographically comparable healthy seniors (n?=?34). FA was calculated and analyzed using a white matter (WM) tract-specific analysis approach. This approach utilizes anatomically guided data reduction to increase sensitivity and localizes results within canonically defined tracts. We used non-parametric, cluster-based statistical analysis to relate language performance to FA and determine regions of reduced FA in patients.We found widespread FA reductions in WM for both variants of PPA. FA was related to both confrontation naming and category naming fluency performance in left uncinate fasciculus and corpus callosum in svPPA and left superior and inferior longitudinal fasciculi in lvPPA.SvPPA and lvPPA are associated with distinct disruptions of a large-scale network implicated in lexical retrieval, and the WM disease in each phenotype may contribute to language impairments including lexical retrieval.