Clinical marker for Alzheimer disease pathology in logopenic primary progressive aphasia.
ABSTRACT: OBJECTIVE:To determine whether logopenic features of phonologic loop dysfunction reflect Alzheimer disease (AD) neuropathology in primary progressive aphasia (PPA). METHODS:We performed a retrospective case-control study of 34 patients with PPA with available autopsy tissue. We compared baseline and longitudinal clinical features in patients with primary AD neuropathology to those with primary non-AD pathologies. We analyzed regional neuroanatomic disease burden in pathology-defined groups using postmortem neuropathologic data. RESULTS:A total of 19/34 patients had primary AD pathology and 15/34 had non-AD pathology (13 frontotemporal lobar degeneration, 2 Lewy body disease). A total of 16/19 (84%) patients with AD had a logopenic spectrum phenotype; 5 met published criteria for the logopenic variant (lvPPA), 8 had additional grammatical or semantic deficits (lvPPA+), and 3 had relatively preserved sentence repetition (lvPPA-). Sentence repetition was impaired in 68% of patients with PPA with AD pathology; forward digit span (DF) was impaired in 90%, substantially higher than in non-AD PPA (33%, p < 0.01). Lexical retrieval difficulty was common in all patients with PPA and did not discriminate between groups. Compared to non-AD, PPA with AD pathology had elevated microscopic neurodegenerative pathology in the superior/midtemporal gyrus, angular gyrus, and midfrontal cortex (p < 0.01). Low DF scores correlated with high microscopic pathologic burden in superior/midtemporal and angular gyri (p ? 0.03). CONCLUSIONS:Phonologic loop dysfunction is a central feature of AD-associated PPA and specifically correlates with temporoparietal neurodegeneration. Quantitative measures of phonologic loop function, combined with modified clinical lvPPA criteria, may help discriminate AD-associated PPA.
Project description:The differentiation of subtypes of primary progressive aphasia (PPA) remains challenging. We aimed to identify optimum neuropsychological measures for characterizing PPA, to examine the relationship between behavioural change and subtypes of PPA and to determine whether characteristic profiles of language, working memory, and behavioural changes occur in PPA. Forty-seven patients with PPA and multi-domain Alzheimer's disease (AD) together with 19 age-matched controls underwent a large battery of working memory and language tests. We found that simple tasks of sentence ordering, narrative production, and buccofacial praxis were particularly useful in differentiating non-fluent/agrammatic variant PPA (nfvPPA) from other PPA subtypes, whereas a test of single word comprehension was useful in detecting semantic dementia (SD). No individual tests were discriminating for logopenic variant PPA (lvPPA) relative to nfvPPA. LvPPA and multidomain AD exhibited similar language profiles. A principal components analysis revealed that characteristic PPA profiles extended beyond the realms of language, in particular, the presence of apraxia in nfvPPA, behavioural changes in SD, and working memory deficits in lvPPA. These findings suggest that not all tests are equally discriminatory for PPA and highlight the importance of a test profile in differentiating PPA. These results also support the view that lvPPA is a focal form of AD and emphasize the difficulties classifying lvPPA.
Project description: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:The logopenic variant of primary progressive aphasia (PPA) is characterised by impaired sentence repetition and word retrieval difficulties. Post mortem studies, amyloid imaging and CSF tau/A? measurements suggest Alzheimer's disease (AD) pathology as the underlying cause. Relatively little is known about patterns of progression in patients with the logopenic variant of PPA. 21 patients (3 with post mortem confirmation of AD and 5 with positive amyloid PIB-PET scans) were studied with longitudinal T1-weighted MR imaging (mean interscan interval 1.2years) using volumetric analysis and voxel-based morphometry (VBM). Baseline imaging showed asymmetrical (left greater than right) involvement of the posterior superior temporal and inferior parietal lobes as well as posterior cingulate and medial temporal lobes. The whole brain rate of volume loss was 2.0% per year with a greater rate of left hemisphere atrophy (2.3%/year) than right hemisphere (1.6%/year). Longitudinal VBM analysis showed increasing involvement of other areas in the left hemisphere (temporal, parietal, frontal and caudate) and atrophy of areas in the right hemisphere that had been involved earlier in the disease in the left hemisphere, particularly posterior cingulate/precuneus. With disease progression there was worsening of anomia, sentence repetition and sentence comprehension but consistent with the spread of imaging changes also deficits in single word comprehension, single word repetition and verbal memory. This study shows that the logopenic variant of PPA remains an asymmetrical disease, with spread through the left hemisphere language network but also involvement to a lesser degree of regions in the right hemisphere that mirror the earlier left hemisphere changes.
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: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 identify features of primary progressive aphasia (PPA) associated with Alzheimer disease (AD) neuropathology. A related objective was to determine whether logopenic PPA is a clinical marker for AD.A total of 139 prospectively enrolled participants with a root diagnosis of PPA constituted the reference set. Those with autopsy or biomarker evidence of AD, and who had been evaluated at mild disease stages (Aphasia Quotient ?85), were included (n = 19). All had quantitative language testing and APOE genotyping. Fifteen had MRI morphometry.Impaired word-finding was the universal presenting complaint in the aphasic AD group. PPA clinical subtype was logopenic (n = 13) and agrammatic (n = 6). Fluency, repetition, naming, and grammaticality ranged from preserved to severely impaired. All had relative preservation of word comprehension. Eight of the 15 aphasic participants with AD showed no appreciable cortical atrophy at the individual level on MRI. As a group, atrophy was asymmetrically concentrated in the left perisylvian cortex. APOE ?4 frequency was not elevated.There is a close, but not obligatory, association between logopenic PPA and AD. No language measure, with the possible exception of word comprehension, can confirm or exclude AD in PPA. Biomarkers are therefore essential for diagnosis. Asymmetry of cortical atrophy and normal APOE ?4 prevalence constitute deviations from typical AD. These and additional neuropathologic features suggest that AD has biological subtypes, one of which causes PPA. Better appreciation of this fact should promote the inclusion of individuals with PPA and positive AD biomarkers into relevant clinical trials.
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.
Project description:Logopenic primary progressive aphasia (lvPPA) typically results from underlying Alzheimer's disease, but subjects have been reported that do not show beta-amyloid (A?) deposition. These subjects do not differ on neurological and speech-language testing from A?-positive lvPPA, but they impressionistically show increased grammatical deficits. We performed a quantitative linguistic analysis of grammatical characteristics in A?-negative lvPPA compared to A?-positive lvPPA and agrammatic PPA, which is characterized by increased grammatical difficulties. A?-negative lvPPA used fewer function words and correct verbs but more syntactic and semantic errors compared to A?-positive lvPPA. These measures did not differ between A?-negative lvPPA and agPPA. Both lvPPA cohorts showed a higher mean length of utterance, more complex sentences, and fewer nouns than agPPA. A?-negative lvPPA subjects appear unique and share linguistic features with both agPPA and A?-positive lvPPA. Quantitative language analysis in lvPPA may be able to distinguish those with and without A? deposition.
Project description:Behavioral assessment has been investigated in frontotemporal lobar degeneration and Alzheimer's disease, but has not been explored extensively in subtypes of primary progressive aphasia (PPA). We explored the ability of a modified version of the Frontal Behavioral Inventory (FBI-mod) to discriminate between patients with distinct subtypes of PPA and patients with mild cognitive impairment (MCI). We hypothesized that individuals with nonfluent agrammatic PPA (nfaPPA) would have higher negative behavior scores than other groups and that individuals with semantic variant PPA (svPPA) would have higher disinhibition scores than other groups. Family members and/or caregivers of 120 individuals with PPA and MCI (mean age 69.54+8.75 years; 65 (54%) female; education 16.06±2.68 years; disease duration 46.47±34.26 months) completed the FBI-mod [logopenic PPA (lvPPA) n = 40. nfaPPA n = 29, svPPA n = 27, MCI n = 24]. The groups were not significantly different in age, gender, education, or disease duration. There were no significant differences between the groups for negative behaviors (p = 0.72) and disinhibition scores (p = 0.14). When comparing negative and disinhibition scores (in percent), negative scores were significantly higher in all groups (p < 0.001). When comparing subtest items, there was a pairwise difference between lvPPA and svPPA for restlessness (lvPPA < svPPA, p = 0.02, after adjusting for multiple between-group comparisons). There was a significant difference in the proportion of severe neglect between the groups with lvPPA having a lower proportion than the other two variants (p = 0.05), and there was a significant difference in the proportion of severe poor judgment between the groups with lvPPA also having a lower proportion than nfaPPA (p = 0.04). This study reveals the greater negative behavioral disturbance than disinhibition in the PPA and MCI groups of similar age and duration since onset and identifies different profiles for some specific behaviors for the PPA groups. These findings may have clinical and practical implications.
Project description:Logopenic primary progressive aphasia (lvPPA) is a progressive language disorder characterized by anomia, difficulty repeating complex sentences, and phonological errors. The majority, although not all, lvPPA patients have underlying Alzheimer's disease. We aimed to determine whether clinical or neuroimaging features differ according to the deposition of A? on Pittsburgh-compound B PET in lvPPA. Clinical features, patterns of atrophy on MRI, hypometabolism on FDG-PET, and white matter tract degeneration were compared between six PiB-negative and 20 PiB-positive lvPPA patients. PiB-negative patients showed more asymmetric left-sided patterns of atrophy, hypometabolism and white matter tract degeneration, with greater left anteromedial temporal and medial prefrontal involvement, than PiB-positive patients. PiB-positive patients showed greater involvement of right temporoparietal and frontal lobes. There was very little evidence for clinical differences between the groups. Strikingly asymmetric neuroimaging findings with relatively preserved right hemisphere may provide clues that AD pathology is absent in lvPPA.