Clinical Correlates of Alzheimer's Disease Cerebrospinal Fluid Analytes in Primary Progressive Aphasia.

Background: While primary progressive aphasia (PPA) is associated with frontotemporal lobar degeneration (FTLD) pathology due to tau or TDP, clinical-pathological studies also demonstrate many cases have Alzheimer's disease (AD) pathology. The logopenic variant of PPA (lvPPA) is most often associated with AD pathology, but this has proven to be the least reliable PPA to diagnose using published clinical criteria. In this study, we used cerebrospinal fluid (CSF) analytes to identify patients with likely AD pathology, and relate phenotypic features of lvPPA to CSF. Methods: We studied 46 PPA patients who had available CSF analytes, including 26 with a clinical diagnosis of lvPPA, 9 with non-fluent/agrammatic variant (naPPA), and 11 with semantic variant (svPPA). We identified patients with likely AD pathology using amyloid-beta 1-42 (Aß1-42) < 192 pg/ml and assessed MRI gray matter atrophy in these patients. Results: We found that 23 (49%) of 46 PPA patients have a low CSF Aß1-42 level consistent with AD pathology. Twenty-one (91%) of 23 patients had a lvPPA phenotype, and 18 (79%) of 23 cases with an elevated CSF Aß1-42 level did not have a lvPPA phenotype. Patients with a lvPPA phenotype demonstrated GM atrophy in the left lateral temporal lobe, and this was also seen in those with a CSF Aß1-42 level < 192 pg/ml. Conclusion: The lvPPA clinical phenotype may be a useful screen for CSF analytes that are a surrogate for likely AD pathology, and may help establish eligibility of these patients for disease-modifying treatment trials.

Divergent patterns of TDP-43 and tau pathologies in primary progressive aphasia.

OBJECTIVE: To measure postmortem burden of frontotemporal lobar degeneration (FTLD) with TDP-43 (FTLD-TDP) or tau (FTLD-Tau) proteinopathy across hemispheres in primary progressive aphasia (PPA) using digital histopathology and to identify clinicopathological correlates of these distinct proteinopathies. METHODS: In an autopsy cohort of PPA (FTLD-TDP = 13, FTLD-Tau = 14), we analyzed laterality and regional distribution of postmortem pathology, quantified using a validated digital histopathological approach, in available brain tissue from up to 8 cortical regions bilaterally. We related digital pathology to antemortem structural neuroimaging and specific clinical language features. RESULTS: Postmortem cortical pathology was left-lateralized in both FTLD-TDP (beta = -0.15, standard error [SE] = 0.05, p = 0.007) and FTLD-Tau (beta = -0.09, SE = 0.04, p = 0.015), but the degree of lateralization decreased with greater overall dementia severity before death (beta = -8.18, SE = 3.22, p = 0.015). Among 5 core pathology regions sampled, we found greatest pathology in left orbitofrontal cortex (OFC) in FTLD-TDP, which was greater than in FTLD-Tau (F = 47.07, df = 1,17, p < 0.001), and in left midfrontal cortex (MFC) in FTLD-Tau, which was greater than in FTLD-TDP (F = 19.34, df = 1,16, p < 0.001). Postmortem pathology was inversely associated with antemortem magnetic resonance imaging cortical thickness (beta = -0.04, SE = 0.01, p = 0.007) in regions matching autopsy sampling. Irrespective of PPA syndromic variant, single-word comprehension impairment was associated with greater left OFC pathology (t = -3.72, df = 10.72, p = 0.004) and nonfluent speech with greater left MFC pathology (t = -3.62, df = 12.00, p = 0.004) among the 5 core pathology regions. INTERPRETATION: In PPA, FTLD-TDP and FTLD-Tau have divergent anatomic distributions of left-lateralized postmortem pathology that relate to antemortem structural imaging and distinct language deficits. Although other brain regions may be implicated in neural networks supporting these complex language measures, our observations may eventually help to improve antemortem diagnosis of neuropathology in PPA. Ann Neurol 2019;85:630-643.

Perfusion alterations converge with patterns of pathological spread in transactive response DNA-binding protein 43 proteinopathies.

Amyotrophic lateral sclerosis (ALS) and the behavioral variant of frontotemporal dementia (bvFTD) commonly share the presence of transactive response DNA-binding protein 43 (TDP-43) inclusions. Structural magnetic resonance imaging studies demonstrated evidence for TDP-43 pathology spread, but while structural imaging usually reveals overt neuronal loss, perfusion imaging may detect more subtle neural activity alterations. We evaluated perfusion as an early marker for incipient pathology-associated brain alterations in TDP-43 proteinopathies. Cortical thickness (CT) and perfusion measurements were obtained in ALS (N = 18), pathologically and/or genetically confirmed bvFTD-TDP (N = 12), and healthy controls (N = 33). bvFTD showed reduced frontotemporal CT, hypoperfusion encompassing orbitofrontal and temporal cortices, and hyperperfusion in motor and occipital regions. ALS did not show reduced CT, but exhibited hypoperfusion in motor and temporal regions, and hyperperfusion in frontal and occipital cortices. Frontotemporal hypoperfusion and reduced CT correlated with cognitive and behavioral impairments as investigated using Mini-Mental State Examination and Philadelphia Brief Assessment of Cognition in bvFTD, and hypoperfusion in motor regions correlated with motor disability as measured by the ALS Functional Rating Scale-Revised in ALS. Hypoperfusion marked early pathologically involved regions, while hyperperfusion characterized regions of late pathological involvement. Distinct perfusion patterns may provide early markers of pathology distribution in TDP-43 proteinopathies.

Automatic measurement of prosody in behavioral variant FTD.

OBJECTIVE: To help understand speech changes in behavioral variant frontotemporal dementia (bvFTD), we developed and implemented automatic methods of speech analysis for quantification of prosody, and evaluated clinical and anatomical correlations. METHODS: We analyzed semi-structured, digitized speech samples from 32 patients with bvFTD (21 male, mean age 63 ± 8.5, mean disease duration 4 ± 3.1 years) and 17 matched healthy controls (HC). We automatically extracted fundamental frequency (f0, the physical property of sound most closely correlating with perceived pitch) and computed pitch range on a logarithmic scale (semitone) that controls for individual and sex differences. We correlated f0 range with neuropsychiatric tests, and related f0 range to gray matter (GM) atrophy using 3T T1 MRI. RESULTS: We found significantly reduced f0 range in patients with bvFTD (mean 4.3 ± 1.8 ST) compared to HC (5.8 ± 2.1 ST; p = 0.03). Regression related reduced f0 range in bvFTD to GM atrophy in bilateral inferior and dorsomedial frontal as well as left anterior cingulate and anterior insular regions. CONCLUSIONS: Reduced f0 range reflects impaired prosody in bvFTD. This is associated with neuroanatomic networks implicated in language production and social disorders centered in the frontal lobe. These findings support the feasibility of automated speech analysis in frontotemporal dementia and other disorders.

Longitudinal decline in speech production in Parkinson's disease spectrum disorders.

We examined narrative speech production longitudinally in non-demented (n=15) and mildly demented (n=8) patients with Parkinson's disease spectrum disorder (PDSD), and we related increasing impairment to structural brain changes in specific language and motor regions. Patients provided semi-structured speech samples, describing a standardized picture at two time points (mean±SD interval=38±24months). The recorded speech samples were analyzed for fluency, grammar, and informativeness. PDSD patients with dementia exhibited significant decline in their speech, unrelated to changes in overall cognitive or motor functioning. Regression analysis in a subset of patients with MRI scans (n=11) revealed that impaired language performance at Time 2 was associated with reduced gray matter (GM) volume at Time 1 in regions of interest important for language functioning but not with reduced GM volume in motor brain areas. These results dissociate language and motor systems and highlight the importance of non-motor brain regions for declining language in PDSD.

Narrative Organization Deficit in Lewy Body Disorders Is Related to Alzheimer Pathology.

Background: Day-to-day interactions depend on conversational narrative, and we examine here the neurobiological basis for difficulty organizing narrative discourse in patients with Lewy body disorders (LBD). Method: Narrative organization was examined in 56 non-aphasic LBD patients, including a non-demented cohort (n = 30) with Parkinson's disease (PD) or PD-Mild Cognitive Impairment PD-MCI,) and a cohort with mild dementia (n = 26) including PD-dementia (PDD) and dementia with Lewy bodies (DLB), with similar age and education but differing in MMSE (p < 0.001). We used a previously reported procedure that probes patients' judgments of the organization of brief, familiar narratives (e.g., going fishing, wrapping a present). A subgroup of 24 patients had MRI assessment of regional gray matter (GM) atrophy and cerebrospinal fluid (CSF) levels of biomarkers for Alzheimer's disease (AD) pathology, including beta amyloid (Aß), total-tau (t-tau), and phosphorylated-tau (p-tau). Results: Mildly demented LBD patients had a significant deficit judging narratives compared to non-demented patients, but this deficit was not correlated with MMSE. Regression analyses instead related narrative organization to regions of frontal GM atrophy, and CSF levels of Aß and t-tau associated with presumed AD pathology in these frontal regions. Conclusion: These findings are consistent with the hypothesis that CSF markers of AD pathology associated with frontal regions play a role in difficulty organizing narratives in LBD.