Josephs, Keith A.

Objective: To determine if subcortical, brainstem and cerebellar lesion pattern characteristics of the different types of tau‐negative frontotemporal lobar degeneration (FTLD) would be similar to neocortical and hippocampal patterns [Type 1 has neuronal cytoplasmic inclusions (NCI) and dystrophic neurites (DN), type 2 mainly DN, and type 3 mainly NCI (Mackenzie et al., 2006)]. Design/Methods: We analyzed 40 cases of tau‐negative FTLD from Mayo Clinic, Florida. For each case, 12 standardized sections covering 16 different brain regions or nuclei were sampled including neocortex, hippocampus, subcortical grey, brainstem and cerebellum. TDP‐43 immunohistochemistry was performed and abnormal immunoreactivity semiquantitated. Results: Thirty‐six cases were classified into one of the three types. For subcortical grey and brainstem regions, we did not see predominance of DN in type 2, and the density of NCI and DN were similar in type 3. Type 2 cases had significantly more NCI in basal ganglia compared to the other types (p<0.05). We found a trend that fine DN in hippocampal CA1 region was more frequent in type 1 compared to type 2 and 3 (p=0.07). A novel finding was that NCI were Pick body‐like in type 2 but granular‐like in type 3. Conclusion: This study extends the patterns of pathology previously described in the three variants of tau‐negative FTLD and shows how subcortical areas are affected by TDP‐43.

Objective: To determine whether all cases of tau‐negative frontotemporal lobar degeneration (FTLD) show abnormal TDP‐43 immunoreactivity. Design/methods: The neuropathological database at Mayo Clinic, Florida, was queried to identify all cases of tau‐negative FTLD. Forty cases were identified that underwent analysis with TDP‐43 immunohistochemistry. Cases without abnormal TDP‐43 immunoreactivity were further analyzed with H&E, PAS and silver stains, and with immunohistochemistry for phosphorylated tau, alpha‐synuclein, ubiquitin, neurofilament, alpha‐internexin and p62. Results: Of the 40 cases, 3 did not show abnormal TDP‐43 immunoreactivity. Cases 1 and 3 had clinical features of behavioral variant FTD while case 2 had features of the corticobasal syndrome. Case 3 had a positive family history. Case 1 had a pathological diagnosis of dementia lacking distinctive histology (DLDH) and case 2 basophilic inclusion body disease. Case 3 had ubiquitin‐positive but TDP‐43 negative neuronal inclusions and dystrophic neurites. Conclusion: Not all cases of tau‐negative FTLD have abnormal TDP‐43 immunoreactivity; basophilic inclusion body disease and DLDH are rare examples that do not. Given the positive family history and histological findings in case 3, there likely exists a yet to be identified gene and protein associated with tau negative FTLD.

Abstract Aims To assess the burden of transactive response DNA‐binding protein of 43 kDa (TDP‐43) inclusions in a unique cohort of old‐age patients with genetic frontotemporal lobar degeneration (gFTLD‐TDP) and compare these patients with sporadic old‐age individuals with TDP‐43, either in the presence of Alzheimer's disease (AD‐TDP) or in isolation (pure‐TDP). Methods The brain bank at Mayo Clinic‐Jacksonville was searched for cases ≥75 years old at death with TDP‐43 extending into middle frontal cortex. Cases were split into the following groups: (1) gFTLD‐TDP ( n = 15) with progranulin ( GRN )/ C9ORF72 mutations; (2) AD‐TDP ( n = 10)—cases with median Braak neurofibrillary tangle (NFT) stage VI, Thal phase V; (3) pure‐TDP ( n = 10)—cases with median Braak NFT stage I, Thal phase I. Clinical data were abstracted; TDP‐43 burden was calculated using digital pathology. Results Amnestic Alzheimer's dementia was the clinical diagnosis in ≥50% patients in each group. The distribution of TDP‐43 burden in gFTLD‐TDP and AD‐TDP, but not pure‐TDP, was limbic‐predominant targeting CA1 and subiculum. Patients with gFTLD‐TDP had higher burden in entorhinal cortex compared to AD‐TDP. TDP‐43 burden in middle frontal cortex did not differ between the three groups. Conclusions In old age it is challenging to clinically and pathologically differentiate gFTLD‐TDP from AD‐TDP and pure‐TDP‐43 based on burden. Like AD‐TDP, old age gFTLD‐TDP have a limbic predominant TDP‐43 distribution. The finding that amnestic Alzheimer's dementia was the most common clinical diagnosis regardless of group suggests that TDP‐43 directly and indirectly targets limbic regions.

Purpose This study investigated the relationship between word production rates (WPRs) and phonological error rates (PERs) in generative and responsive tasks in logopenic progressive aphasia (lvPPA). We examined whether a portion of the reduced WPR during generative tasks related directly to phonological impairments affecting PER on all tasks, irrespective of other task differences that contributed to WPR. Method Two cognitive psychometric models were hypothesized and fit to the total number of words produced and the number of phonological errors produced by 22 participants on 10 tasks. Bayesian inference was used to construct posterior distributions of participant ability and task difficulty parameters. Model fit statistics were compared. Association strengths for average generative WPR and average responsive PER were also evaluated with linear least-squares regression. Results Average generative WPR and average responsive PER were significantly associated ( r = −.77, p = .00002). A cognitive psychometric model that assumed reduced WPR on generative tasks reflects a portion of general phonological impairment yielded better fit than a model that ignored performance differences between generative and responsive tasks. Generative fluency tasks that elicited few phonological errors still reflected phonological impairment, via suppression. Individual participants were estimated to suppress between 62% and 93% of phonological errors on generative tasks that would have emerged on responsive tasks. Conclusions Suppression of phonological errors may present as decreased WPR on generative tasks in lvPPA. Failure to account for this suppression tendency may lead to overestimation of phonological ability. The findings indicate the need to account for task demands in assessing lvPPA.

Purpose This study describes motor speech disorders and associated communication limitations in six variants of progressive supranuclear palsy (PSP). Method The presence, nature, and severity of dysarthria and apraxia of speech (AOS) were documented, along with scores on the Apraxia of Speech Rating Scale–Version 3 (ASRS-3) for 77 (40 male and 37 female) patients with PSP. Clinician-estimated and patient-estimated communication limitations were rated using the Motor Speech Disorders Severity Rating (MSDSR) Scale and the Communicative Effectiveness Survey (CES), respectively. Descriptive statistics were calculated for each of these dependent variables. One-tailed t tests were conducted to test mean differences in ASRS-3 and CES between participants with and without AOS and between participants with and without dysarthria. Spearman rank correlations were calculated between ASRS-3 scores and clinical judgments of AOS and dysarthria severity and between MSDSR and CES ratings. Results Nine participants (12%) had normal speech. Eighty-seven percent exhibited dysarthria; hypokinetic and mixed hypokinetic–spastic dysarthria were observed most frequently. AOS was observed in 19.5% of participants across all variants, but in only 10% exclusive of the PSP speech and language variant. Nearly half presented with AOS in which neither phonetic nor prosodic features clearly predominated. The mean ASRS-3 score for participants with AOS was significantly higher than for those without and correlated strongly with clinician judgment of AOS severity. Mean ASRS-3 was higher for participants with dysarthria than for those without but correlated weakly with dysarthria severity. Mean MSDSR and CES ratings were lower in participants with AOS compared to those without and moderately correlated with each other. Conclusions Motor speech disorders that negatively impact communicative effectiveness are common in PSP and occur in many variants. This is the first description of motor speech disorders across PSP variants, setting the stage for future research characterizing neuroanatomical correlates, progression of motor speech disorders, and benefits of targeted interventions. Supplemental Material https://doi.org/10.23641/asha.14111837

Background: Transactive response DNA-binding protein of 43 kDa (TDP-43) is associated with memory impairment and overall cognitive decline. It is unclear how TDP-43 contributes to the rate of clinical decline. Objective: To determine whether cross-sectional and longitudinal cognitive and functional decline are associated with anatomical distribution of TDP-43 in the brain. Methods: Longitudinal clinical-neuropathologic autopsy cohort study of 385 initially cognitively normal/mildly impaired older adults prospectively followed until death. We investigated how TDP-43, amyloid-β (Aβ), tau neurofibrillary tangles (NFT), Lewy body disease (LBD), age, sex, and genetics are associated with clinical scores and rates of their longitudinal decline. Results: Of 385 participants, 260 (68%) had no TDP-43, 32 (8%) had TDP-43 limited to amygdala, and 93 (24%) had TDP-43 in the hippocampus and beyond. Higher TDP-43 and Braak NFT stages independently were associated with faster decline in global cognition, functional performance measured by Clinical Dementia Rating scale, and naming and episodic memory, whereas older age was associated with slower rate of cognitive, psychiatric, and functional decline. Cross-sectionally the following associations were found: higher TDP-43 and Braak NFT - worse performance; higher Aβ burden - worse global cognition, more behavioral changes, the latter also with higher LBD; older age - worse naming, lower frequency of behavioral changes; female sex - more impaired naming and better preserved episodic memory. There were no genetic associations. Conclusion: The association of TDP-43 distribution with decline in cognitive and functional performance suggests that TDP-43 is playing a role in the clinical progression to dementia. Further characterization of clinical features associated with TDP-43 can facilitate establishment of antemortem diagnosis.

Purpose Individuals with primary progressive apraxia of speech (PPAOS) have apraxia of speech (AOS) in which disruptions in articulation or prosody predominate the speech pattern, referred to, respectively, as phonetic or prosodic subtypes. Many develop aphasia and/or dysarthria. Past research has demonstrated that simple temporal acoustic measures are sensitive to the presence of AOS. The aim of this study was to describe the change in temporal acoustic measures over time and assess if specific patterns of AOS or co-occurring aphasia or dysarthria impact the rate of change over time. Method Durations for multiple productions of the words cat , catnip , catapult , and catastrophe , in an imitative speech task, were recorded for 73 patients, with two to six visits each. A linear mixed-effects model was used to assess the cross-sectional differences and longitudinal influence of AOS subtype and presence of aphasia/dysarthria on speech rate. Pearson correlations were calculated between rate measures and performance on other clinical measures. Results Cross-sectionally, patients with prosodic-predominant PPAOS produced words more slowly than those with phonetic-predominant PPAOS. Patients with either aphasia or dysarthria produced words more slowly than those without. Longitudinally, the speech rate of patients with phonetic-predominant PPAOS had a reduction of 0.5 syllables per second per year. Patients with prosodic-predominant AOS changed less quickly, as did those who developed aphasia. Dysarthria did not impact rate of change. There were strong associations between speech rate measures and other clinical indices of speech and language functioning. Conclusion Simple temporal acoustic measures may reflect the subtype of AOS (phonetic or prosodic predominant), serve as an index of progression of AOS, and inform prognostication relative to the presenting combination of speech and language features. Supplemental Material https://doi.org/10.23641/asha.13564724

AbstractTo examine the length of a hexanucleotide expansion in C9orf72, which represents the most frequent genetic cause of frontotemporal lobar degeneration and motor neuron disease, we employed a targeted amplification-free long-read sequencing technology: No-Amp sequencing. In our cross-sectional study, we assessed cerebellar tissue from 28 well-characterized C9orf72 expansion carriers. We obtained 3507 on-target circular consensus sequencing reads, of which 814 bridged the C9orf72 repeat expansion (23%). Importantly, we observed a significant correlation between expansion sizes obtained using No-Amp sequencing and Southern blotting (P = 5.0 × 10−4). Interestingly, we also detected a significant survival advantage for individuals with smaller expansions (P = 0.004). Additionally, we uncovered that smaller expansions were significantly associated with higher levels of C9orf72 transcripts containing intron 1b (P = 0.003), poly(GP) proteins (P = 1.3 × 10− 5), and poly(GA) proteins (P = 0.005). Thorough examination of the composition of the expansion revealed that its GC content was extremely high (median: 100%) and that it was mainly composed of GGGGCC repeats (median: 96%), suggesting that expanded C9orf72 repeats are quite pure. Taken together, our findings demonstrate that No-Amp sequencing is a powerful tool that enables the discovery of relevant clinicopathological associations, highlighting the important role played by the cerebellar size of the expanded repeat in C9orf72-linked diseases.