Longitudinal flortaucipir, metabolism and volume differ between phonetic and prosodic speech apraxia.

Progressive apraxia of speech (PAOS) is a neurodegenerative motor-speech disorder that most commonly arises from a four-repeat tauopathy. Recent studies have established that progressive apraxia of speech is not a homogenous disease but rather there are distinct subtypes: the phonetic subtype is characterized by distorted sound substitutions, the prosodic subtype by slow and segmented speech and the mixed subtype by a combination of both but lack of predominance of either. There is some evidence that cross-sectional patterns of neurodegeneration differ across subtypes, although it is unknown whether longitudinal patterns of neurodegeneration differ. We examined longitudinal patterns of atrophy on MRI, hypometabolism on 18F-fluorodeoxyglucose-PET and tau uptake on flortaucipir-PET in a large cohort of subjects with PAOS that had been followed for many years. Ninety-one subjects with PAOS (51 phonetic, 40 prosodic) were recruited by the Neurodegenerative Research Group. Of these, 54 (27 phonetic, 27 prosodic) returned for annual follow-up, with up to seven longitudinal visits (total visits analysed = 217). Volumes, metabolism and flortaucipir uptake were measured for subcortical and cortical regions, for all scans. Bayesian hierarchical models were used to model longitudinal change across imaging modalities with PAOS subtypes being compared at baseline, 4 years from baseline, and in terms of rates of change. The phonetic group showed smaller volumes and worse metabolism in Broca's area and the striatum at baseline and after 4 years, and faster rates of change in these regions, compared with the prosodic group. There was also evidence of faster spread of hypometabolism and flortaucipir uptake into the temporal and parietal lobes in the phonetic group. In contrast, the prosodic group showed smaller cerebellar dentate, midbrain, substantia nigra and thalamus volumes at baseline and after 4 years, as well as faster rates of atrophy, than the phonetic group. Greater hypometabolism and flortaucipir uptake were also observed in the cerebellar dentate and substantia nigra in the prosodic group. Mixed findings were observed in the supplementary motor area and precentral cortex, with no clear differences observed across phonetic and prosodic groups. These findings support different patterns of disease spread in PAOS subtypes, with corticostriatal patterns in the phonetic subtype and brainstem and thalamic patterns in the prosodic subtype, providing insight into the pathophysiology and heterogeneity of PAOS.

The yes-no reversal phenomenon in patients with primary progressive apraxia of speech.

Patients who have a yes-no reversal respond "yes" when they mean no and vice versa. The unintentional response can be made both verbally and with gestures (e.g., head shake or nod, thumbs up or down). Preliminary reports associate this phenomenon with 4-repeat tauopathies including primary progressive apraxia of speech (PPAOS), nonfluent/agrammatic primary progressive aphasia, and corticobasal syndrome; however, the significance and timing of this symptom relative to others are not well understood. Whereas some accounts associate yes-no reversals with other binary reversals (e.g., up/down, hot/cold) and attribute the reversals to disturbances of selection within the language system, others implicate more general inhibitory control processes. Here, we compared clinical and neuroimaging findings across 30 patients with PPAOS (apraxia of speech in the absence of aphasia), 15 of whom had a yes-no reversal complaint and 15 who did not. The two groups did not differ on any of the language or motor speech measures; however, patients who had the yes-no reversal received lower scores on the Frontal Assessment Battery and motor assessments. They also had greater hypometabolism in the left supplementary motor area and bilateral caudate nuclei on [18F]-fluorodeoxyglucose PET, but only the right caudate nucleus cluster survived correction for multiple comparisons. We interpret these results to suggest that the yes-no reversal phenomenon is associated with cognitive abilities that are supported by the frontostriatal network; more specifically, impaired response inhibition.

Comparing classic-onset corticobasal syndrome to speech/language-onset corticobasal syndrome.

INTRODUCTION: Patients with classic-onset corticobasal syndrome (CBS) present with asymmetric limb apraxia and parkinsonism. We have, however, observed patients who initially present with speech and/or language (SL) problems and several years later develop CBS (i.e., SL-onset CBS). We aimed to compare clinical, neuroimaging and pathological characteristics of classic-onset CBS with SL-onset CBS. METHODS: We conducted a retrospective cohort study of 62 patients who met criteria for CBS (17 presented with classic-onset CBS and 45 had SL-onset CBS). We compared demographics, clinical characteristics, and grey and white matter volume loss with SPM12 between groups and assessed pathology and corticobasal degeneration (CBD) pathological lesion counts in patients who had died and undergone autopsy. RESULTS: Median age at CBS diagnosis was 66.4 years in classic-onset CBS and 73.6 years in SL-onset CBS. Classic-onset CBS had higher frequencies of dystonia, myoclonus, and alien limb phenomenon, while SL-onset CBS had a higher frequency of vertical supranuclear gaze palsy. Both groups showed smaller frontoparietal volumes than controls, with SL-onset CBS having greater volume loss in the left supplementary motor area than classic-onset CBS. All three classic-onset CBS cases with autopsy (100 %) had CBD pathology while 8/21 of SL-onset CBS cases (38 %) had CBD. Pathological lesion burden (including astrocytic plaques) did not differ between classic-onset and SL-onset CBS. CONCLUSION: Classic-onset and SL-onset CBS appear to be different syndromes, with the former being a more profuse motor syndrome. The more widespread volume loss in SL-onset CBS likely reflects longer disease course.

Volumetric analysis of hippocampal subregions and subfields in left and right semantic dementia.

Two variants of semantic dementia are recognized based on the laterality of temporal lobe involvement: a left-predominant variant associated with verbal knowledge impairment and a right-predominant variant associated with behavioural changes and non-verbal knowledge loss. This cross-sectional clinicoradiologic study aimed to assess whole hippocampal, subregion, and/or subfield volume loss in semantic dementia versus controls and across its variants. Thirty-five semantic dementia participants and 15 controls from the Neurodegenerative Research Group at Mayo Clinic who had completed 3.0-T volumetric magnetic resonance imaging and 18F-fluorodeoxyglucose-positron emission tomography were included. Classification as left-predominant (n = 25) or right-predominant (n = 10) variant was based on temporal lobe hypometabolism. Volumes of hippocampal subregions (head, body, and tail) and subfields (parasubiculum, presubiculum, subiculum, cornu ammonis 1, cornu ammonis 3, cornu ammonis 4, dentate gyrus, molecular layer, hippocampal-amygdaloid transition area, and fimbria) were obtained using FreeSurfer 7. Subfield volumes were measured separately from head and body subregions. We fit linear mixed-effects models using log-transformed whole hippocampal/subregion/subfield volumes as dependent variables; age, sex, total intracranial volume, hemisphere and a group-by-hemisphere interaction as fixed effects; and subregion/subfield nested within hemisphere as a random effect. Significant results (P < 0.05) are hereby reported. At the whole hippocampal level, the dominant (predominantly involved) hemisphere of both variants showed 23-27% smaller volumes than controls. The non-dominant (less involved) hemisphere of the right-predominant variant also showed volume loss versus controls and the left-predominant variant. At the subregional level, both variants showed 17-28% smaller dominant hemisphere head, body, and tail than controls, with the right-predominant variant also showing 8-12% smaller non-dominant hemisphere head than controls and left-predominant variant. At the subfield level, the left-predominant variant showed 12-36% smaller volumes across all dominant hemisphere subfields and 14-15% smaller non-dominant hemisphere parasubiculum, presubiculum (head and body), subiculum (head) and hippocampal-amygdaloid transition area than controls. The right-predominant variant showed 16-49% smaller volumes across all dominant hemisphere subfields and 14-22% smaller parasubiculum, presubiculum, subiculum, cornu ammonis 3, hippocampal-amygdaloid transition area (all from the head) and fimbria of non-dominant hemisphere versus controls. Comparison of dominant hemispheres showed 16-29% smaller volumes of the parasubiculum, presubiculum (head) and fimbria in the right-predominant than left-predominant variant; comparison of non-dominant hemispheres showed 12-15% smaller cornu ammonis 3, cornu ammonis 4, dentate gyrus, hippocampal-amygdaloid transition area (all from the head) and cornu ammonis 1, cornu ammonis 3 and cornu ammonis 4 (all from the body) in the right-predominant variant. All hippocampal subregion/subfield volumes are affected in semantic dementia, although some are more affected in both dominant and non-dominant hemispheres of the right-predominant than the left-predominant variant by the time of presentation. Involvement of hippocampal structures is apparently more subregion dependent than subfield dependent, indicating possible superiority of subregion volumes as disease biomarkers.

Automated Hippocampal Subfield Volumetric Analyses in Atypical Alzheimer's Disease.

BACKGROUND: Posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) are two of the most common variants of atypical Alzheimer's disease (AD). Both PCA and LPA are associated with relative sparing of hippocampus compared to neocortex, although hippocampal atrophy is observed. It is unclear whether regional patterns of hippocampal subfield involvement differ between PCA and LPA, and whether they differ from typical AD. OBJECTIVE: To assess volume of specific subfields of the hippocampus in PCA, LPA, and typical AD. METHODS: Fifty-nine patients with PCA and 77 patients with LPA were recruited and underwent T1-weighted MRI and Pittsburgh Compound B (PiB) PET at Mayo Clinic. Thirty-six probable AD patients and 100 controls were identified from the Alzheimer's Disease Neuroimaging Initiative. Hippocampal subfield volumes were calculated using Freesurfer, and volumes were compared between PCA, LPA, AD, and controls using Kruskal-Wallis and Dunn tests. RESULTS: The LPA and PCA groups both showed the most striking abnormalities in CA4, presubiculum, molecular layer of the hippocampus, molecular and granule cell layers of the dentate gyrus, and the hippocampal-amygdala transition area, although atrophy was left-sided in LPA. PCA showed smaller volume of right presubiculum compared to LPA, with trends for smaller volumes of right parasubiculum and fimbria. LPA showed a trend for smaller volumes of left CA1 compared to PCA. The AD group showed smaller volumes of the right subiculum, CA1, and presubiculum compared to LPA. CONCLUSION: Patterns of hippocampal subfield atrophy differ across the different syndromic variants of AD.

The evolution of parkinsonism in primary progressive apraxia of speech: A 6-year longitudinal study.

INTRODUCTION: Primary progressive apraxia of speech (PPAOS) is a neurodegenerative syndrome in which patients present with an isolated motor speech disorder. Some PPAOS patients develop parkinsonism and other features of progressive supranuclear palsy (PSP) and/or corticobasal syndrome (CBS) over time. We aimed to assess the evolution of parkinsonian characteristics in PPAOS patients who had been followed yearly for at least six years. METHODS: From a large cohort of 46 PPAOS patients, eight were followed yearly for > 6-years in multiple NIH-funded grants. Parkinsonian and other features, including bradykinesia, tremor, rigidity, postural instability, apraxia, ocular motor function and cognition were assessed at each visit, and research criteria applied for PSP and CBS diagnosis. Neurological, speech-language test scores, and [18F]fluorodeoxyglucose PET (FDG-PET) and MRI midbrain volumes were assessed. RESULTS: A Parkinson's plus syndrome developed in all eight patients (100%). Bradykinesia was the earliest feature, followed by rigidity and postural instability. Tremor was not a significant feature. Parkinsonism, limb apraxia and ocular motor impairment tended to develop four-to-five years after onset with some patients having slight asymmetric parkinsonism. Six patients (75%) met research criteria for probable PSP, although only one for PSP-Richardson's syndrome; three patients met criteria for possible CBS. Slightly asymmetric, left-sided, hypometabolism was observed on FDG-PET, not matching asymmetry of Parkinsonism. Midbrain hypometabolism was absent-minimal. Three patients had progressive midbrain volumes in the PSP-Richardson's syndrome range. CONCLUSIONS: A Parkinson's plus syndrome may inevitably develop in PPAOS supporting PPAOS as an early presentation of a Parkinson's plus disorder.