Lewy Body Disease is a Contributor to Logopenic Progressive Aphasia Phenotype.

OBJECTIVE: The objective of this study was to describe clinical features, [18 F]-fluorodeoxyglucose (FDG)-positron emission tomography (PET) metabolism and digital pathology in patients with logopenic progressive aphasia (LPA) and pathologic diagnosis of diffuse Lewy body disease (DLBD) and compare to patients with LPA with other pathologies, as well as patients with classical features of probable dementia with Lewy bodies (pDLB). METHODS: This is a clinicopathologic case-control study of 45 patients, including 20 prospectively recruited patients with LPA among whom 6 were diagnosed with LPA-DLBD. We analyzed clinical features and compared FDG-PET metabolism in LPA-DLBD to an independent group of patients with clinical pDLB and regional α-synuclein burden on digital pathology to a second independent group of autopsied patients with DLBD pathology and antemortem pDLB (DLB-DLBD). RESULTS: All patients with LPA-DLBD were men. Neurological, speech, and neuropsychological characteristics were similar across LPA-DLBD, LPA-Alzheimer's disease (LPA-AD), and LPA-frontotemporal lobar degeneration (LPA-FTLD). Genetic screening of AD, DLBD, and FTLD linked genes were negative with the exception of APOE ε4 allele present in 83% of LPA-DLBD patients. Seventy-five percent of the patients with LPA-DLBD showed a parietal-dominant pattern of hy pometabolism; LPA-FTLD - temporal-dominant pattern, whereas LPA-AD showed heterogeneous patterns of hypometabolism. LPA-DLBD had more asymmetrical hypometabolism affecting frontal lobes, with relatively spared occipital lobe in the nondominantly affected hemisphere, compared to pDLB. LPA-DLBD had minimal atrophy on gross brain examination, higher cortical Lewy body counts, and higher α-synuclein burden in the middle frontal and inferior parietal cortices compared to DLB-DLBD. INTERPRETATION: Whereas AD is the most frequent underlying pathology of LPA, DLBD can also be present and may contribute to the LPA phenotype possibly due to α-synuclein-associated functional impairment of the dominant parietal lobe. ANN NEUROL 2021;89:520-533.

Cross-Sectional and Longitudinal Assessment of Behavior in Primary Progressive Apraxia of Speech and Agrammatic Aphasia.

INTRODUCTION: Progressive agrammatic aphasia (PAA) can be associated with abnormal behaviors; however, it is unknown whether behaviors occur and/or are different in patients with primary progressive apraxia of speech (PPAOS). We aimed to compare baseline and longitudinal behavioral symptomatology between PPAOS, patients with PAA, and patients with both apraxia of speech and PAA (AOS-PAA). METHODS: We recruited 89 patients for this study, 40 with PPAOS, 11 with PAA, and 38 with AOS-PAA. Behavioral disturbances were evaluated using the frontal behavior inventory (FBI) which was also split into negative behaviors and disinhibition, and the 20-item behavioral assessment scale (20-BAS). Data analysis was performed using linear regression and linear mixed models. RESULTS: Of the 89 patients in the study, 54% were women and the mean age at onset was 68 years. All patients, regardless of diagnosis, endorsed at least one symptom on the FBI at baseline, most frequently verbal apraxia (100%), logopenia (95.6%), irritability (55.9%), and apathy (42.6%). On the 20-BAS, 47.6% of the patients endorsed at least one symptom, most commonly "crying more easily" (19.5%) and personality change (18.3%). PPAOS was the least behaviorally affected group, with differences between PPAOS and AOS-PAA mainly driven by negative behaviors as opposed to disinhibition for PPAOS and PAA. The behavioral metrics showed average sensitivity and specificity to distinguish between groups. Behavioral disturbances worsened over time although rate of behavioral change across groups was similar. CONCLUSION: Behavioral disturbances are more common and severe in patients with agrammatic aphasia with or without AOS compared to patients with isolated apraxia of speech.

Phonological Errors in Posterior Cortical Atrophy.

BACKGROUND: Posterior cortical atrophy (PCA) is an atypical variant of Alzheimer's disease (AD) that presents with visuospatial/perceptual deficits. PCA is characterized by atrophy in posterior brain regions, which overlaps with atrophy occurring in logopenic variant of primary progressive aphasia (lvPPA), another atypical AD variant characterized by language difficulties, including phonological errors. Language abnormalities have been observed in PCA, although the prevalence of phonological errors is unknown. We aimed to compare the frequency and severity of phonological errors in PCA and lvPPA and determine the neuroanatomical correlates of phonological errors and language abnormalities in PCA. METHODS: The presence and number of phonological errors were recorded during the Boston Naming Test and Western Aphasia Battery repetition subtest in 27 PCA patients and 27 age- and disease duration-matched lvPPA patients. Number of phonological errors and scores from language tests were correlated with regional gray matter volumes using Spearman correlations. RESULTS: Phonological errors were evident in 55% of PCA patients and 70% of lvPPA patients, with lvPPA having higher average number of errors. Phonological errors in PCA correlated with decreased left inferior parietal and lateral temporal volume. Naming and fluency were also associated with decreased left lateral temporal lobe volume. CONCLUSIONS: Phonological errors are common in PCA, although they are not as prevalent or severe as in lvPPA, and they are related to involvement of left temporoparietal cortex. This highlights the broad spectrum of clinical symptoms associated with AD and overlap between PCA and lvPPA.

A set of regulatory genes co-expressed in embryonic human brain is implicated in disrupted speech development.

Genetic investigations of people with impaired development of spoken language provide windows into key aspects of human biology. Over 15 years after FOXP2 was identified, most speech and language impairments remain unexplained at the molecular level. We sequenced whole genomes of nineteen unrelated individuals diagnosed with childhood apraxia of speech, a rare disorder enriched for causative mutations of large effect. Where DNA was available from unaffected parents, we discovered de novo mutations, implicating genes, including CHD3, SETD1A and WDR5. In other probands, we identified novel loss-of-function variants affecting KAT6A, SETBP1, ZFHX4, TNRC6B and MKL2, regulatory genes with links to neurodevelopment. Several of the new candidates interact with each other or with known speech-related genes. Moreover, they show significant clustering within a single co-expression module of genes highly expressed during early human brain development. This study highlights gene regulatory pathways in the developing brain that may contribute to acquisition of proficient speech.

Progressive agrammatic aphasia without apraxia of speech as a distinct syndrome.

Agrammatic aphasia affects grammatical language production and can result from a neurodegenerative disease. Although it typically presents with concomitant apraxia of speech, this is not always the case. Little is known about the clinical course and imaging features of patients that present with agrammatism in the absence of apraxia of speech, which we will refer to as progressive agrammatic aphasia. We aimed to make a detailed description of the longitudinal clinical, linguistic, and neuroimaging features of a cohort of 11 patients with progressive agrammatic aphasia to provide a complete picture of this syndrome. All patients underwent detailed speech and language, neurological and neuropsychological assessments, 3 T structural and diffusion tensor imaging MRI, 18F-fluorodeoxyglucose and Pittsburgh compound B PET. The 11 patients were matched by age and gender to 22 patients who had mixed apraxia of speech and agrammatism. The progressive agrammatic aphasia patients performed abnormally on tests of language, general cognition, executive function, and functional ability at baseline and declined in these measures over time. Only two patients eventually developed apraxia of speech, while parkinsonism was absent-to-mild throughout all visits for all patients. When compared to the patients with mixed apraxia of speech and agrammatism, the patients with progressive agrammatic aphasia performed better on tests of motor speech and parkinsonism but more poorly, and declined faster over time, on tests of general aphasia severity, agrammatism, and naming. The patients with progressive agrammatic aphasia also showed different neuroimaging abnormalities, with greater atrophy, hypometabolism and white matter tract degeneration in the prefrontal and anterior temporal lobes compared to patients with mixed apraxia of speech and agrammatism. These differences were more pronounced as the disease progressed. These results demonstrate that progressive agrammatic aphasia has a different clinical disease course and different underlying neuroanatomical abnormalities than patients with the more common syndrome of mixed agrammatism and apraxia of speech. This supports the distinction of progressive agrammatic aphasia and has implications for the classification of patients with agrammatic aphasia.

Longitudinal structural and molecular neuroimaging in agrammatic primary progressive aphasia.

The agrammatic variant of primary progressive aphasia affects normal grammatical language production, often occurs with apraxia of speech, and is associated with left frontal abnormalities on cross-sectional neuroimaging studies. We aimed to perform a detailed assessment of longitudinal change on structural and molecular neuroimaging to provide a complete picture of neurodegeneration in these patients, and to determine how patterns of progression compare to patients with isolated apraxia of speech (primary progressive apraxia of speech). We assessed longitudinal structural MRI, diffusion tensor imaging and 18F-fluorodeoxyglucose PET in 11 agrammatic aphasia subjects, 20 primary progressive apraxia of speech subjects, and 62 age and gender-matched controls with two serial assessments. Rates of change in grey matter volume and hypometabolism, and white matter fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity were assessed at the voxel-level and for numerous regions of interest. The greatest rates of grey matter atrophy in agrammatic aphasia were observed in inferior, middle, and superior frontal gyri, premotor and motor cortices, as well as medial temporal lobe, insula, basal ganglia, and brainstem compared to controls. Longitudinal decline in metabolism was observed in the same regions, with additional findings in medial and lateral parietal lobe. Diffusion tensor imaging changes were prominent bilaterally in inferior and middle frontal white matter and superior longitudinal fasciculus, as well as right inferior fronto-occipital fasciculus, superior frontal and precentral white matter. More focal patterns of degeneration of motor and premotor cortex were observed in primary progressive apraxia of speech. Agrammatic aphasia showed greater rates of grey matter atrophy, decline in metabolism, and white matter degeneration compared to primary progressive apraxia of speech in the left frontal lobe, predominantly inferior and middle frontal grey and white matter. Correlations were also assessed between rates of change on neuroimaging and rates of clinical decline. Progression of aphasia correlated with rates of degeneration in frontal and temporal regions within the language network, while progression of parkinsonism and limb apraxia correlated with degeneration of motor cortex and brainstem. These findings demonstrate that disease progression in agrammatic aphasia is associated with widespread neurodegeneration throughout regions of the language network, as well as connecting white matter tracts, but also with progression to regions outside of the language network that are responsible for the development of motor symptoms. The fact that patterns of progression differed from primary progressive apraxia of speech supports the clinical distinction of these syndromes.

Estimates of the prevalence of speech and motor speech disorders in persons with complex neurodevelopmental disorders.

Estimates of the prevalence of speech and motor speech disorders in persons with complex neurodevelopmental disorders (CND) can inform research in the biobehavioural origins and treatment of CND. The goal of this research was to use measures and analytics in a diagnostic classification system to estimate the prevalence of speech and motor speech disorders in convenience samples of speakers with one of eight types of CND. Audio-recorded conversational speech samples from 346 participants with one of eight types of CND were obtained from a database of participants recruited for genetic and behavioural studies of speech sound disorders (i.e., excluding dysfluency) during the past three decades. Data reduction methods for the speech samples included narrow phonetic transcription, prosody-voice coding, and acoustic analyses. Standardized measures were used to cross-classify participants' speech and motor speech status. Compared to the 17.8% prevalence of four types of motor speech disorders reported in a study of 415 participants with idiopathic Speech Delay (SD), 47.7% of the present participants with CND met criteria for one of four motor speech disorders, including Speech Motor Delay (25.1%), Childhood Dysarthria (13.3%), Childhood Apraxia of Speech (4.3%), and concurrent Childhood Dysarthria and Childhood Apraxia of Speech (4.9%). Findings are interpreted to indicate a substantial prevalence of speech disorders, and notably, a substantial prevalence of motor speech disorders in persons with some types of CND. We suggest that diagnostic classification information from standardized motor speech assessment protocols can contribute to research in the pathobiologies of CND. Abbreviations: 16p: 16p11.2 deletion and duplication syndrome; 22q: 22q11.2 deletion syndrome; ASD: Autism Spectrum Disorder; CAS: Childhood Apraxia of Speech; CD: Childhood Dysarthria; CND: Complex Neurodevelopmental Disorder; DS: Down syndrome; FXS: Fragile X syndrome; GAL: Galactosemia; IID: Idiopathic Intellectual Disability; MSD: Motor Speech Disorder; No MSD: No Motor Speech Disorder; NSA: Normal(ized) Speech Acquisition; PEPPER: Programs to Examine Phonetic and Phonologic Evaluation Records; PSD: Persistent Speech Delay; PSE: Persistent Speech Errors; SD: Speech Delay; SDCS: Speech Disorders Classification System; SDCSS: Speech Disorders Classification System Summary; SE: Speech Errors; SMD: Speech Motor Delay; SSD: Speech Sound Disorders; TBI: Traumatic Brain Injury.

Clinical and imaging progression over 10 years in a patient with primary progressive apraxia of speech and autopsy-confirmed corticobasal degeneration.

Primary progressive apraxia of speech (PPAOS) is a neurodegenerative disorder in which AOS is the sole presenting complaint. We report clinical and neuroimaging data spanning 10 years from disease onset-to-death in a 49 year-old male PPAOS patient, DY, who died with corticobasal degeneration. He presented with AOS with normal neuroimaging. Abnormalities in the caudate nucleus, supplementary motor area, cingulate, insula, and Broca's area were observed after five years, with involvement of motor cortex and development of agrammatism, Parkinsonism, and dysarthria three years later. Cognitive impairment and temporoparietal atrophy were late features. This data provides important insight into disease progression of corticobasal degeneration when presenting as PPAOS.

Neuropsychiatric symptoms in primary progressive aphasia and apraxia of speech.

AIM: To conduct a prospective analysis of the neuropsychiatric symptoms (NPS) across the three categories of primary progressive aphasia (PPA) and progressive apraxia of speech (PAOS), compare the prevalence and nature of the symptoms, and look at which symptoms could be helpful to better differentiate these PPA and PAOS categories. METHODS: A total of 106 consecutive patients with a diagnosis of semantic variant (n = 13), logopenic variant (n = 37), agrammatic variant (n = 15) or PAOS (n = 41) were included in this prospective study. The NPS were measured by the Neuropsychiatric Inventory Questionnaire. RESULTS: There were 65 patients with PPA and 41 with PAOS diagnosis. The most distinguishing features between the two groups were anxiety, apathy, aberrant motor behavior and appetite, while among the subtypes of PPA they were disinhibition and appetite changes. PPA and PAOS patients initially exhibited depression, but with increased disease duration, PAOS patients showed apathy (55.5%) while PPA patients showed disinhibition (28.6%) and aberrant motor behavior (14.3%). CONCLUSION: Mood symptoms like anxiety and appetite changes are more likely to be present at initial stages of PPA, whereas behavioral symptoms like aberrant motor behavior and apathy are likely to occur early in PAOS. The NPS seem to evolve with the progression of the disease in both PPA and PAOS.

Dominant frontotemporal dementia mutations in 140 cases of primary progressive aphasia and speech apraxia.

BACKGROUND: Mutations in three genes [chromosome 9 open-reading-frame 72 (C9ORF72); microtubule-associated protein tau (MAPT) and progranulin (GRN)] account for the vast majority of familial, and a proportion of sporadic, frontotemporal dementia (FTD) cases. Progressive apraxia of speech (PAOS) is a type of FTD characterized by speech production deficits without a known cause. METHODS: We therefore assessed for genetic mutations in C9ORF72, MAPT and GRN in 40 prospectively recruited PAOS patients. For comparison, we also assessed these mutations in 100 patients with primary progressive aphasia (PPA), including logopenic PPA (n = 54), nonfluent/agrammatic PPA (n = 17), semantic PPA (n = 16), and unclassifiable PPA (n = 13). RESULTS: The mean age at onset of PAOS patients was 66.7 years (± 9.3); 50% were women. Ten patients (25%) had ≥1 first-degree relative with a neurodegenerative disease. No mutations were found in any PAOS patient. In comparison, 36% of the PPA patients had a family history and 5 (5%) had a genetic mutation detected: MAPT (n = 0), GRN (n = 3) and C9ORF72 (n = 2). CONCLUSIONS: Although limited by an overrepresentation of logopenic PPA, which frequently predicts Alzheimer's disease pathology, this study suggests that mutations in the three genes most commonly associated with FTD are not associated with PAOS and are not commonly associated with PPA.

Neuropsychological Profiles Differ among the Three Variants of Primary Progressive Aphasia.

The objective of this study was to describe the neuropsychological profiles of the three variants of primary progressive aphasia (PPA). Based on a comprehensive speech and language evaluation, 91 subjects were classified as logopenic (lvPPA=51), semantic (svPPA=13), or agrammatic (agPPA=27). All subjects completed a separate neuropsychological evaluation assessing verbal and visual memory, processing speed, executive function, and visuospatial function. The groups did not differ on demographic variables or on measures of disease duration or aphasia severity. There were group differences on aspects of learning and memory, as well as aspects of executive and visuospatial functions, primarily with the lvPPA group performing lower than the agPPA and svPPA groups. The agPPA group showed subtle deficits consistent with frontal lobe impairment, whereas neurocognitive weaknesses in the svPPA group were restricted to temporal lobe functions. The pattern of neurocognitive dysfunction in lvPPA suggests disease involvement of frontal lobe functions in addition to temporoparietal functions. These neurocognitive findings emphasize the value of a comprehensive neuropsychological evaluation of individuals who present with primary language disturbance, given the pattern of cognitive deficits may provide additive information for differentiating these clinical syndromes.

The evolution of primary progressive apraxia of speech.

Primary progressive apraxia of speech is a recently described neurodegenerative disorder in which patients present with an isolated apraxia of speech and show focal degeneration of superior premotor cortex. Little is known about how these individuals progress over time, making it difficult to provide prognostic estimates. Thirteen subjects with primary progressive apraxia of speech underwent two serial comprehensive clinical and neuroimaging evaluations 2.4 years apart [median age of onset = 67 years (range: 49-76), seven females]. All underwent detailed speech and language, neurological and neuropsychological assessments, and magnetic resonance imaging, diffusion tensor imaging and (18)F-fluorodeoxyglucose positron emission tomography at both baseline and follow-up. Rates of change of whole brain, ventricle, and midbrain volumes were calculated using the boundary-shift integral and atlas-based parcellation, and rates of regional grey matter atrophy were assessed using tensor-based morphometry. White matter tract degeneration was assessed on diffusion-tensor imaging at each time-point. Patterns of hypometabolism were assessed at the single subject-level. Neuroimaging findings were compared with a cohort of 20 age, gender, and scan-interval matched healthy controls. All subjects developed extrapyramidal signs. In eight subjects the apraxia of speech remained the predominant feature. In the other five there was a striking progression of symptoms that had evolved into a progressive supranuclear palsy-like syndrome; they showed a combination of severe parkinsonism, near mutism, dysphagia with choking, vertical supranuclear gaze palsy or slowing, balance difficulties with falls and urinary incontinence, and one was wheelchair bound. Rates of whole brain atrophy (1.5% per year; controls = 0.4% per year), ventricular expansion (8.0% per year; controls = 3.3% per year) and midbrain atrophy (1.5% per year; controls = 0.1% per year) were elevated (P ≤ 0.001) in all 13, compared to controls. Increased rates of brain atrophy over time were observed throughout the premotor cortex, as well as prefrontal cortex, motor cortex, basal ganglia and midbrain, while white matter tract degeneration spread into the splenium of the corpus callosum and motor cortex white matter. Hypometabolism progressed over time in almost all subjects. These findings demonstrate that some subjects with primary progressive apraxia of speech will rapidly evolve and develop a devastating progressive supranuclear palsy-like syndrome ∼ 5 years after onset, perhaps related to progressive involvement of neocortex, basal ganglia and midbrain. These findings help improve our understanding of primary progressive apraxia of speech and provide some important prognostic guidelines.

Psychiatric Autoimmunity: N-Methyl-D-Aspartate Receptor IgG and Beyond.

BACKGROUND: Descriptions of psychiatric autoimmunity beyond N-methyl-D-aspartate (NMDA) receptor encephalitis are sparse. OBJECTIVE: To report the autoimmune psychiatric spectrum currently recognized in Mayo Clinic practice. METHODS: Medical record review, testing of stored serum and cerebrospinal fluid for IgGs reactive with synaptic receptors and ion channels, neuronal nuclear and cytoplasmic antigens (including glutamic acid decarboxylase 65-kDa isoform) and case-control comparison were conducted. Patients were categorized into group 1, all adult psychiatric inpatients tested for neural autoantibodies (2002-2011; n = 213), and group 2, all Mayo NMDA receptor IgG-positive patients (2009-2013; n = 13); healthy control subjects were also included (n = 173). RESULTS: In group 1, at least 1 serum autoantibody (but not NMDA receptor IgG) was detected in 36 of 213 psychiatric inpatients. In total, 12 patients were determined retrospectively to have high-likelihood autoimmune encephalitic diagnoses. The most commonly detected autoantibody specificities were voltage-gated potassium channel ([Kv1] VGKC) complex (6) and calcium channel (P/Q type or N type; 5). Symptoms seen were as follows: depressive (8), anxious (7), psychotic (7), disorganized (5), suicidal (3), manic (1) and catatonic (1). In group 2, among 13 NMDA receptor IgG-positive patients, 12 had encephalitis; their psychiatric symptoms were as follows: depressive (9), catatonic (9), disorganized (8), anxious (8), psychotic (7), manic (6), and suicidal (3). Catatonic symptoms were more common in the 12 NMDA receptor IgG-positive patients than in the 12 group 1 patients with high likelihood of encephalitis (p = 0.002). Antibody positivities were usually low positive in value among healthy controls (12 of 16 vs 3 of 12 group 1 encephalitis cases, p = 0.025). NMDA receptor IgG was not detected in any healthy control subject. CONCLUSIONS: A spectrum of psychiatric autoimmunity beyond NMDA-R IgG may be under-recognized. Diagnosis is facilitated by combining results of comprehensive psychiatric, laboratory, radiologic, and electrophysiologic evaluations.

APOE ε4 influences ß-amyloid deposition in primary progressive aphasia and speech apraxia.

BACKGROUND: Apolipoprotein E ε4 (APOE ε4) is a risk factor for ß-amyloid deposition in Alzheimer's disease dementia. Its influence on ß-amyloid deposition in speech and language disorders, including primary progressive aphasia (PPA), is unclear. METHODS: One hundred thirty subjects with PPA or progressive speech apraxia underwent APOE genotyping and Pittsburgh compound B (PiB) PET scanning. The relationship between APOE ε4 and PiB status, as well as severity and regional distribution of PiB, was assessed. RESULTS: Forty-five subjects had an APOE ε4 allele and 60 subjects were PiB-positive. The odds ratio for a subject with APOE ε4 being PiB-positive compared with a subject without APOE ε4 being PiB-positive was 10.2 (95% confidence interval, 4.4-25.5; P < .0001). The APOE ε4 allele did not influence regional PiB distribution or severity. CONCLUSION: APOE ε4 increases the risk of ß-amyloid deposition in PPA and progressive speech apraxia but does not influence regional ß-amyloid distribution or severity.

Microbleeds in the logopenic variant of primary progressive aphasia.

BACKGROUND: Microbleeds have been associated with Alzheimer's disease (AD), although it is unclear whether they occur in atypical presentations of AD, such as the logopenic variant of primary progressive aphasia (lvPPA). We aimed to assess the presence and clinical correlates of microbleeds in lvPPA. METHODS: Thirteen lvPPA subjects underwent 3T T2*-weighted and fluid-attenuated inversion recovery magnetic resonance imaging and Pittsburgh compound B (PiB) positron emission tomography imaging. Microbleeds were identified on manual review and assigned a regional location. Total and regional white matter hyperintensity (WMH) burden was measured. RESULTS: Microbleeds were observed in four lvPPA subjects (31%), most commonly in the frontal lobe. Subjects with microbleeds were older, more likely female, and had a greater burden of WMH than those without microbleeds. The regional distribution of microbleeds did not match the regional distribution of WMH. All cases were PiB positive. CONCLUSIONS: Microbleeds occur in approximately one third of subjects with lvPPA, with older women at the highest risk.

Elevated occipital ß-amyloid deposition is associated with widespread cognitive impairment in logopenic progressive aphasia.

BACKGROUND: Most subjects with logopenic variant of primary progressive aphasia (lvPPA) have ß-amyloid (Aß) deposition on Pittsburgh Compound B positron emission tomography (PiB-PET), usually affecting prefrontal and temporoparietal cortices, with less occipital involvement. OBJECTIVES: To assess clinical and imaging features in lvPPA subjects with unusual topographic patterns of Aß deposition with highest uptake in occipital lobe. METHODS: Thirty-three lvPPA subjects with Aß deposition on PiB-PET were included in this case-control study. Line plots of regional PiB uptake were created, including frontal, temporal, parietal and occipital regions, for each subject. Subjects in which the line sloped downwards in occipital lobe (lvPPA-low), representing low uptake, were separated from those where the line sloped upwards in occipital lobe (lvPPA-high), representing unusually high occipital uptake compared to other regions. Clinical variables, atrophy on MRI, hypometabolism on 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), and presence and distribution of microbleeds and white matter hyperintensities (WMHs) were assessed. RESULTS: Seventeen subjects (52%) were classified as lvPPA-high. Mean occipital PiB uptake in lvPPA-high was higher than all other regions and higher than all regions in lvPPA-low. The lvPPA-high subjects performed more poorly on cognitive testing, including executive and visuospatial testing, but the two groups did not differ in aphasia severity. Proportion of microbleeds and WMH was higher in lvPPA-high than lvPPA-low. Parietal hypometabolism was greater in lvPPA-high than lvPPA-low. CONCLUSIONS: Unusually high occipital Aß deposition is associated with widespread cognitive impairment and different imaging findings in lvPPA. These findings help explain clinical heterogeneity in lvPPA and suggest that Aß influences severity of overall cognitive impairment but not aphasia.

Characterizing a neurodegenerative syndrome: primary progressive apraxia of speech.

Apraxia of speech is a disorder of speech motor planning and/or programming that is distinguishable from aphasia and dysarthria. It most commonly results from vascular insults but can occur in degenerative diseases where it has typically been subsumed under aphasia, or it occurs in the context of more widespread neurodegeneration. The aim of this study was to determine whether apraxia of speech can present as an isolated sign of neurodegenerative disease. Between July 2010 and July 2011, 37 subjects with a neurodegenerative speech and language disorder were prospectively recruited and underwent detailed speech and language, neurological, neuropsychological and neuroimaging testing. The neuroimaging battery included 3.0 tesla volumetric head magnetic resonance imaging, [(18)F]-fluorodeoxyglucose and [(11)C] Pittsburg compound B positron emission tomography scanning. Twelve subjects were identified as having apraxia of speech without any signs of aphasia based on a comprehensive battery of language tests; hence, none met criteria for primary progressive aphasia. These subjects with primary progressive apraxia of speech included eight females and four males, with a mean age of onset of 73 years (range: 49-82). There were no specific additional shared patterns of neurological or neuropsychological impairment in the subjects with primary progressive apraxia of speech, but there was individual variability. Some subjects, for example, had mild features of behavioural change, executive dysfunction, limb apraxia or Parkinsonism. Voxel-based morphometry of grey matter revealed focal atrophy of superior lateral premotor cortex and supplementary motor area. Voxel-based morphometry of white matter showed volume loss in these same regions but with extension of loss involving the inferior premotor cortex and body of the corpus callosum. These same areas of white matter loss were observed with diffusion tensor imaging analysis, which also demonstrated reduced fractional anisotropy and increased mean diffusivity of the superior longitudinal fasciculus, particularly the premotor components. Statistical parametric mapping of the [(18)F]-fluorodeoxyglucose positron emission tomography scans revealed focal hypometabolism of superior lateral premotor cortex and supplementary motor area, although there was some variability across subjects noted with CortexID analysis. [(11)C]-Pittsburg compound B positron emission tomography binding was increased in only one of the 12 subjects, although it was unclear whether the increase was actually related to the primary progressive apraxia of speech. A syndrome characterized by progressive pure apraxia of speech clearly exists, with a neuroanatomic correlate of superior lateral premotor and supplementary motor atrophy, making this syndrome distinct from primary progressive aphasia.

The Apraxia of Speech Rating Scale: Reliability, Validity, and Utility.

PURPOSE: The purpose of this study was to examine the interrater reliability and validity of the Apraxia of Speech Rating Scale (ASRS-3.5) as an index of the presence and severity of apraxia of speech (AOS) and the prominence of several of its important features. METHOD: Interrater reliability was assessed for 27 participants. Validity was examined in a cohort of 308 participants (120 with and 188 without progressive AOS) through item analysis; item-Total score correlations; correlations among ASRS Total score and component subscores and independent clinical ratings of AOS, dysarthria and aphasia severity, intelligibility, and articulatory errors, as well as years postonset and age; and regression models assessing item and Total score prediction of AOS presence. RESULTS: Interrater reliability was good or excellent for most items and excellent for the Total score. Item and Total score analyses revealed good separation of participants with versus without AOS. Inter-item and item-Total score correlations were generally moderately high as were correlations between the ASRS Total score and independent ratings of AOS severity, intelligibility, and articulatory errors. The Total score was not meaningfully correlated with ratings of aphasia and dysarthria severity, years postonset, or age. Total scores below 7 and above 10 revealed excellent diagnostic sensitivity and specificity for AOS. The presence of eight or more abnormal features was also highly predictive of AOS presence. CONCLUSIONS: The ASRS-3.5 is a reliable and valid scale for identifying the presence and severity of AOS and its predominant features. It has excellent sensitivity to AOS presence and excellent specificity relative to aphasia and dysarthria in patients with neurodegenerative disease. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.21817584.

Novel candidate genes and regions for childhood apraxia of speech identified by array comparative genomic hybridization.

PURPOSE: The goal of this study was to identify new candidate genes and genomic copy-number variations associated with a rare, severe, and persistent speech disorder termed childhood apraxia of speech. Childhood apraxia of speech is the speech disorder segregating with a mutation in FOXP2 in a multigenerational London pedigree widely studied for its role in the development of speech-language in humans. METHODS: A total of 24 participants who were suspected to have childhood apraxia of speech were assessed using a comprehensive protocol that samples speech in challenging contexts. All participants met clinical-research criteria for childhood apraxia of speech. Array comparative genomic hybridization analyses were completed using a customized 385K Nimblegen array (Roche Nimblegen, Madison, WI) with increased coverage of genes and regions previously associated with childhood apraxia of speech. RESULTS: A total of 16 copy-number variations with potential consequences for speech-language development were detected in 12 or half of the 24 participants. The copy-number variations occurred on 10 chromosomes, 3 of which had two to four candidate regions. Several participants were identified with copy-number variations in two to three regions. In addition, one participant had a heterozygous FOXP2 mutation and a copy-number variation on chromosome 2, and one participant had a 16p11.2 microdeletion and copy-number variations on chromosomes 13 and 14. CONCLUSION: Findings support the likelihood of heterogeneous genomic pathways associated with childhood apraxia of speech.

Encoding, memory, and transcoding deficits in Childhood Apraxia of Speech.

A central question in Childhood Apraxia of Speech (CAS) is whether the core phenotype is limited to transcoding (planning/programming) deficits or if speakers with CAS also have deficits in auditory-perceptual encoding (representational) and/or memory (storage and retrieval of representations) processes. We addressed this and other questions using responses to the Syllable Repetition Task (SRT) [Shriberg, L. D., Lohmeier, H. L., Campbell, T. F., Dollaghan, C. A., Green, J. R., & Moore, C. A. (2009). A nonword repetition task for speakers with misarticulations: The syllable repetition task (SRT). Journal of Speech, Language, and Hearing Research, 52, 1189-1212]. The SRT was administered to 369 individuals in four groups: (a) typical speech-language (119), (b) speech delay-typical language (140), (c) speech delay-language impairment (70), and (d) idiopathic or neurogenetic CAS (40). CAS participants had significantly lower SRT competence, encoding, memory, and transcoding scores than controls. They were 8.3 times more likely than controls to have SRT transcoding scores below 80%. We conclude that speakers with CAS have speech processing deficits in encoding, memory, and transcoding. The SRT currently has moderate diagnostic accuracy to identify transcoding deficits, the signature feature of CAS.