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, [18F]-fluorodeoxyglucose and [11C] 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 [18F]-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. [11C]-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.

This report describes three extensions to a classification system for pediatric speech sound disorders termed the Speech Disorders Classification System (SDCS). Part I describes a classification extension to the SDCS to differentiate motor speech disorders from speech delay and to differentiate among three subtypes of motor speech disorders. Part II describes the Madison Speech Assessment Protocol (MSAP), an approximately two-hour battery of 25 measures that includes 15 speech tests and tasks. Part III describes the Competence, Precision, and Stability Analytics (CPSA) framework, a current set of approximately 90 perceptual- and acoustic-based indices of speech, prosody, and voice used to quantify and classify subtypes of Speech Sound Disorders (SSD). A companion paper, Shriberg, Fourakis, et al. (2010) provides reliability estimates for the perceptual and acoustic data reduction methods used in the SDCS. The agreement estimates in the companion paper support the reliability of SDCS methods and illustrate the complementary roles of perceptual and acoustic methods in diagnostic analyses of SSD of unknown origin. Examples of research using the extensions to the SDCS described in the present report include diagnostic findings for a sample of youth with motor speech disorders associated with galactosemia (Shriberg, Potter, & Strand, 2010) and a test of the hypothesis of apraxia of speech in a group of children with autism spectrum disorders (Shriberg, Paul, Black, & van Santen, 2010). All SDCS methods and reference databases running in the PEPPER (Programs to Examine Phonetic and Phonologic Evaluation Records; [Shriberg, Allen, McSweeny, & Wilson, 2001]) environment will be disseminated without cost when complete.

Objective: We assessed whether clinical and imaging features of subjects with apraxia of speech (AOS) more severe than aphasia (dominant AOS) are more similar to agrammatic primary progressive aphasia (agPPA) or to primary progressive AOS (PPAOS).Methods: Sixty-seven subjects (PPAOS 5 18, dominant AOS 5 10, agPPA 5 9, age-matched controls 5 30) who all had volumetric MRI, diffusion tensor imaging, F18-fluorodeoxyglucose and C11-labeled Pittsburgh compound B (PiB)-PET scanning, as well as neurologic and speech and language assessments, were included in this case-control study. AOS was classified as either type 1, predominated by sound distortions and distorted sound substitutions, or type 2, predominated by syllabically segmented prosodic speech patterns. Results:The dominant AOS subjects most often had AOS type 2, similar to PPAOS. In contrast, agPPA subjects most often had type 1 (p 5 0.01). Both dominant AOS and PPAOS showed focal imaging abnormalities in premotor cortex, whereas agPPA showed widespread involvement affecting premotor, prefrontal, temporal and parietal lobes, caudate, and insula. Only the dominant AOS and PPAOS groups showed midbrain atrophy compared with controls. No differences were observed in PiB binding across all 3 groups, with the majority being PiB negative. Conclusion:These results suggest that dominant AOS is more similar to PPAOS than agPPA, with dominant AOS and PPAOS exhibiting a clinically distinguishable subtype of progressive AOS compared with agPPA. Neurology â 2013;81:337-345 GLOSSARY agPPA 5 agrammatic primary progressive aphasia; AOS 5 apraxia of speech; ASRS 5 Apraxia of Speech Rating Scale; DTI 5 diffusion tensor imaging; FA 5 fractional anisotropy; FDG 5 F18-fluorodeoxyglucose; MD 5 mean diffusivity; NOS 5 not otherwise specified; PiB 5 Pittsburgh compound B; PPA 5 primary progressive aphasia; PPAOS 5 primary progressive apraxia of speech; PSPS 5 progressive supranuclear palsy syndrome; TDP-43 5 TAR DNA binding protein of 43 kDa; WAB 5 Western Aphasia Battery.The term apraxia of speech (AOS) is used to denote a motor speech disorder in which abnormalities reflect deficits in the programming of movements for speech production.1,2 Although usually caused by left hemisphere stroke, AOS can also be associated with neurodegenerative disease, and when it is the only sign or symptom, it is labeled primary progressive AOS (PPAOS).3,4 Unlike PPAOS, the term primary progressive aphasia (PPA) is reserved for a neurodegenerative disorder in which the most salient feature is language dysfunction. 5-7 Agrammatic PPA (agPPA) is one subtype of PPA, characterized by specific abnormalities that affect grammar and syntax in verbal or written expression. 8,9 Although it is recognized that many subjects with agPPA may have AOS, the most salient feature of agPPA is aphasia. In fact, to be diagnosed with any variant of PPA, 8 language difficulty must be the most prominent clinical feature at symptom onset and for the initial phases of the disease; deficits cannot be due to "disruption o...

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.

Purpose-We address the hypothesis that the severe and persistent speech disorder reported in persons with galactosemia meets contemporary diagnostic criteria for Childhood Apraxia of Speech (CAS). A positive finding for CAS in this rare metabolic disorder has the potential to impact treatment of persons with galactosemia and inform explanatory perspectives on CAS in neurological, neurodevelopmental, and idiopathic contexts.Method-Thirty-three youth with galactosemia and significant prior or persistent speech sound disorder were assessed in their homes in 17 states. Participants completed a protocol yielding information on their cognitive, structural, sensorimotor, language, speech, prosody, and voice status and function.Results-Eight of the 33 participants (24%) met contemporary diagnostic criteria for CAS. Two participants, one of whom was among the 8 with CAS, met criteria for ataxic or hyperkinetic dysarthria. Group-wise findings for the remaining 24 participants are consistent with a classification category termed Motor Speech Disorder-Not Otherwise Specified (MSD-NOS; Shriberg, Fourakis, et al., in press-a).Conclusion-We estimate the prevalence of CAS in galactosemia at 18 per hundred, 180 times the estimated risk for idiopathic CAS. Findings support the need to study risk factors for the high occurrence of motor speech disorders in galactosemia, despite early compliant dietary management. Keywords apraxia; dyspraxia; genetics; motor speech disorder; speech sound disorder Consistent trends in the sparse literature on galactosemia and communicative disorders indicate high occurrence of significant and persistent speech sound disorder (SSD) in persons with galactosemia, with most reported speech findings consistent with developmental verbal dyspraxia. As recommended by the American Speech-LanguageHearing Association (ASHA, 2007), we hereafter reference apraxia of speech in children as Childhood Apraxia of Speech (CAS). The following three sections, respectively, review cognitive, language, and speech findings in galactosemia, summarize contemporary research issues in CAS, and describe rationale for the three questions about galactosemia and CAS addressed in this study. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript Galactosemia DescriptionGalactosemia is an autosomal recessive metabolic disorder estimated to occur in 1 in 53,000 infants in the United States (National Newborn Screening and Genetics Resource Center; Newborn Screening and Genetic Testing Symposium, 2002). Galactose is one of two sugars that make up the complex milk sugar, lactose. Individuals with galactosemia lack or have insufficient amounts of the galactose-1-phosphate uridylyltransferase enzyme needed to break down galactose, resulting in a toxic build-up of galactose -1-phosphate in the red blood cells. The most common genotype for galactosemia, Q188R/Q188R, was found in 62% of 107 cases of galactosemia described in Elsas, Langley, Paulk, Hjelm, and Dembure (1995). Individuals homozygous for galactosemia ...

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The consensus criteria for the diagnosis and classification of primary progressive aphasia (PPA) have served as an important tool in studying this group of disorders. However, a large proportion of patients remain unclassifiable whilst others simultaneously meet criteria for multiple subtypes. We prospectively evaluated a large cohort of patients with degenerative aphasia and/or apraxia of speech using multidisciplinary clinical assessments and multimodal imaging. Blinded diagnoses were made using operational definitions with important differences compared to the consensus criteria. Of the 130 included patients, 40 were diagnosed with progressive apraxia of speech (PAOS), 12 with progressive agrammatic aphasia, 9 with semantic dementia, 52 with logopenic progressive aphasia, and 4 with progressive fluent aphasia, while 13 were unclassified. The PAOS and progressive fluent aphasia groups were least impaired. Performance on repetition and sentence comprehension was especially poor in the logopenic group. The semantic and progressive fluent aphasia groups had prominent anomia, but only semantic subjects had loss of word meaning and object knowledge. Distinct patterns of grey matter loss and white matter changes were found in all groups compared to controls. PAOS subjects had bilateral frontal grey matter loss, including the premotor and supplementary motor areas, and bilateral frontal white matter involvement. The agrammatic group had more widespread, predominantly left sided grey matter loss and white matter abnormalities. Semantic subjects had bitemporal grey matter loss and white matter changes, including the uncinate and inferior occipitofrontal fasciculi, whereas progressive fluent subjects only had left sided temporal involvement. Logopenic subjects had diffuse and bilateral grey matter loss and diffusion tensor abnormalities, maximal in the posterior temporal region. A diagnosis of logopenic aphasia was strongly associated with being amyloid positive, (46/52 positive). Our findings support consideration of an alternative way of identifying and categorizing subtypes of degenerative speech and language disorders.

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.