RESUMO
Severe speech disorders lead to poor literacy, reduced academic attainment and negative psychosocial outcomes. As early as the 1950s, the familial nature of speech disorders was recognized, implying a genetic basis; but the molecular genetic basis remained unknown. In 2001, investigation of a large three generational family with severe speech disorder, known as childhood apraxia of speech (CAS), revealed the first causative gene; FOXP2. A long hiatus then followed for CAS candidate genes, but in the past three years, genetic analysis of cohorts ascertained for CAS have revealed over 30 causative genes. A total of 36 pathogenic variants have been identified from 122 cases across 3 cohorts in this nascent field. All genes identified have been in coding regions to date, with no apparent benefit at this stage for WGS over WES in identifying monogenic conditions associated with CAS. Hence current findings suggest a remarkable one in three children have a genetic variant that explains their CAS, with significant genetic heterogeneity emerging. Around half of the candidate genes identified are currently supported by medium (6 genes) to strong (9 genes) evidence supporting the association between the gene and CAS. Despite genetic heterogeneity; many implicated proteins functionally converge on pathways involved in chromatin modification or transcriptional regulation, opening the door to precision diagnosis and therapies. Most of the new candidate genes for CAS are associated with previously described neurodevelopmental conditions that include intellectual disability, autism and epilepsy; broadening the phenotypic spectrum to a distinctly milder presentation defined by primary speech disorder in the setting of normal intellect. Insights into the genetic bases of CAS, a severe, rare speech disorder, are yet to translate to understanding the heritability of more common, typically milder forms of speech or language impairment such as stuttering or phonological disorder. These disorders likely follow complex inheritance with polygenic contributions in many cases, rather than the monogenic patterns that underly one-third of patients with CAS. Clinical genetic testing for should now be implemented for individuals with CAS, given its high diagnostic rate, which parallels many other neurodevelopmental disorders where this testing is already standard of care. The shared mechanisms implicated by gene discovery for CAS highlight potential new targets for future precision therapies.
Assuntos
Distúrbios da Fala , Humanos , Distúrbios da Fala/genética , Criança , Predisposição Genética para Doença/genética , Apraxias/genética , Fatores de Transcrição Forkhead/genética , Masculino , FemininoRESUMO
It is debated whether primary progressive apraxia of speech (PPAOS) and progressive agrammatic aphasia (PAA) belong to the same clinical spectrum, traditionally termed non-fluent/agrammatic variant primary progressive aphasia (nfvPPA), or exist as two completely distinct syndromic entities with specific pathologic/prognostic correlates. We analysed speech, language and disease severity features in a comprehensive cohort of patients with progressive motor speech impairment and/or agrammatism to ascertain evidence of naturally occurring, clinically meaningful non-overlapping syndromic entities (e.g. PPAOS and PAA) in our data. We also assessed if data-driven latent clinical dimensions with aetiologic/prognostic value could be identified. We included 98 participants, 43 of whom had an autopsy-confirmed neuropathological diagnosis. Speech pathologists assessed motor speech features indicative of dysarthria and apraxia of speech (AOS). Quantitative expressive/receptive agrammatism measures were obtained and compared with healthy controls. Baseline and longitudinal disease severity was evaluated using the Clinical Dementia Rating Sum of Boxes (CDR-SB). We investigated the data's clustering tendency and cluster stability to form robust symptom clusters and employed principal component analysis to extract data-driven latent clinical dimensions (LCD). The longitudinal CDR-SB change was estimated using linear mixed-effects models. Of the participants included in this study, 93 conformed to previously reported clinical profiles (75 with AOS and agrammatism, 12 PPAOS and six PAA). The remaining five participants were characterized by non-fluent speech, executive dysfunction and dysarthria without apraxia of speech or frank agrammatism. No baseline clinical features differentiated between frontotemporal lobar degeneration neuropathological subgroups. The Hopkins statistic demonstrated a low cluster tendency in the entire sample (0.45 with values near 0.5 indicating random data). Cluster stability analyses showed that only two robust subgroups (differing in agrammatism, executive dysfunction and overall disease severity) could be identified. Three data-driven components accounted for 71% of the variance [(i) severity-agrammatism; (ii) prominent AOS; and (iii) prominent dysarthria]. None of these data-driven LCDs allowed an accurate prediction of neuropathology. The severity-agrammatism component was an independent predictor of a faster CDR-SB increase in all the participants. Higher dysarthria severity, reduced words per minute and expressive and receptive agrammatism severity at baseline independently predicted accelerated disease progression. Our findings indicate that PPAOS and PAA, rather than exist as completely distinct syndromic entities, constitute a clinical continuum. In our cohort, splitting the nfvPPA spectrum into separate clinical phenotypes did not improve clinical-pathological correlations, stressing the need for new biological markers and consensus regarding updated terminology and clinical classification.
Assuntos
Afasia Primária Progressiva , Apraxias , Afasia Primária Progressiva não Fluente , Humanos , Afasia de Broca/patologia , Disartria , Apraxias/patologia , Idioma , FalaRESUMO
The non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) is a neurodegenerative syndrome primarily defined by the presence of apraxia of speech (AoS) and/or expressive agrammatism. In addition, many patients exhibit dysarthria and/or receptive agrammatism. This leads to substantial phenotypic variation within the speech-language domain across individuals and time, in terms of both the specific combination of symptoms as well as their severity. How to resolve such phenotypic heterogeneity in nfvPPA is a matter of debate. 'Splitting' views propose separate clinical entities: 'primary progressive apraxia of speech' when AoS occurs in the absence of expressive agrammatism, 'progressive agrammatic aphasia' (PAA) in the opposite case, and 'AOS + PAA' when mixed motor speech and language symptoms are clearly present. While therapeutic interventions typically vary depending on the predominant symptom (e.g. AoS versus expressive agrammatism), the existence of behavioural, anatomical and pathological overlap across these phenotypes argues against drawing such clear-cut boundaries. In the current study, we contribute to this debate by mapping behaviour to brain in a large, prospective cohort of well characterized patients with nfvPPA (n = 104). We sought to advance scientific understanding of nfvPPA and the neural basis of speech-language by uncovering where in the brain the degree of MRI-based atrophy is associated with inter-patient variability in the presence and severity of AoS, dysarthria, expressive agrammatism or receptive agrammatism. Our cross-sectional examination of brain-behaviour relationships revealed three main observations. First, we found that the neural correlates of AoS and expressive agrammatism in nfvPPA lie side by side in the left posterior inferior frontal lobe, explaining their behavioural dissociation/association in previous reports. Second, we identified a 'left-right' and 'ventral-dorsal' neuroanatomical distinction between AoS versus dysarthria, highlighting (i) that dysarthria, but not AoS, is significantly influenced by tissue loss in right-hemisphere motor-speech regions; and (ii) that, within the left hemisphere, dysarthria and AoS map onto dorsally versus ventrally located motor-speech regions, respectively. Third, we confirmed that, within the large-scale grammar network, left frontal tissue loss is preferentially involved in expressive agrammatism and left temporal tissue loss in receptive agrammatism. Our findings thus contribute to define the function and location of the epicentres within the large-scale neural networks vulnerable to neurodegenerative changes in nfvPPA. We propose that nfvPPA be redefined as an umbrella term subsuming a spectrum of speech and/or language phenotypes that are closely linked by the underlying neuroanatomy and neuropathology.
Assuntos
Afasia Primária Progressiva , Apraxias , Afasia Primária Progressiva não Fluente , Humanos , Afasia de Broca/patologia , Estudos Prospectivos , Disartria , Fala , Estudos Transversais , Apraxias/patologia , Afasia Primária Progressiva/patologia , Afasia Primária Progressiva não Fluente/complicaçõesRESUMO
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.
Assuntos
Apraxias , Carbolinas , Tomografia por Emissão de Pósitrons , Humanos , Masculino , Feminino , Idoso , Apraxias/diagnóstico por imagem , Apraxias/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Pessoa de Meia-Idade , Estudos Longitudinais , Imageamento por Ressonância Magnética , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Atrofia/patologia , Fluordesoxiglucose F18 , Fonética , Idoso de 80 Anos ou mais , Proteínas tau/metabolismoRESUMO
Apraxia localization has relied on voxel-based, lesion-symptom mapping studies in left hemisphere stroke patients. Studies on the neural substrates of different manifestations of apraxia in neurodegenerative disorders are scarce. The primary aim of this study was to look into the neural substrates of different manifestations of apraxia in a cohort of corticobasal syndrome patients (CBS) by use of cortical thickness. Twenty-six CBS patients were included in this cross-sectional study. The Goldenberg apraxia test (GAT) was applied. 3D-T1-weighted images were analyzed via the automated recon-all Freesurfer version 6.0 pipeline. Vertex-based multivariate General Linear Model analysis was applied to correlate GAT scores with cortical thickness. Deficits in imitation of meaningless gestures correlated with bilateral superior parietal atrophy, extending to the angular and supramarginal gyri, particularly on the left. Finger imitation relied predominantly on superior parietal lobes, whereas the left angular and supramarginal gyri, in addition to superior parietal lobes, were critical for hand imitation. The widespread bilateral clusters of atrophy in CBS related to apraxia indicate different pathophysiological mechanisms mediating praxis in neurodegenerative disorders compared to vascular lesions, with implications both for our understanding of praxis and for the rehabilitation approaches of patients with apraxia.
Assuntos
Apraxias , Degeneração Corticobasal , Doenças Neurodegenerativas , Humanos , Estudos Transversais , Apraxias/diagnóstico por imagem , Apraxias/etiologia , Apraxias/patologia , Imageamento por Ressonância Magnética , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/diagnóstico por imagem , Atrofia , Comportamento Imitativo/fisiologiaRESUMO
Mutations in the SETX gene, which encodes Senataxin, are associated with the progressive neurodegenerative diseases ataxia with oculomotor apraxia 2 (AOA2) and amyotrophic lateral sclerosis 4 (ALS4). To identify the causal defect in AOA2, patient-derived cells and SETX knockouts (human and mouse) were analyzed using integrated genomic and transcriptomic approaches. A genome-wide increase in chromosome instability (gains and losses) within genes and at chromosome fragile sites was observed, resulting in changes to gene-expression profiles. Transcription stress near promoters correlated with high GCskew and the accumulation of R-loops at promoter-proximal regions, which localized with chromosomal regions where gains and losses were observed. In the absence of Senataxin, the Cockayne syndrome protein CSB was required for the recruitment of the transcription-coupled repair endonucleases (XPG and XPF) and RAD52 recombination protein to target and resolve transcription bubbles containing R-loops, leading to genomic instability. These results show that transcription stress is an important contributor to SETX mutation-associated chromosome fragility and AOA2.
Assuntos
Instabilidade Cromossômica/genética , DNA Helicases/metabolismo , Enzimas Multifuncionais/metabolismo , RNA Helicases/metabolismo , Ataxias Espinocerebelares/congênito , Animais , Apraxias/genética , Ataxia/genética , Linhagem Celular , Ataxia Cerebelar/genética , DNA Helicases/genética , Reparo do DNA/genética , Perfilação da Expressão Gênica/métodos , Instabilidade Genômica/genética , Genômica/métodos , Humanos , Camundongos , Células-Tronco Embrionárias Murinas , Enzimas Multifuncionais/genética , Mutação/genética , Doenças Neurodegenerativas/genética , Cultura Primária de Células , Regiões Promotoras Genéticas/genética , RNA Helicases/genética , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/fisiopatologia , Transcriptoma/genéticaRESUMO
Progressive apraxia of speech (PAOS) is a 4R tauopathy characterized by difficulties with motor speech planning. Neurodegeneration in PAOS targets the premotor cortex, particularly the supplementary motor area (SMA), with degeneration of white matter (WM) tracts connecting premotor and motor cortices and Broca's area observed on diffusion tensor imaging (DTI). We aimed to assess flortaucipir uptake across speech-language-related WM tracts identified using DTI tractography in PAOS. Twenty-two patients with PAOS and 26 matched healthy controls were recruited by the Neurodegenerative Research Group (NRG) and underwent MRI and flortaucipir-PET. The patient population included patients with primary progressive apraxia of speech (PPAOS) and non-fluent variant/agrammatic primary progressive aphasia (agPPA). Flortaucipir PET scans and DTI were coregistered using rigid registration with a mutual information cost function in subject space. Alignments between DTI and flortaucipir PET were inspected in all cases. Whole-brain tractography was calculated using deterministic algorithms by a tractography reconstruction tool (DSI-studio) and specific tracts were identified using an automatic fiber tracking atlas-based method. Fractional anisotropy (FA) and flortaucipir standardized uptake value ratios (SUVRs) were averaged across the frontal aslant tract, arcuate fasciculi, inferior frontal-occipital fasciculus, inferior and middle longitudinal fasciculi, as well as the SMA commissural fibers. Reduced FA (p < .0001) and elevated flortaucipir SUVR (p = .0012) were observed in PAOS cases compared to controls across all combined WM tracts. For flortaucipir SUVR, the greatest differentiation of PAOS from controls was achieved with the SMA commissural fibers (area under the receiver operator characteristic curve [AUROC] = 0.83), followed by the left arcuate fasciculus (AUROC = 0.75) and left frontal aslant tract (AUROC = 0.71). Our findings demonstrate that flortaucipir uptake is increased across WM tracts related to speech/language difficulties in PAOS.
Assuntos
Carbolinas , Imagem de Tensor de Difusão , Imagem Multimodal , Tomografia por Emissão de Pósitrons , Humanos , Imagem de Tensor de Difusão/métodos , Masculino , Feminino , Idoso , Tomografia por Emissão de Pósitrons/métodos , Pessoa de Meia-Idade , Carbolinas/farmacocinética , Imagem Multimodal/métodos , Apraxias/diagnóstico por imagem , Apraxias/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Proteínas tau/metabolismo , Afasia Primária Progressiva/diagnóstico por imagem , Afasia Primária Progressiva/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologiaRESUMO
Childhood apraxia of speech (CAS), the prototypic severe childhood speech disorder, is characterized by motor programming and planning deficits. Genetic factors make substantive contributions to CAS aetiology, with a monogenic pathogenic variant identified in a third of cases, implicating around 20 single genes to date. Here we aimed to identify molecular causation in 70 unrelated probands ascertained with CAS. We performed trio genome sequencing. Our bioinformatic analysis examined single nucleotide, indel, copy number, structural and short tandem repeat variants. We prioritised appropriate variants arising de novo or inherited that were expected to be damaging based on in silico predictions. We identified high confidence variants in 18/70 (26%) probands, almost doubling the current number of candidate genes for CAS. Three of the 18 variants affected SETBP1, SETD1A and DDX3X, thus confirming their roles in CAS, while the remaining 15 occurred in genes not previously associated with this disorder. Fifteen variants arose de novo and three were inherited. We provide further novel insights into the biology of child speech disorder, highlighting the roles of chromatin organization and gene regulation in CAS, and confirm that genes involved in CAS are co-expressed during brain development. Our findings confirm a diagnostic yield comparable to, or even higher, than other neurodevelopmental disorders with substantial de novo variant burden. Data also support the increasingly recognised overlaps between genes conferring risk for a range of neurodevelopmental disorders. Understanding the aetiological basis of CAS is critical to end the diagnostic odyssey and ensure affected individuals are poised for precision medicine trials.
Assuntos
Apraxias , Distúrbios da Fala , Criança , Humanos , Distúrbios da Fala/genética , Apraxias/genética , Mapeamento Cromossômico , Causalidade , Encéfalo , Histona-Lisina N-MetiltransferaseRESUMO
OBJECTIVE: Semantic tool knowledge underlies the ability to perform activities of daily living. Models of apraxia have emphasized the role of functional knowledge about the action performed with tools (e.g., a hammer and a mallet allow a "hammering" action), and contextual knowledge informing individuals about where to find tools in the social space (e.g., a hammer and a mallet can be found in a workshop). The goal of this study was to test whether contextual or functional knowledge, would be central in the organization of tool knowledge. It was assumed that contextual knowledge would be more salient than functional knowledge for healthy controls and that patients with dementia would show impaired contextual knowledge. METHODS: We created an original, open-ended categorization task with ambiguity, in which the same familiar tools could be matched on either contextual or functional criteria. RESULTS: In our findings, healthy controls prioritized a contextual, over a functional criterion. Patients with dementia had normal visual categorization skills (as demonstrated by an original picture categorization task), yet they made less contextual, but more functional associations than healthy controls. CONCLUSION: The findings support a dissociation between functional knowledge ("what for") on the one hand, and contextual knowledge ("where") on the other hand. While functional knowledge may be distributed across semantic and action-related factors, contextual knowledge may actually be the name of higher-order social norms applied to tool knowledge. These findings may encourage researchers to test both functional and contextual knowledge to diagnose semantic deficits and to use open-ended categorization tests.
Assuntos
Apraxias , Demência , Humanos , Atividades Cotidianas , Apraxias/etiologia , Nível de Saúde , ConhecimentoRESUMO
BACKGROUND: Heterozygous disruptions of FOXP2 were the first identified molecular cause for severe speech disorder: childhood apraxia of speech (CAS), and yet few cases have been reported, limiting knowledge of the condition. METHODS: Here we phenotyped 28 individuals from 17 families with pathogenic FOXP2-only variants (12 loss-of-function, five missense variants; 14 males; aged 2 to 62 years). Health and development (cognitive, motor, social domains) were examined, including speech and language outcomes with the first cross-linguistic analysis of English and German. RESULTS: Speech disorders were prevalent (23/25, 92%) and CAS was most common (22/25, 88%), with similar speech presentations across English and German. Speech was still impaired in adulthood, and some speech sounds (eg, 'th', 'r', 'ch', 'j') were never acquired. Language impairments (21/25, 84%) ranged from mild to severe. Comorbidities included feeding difficulties in infancy (10/26, 38%), fine (13/26, 50%) and gross (13/26, 50%) motor impairment, anxiety (5/27, 19%), depression (6/27, 22%) and sleep disturbance (10/24, 42%). Physical features were common (22/27, 81%) but with no consistent pattern. Cognition ranged from average to mildly impaired and was incongruent with language ability; for example, seven participants with severe language disorder had average non-verbal cognition. CONCLUSIONS: Although we identify an increased prevalence of conditions like anxiety, depression and sleep disturbance, we confirm that the consequences of FOXP2 dysfunction remain relatively specific to speech disorder, as compared with other recently identified monogenic conditions associated with CAS. Thus, our findings reinforce that FOXP2 provides a valuable entry point for examining the neurobiological bases of speech disorder.
Assuntos
Apraxias , Transtornos da Linguagem , Masculino , Humanos , Criança , Distúrbios da Fala/genética , Transtornos da Linguagem/epidemiologia , Transtornos da Linguagem/genética , Fala , Apraxias/genética , Mutação de Sentido Incorreto/genética , Fatores de Transcrição Forkhead/genéticaRESUMO
OBJECTIVE: To demonstrate nerve-sparing laparoscopic eradication of deep endometriosis with rectal and parametrial resection based on the Negrar method [1] using the "touchless" technique. DESIGN: Stepwise video case demonstration with narration. SETTING: Tertiary level endometriosis unit. The patient was a 28 year-old nulliparous patient referred for surgery with persistent dysmenorrhea, dyspareunia, and dyschezia despite medical management (progestin-containing hormonal pills). Preoperative ultrasound demonstrated bilateral endometriomas, diffuse adenomyosis, and 35 mm × 17 mm stenosing rectal nodule. Histopathology confirmed 60% stenosis of the rectum secondary to the endometriotic nodule up to submucosal layer with margins free of endometriosis. She was discharged 7 days postoperatively with no postoperative complications. INTERVENTIONS: Laparoscopic nerve-sparing eradication of deep endometriosis with segmental rectosigmoid resection and bilateral posterior parametrectomy [2] according to the "Negrar method" with nerve-sparing "touchless" technique, sliding the nerve bundles laterocaudally, and keeping intact the visceral pelvic fascia covering them, thus without direct contact with the nerves. CONCLUSION: In our experience, based on more than 3000 of these procedures [3], this nerve-sparing procedure, based on identifying the nerves and their laterocaudad dissection, without a direct impact on their fibers but just on their fascial envelopes has proven successful in lowering the rates of postoperative dysfunctions and neural impairment related to neuro-apraxia and edema that occurs by directly affecting them [1]. Although there are no robust data to demonstrate benefit of "touchless" nerve-sparing dissection techniques, neuro-apraxia from compression of neural fibers that has been observed can be minimized [1,4,5].
Assuntos
Apraxias , Endometriose , Laparoscopia , Doenças Retais , Feminino , Humanos , Adulto , Endometriose/patologia , Laparoscopia/métodos , Reto/cirurgia , Pelve/cirurgia , Apraxias/complicações , Apraxias/patologia , Apraxias/cirurgia , Doenças Retais/patologiaRESUMO
Behçet's syndrome and Cogan's syndrome constitute the group of variable vessel vasculitides in the Chapel-Hill Nomenclature. They involve arteries and veins of all sizes. As reflected in the name "syndrome", both diseases can manifest with different individual symptoms. Both formally are rare diseases, but the Cogan syndrome is much rarer than Behçet`s. For the latter, there are diagnosis and classification criteria as well as European (EULAR, European Alliance of Associations for Rheumatology) treatment recommendations. The symptomatology, diagnostic measures and treatment as well as some considerations about pathogenesis will be discussed in this article.
Assuntos
Apraxias/congênito , Síndrome de Behçet , Síndrome de Cogan , Vasculite , Humanos , Síndrome de Cogan/diagnóstico , Síndrome de Behçet/diagnóstico , Vasculite/diagnóstico , Diagnóstico DiferencialRESUMO
Background and Objectives: Despite the increasing use of biomarkers, differentiation between Alzheimer's disease (AD), behavioral variant Frontotemporal Dementia (bvFTD), and Primary Progressive Aphasia (PPA) remains a challenge. Apraxia is a supportive feature for diagnosing AD but is underrepresented in other dementia types. Herein, we investigated the presence and characteristic profiles of limb, verbal, and non-verbal apraxia in three major dementia types. Materials and Methods: Test for Upper Limb Apraxia (TULIA) and Apraxia Battery for Adults-2 (ABA-2) were administered in patients with AD (n = 22), bvFTD (n = 41), and PPA (n = 22), with 20 individuals serving as healthy controls (HC). Composite and subdomain scores were compared between each patient group and the HC. Praxis profiles indicative of each dementia type and a possible predictive value were sought. Results: Apraxia provided high diagnostic accuracy for detecting dementia compared with HC (sensitivity: 63.6-100%, specificity: 79.2-100%). Patients with AD performed worse when imitating intransitive gestures as well as pantomiming transitive gestures (mean differences: 2.10 and 3.12, respectively), compared with bvFTD. PPA patients, compared with bvFTD, had comparable results in limb, verbal, and non-verbal praxis assessments, despite the greater deterioration in the outcome. Compared with patients with AD, PPA had increased pathological outcomes in verbal (86.4% vs. 40.9%) and non-verbal apraxia (31.8% vs. 0%), while bvFTD had increased pathological outcomes in verbal apraxia (85.4% vs. 44.5%). Finally, apraxia is correlated with cognitive decline. Conclusions: Apraxia profile evaluation could contribute to the differentiation between AD and Frontotemporal Dementia (FTD). Both TULIA and ABA-2 are reliable tools that can be performed as bed-side tests in clinical practice.
Assuntos
Doença de Alzheimer , Apraxias , Disfunção Cognitiva , Demência Frontotemporal , Adulto , Humanos , Doença de Alzheimer/diagnóstico , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/patologia , Demência Frontotemporal/psicologia , Apraxias/diagnóstico , Testes NeuropsicológicosRESUMO
Stroke is a leading cause of disability worldwide. Limb apraxia is a group of higher order motor disorders associated with greater disability and dependence after stroke. Original neuropsychology studies distinguished separate brain pathways involved in perception and action, known as the dual stream hypothesis. This framework has allowed a better understanding of the deficits identified in Limb Apraxia. In this review, we propose a hierarchical organization of this disorder, in which a distinction can be made between several visuomotor pathways that lead to purposeful actions. Based on this, executive apraxias (such as limb kinetic apraxia) cause deficits in executing fine motor hand skills, and intermediate apraxias (such as optic ataxia and tactile apraxia) cause deficits in reaching to grasp and manipulating objects in space. These disorders usually affect the contralesional limb. A further set of disorders collectively known as limb apraxias include deficits in gesture imitation, pantomime, gesture recognition, and object use. These deficits are due to deficits in integrating perceptual and semantic information to generate complex movements. Limb apraxias are usually caused by left-hemisphere lesions in right-handed stroke patients, affecting both limbs. The anterior- to posterior-axis of brain areas are disrupted depending on the increasing involvement of perceptual and semantic processes with each condition. Lower-level executive apraxias are linked to lesions in the frontal lobe and the basal ganglia, while intermediate apraxias are linked to lesions in dorso-dorsal subdivisions of the dorsal fronto-parietal networks. Limb apraxias can be caused by lesions in both dorsal and ventral subdivisions including the ventro-dorsal stream and a third visuomotor pathway, involved in body schema and social cognition. Rehabilitation of these disorders with behavioral therapies has aimed to either restore perceptuo-semantic deficits or compensate to overcome these deficits. Further studies are required to better stratify patients, using modern neurophysiology and neuroimaging techniques, to provide targeted and personalized therapies for these disorders in the future.
Assuntos
Apraxias , Acidente Vascular Cerebral , Humanos , Semântica , Apraxias/complicações , Apraxias/patologia , Acidente Vascular Cerebral/complicações , Encéfalo/patologia , MãosRESUMO
In this issue of European Journal of Neurology, Robinson et al. present a novel study on primary progressive apraxia of speech. The authors describe different clinicopathological profiles in patients with left-dominant, right-dominant, and bilateral atrophy of the supplementary motor area and lateral premotor cortex. This commentary discusses the importance of this evidence for understanding individual differences among these patients, distinguishing them from those with nonfluent variant primary progressive aphasia, and analyzing the relations between motor speech deficits and underlying pathology.
Assuntos
Afasia Primária Progressiva , Apraxias , Humanos , Afasia Primária Progressiva/diagnóstico , Encéfalo/patologia , Fala , Diagnóstico Diferencial , Apraxias/diagnósticoRESUMO
OBJECTIVE: Primary progressive apraxia of speech (PPAOS) is associated with imaging abnormalities in the lateral premotor cortex (LPC) and supplementary motor area (SMA). It is not known whether greater involvement of these regions in either hemisphere is associated with demographics, presenting, and/or longitudinal features. METHODS: In 51 prospectively recruited PPAOS patients who completed [18 F]-fluorodeoxyglucose (FDG) positron emission tomography (PET), we classified patients as left-dominant, right-dominant, or symmetric, based on visual assessment of the LPC and SMA on FDG-PET. SPM and statistical analyses of regional metabolic values were performed. Diagnosis of PPAOS was made if apraxia of speech was present and aphasia absent. Thirteen patients completed ioflupane-123I (dopamine transporter [DAT]) scans. We compared cross-sectional and longitudinal clinicopathological, genetic, and neuroimaging characteristics across the three groups, with area under the receiver-operating curve (AUROC) determined as a measure of effect size. RESULTS: In all, 49% of the PPAOS patients were classified as left-dominant, 31% as right-dominant, and 20% as symmetric, which was supported by results from the SPM and regional analyses. There were no differences in baseline characteristics. Longitudinally, right-dominant PPAOS showed faster rates of progression of ideomotor apraxia (AUROC 0.79), behavioral disturbances (AUROC 0.84), including disinhibition symptoms (AUROC 0.82) and negative behaviors (AUROC 0.82), and parkinsonism (AUROC 0.75) compared to left-dominant PPAOS. Symmetric PPAOS showed faster rates of dysarthria progression compared to left-dominant (AUROC 0.89) and right-dominant PPAOS (AUROC 0.79). Five patients showed abnormal DAT uptake. Braak neurofibrillary tangle stage differed across groups (p = 0.01). CONCLUSIONS: Patients with PPAOS and a right-dominant pattern of hypometabolism on FDG-PET have the fastest rates of decline of behavioral and motor features.
Assuntos
Afasia Primária Progressiva , Apraxias , Humanos , Fala/fisiologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Fluordesoxiglucose F18 , Estudos Transversais , Apraxias/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Afasia Primária Progressiva/diagnóstico por imagemRESUMO
PURPOSE OF REVIEW: Apraxia of speech (AOS) is a motor speech disorder that has long been recognized to occur secondary to acute neurologic insults and, more recently, to neurodegenerative diseases as a harbinger for progressive supranuclear palsy and corticobasal syndrome. This article reviews recent findings regarding the clinic phenotypes of AOS, neuroimaging correlates, and the underlying disease processes. RECENT FINDINGS: Two clinical subtypes of AOS map onto two underlying 4-repeat tauopathies. New imaging techniques have recently been applied to the study of progressive AOS. There is no data on the impact of behavioral intervention, although studies of nonfluent/agrammatic primary progressive aphasia that include patients with AOS suggest some benefit in speech intelligibility and maintenance. While recent findings suggest subtypes of AOS exist that are linked to molecular pathology and have important implications for disease progression, further research is needed to assess outcome of behavioral and other types of intervention.
Assuntos
Apraxias , Doenças Neurodegenerativas , Paralisia Supranuclear Progressiva , Humanos , Fala , Apraxias/diagnóstico , Paralisia Supranuclear Progressiva/diagnóstico , Neuroimagem/métodos , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/genéticaRESUMO
Childhood apraxia of speech (CAS) is a pediatric motor speech disorder. The genetic etiology of this complex neurological condition is not yet well understood, although some genes have been linked to it. We describe the case of a boy with a severe and persistent motor speech disorder, consistent with CAS, and a coexisting language impairment.Whole exome sequencing in our case revealed a de novo and splicing mutation in the CSMD1 gene.
Assuntos
Apraxias , Fala , Masculino , Criança , Humanos , Apraxias/genética , Distúrbios da Fala/genética , Mutação/genética , Sequenciamento do Exoma , Proteínas de Membrana/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair. Here we show that biallelic mutations in the human XRCC1 gene are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. Cells from a patient with mutations in XRCC1 exhibited not only reduced rates of single-strand break repair but also elevated levels of protein ADP-ribosylation. This latter phenotype is recapitulated in a related syndrome caused by mutations in the XRCC1 partner protein PNKP and implicates hyperactivation of poly(ADP-ribose) polymerase/s as a cause of cerebellar ataxia. Indeed, remarkably, genetic deletion of Parp1 rescued normal cerebellar ADP-ribose levels and reduced the loss of cerebellar neurons and ataxia in Xrcc1-defective mice, identifying a molecular mechanism by which endogenous single-strand breaks trigger neuropathology. Collectively, these data establish the importance of XRCC1 protein complexes for normal neurological function and identify PARP1 as a therapeutic target in DNA strand break repair-defective disease.
Assuntos
Ataxia Cerebelar/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Mutação , Poli(ADP-Ribose) Polimerase-1/metabolismo , Adenosina Difosfato Ribose/metabolismo , Alelos , Animais , Apraxias/congênito , Apraxias/genética , Ataxia/genética , Axônios/patologia , Ataxia Cerebelar/patologia , Cerebelo/metabolismo , Cerebelo/patologia , Cromatina/metabolismo , Síndrome de Cogan/genética , Quebras de DNA de Cadeia Simples , Reparo do DNA/genética , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Proteínas de Ligação a DNA/deficiência , Feminino , Humanos , Interneurônios/metabolismo , Interneurônios/patologia , Masculino , Camundongos , Linhagem , Fenótipo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Poli(ADP-Ribose) Polimerase-1/deficiência , Poli(ADP-Ribose) Polimerase-1/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-XRESUMO
Individuals with childhood apraxia of speech often exhibit greater difficulty with expressive language than with receptive language. As a result, they may benefit from alternative modes of communication. Here, we present a patient with childhood apraxia of speech who used pointing as a means of communication at age 2 » years and self-made gestures at age 3½, when he had severe difficulties speaking in spite of probable normal comprehension abilities. His original gestures included not only word-level expressions, but also sentence-length ones. For example, when expressing "I am going to bed," he pointed his index finger at himself (meaning I ) and then put both his hands together near his ear ( sleep ). When trying to convey the meaning of "I enjoyed the meal and am leaving," he covered his mouth with his right hand ( delicious ), then joined both of his hands in front of himself ( finish ) and finally waved his hands ( goodbye ). These original gestures and pointing peaked at the age of 4 and then subsided and completely disappeared by the age of 7, when he was able to make himself understood to some extent with spoken words. The present case demonstrates an adaptive strategy for communication that might be an inherent competence for human beings.