RESUMO
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.
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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
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.
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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
BACKGROUND: Primary progressive aphasia (PPA) defines a group of neurodegenerative disorders characterised by language decline. Three PPA variants correlate with distinct underlying pathologies: semantic variant PPA (svPPA) with transactive response DNA-binding protein of 43 kD (TDP-43) proteinopathy, agrammatic variant PPA (agPPA) with tau deposition and logopenic variant PPA (lvPPA) with Alzheimer's disease (AD). Our objectives were to differentiate PPA variants using clinical and neuroimaging features, assess progression and evaluate structural MRI and a novel 18-F fluorodeoxyglucose positron emission tomography (FDG-PET) image decomposition machine learning algorithm for neuropathology prediction. METHODS: We analysed 82 autopsied patients diagnosed with PPA from 1998 to 2022. Clinical histories, language characteristics, neuropsychological results and brain imaging were reviewed. A machine learning framework using a k-nearest neighbours classifier assessed FDG-PET scans from 45 patients compared with a large reference database. RESULTS: PPA variant distribution: 35 lvPPA (80% AD), 28 agPPA (89% tauopathy) and 18 svPPA (72% frontotemporal lobar degeneration-TAR DNA-binding protein (FTLD-TDP)). Apraxia of speech was associated with 4R-tauopathy in agPPA, while pure agrammatic PPA without apraxia was linked to 3R-tauopathy. Longitudinal data revealed language dysfunction remained the predominant deficit for patients with lvPPA, agPPA evolved to corticobasal or progressive supranuclear palsy syndrome (64%) and svPPA progressed to behavioural variant frontotemporal dementia (44%). agPPA-4R-tauopathy exhibited limited pre-supplementary motor area atrophy, lvPPA-AD displayed temporal atrophy extending to the superior temporal sulcus and svPPA-FTLD-TDP had severe temporal pole atrophy. The FDG-PET-based machine learning algorithm accurately predicted clinical diagnoses and underlying pathologies. CONCLUSIONS: Distinguishing 3R-taupathy and 4R-tauopathy in agPPA may rely on apraxia of speech presence. Additional linguistic and clinical features can aid neuropathology prediction. Our data-driven brain metabolism decomposition approach effectively predicts underlying neuropathology.
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Afasia Primária Progressiva , Encéfalo , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Humanos , Afasia Primária Progressiva/patologia , Afasia Primária Progressiva/diagnóstico por imagem , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Aprendizado de Máquina , Doença de Alzheimer/patologia , Doença de Alzheimer/diagnóstico por imagem , Idoso de 80 Anos ou mais , Fluordesoxiglucose F18 , Neuroimagem , Progressão da DoençaRESUMO
Primary progressive aphasia (PPA) and primary progressive apraxia of speech (PPAOS) are neurodegenerative syndromes characterized by progressive decline in language or speech. There is a growing number of studies investigating speech-language interventions for PPA/PPAOS. An updated systematic evaluation of the treatment evidence is warranted to inform best clinical practice and guide future treatment research. We systematically reviewed the evidence for behavioral treatment for speech and language in this population. Reviewed articles were published in peer-reviewed journals through 31 May 2021. We evaluated level of evidence, reporting quality, and risk of bias using a modified version of the American Speech-Language Hearing Association (ASHA) Levels of Evidence, an appraisal point system, additional reporting quality and internal/external validity items, and, as appropriate, the Single Case Experimental Design Scale or the Physiotherapy Evidence Database - PsycBITE Rating Scale for Randomized and Non-Randomized Controlled Trials. Results were synthesized using quantitative summaries and narrative review. A total of 103 studies reported treatment outcomes for 626 individuals with PPA; no studies used the diagnostic label PPAOS. Most studies evaluated interventions for word retrieval. The highest-quality evidence was provided by 45 experimental and quasi-experimental studies (16 controlled group studies, 29 single-subject designs). All (k = 45/45) reported improvement on a primary outcome measure; most reported generalization (k = 34/43), maintenance (k = 34/39), or social validity (k = 17/19) of treatment for at least one participant. The available evidence supports speech-language intervention for persons with PPA; however, treatment for PPAOS awaits systematic investigation. Implications and limitations of the evidence and the review are discussed.
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BACKGROUND: Globular glial tauopathy (GGT) has been associated with frontotemporal dementia syndromes; little is known about the clinical and imaging characteristics of GGT and how they differ from other non-globular glial 4-repeat tauopathies (N4GT) such as progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD). METHODS: For this case-control study the Mayo Clinic brain banks were queried for all cases with an autopsy-confirmed diagnosis of GGT between 1 January 2011 and 31 October 2021. Fifty patients with N4GT (30 PSP, 20 CBD) were prospectively recruited and followed by the Neurodegenerative Research Group at Mayo Clinic, Minnesota. Magnetic resonance imaging was used to characterize patterns of gray/white matter atrophy, MR-parkinsonism index, midbrain volume, and white matter hyperintensities.18 F-Fluorodeoxyglucose-, 11 C Pittsburg compound-, and 18 F-flortaucipir-positron emission tomography scans were reviewed. RESULTS: Twelve patients with GGT were identified: 83% were women compared to 42% in NG4T (p = 0.02) with median age at death 76.5 years (range: 55-87). The most frequent clinical features were eye movement abnormalities, parkinsonism, behavioral changes followed by pyramidal tract signs and motor speech abnormalities. Lower motor neuron involvement was present in 17% and distinguished GGT from NG4T (p = 0.035). Primary progressive apraxia of speech was the most frequent initial diagnosis (25%); 50% had a Parkinson-plus syndrome before death. Most GGT patients had asymmetric frontotemporal atrophy with matching hypometabolism. GGT patients had more gray matter atrophy in temporal lobes, normal MR-parkinsonism index, and larger midbrain volumes. CONCLUSIONS: Female sex, lower motor neuron involvement in the context of a frontotemporal dementia syndrome, and asymmetric brain atrophy with preserved midbrain might be suggestive of underlying GGT.
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Demência Frontotemporal , Paralisia Supranuclear Progressiva , Tauopatias , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Masculino , Estudos de Casos e Controles , Demência Frontotemporal/diagnóstico por imagem , Tauopatias/diagnóstico por imagem , Tauopatias/patologia , Neuroglia/patologia , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Paralisia Supranuclear Progressiva/patologia , Imageamento por Ressonância Magnética , Atrofia/patologiaRESUMO
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.
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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
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.
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Doença de Alzheimer/diagnóstico por imagem , Afasia Primária Progressiva/diagnóstico por imagem , Doença por Corpos de Lewy/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Afasia Primária Progressiva/patologia , Afasia Primária Progressiva/fisiopatologia , Feminino , Fluordesoxiglucose F18 , Degeneração Lobar Frontotemporal/diagnóstico por imagem , Degeneração Lobar Frontotemporal/patologia , Degeneração Lobar Frontotemporal/fisiopatologia , Humanos , Testes de Linguagem , Doença por Corpos de Lewy/patologia , Doença por Corpos de Lewy/fisiopatologia , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Compostos RadiofarmacêuticosRESUMO
BACKGROUND: Progressive supranuclear palsy (PSP) may present as a speech/language disorder (PSP-SL). OBJECTIVE: We assessed pathological correlates of patients with PSP-SL who retained the suggestive of PSP-SL (s.o. PSP-SL) diagnosis versus those who progressed to possible/probable (poss./prob.) PSP. METHODS: Thirty-four prospectively recruited patient with s.o. PSP-SL completed comprehensive speech/language and neurological assessments longitudinally, died, and underwent autopsy. RESULTS: Twelve patients (35%) evolved to poss./prob PSP, while 22 (65%) remained as s.o. PSP-SL. Pathological diagnoses differed across the groups (P = 0.025). Patients with s.o. PSP-SL had four different neuropathologies (corticobasal degeneration [59%], PSP [13%], Pick's disease [14%], and frontotemporal lobar degeneration with TDP-43 [14%]), while all patients with poss./prob. PSP had a 4R-tauopathy (PSP [67%] and corticobasal degeneration [33%]). Development of poss./prob. PSP increased the chance of having PSP pathology by 2.38 times. CONCLUSIONS: PSP-SL is associated with heterogenous pathologies. Evolution of PSP-SL into poss./prob. PSP is more predictive of underlying PSP pathology than s.o. PSP-SL. © 2021 International Parkinson and Movement Disorder Society.
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Transtornos da Linguagem , Paralisia Supranuclear Progressiva , Tauopatias , Autopsia , Humanos , Fala , Paralisia Supranuclear Progressiva/diagnóstico , Paralisia Supranuclear Progressiva/patologia , Tauopatias/patologiaRESUMO
BACKGROUND: Magnetic resonance brainstem measurements are useful structural biomarkers in the Richardson's syndrome variant of progressive supranuclear palsy (PSP). However, it is unclear how these biomarkers differ across the phenotypic spectrum of PSP and how they relate to underlying pathology. OBJECTIVE: The aim of this study was to compare brainstem imaging measures across clinical variants of PSP and determine sensitivity and specificity based on pathologically diagnosed cases. METHODS: A total of 153 patients with PSP who represented eight clinical variants were recruited at Mayo Clinic (Rochester, MN, USA) and underwent structural magnetic resonance imaging (MRI). Midbrain and pons area and superior and middle cerebellar peduncle width measurements were performed, and midbrain/pons ratio and Magnetic Resonance Parkinsonism Index (MRPI) were calculated. Among the 43 patients who later died, PSP pathology was confirmed in 29, whereas 14 had other pathology. RESULTS: Brainstem measurements varied across PSP clinical variants and were most abnormal in PSP-Richardson's syndrome and frontal variants, followed by PSP-corticobasal, PSP-speech/language, and PSP-parkinsonism variants. All these variants showed abnormalities compared with controls. The PSP-gait freezing variant and patients with prominent corticospinal tract signs showed normal brainstem measures. Among cases with confirmed PSP pathology, the midbrain area, midbrain/pons ratio, and MRPI were all more abnormal compared to those with other pathologies, with best differentiation obtained with the MRPI (sensitivity = 83%; specificity = 85%). CONCLUSIONS: MRI brainstem measures show utility as diagnostic biomarkers across PSP clinical variants and have the potential to be useful in predicting underlying pathology. © 2021 International Parkinson and Movement Disorder Society.
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Doença de Parkinson , Transtornos Parkinsonianos , Paralisia Supranuclear Progressiva , Biomarcadores , Tronco Encefálico/diagnóstico por imagem , Tronco Encefálico/patologia , Humanos , Imageamento por Ressonância Magnética/métodos , Doença de Parkinson/patologia , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Paralisia Supranuclear Progressiva/patologiaRESUMO
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.
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Afasia Primária Progressiva , Afasia , Apraxias , Afasia Primária Progressiva/diagnóstico , Apraxias/complicações , Apraxias/diagnóstico , Estudos Transversais , Feminino , Humanos , Masculino , FalaRESUMO
OBJECTIVE: To characterize and compare the neuropsychological profiles of patients with primary progressive apraxia of speech (PPAOS) and apraxia of speech with progressive agrammatic aphasia (AOS-PAA). METHOD: Thirty-nine patients with PPAOS and 49 patients with AOS-PAA underwent formal neurological, speech, language, and neuropsychological evaluations. Cognitive domains assessed included immediate and delayed episodic memory (Wechsler Memory Scale-Third edition; Logical Memory; Visual Reproduction; Rey Auditory Verbal Learning Test), processing speed (Trail Making Test A), executive functioning (Trail Making Test B; Delis-Kaplan Executive Functioning Scale - Sorting), and visuospatial ability (Rey-Osterrieth Complex Figure copy). RESULTS: The PPAOS patients were cognitively average or higher in the domains of immediate and delayed episodic memory, processing speed, executive functioning, and visuospatial ability. Patients with AOS-PAA performed more poorly on tests of immediate and delayed episodic memory and executive functioning compared to those with PPAOS. For every 1 unit increase in aphasia severity (e.g. mild to moderate), performance declined by 1/3 to 1/2 a standard deviation depending on cognitive domain. The degree of decline was stronger within the more verbally mediated domains, but was also notable in less verbally mediated domains. CONCLUSION: The study provides neuropsychological evidence further supporting the distinction of PPAOS from primary progressive aphasia and should be used to inform future diagnostic criteria. More immediately, it informs prognostication and treatment planning.
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Afasia Primária Progressiva , Afasia , Apraxias , Afasia Primária Progressiva/complicações , Afasia Primária Progressiva/diagnóstico , Apraxias/etiologia , Humanos , Idioma , Testes Neuropsicológicos , FalaRESUMO
OBJECTIVE: To examine associations between tau and amyloid ß (Aß) molecular positron emission tomography (PET) and both Alzheimer-related pathology and 4-repeat tau pathology in autopsy-confirmed frontotemporal lobar degeneration (FTLD). METHODS: Twenty-four patients had [18 F]-flortaucipir-PET and died with FTLD (progressive supranuclear palsy [PSP], n = 10; corticobasal degeneration [CBD], n = 10; FTLD-TDP, n = 3; and Pick disease, n = 1). All but 1 had Pittsburgh compound B (PiB)-PET. Braak staging, Aß plaque and neurofibrillary tangle counts, and semiquantitative tau lesion scores were performed. Flortaucipir standard uptake value ratios (SUVRs) were calculated in a temporal meta region of interest (meta-ROI), entorhinal cortex and cortical/subcortical regions selected to match the tau lesion analysis. Global PiB SUVR was calculated. Autoradiography was performed in 1 PSP patient, with digital pathology used to quantify tau burden. RESULTS: Nine cases (37.5%) had Aß plaques. Global PiB SUVR correlated with Aß plaque count, with 100% specificity and 50% sensitivity for diffuse plaques. Twenty-one (87.5%) had Braak stages I to IV. Flortaucipir correlated with neurofibrillary tangle counts in entorhinal cortex, but entorhinal and meta-ROI SUVRs were not elevated in Braak IV or primary age-related tauopathy. Flortaucipir uptake patterns differed across FTLD pathologies and could separate PSP and CBD. Flortaucipir correlated with tau lesion score in red nucleus and midbrain tegmentum across patients, but not in cortical or basal ganglia regions. Autoradiography demonstrated minimal uptake of flortaucipir, although flortaucipir correlated with quantitative tau burden across regions. INTERPRETATION: Molecular PET shows expected correlations with Alzheimer-related pathology but lacks sensitivity to detect mild Alzheimer pathology in FTLD. Regional flortaucipir uptake was able to separate CBD and PSP. ANN NEUROL 2020;88:1009-1022.
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Peptídeos beta-Amiloides/metabolismo , Degeneração Lobar Frontotemporal/diagnóstico por imagem , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Autopsia , Autorradiografia , Carbolinas , Estudos de Coortes , Feminino , Degeneração Lobar Frontotemporal/patologia , Humanos , Masculino , Mesencéfalo/diagnóstico por imagem , Mesencéfalo/patologia , Pessoa de Meia-Idade , Emaranhados Neurofibrilares/patologia , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Núcleo Rubro/diagnóstico por imagem , Núcleo Rubro/patologia , Sensibilidade e EspecificidadeRESUMO
Communication problems (eg, dysphonia, dysfluency and language and articulation disorders), swallowing disorders (dysphagia and globus), cough and upper airway symptoms, resulting from functional neurological disorder (FND), are commonly encountered by speech and language professionals. However, there are few descriptions in the literature of the most effective practical management approaches. This consensus document aims to provide recommendations for assessment and intervention that are relevant to both adults and young people. An international panel of speech and language professionals with expertise in FND were approached to take part. Participants responded individually by email to a set of key questions regarding best practice for assessment and interventions. Next, a video conference was held in which participants discussed and debated the answers to these key questions, aiming to achieve consensus on each issue. Drafts of the collated consensus recommendations were circulated until consensus was achieved. FND should be diagnosed on the basis of positive clinical features. Speech and language therapy for FND should address illness beliefs, self-directed attention and abnormal movement patterns through a process of education, symptomatic treatment and cognitive behavioural therapy within a supportive therapeutic environment. We provide specific examples of these strategies for different symptoms. Speech and language professionals have a key role in the management of people with communication and related symptoms of FND. It is intended that these expert recommendations serve as both a practical toolkit and a starting point for further research into evidence-based treatments.
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Transtorno Conversivo/terapia , Tosse/terapia , Transtornos de Deglutição/terapia , Terapia da Linguagem , Fonoterapia , Consenso , Transtorno Conversivo/fisiopatologia , Tosse/fisiopatologia , Deglutição/fisiologia , Transtornos de Deglutição/fisiopatologia , Humanos , Fala/fisiologiaRESUMO
A mild condition via PPh3/I2/imidazole for the deoxygenation of substituted methanol derivatives has been identified. This metal-free process was found to proceed well on secondary or tertiary alcohols substituted with one or two heteroaryl groups, and it tolerates acid-sensitive heterocycles. This condition works for methanol derivatives substituted with 2-pyridyl, 4-pyridyl, or other heterocyclic groups, allowing the negative charge formed during the reaction to resonate to a nitrogen atom. Methanol derivatives substituted with 3-pyridyl or heterocyclic groups that do not allow the negative charge formed during the reaction to resonate to a nitrogen atom will not undergo deoxygenation under this condition.
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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.
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Doença de Alzheimer , Afasia Primária Progressiva , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Afasia Primária Progressiva/diagnóstico por imagem , Atrofia/patologia , Encéfalo , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Humanos , Imageamento por Ressonância Magnética , Testes NeuropsicológicosRESUMO
INTRODUCTION: Semantic dementia (SD) is characterized by fluent speech, anomia, and loss of word and object knowledge with varying degrees of right and left anterior-medial temporal lobe hypometabolism on [18F] fluorodeoxyglucose (FDG)-PET. We assessed neurobehavioral features in SD patients across 3 FDG-PET-defined metabolic patterns and investigated progression over time. METHODS: Thirty-four patients with SD who completed FDG-PET were classified into a left- and right-dominant group based on the degree of hypometabolism in each temporal lobe. The left-dominant group was further subdivided depending on whether hypometabolism in the right temporal lobe was more or less than 2 standard deviations from controls (left+ group). Neurobehavioral characteristics determined using the Neuropsychiatric Inventory Questionnaire (NPI-Q) were compared across groups. Progression of NPI-Q scores and FDG-PET hypometabolism was assessed in 14 patients with longitudinal follow-up. RESULTS: The right-dominant group performed worse on the NPI-Q and had a greater frequency of abnormal behaviors and more severe disinhibition compared to the left-dominant group. Performance on the NPI-Q and severity of disinhibition correlated with right medial and lateral, but not left, temporal lobe hypometabolism. Severity of abnormal behaviors worsened over time in most left-dominant and left+ patients but appeared to improve in the 2 right-dominant patients with longitudinal follow-up. All groups showed progressive worsening of metabolism in both temporal lobes over time, with hypometabolism spreading from anteromedial to posterior temporal regions. However, the degree of temporal lobe asymmetry remained relatively constant over time. CONCLUSION: In SD, neurobehavioral features, especially disinhibition, are associated with right medial and lateral temporal lobe hypometabolism and commonly develop over time even in patients that present with left-dominant patterns of hypometabolism.
Assuntos
Fluordesoxiglucose F18 , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/psicologia , Tomografia por Emissão de Pósitrons , Feminino , Demência Frontotemporal/patologia , Demência Frontotemporal/fisiopatologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/patologia , Lobo Temporal/fisiopatologiaRESUMO
Cholesteryl ester transfer protein (CETP) inhibitors reduce the transfer of cholesteryl esters from the high-density lipoprotein (HDL-C) to apolipoprotein such as VLDL/LDL, with exchange of triglycerides. Thus, this inhibition increases the HDL-C levels, which is believed to lower the risk for heart disease and stroke. We report here a series of CETP inhibitors based on the cyclic, bicyclic urea and sulfamide cores. These CETP inhibitors exemplified by 15, 31, and 45 demonstrated in vitro potency in inhibiting the CETP transfer activity, and 15, 31 showing in vivo efficacy to increase HDL-C levels in cynomolgus-CETP transgenic mice. The synthesis and biological evaluations of these CETP inhibitors are described.
Assuntos
Anticolesterolemiantes/síntese química , Compostos Bicíclicos com Pontes/química , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Sulfonamidas/química , Ureia/análogos & derivados , Animais , Anticolesterolemiantes/metabolismo , Anticolesterolemiantes/uso terapêutico , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , HDL-Colesterol/sangue , Ciclização , Dislipidemias/tratamento farmacológico , Dislipidemias/patologia , Humanos , Camundongos , Camundongos Transgênicos , Relação Estrutura-Atividade , Sulfonamidas/metabolismo , Sulfonamidas/uso terapêutico , Ureia/metabolismo , Ureia/uso terapêuticoRESUMO
We describe two individuals with progressive verbal difficulty who exhibited impairment of propositional language, with relatively well-preserved auditory comprehension, naming, and repetition-a profile that is consistent with dynamic aphasia. By providing a brief review of pertinent literature and the results from our neurologic, speech and language, neuropsychological, and neuroimaging testing, this report sheds light on the infrequently reported dynamic aphasia in the context of frontotemporal dementia. Our patients' insights into their verbal difficulty tend to support the notion that dynamic aphasia results from interference at the stage where thoughts are converted into verbal messages-that is, the thought-verbal interface.
Assuntos
Afasia , Demência Frontotemporal , Afasia/diagnóstico , Afasia/etiologia , Compreensão , Demência Frontotemporal/diagnóstico por imagem , Humanos , Testes Neuropsicológicos , FalaRESUMO
Although significant advances have been made in measuring the outcomes of rehabilitation interventions, comparably less progress has been made in measuring the treatment processes that lead to improved outcomes. A recently developed framework called the Rehabilitation Treatment Specification System (RTSS) has potential to identify which clinician actions (ie, ingredients) actively improve specific patient functions (ie, targets). However, the RTSS does not provide methodology for standardly identifying specific unique targets or ingredients. Without a method to evaluate the uniqueness of an individual target or ingredient, it is difficult to know whether variations in treatment descriptions are synonymous (ie, different words describing the same treatment) or meaningfully different (eg, different words describing different treatments or variations of the same treatment). A recent project used vocal rehabilitation ingredients and targets to create RTSS-based lists of unique overarching target and ingredient categories with underlying dimensions describing how individual ingredients and targets vary within those categories. The primary purpose of this article is to describe the challenges encountered during the project and the methodology developed to address those challenges. Because the methodology was based on the RTSS's broadly applicable framework, it can be used across all areas of rehabilitation regardless of the discipline (speech-language pathology, physical therapy, occupational therapy, psychology, etc) or impairment domain (language, cognition, ambulation, upper extremity training, etc). The resulting standard operationalized lists of targets and ingredients have high face and content validity. The lists may also facilitate implementation of the RTSS in research, education, interdisciplinary communication, and everyday treatment.
Assuntos
Tomada de Decisão Clínica , Protocolos Clínicos/normas , Avaliação de Resultados em Cuidados de Saúde , Planejamento de Assistência ao Paciente/normas , Reabilitação/normas , Técnica Delphi , Humanos , Reprodutibilidade dos TestesRESUMO
Treatments for cognitive deficits associated with central nervous system (CNS) disorders such as Alzheimer disease and schizophrenia remain significant unmet medical needs that incur substantial pressure on the health care system. The α7 nicotinic acetylcholine receptor (nAChR) has garnered substantial attention as a target for cognitive deficits based on receptor localization, robust preclinical effects, genetics implicating its involvement in cognitive disorders, and encouraging, albeit mixed, clinical data with α7 nAChR orthosteric agonists. Importantly, previous orthosteric agonists at this receptor suffered from off-target activity, receptor desensitization, and an inverted U-shaped dose-effect curve in preclinical assays that limit their clinical utility. To overcome the challenges with orthosteric agonists, we have identified a novel selective α7 positive allosteric modulator (PAM), BNC375. This compound is selective over related receptors and potentiates acetylcholine-evoked α7 currents with only marginal effect on the receptor desensitization kinetics. In addition, BNC375 enhances long-term potentiation of electrically evoked synaptic responses in rat hippocampal slices and in vivo. Systemic administration of BNC375 reverses scopolamine-induced cognitive deficits in rat novel object recognition and rhesus monkey object retrieval detour (ORD) task over a wide range of exposures, showing no evidence of an inverted U-shaped dose-effect curve. The compound also improves performance in the ORD task in aged African green monkeys. Moreover, ex vivo 13C-NMR analysis indicates that BNC375 treatment can enhance neurotransmitter release in rat medial prefrontal cortex. These findings suggest that α7 nAChR PAMs have multiple advantages over orthosteric α7 nAChR agonists for the treatment of cognitive dysfunction associated with CNS diseases. SIGNIFICANCE STATEMENT: BNC375 is a novel and selective α7 nicotinic acetylcholine receptor (nAChR) positive allosteric modulator (PAM) that potentiates acetylcholine-evoked α7 currents in in vitro assays with little to no effect on the desensitization kinetics. In vivo, BNC375 demonstrated robust procognitive effects in multiple preclinical models across a wide exposure range. These results suggest that α7 nAChR PAMs have therapeutic potential in central nervous system diseases with cognitive impairments.