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PURPOSE: Due to the indistinguishable clinical features of corticobasal syndrome (CBS), the antemortem differentiation between corticobasal degeneration (CBD) and its mimics remains challenging. However, the utility of conventional magnetic resonance imaging (MRI) for the diagnosis of CBD has not been sufficiently evaluated. This study aimed to investigate the diagnostic performance of conventional MRI findings in differentiating pathologically confirmed CBD from its mimics. METHODS: Semiquantitative visual rating scales were employed to assess the degree and distribution of atrophy and asymmetry on conventional T1-weighted and T2-weighted images. Additionally, subcortical white matter hyperintensity (SWMH) on fluid-attenuated inversion recovery images were visually evaluated. RESULTS: In addition to 19 patients with CBD, 16 with CBD mimics (progressive supranuclear palsy (PSP): 9, Alzheimer's disease (AD): 4, dementia with Lewy bodies (DLB): 1, frontotemporal lobar degeneration with TAR DNA-binding protein of 43 kDa(FTLD-TDP): 1, and globular glial tauopathy (GGT): 1) were investigated. Compared with the CBD group, the PSP-CBS subgroup showed severe midbrain atrophy without SWMH. The non-PSP-CBS subgroup, comprising patients with AD, DLB, FTLD-TDP, and GGT, showed severe temporal atrophy with widespread asymmetry, especially in the temporal lobes. In addition to over half of the patients with CBD, two with FTLD-TDP and GGT showed SWMH, respectively. CONCLUSION: This study elucidates the distinct structural changes between the CBD and its mimics based on visual rating scales. The evaluation of atrophic distribution and SWMH may serve as imaging biomarkers of conventional MRI for detecting background pathologies.
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Corticobasal syndrome (CBS) is a rare cause of dementia and comprises varied combinations of subcortical signs (akinetic-rigid parkinsonism, dystonia, or myoclonus) with cortical signs (apraxia, alien hand or cortical sensory deficit), usually asymmetric. We aimed to report and compare the clinical and neuroimaging presentation of two patients diagnosed with CBS. While case 1 had severe non-fluent aphasia associated with mild apraxia and limb rigidity, case 2 had a more posterior cognitive impairment, with a different language pattern associated with marked visuospatial errors and hemineglect. FDG PET played a significant role in diagnosis, suggesting, in the first case, corticobasal degeneration and, in the second, Alzheimer's disease pattern. CBS has been widely studied with the advent of new in vivo methods such as brain FDG PET. Studies that deepen the phenotypic and biomarker heterogeneity of CBS will be of great importance for better classification, prognosis, and treatment of the condition.
A síndrome corticobasal (SCB) é uma causa rara de demência e compreende combinações variadas de sinais subcorticais (parkinsonismo acinético-rígido, distonia ou mioclonias) com sinais corticais (apraxia, mão alienígena ou déficit sensorial cortical), geralmente assimétricos. Nosso objetivo foi relatar e comparar as apresentações clínica e de neuroimagem de dois pacientes com diagnóstico de SCB. Enquanto o caso 1 apresentava afasia grave não fluente associada a apraxia leve e rigidez de membros, o caso 2 exibia comprometimento cognitivo mais posterior, com padrão de linguagem distinto, erros visuoespaciais e heminegligência. O FDG PET teve papel significativo no diagnóstico, sugerindo, no primeiro caso, degeneração corticobasal e, no segundo, padrão Alzheimer. A SCB tem sido amplamente estudada com o advento de novos métodos in vivo, como o FDG PET cerebral. Estudos que aprofundem a heterogeneidade fenotípica e de biomarcadores da SCB serão de grande importância para melhor classificação, prognóstico e tratamento da doença.
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This case report presents a comprehensive assessment and therapeutic intervention using non-invasive motor cortex neuromodulation for a 70-year-old female patient diagnosed with corticobasal degeneration (CBD). The study followed the CARE guidelines. The patient meets the criteria for probable CBD, with neuroimaging evidence of exclusively cortical impairment. The patient underwent a non-invasive neuromodulation protocol involving transcranial direct current stimulation (tDCS) and action observation plus motor imagery (AO+MI). The neuromodulation protocol comprised 20 sessions involving tDCS over the primary motor cortex and combined AO+MI. Anodal tDCS was delivered a 2 mA excitatory current for 20 minutes. AO+MI focused on lower limb movements, progressing over four weeks with video observation and gradual execution, both weekly and monthly. The neuromodulation techniques were delivered online (i.e. applied simultaneously in each session). Outcome measures were obtained at baseline, post-intervention and follow-up (1 month later), and included motor (lower limb), cognitive/neuropsychological and functional assessments. Walking speed improvements were not observed, but balance (Berg Balance Scale) and functional strength (Five Times Sit-to-Stand Test) improved post-treatment. Long-term enhancements in attentional set-shifting, inhibitory control, verbal attentional span, and working memory were found. There was neurophysiological evidence of diminished intracortical inhibition. Functional changes included worsening in Cortico Basal Ganglia Functional Scale score. Emotional well-being and general health (SF-36) increased immediately after treatment but were not sustained, while Falls Efficacy Scale International showed only long-term improvement. The findings suggest potential benefits of the presented neuromodulation protocol for CBD patients, highlighting multifaceted outcomes in motor, cognitive, and functional domains.
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To conduct a meta-analysis investigating the relationship between the chromosome 9 open reading frame 72 (C9orf72) GGGGCC (G4C2) and neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We searched the EMBASE, PubMed, Web of Science, and Cochrane databases. Twenty-seven case-control studies were included, comprising 7202 AD, 5856 PD, 644 MSA, 439 PSP, and 477 CBD cases. This study demonstrated that C9orf72 repeat expansions (>30) were associated with AD, MSA, PSP, and CBD (AD: OR = 4.88, 95% CI = 2.71-8.78; MSA: OR = 6.98, 95% CI = 1.48-33.01; PSP: OR =10.04, 95% CI = 2.72-37.10; CBD: OR = 28.04, 95% CI = 10.17-77.31). C9orf72 intermediate repeat expansions (20-30) were not associated with AD and MSA (AD: OR = 1.16, 95% CI = 0.39-3.45; MSA: OR = 5.65, 95% CI = 0.69-46.19), while C9orf72 repeat expansions (>30) were not associated with the risk of PD (OR = 1.51, 95% CI = 0.55-4.17), C9orf72 intermediate repeat expansions (20-30) were indeed associated with PD (OR = 2.43, 95% CI = 1.20-4.9). The pathological mechanism of C9orf72 G4C2 repeat expansions differs across various NDs due to the varying number of pathogenic expansions. Measuring the number of C9orf72 G4C2 repeats may be useful in the early-stage differential diagnosis of various NDs.
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Proteína C9orf72 , Expansión de las Repeticiones de ADN , Enfermedades Neurodegenerativas , Proteína C9orf72/genética , Humanos , Enfermedades Neurodegenerativas/genética , Expansión de las Repeticiones de ADN/genética , Predisposición Genética a la Enfermedad , Atrofia de Múltiples Sistemas/genética , Enfermedad de Alzheimer/genética , Enfermedad de Parkinson/genética , Proteínas/genéticaRESUMEN
Cortico-basal degeneration is a relatively uncommon cause of degenerative parkinsonism in the elderly. From a clinical point of view, it manifests as a cortico-basal syndrome (CBS), featuring a highly asymmetrical akinetic-rigid syndrome, dystonia, myoclonus and cognitive-behavioral impairment with predominant apraxia. Other clinical phenotypes are possible, including variants with mainly language or behavioral impairment, or with axial, symmetrical parkinsonism resembling progressive supranuclear palsy (PSP). Current diagnostic criteria take into account the heterogeneity of clinical presentations. However, a diagnosis of certainty can only be reached by a pathological study, with the evidence of TAU-positive intraneuronal inclusions. Indeed SCB may be underpinned by other lesional substrates, ranging from frontotemporal degeneration to Alzheimer's disease. Symptom management must be early, multidisciplinary and adapted to the progression of the disorder. The identification of the pathological substrate is an essential prerequisite for pathophysiological therapeutic trials.
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Enfermedad de Alzheimer , Degeneración Corticobasal , Trastornos Parkinsonianos , Anciano , Humanos , Síndrome , Enfermedad de Alzheimer/diagnóstico , Atrofia , Trastornos Parkinsonianos/diagnósticoRESUMEN
BACKGROUND: We conducted a systematic review to identify existing ICD-10 coding validation studies in progressive supranuclear palsy and corticobasal syndrome [PSP/CBS]) and, in a new study, evaluated the accuracy of ICD-10 diagnostic codes for PSP/CBS in Scottish hospital inpatient and death certificate data. METHODS: Original studies that assessed the accuracy of specific ICD-10 diagnostic codes in PSP/CBS were sought. Separately, we estimated the positive predictive value (PPV) of specific codes for PSP/CBS in inpatient hospital data (SMR01, SMR04) compared to clinical diagnosis in four regions. Sensitivity was assessed in one region due to a concurrent prevalence study. For PSP, the consistency of the G23.1 code in inpatient and death certificate coding was evaluated across Scotland. RESULTS: No previous ICD-10 validation studies were identified. 14,767 records (SMR01) and 1497 records (SMR04) were assigned the candidate ICD-10 diagnostic codes between February 2011 and July 2019. The best PPV was achieved with G23.1 (1.00, 95% CI 0.93-1.00) in PSP and G23.9 in CBS (0.20, 95% CI 0.04-0.62). The sensitivity of G23.1 for PSP was 0.52 (95% CI 0.33-0.70) and G31.8 for CBS was 0.17 (95% CI 0.05-0.45). Only 38.1% of deceased G23.1 hospital-coded cases also had this coding on their death certificate: the majority (49.0%) erroneously assigned the G12.2 code. DISCUSSION: The high G23.1 PPV in inpatient data shows it is a useful tool for PSP case ascertainment, but death certificate coding is inaccurate. The PPV and sensitivity of existing ICD-10 codes for CBS are poor due to a lack of a specific code.
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Certificado de Defunción , Clasificación Internacional de Enfermedades , Parálisis Supranuclear Progresiva , Humanos , Parálisis Supranuclear Progresiva/diagnóstico , Parálisis Supranuclear Progresiva/mortalidad , Clasificación Internacional de Enfermedades/normas , Alta del Paciente/estadística & datos numéricos , Enfermedades de los Ganglios Basales/diagnóstico , Codificación Clínica/normasRESUMEN
Neurodegenerative pathologies such as Alzheimer disease neuropathologic change (ADNC), Lewy body disease (LBD), limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and cerebrovascular disease (CVD) frequently coexist, but little is known about the exact contribution of each pathology to cognitive decline and dementia in subjects with mixed pathologies. We explored the relative cognitive impact of concurrent common and rare neurodegenerative pathologies employing multivariate logistic regression analysis adjusted for age, gender, and level of education. We analyzed a cohort of 6,262 subjects from the National Alzheimer's Coordinating Center database, ranging from 0 to 6 comorbid neuropathologic findings per individual, where 95.7% of individuals had at least 1 neurodegenerative finding at autopsy and 75.5% had at least 2 neurodegenerative findings. We identified which neuropathologic entities correlate most frequently with one another and demonstrated that the total number of pathologies per individual was directly correlated with cognitive performance as assessed by Clinical Dementia Rating (CDR®) and Mini-Mental State Examination (MMSE). We show that ADNC, LBD, LATE-NC, CVD, hippocampal sclerosis, Pick disease, and FTLD-TDP significantly impact overall cognition as independent variables. More specifically, ADNC significantly affected all assessed cognitive domains, LBD affected attention, processing speed, and language, LATE-NC primarily affected tests related to logical memory and language, while CVD and other less common pathologies (including Pick disease, progressive supranuclear palsy, and corticobasal degeneration) had more variable neurocognitive effects. Additionally, ADNC, LBD, and higher numbers of comorbid neuropathologies were associated with the presence of at least one APOE ε4 allele, and ADNC and higher numbers of neuropathologies were inversely correlated with APOE ε2 alleles. Understanding the mechanisms by which individual and concomitant neuropathologies affect cognition and the degree to which each contributes is an imperative step in the development of biomarkers and disease-modifying therapeutics, particularly as these medical interventions become more targeted and personalized.
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Enfermedad de Alzheimer , Enfermedades Cardiovasculares , Demencia , Demencia Frontotemporal , Enfermedad por Cuerpos de Lewy , Enfermedad de Pick , Proteinopatías TDP-43 , Humanos , Enfermedad de Pick/patología , Encéfalo/patología , Enfermedad de Alzheimer/patología , Enfermedad por Cuerpos de Lewy/complicaciones , Enfermedad por Cuerpos de Lewy/patología , Demencia Frontotemporal/patología , CogniciónRESUMEN
Recent studies suggest that increased cerebrospinal fluid (CSF) phospho-tau is associated with brain amyloid pathology rather than the tau pathology. However, confirmation using gold standard neuropathological assessments remains limited. This study aimed to determine background pathologies associated with aberrant CSF p-tau181 and amyloid-beta 1-42 (Aß42) in Alzheimer's disease (AD) and other neurodegenerative diseases. We retrospectively studied all patients with antemortem CSF and postmortem neuropathologic data at our institution. Comprehensive neuropathologic assessments were conducted for all patients, including Thal phase, Braak NFT stage, and CERAD score for AD. CSF concentrations of p-tau181 and Aß42 were compared between AD neuropathological scores at autopsy by one-way ANOVA stratified by other pathologies. A total of 127 patients with AD (n = 22), Lewy body disease (n = 26), primary tauopathies (n = 30), TDP-43 proteinopathy (n = 16), and other diseases (n = 33) were included. The age at lumbar puncture was 76.3 ± 9.1 years, 40.8% were female, and median time from lumbar puncture to autopsy was 637 (175-1625) days. While Braak NFT 0-II was prevalent without amyloid pathology, Braak NFT ≥IV was observed exclusively in patients with amyloid pathology. Stratified analyses showed that CSF p-tau181 was slightly but significantly higher in patients with high Thal phase or CERAD score even in those with Braak NFT 0-II at autopsy. In patients with amyloid pathology, CSF p-tau181 was significantly and more profoundly elevated in those with Braak NFT ≥III at autopsy. CSF Aß42 was lower in patients with high amyloid pathological scores. However, 34% with Thal ≤ 2 and 38% with CERAD ≤ sparse also showed decreased Aß42. Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) were overrepresented in this group. These results neuropathologically confirmed previous studies that CSF p-tau181 levels were slightly elevated with amyloid pathology alone and were even higher with tau pathology, and that CSFAß42 can be decreased in PSP/CBD.
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Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Humanos , Femenino , Masculino , Enfermedad de Alzheimer/patología , Estudios Retrospectivos , Proteínas tau/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Amiloide , Biomarcadores/líquido cefalorraquídeoRESUMEN
The hypothesis that neurodegenerative diseases are proteinopathies due to toxic effect of different underlying proteins, such as amyloid-beta and 3+4R-tau in Alzheimer's disease (AD) and alpha-synuclein in Parkinson's disease (PD), while still controversial is supported by several studies in the literature. This has led to conduct clinical trials attempting to reduce the load of these allegedly toxic proteins by immunotherapy, mostly but not solely based on antibodies against these proteins. Already completed clinical trials have ranged from initially negative results to recently partial positive outcomes, specifically for anti-amyloid antibodies in AD but also albeit to lesser degree for anti-synuclein antibodies in PD. Currently, there are several ongoing clinical trials in degenerative parkinsonisms with anti-synuclein approaches in PD and multiple system atrophy (MSA), as well as with anti-tau antibodies in 4R-tauopathies such as progressive supranuclear palsy (PSP). While it can be argued that expectations that part of these clinical trials will be positive can be hope or hype, it is reasonable to consider the future possibility of "cocktail" combination of different antibodies after the available experimental evidence of cross-talk between these proteins and neuropathological evidence of coexistence of these proteinopathies more frequently than expected by chance. Moreover, such "cocktail" approaches are widespread and accepted common practice in other fields such as oncology, and the complexity of neurodegenerative parkinsonisms makes reasonable the option for testing and eventually applying such combined approaches, should these prove useful separately, in the setting of patients with evidence of underlying concomitant proteinopathies, for example through biomarkers.
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Inmunoterapia , alfa-Sinucleína , Proteínas tau , Humanos , alfa-Sinucleína/inmunología , Inmunoterapia/métodos , Proteínas tau/inmunología , Animales , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/inmunología , Enfermedad de Parkinson/tratamiento farmacológicoRESUMEN
Elderly human brains are vulnerable to multiple proteinopathies, although each protein has a different transmission pathway. Tau-immunoreactive astrocytes are well-known in elderly brains. In contrast, astrocytic plaques, a hallmark in corticobasal degeneration (CBD), rarely occur in aging and neurodegenerative disease other than CBD. To elucidate the clinicopathological correlation of aging-related pathology in CBD, we examined 21 pathologically proven CBD cases in our institute (12 males and 9 females, with a mean age of death 70.6 years). All CBD cases showed grains and neurofibrillary tangles (NFTs). Fifteen cases (71.4%) showed beta-amyloid deposition such as senile plaques or cerebral amyloid angiopathy. Three cases (14.3%) had Lewy body pathology. One case was classified as amygdala-predominant Lewy body disease, although no cases met the pathological criteria for Alzheimer's disease. Five cases (23.8%) displayed Limbic-predominant and age-related TDP-43 encephalopathy (LATE). NFTs, grains, and TDP-43-positive neuronal inclusions were widely distributed throughout the limbic system of CBD patients, but their densities were low. CBD might a have similar cell vulnerability and transmission pathway to that of multiple proteinopathy in aging brains.
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Enfermedad de Alzheimer , Degeneración Corticobasal , Enfermedad por Cuerpos de Lewy , Enfermedades Neurodegenerativas , Masculino , Femenino , Humanos , Anciano , Enfermedades Neurodegenerativas/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad por Cuerpos de Lewy/metabolismo , Ovillos Neurofibrilares/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas tau/metabolismoRESUMEN
Previous studies have suggested a relationship between the number of CAG triplet repeats in the HTT gene and neurodegenerative diseases not related to Huntington's disease (HD). This study seeks to investigate whether the number of CAG repeats of HTT is associated with the risk of developing certain tauopathies and its influence as a modulator of the clinical and neuropathological phenotype. Additionally, it aims to evaluate the potential of polyglutamine staining as a neuropathological screening. We genotyped the HTT gene CAG repeat number and APOE-â° isoforms in a cohort of patients with neuropathological diagnoses of tauopathies (n=588), including 34 corticobasal degeneration (CBD), 98 progressive supranuclear palsy (PSP) and 456 Alzheimer's disease (AD). Furthermore, we genotyped a control group of 1070 patients, of whom 44 were neuropathologic controls. We identified significant differences in the number of patients with pathological HTT expansions in the CBD group (2.7%) and PSP group (3.2%) compared to control subjects (0.2%). A significant increase in the size of the HTT CAG repeats was found in the AD compared to the control group, influenced by the presence of the Apoliprotein E (APOE)-â°4 isoform. Post-mortem assessments uncovered tauopathy pathology with positive polyglutamine aggregates, with a slight predominance in the neostriatum for PSP and CBD cases and somewhat greater limbic involvement in the AD case. Our results indicated a link between HTT CAG repeat expansion with other non-HD pathology, suggesting they could share common neurodegenerative pathways. These findings support that genetic or histological screening for HTT repeat expansions should be considered in tauopathies.
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Proteína Huntingtina , Tauopatías , Humanos , Masculino , Femenino , Anciano , Tauopatías/genética , Tauopatías/patología , Persona de Mediana Edad , Proteína Huntingtina/genética , Anciano de 80 o más Años , Parálisis Supranuclear Progresiva/genética , Parálisis Supranuclear Progresiva/patología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Repeticiones de Trinucleótidos/genética , Encéfalo/patología , Expansión de Repetición de Trinucleótido/genética , Genotipo , Degeneración Corticobasal/genética , Degeneración Corticobasal/patología , PéptidosRESUMEN
Atypical parkinsonism (AP) is a group of complex neurodegenerative disorders with marked clinical and pathophysiological heterogeneity. The use of systems biology tools may contribute to the characterization of hub-bottleneck genes, and the identification of its biological pathways to broaden the understanding of the bases of these disorders. A systematic search was performed on the DisGeNET database, which integrates data from expert curated repositories, GWAS catalogues, animal models and the scientific literature. The tools STRING 11.0 and Cytoscape 3.8.2 were used for analysis of protein-protein interaction (PPI) network. The PPI network topography analyses were performed using the CytoHubba 0.1 plugin for Cytoscape. The hub and bottleneck genes were inserted into 4 different sets on the InteractiveVenn. Additional functional enrichment analyses were performed to identify Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and gene ontology for a described set of genes. The systematic search in the DisGeNET database identified 485 genes involved with Atypical Parkinsonism. Superimposing these genes, we detected a total of 31 hub-bottleneck genes. Moreover, our functional enrichment analyses demonstrated the involvement of these hub-bottleneck genes in 3 major KEGG pathways. We identified 31 highly interconnected hub-bottleneck genes through a systems biology approach, which may play a key role in the pathogenesis of atypical parkinsonism. The functional enrichment analyses showed that these genes are involved in several biological processes and pathways, such as the glial cell development, glial cell activation and cognition, pathways were related to Alzheimer disease and Parkinson disease. As a hypothesis, we highlight as possible key genes for AP the MAPT (microtubule associated protein tau), APOE (apolipoprotein E), SNCA (synuclein alpha) and APP (amyloid beta precursor protein) genes.
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Redes y Vías Metabólicas , Trastornos Parkinsonianos , Mapas de Interacción de Proteínas , Biología de Sistemas , Humanos , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/metabolismo , Redes y Vías Metabólicas/genética , Mapas de Interacción de Proteínas/genética , Redes Reguladoras de Genes/genética , AnimalesRESUMEN
BACKGROUND: Early diagnosis in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) is important for clinical care and key to developing successful disease-modifying agents. The patient-dependent phases of decision-making made before contact with a healthcare professional have been inadequately studied. OBJECTIVES: To evaluate the patient-dependent phases of decision-making from symptom onset, comparing this to clinician and/or health system delays within the overall diagnostic pathway. METHODS: Using the Anderson General Model of Total Patient Delay and a mixed-methods approach in participants with PSP/CBS and their caregivers recruited to the Scottish PSP and CBS cohort, we quantified and evaluated the determinants of "appraisal", "illness," and "behavioral" delay, comparing this to the clinician and/or health system delays ("treatment" delay) within the overall time from symptom onset to diagnosis. RESULTS: The time from index symptom onset to diagnosis was 3.26 (interquartile range [IQR] = 2.42, 4.75) years in PSP and 2.58 (IQR = 1.69, 4.08) years in CBS. Patient appraisal delay was 24 (IQR = 6, 60) weeks in PSP and 8 (IQR = 5, 24) weeks in CBS, illness delay 0 (IQR = -14, 0) weeks in PSP and 0 (IQR = -4, 0) weeks in CBS, with little perceived behavioral delay. Determinants of delay included the non-specificity of symptoms, normalization of symptoms within the context of age or normal physiological variability, and the extent of insight into new somatic symptoms. CONCLUSIONS: Although patient appraisal delay contributes to overall diagnostic delay in PSP/CBS, the greater proportion of overall diagnostic delay arises after contact with a healthcare professional (treatment delay).
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Diagnóstico Tardío , Parálisis Supranuclear Progresiva , Humanos , Parálisis Supranuclear Progresiva/diagnóstico , Masculino , Femenino , Anciano , Persona de Mediana Edad , Anciano de 80 o más Años , Factores de Tiempo , Estudios de Cohortes , Cuidadores/psicología , Enfermedades de los Ganglios Basales/diagnóstico , Diagnóstico PrecozRESUMEN
Introduction: The present study characterized the degeneration of nigrostriatal dopaminergic neurons in the early stages of parkinsonian disorders using integrative neuroimaging analysis with neuromelanin-sensitive MRI and 123I-FP-CIT dopamine transporter (DAT) SPECT. Methods: Thirty-one, 30, and 29 patients with progressive supranuclear palsy (PSP), corticobasal syndrome (CBS) with abnormal specific binding ratio (SBR) in either hemisphere (mean ± 2SD), and parkinsonism-predominant multiple system atrophy (MSA-P), respectively, were enrolled. Neuromelanin-related contrast (NRC) in the substantia nigra (NRCSN) and locus coeruleus (NRCLC) and the SBR of DAT SPECT were measured. All the patients underwent both examinations simultaneously within five years after symptom onset. After adjusting for interhemispheric asymmetry on neuromelanin-related MRI contrast using the Z-score, linear regression analysis of the NRCSN and SBR was performed for the most- and least-affected hemispheres, as defined by the interhemispheric differences per variable (SBR, NRCSN, standardized [SBR + NRCSN]) in each patient. Results: Although the variables did not differ significantly between PSP and CBS, a significant correlation was found for CBS in the most-affected hemisphere for all the definitions, including the clinically defined, most-affected hemisphere. No significant correlation was found between the NRCSN and SBR for any of the definitions in either PSP or MSA-P. Conclusion: Together with the findings of our previous study of dementia with Lewy bodies (DLB) and Parkinson's disease (PD), the present findings indicated that neural degeneration in the disorders examined may be categorized by the significance of the NRCSN-SBR correlation in PD and CBS and its non-significance in DLB, PSP, and MSA-P.
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Although the initial symptoms of corticobasal degeneration (CBD) are varied, psychiatric symptoms are uncommon. Here, we report the autopsy findings of a patient with early CBD who presented with hallucinations. A 68-year-old man developed memory loss and visions of bears and insects. Because of slow vertical eye movement, postural instability, and levodopa-unresponsive parkinsonism, the patient initially was clinically diagnosed with progressive supranuclear palsy. He died of a urinary tract infection 11 months after the onset of the disease. Histopathological examination revealed neuronal loss and gliosis, which were severe in the substantia nigra and moderate in the globus pallidus and subthalamic nucleus. Astrocytic plaques were scattered throughout the amygdala and premotor cortex. The superficial cortical layers lacked ballooned neurons and spongiosis, and tau deposition was greater in glia than in neurons. The amygdala contained a moderate number of argyrophilic grains and pretangles. Western blot analysis showed a 37-kDa band among the low-molecular-weight tau fragments. Because the CBD pathology was mild, we attributed the patient's visual hallucinations to the marked argyrophilic grain pathology. CBD can occur with psychiatric symptoms, including visual hallucinations, and argyrophilic grain pathology may be associated with psychiatric symptoms.
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Degeneración Corticobasal , Alucinaciones , Humanos , Masculino , Alucinaciones/patología , Alucinaciones/etiología , Anciano , Degeneración Corticobasal/patología , Degeneración Corticobasal/complicacionesRESUMEN
Over the last two decades there have been meaningful developments on biomarkers of neurodegenerative diseases, extensively (but not solely) focusing on their proteinopathic nature. Accordingly, in Alzheimer's disease determination of levels of total and phosphorylated tau (τ and p-τ, usually p-τ181) along with amyloid-beta1-42 (Aß1-42) by immunodetection in cerebrospinal fluid (CSF) and currently even in peripheral blood, have been widely accepted and introduced to routine diagnosis. In the case of Parkinson's disease, α-synuclein as a potential biomarker (both for diagnosis and progression tracking) has proved more elusive under the immunodetection approach. In recent years, the emergence of the so-called seed amplification assays is proving to be a game-changer, with mounting evidence under different technical approaches and using a variety of biofluids or tissues, yielding promising diagnostic accuracies. Currently the least invasive but at once more reliable source of biosamples and techniques are being sought. Here we overview these advances.
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Enfermedad de Alzheimer , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , alfa-Sinucleína/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeoRESUMEN
Depression is one of the most frequent neuropsychiatric symptoms in corticobasal degeneration (CBD), a rare, sporadic, and late-onset progressive neurodegenerative disorder of unknown etiology. It is clinically characterized by a levodopa-poorly responsible akinetic-rigid syndrome, apraxia, limb dystonia, cognitive, mood, behavioral, and language disorders. This 4-repeat (4R) tauopathy is morphologically featured by asymmetric frontoparietal atrophy, neuronal loss, and gliosis in cortex and subcortex including substantia nigra, ballooned/achromatic neurons with filamentous 4R tau aggregates in cortex and striatum, widespread thread-like structures, pathognomonic "astroglial plaques", "tufted astrocytes", and numerous "coiled bodies" (in astrocytes and oligodendroglia) in cerebral white matter. CBD is non-specific, as pathologically proven cases include several clinical phenotypes. Pubmed and Google Scholar were systematically analyzed until October 2023, with focus on the prevalence, clinical manifestation, neuroimaging data, and treatment options of depression in CBD. Its prevalence is about 30-40% which is more frequent than in most other atypical parkinsonian syndromes. Depression usually does not correlate with motor and other clinical parameters, suggesting different pathophysiological mechanisms. Asymmetric atrophy and hypometabolism of frontoparietal cortical areas are associated with disruption of fronto-subcortical circuits, nigrostriatal dopaminergic, and cholinergic deficiency. Since no specific neuroimaging, neuropathological, or biomarker studies of depression in CBD are available, its pathobiological mechanisms and pathogenesis are poorly understood. Antidepressive therapy may be useful, but is often poorly tolerated. Depression in CBD, like in other parkinsonian syndromes, may be related to multi-regional patterns of cerebral disturbances and complex pathogenic mechanisms that deserve further elucidation as a basis for early diagnosis and adequate treatment to improve the quality of life in this fatal disease.
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Degeneración Corticobasal , Trastornos Parkinsonianos , Humanos , Corteza Cerebral/patología , Depresión/epidemiología , Calidad de Vida , Atrofia/patología , MorbilidadRESUMEN
Introduction: Atypical parkinsonian syndromes (APS) are rare neurodegenerative syndromes for which parkinsonism is one significant feature. APS includes progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and corticobasal syndrome (CBS). The diagnosis of APS remains reliant on clinical features with no available diagnostic or prognostic biomarker. Clinical scales remain the gold standard assessment measures in clinical trials and research. The lack of standardised approach for research cohorts has contributed to shortcomings in disease understanding and limits collaboration between researchers. The primary objectives of this study are to (1) establish an assessment protocol for parkinsonian syndromes and (2) to implement it at a single site to establish the viability and utility of populating a clinical and biological databank of patients with APS. Methods: The Monash Alfred Protocol for Assessment of APS was devised by expert consensus within a broad multidisciplinary team. Eligible patients are diagnosed as possible or probable PSP, MSA or CBS by a consultant neurologist with expertise in movement disorders. Participants will be assessed at recruitment and then annually for up to 3 years; individuals within 5 years of index symptom onset will also undergo a once-off 6-month assessment. Ethics and dissemination: Each participant or their legally authorised representative will provide informed written consent prior to commencement of the study. Data will be stored on a locally hosted Research Electronic Data Capture database. Trial registration number: Australian New Zealand Clinical Trials Registry (ANZCTN 12622000923763).
RESUMEN
Objective: To identify the cortical and subcortical distribution of atrophy and the disorganization of white matter bundles underlying the apraxic disorders in a patient with corticobasal degeneration (CBD). Method: Patient underwent appropriate neuropsychological tasks aimed at identifying the nature of the apraxic disorder and morphometric structural MRI with whole-brain voxel-wise analysis. Results: Progressive limbkinetic apraxia (LKA) with onset in the right upper limb with subsequent extension to the limbs, trunk, orofacial district, and eye movements was documented, associated with element of ideomotor apraxia (IMA). The MRI study showed grey matter atrophy extending to much of the frontal cortex bilaterally, including the precentral cortex, and into the inferior parietal regions. Caudate and putamen were involved on the left. Significant clusters of white matter atrophy were found in the bilateral superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus (ILF) and corpus callosum (CC). Sensory evoked potentials (SEPs) and motor evoked potentials (MEPs) were normal. Conclusion: Previous observations in CBD indicate lack of inhibitory control from the sensory to the primary motor cortex with dysfunctional frontoparietal and cortico-motoneuron projections. Our neuroimaging data are partially consistent with these observations suggesting that the apraxic disorder in our patient might be produced by the disconnection of the primary motor cortex from the parietal areas that prevents selection and control of muscle movements, in the presence of preserved cortico-motoneuron as demonstrated by normal PEM. Apraxic disorders in CBD are high-level deficits of movement control that spare the motoneuron.
Asunto(s)
Apraxias , Degeneración Corticobasal , Humanos , Pruebas Neuropsicológicas , Imagen por Resonancia Magnética , Atrofia/complicacionesRESUMEN
Synaptic dysfunction and altered synaptic pruning are present in people with Parkinsonian disorders. Dopamine loss and alpha-synuclein accumulation, two hallmarks of Parkinson's disease (PD) pathology, contribute to synaptic dysfunction and reduced synaptic density in PD. Atypical Parkinsonian disorders are likely to have unique spatiotemporal patterns of synaptic density, differentiating them from PD. Therefore, quantification of synaptic density has the potential to support diagnoses, monitor disease progression, and treatment efficacy. Novel radiotracers for positron emission tomography which target the presynaptic vesicle protein SV2A have been developed to quantify presynaptic density. The radiotracers have successfully investigated synaptic density in preclinical models of PD and people with Parkinsonian disorders. Therefore, this review will summarize the preclinical and clinical utilization of SV2A radiotracers in people with Parkinsonian disorders. We will evaluate how SV2A abundance is associated with other imaging modalities and the considerations for interpreting SV2A in Parkinsonian pathology.