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INTRODUCTION: The objective of this study is to investigate the incremental value of amyloid positron emission tomography (Aß-PET) in a tertiary memory clinic setting in China. METHODS: A total of 1073 patients were offered Aß-PET using 18F-florbetapir. The neurologists determined a suspected etiology (Alzheimer's disease [AD] or non-AD) with a percentage estimate of their confidence and medication prescription both before and after receiving the Aß-PET results. RESULTS: After disclosure of the Aß-PET results, etiological diagnoses changed in 19.3% of patients, and diagnostic confidence increased from 69.3% to 85.6%. Amyloid PET results led to a change of treatment plan in 36.5% of patients. Compared to the late-onset group, the early-onset group had a more frequent change in diagnoses and a higher increase in diagnostic confidence. DISCUSSION: Aß-PET has significant impacts on the changes of diagnoses and management in Chinese population. Early-onset cases are more likely to benefit from Aß-PET than late-onset cases. HIGHLIGHTS: Amyloid PET contributes to diagnostic changes and its confidence in Chinese patients. Amyloid PET leads to a change of treatment plans in Chinese patients. Early-onset cases are more likely to benefit from amyloid PET than late-onset cases.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Amiloide , Doença de Alzheimer/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Proteínas Amiloidogênicas , Compostos de Anilina , China , Peptídeos beta-Amiloides , Disfunção Cognitiva/diagnósticoRESUMO
BACKGROUND: Early prevention of Alzheimer's disease (AD) is a feasible way to delay AD onset and progression. Information on AD prediction at the individual patient level will be useful in AD prevention. In this study, we aim to develop risk models for predicting AD onset at individual level using optimal set of predictors from multiple features. METHODS: A total of 487 cognitively normal (CN) individuals and 796 mild cognitive impairment (MCI) patients were included from Alzheimer's Disease Neuroimaging Initiative. All the participants were assessed for clinical, cognitive, magnetic resonance imaging and cerebrospinal fluid (CSF) markers and followed for mean periods of 5.6 years for CN individuals and 4.6 years for MCI patients to ascertain progression from CN to incident prodromal stage of AD or from MCI to AD dementia. Least Absolute Shrinkage and Selection Operator Cox regression was applied for predictors selection and model construction. RESULTS: During the follow-up periods, 139 CN participants had progressed to prodromal AD (CDR ≥ 0.5) and 321 MCI patients had progressed to AD dementia. In the prediction of individual risk of incident prodromal stage of AD in CN individuals, the AUC of the final CN model was 0.81 within 5 years. The final MCI model predicted individual risk of AD dementia in MCI patients with an AUC of 0.92 within 5 years. The models were also associated with longitudinal change of Mini-Mental State Examination (p < 0.001 for CN and MCI models). An Alzheimer's continuum model was developed which could predict the Alzheimer's continuum for individuals with normal AD biomarkers within 3 years with high accuracy (AUC = 0.91). CONCLUSIONS: The risk models were able to provide personalized risk for AD onset at each year after evaluation. The models may be useful for better prevention of AD.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Sintomas Prodrômicos , Progressão da Doença , Disfunção Cognitiva/complicações , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/patologia , BiomarcadoresRESUMO
BACKGROUND: Plasma glial fibrillary acidic protein (GFAP) has emerged as a promising biomarker in neurological disorders, but further evidence is required in relation to its usefulness for diagnosis and prediction of Alzheimer disease (AD). METHODS: Plasma GFAP was measured in participants with AD, non-AD neurodegenerative disorders, and controls. Its diagnostic and predictive value were analyzed alone or combined with other indicators. RESULTS: A total of 818 participants were recruited (210 followed). Plasma GFAP was significantly higher in AD than in non-AD dementia and non-demented individuals. It increased in a stepwise pattern from preclinical AD, through prodromal AD to AD dementia. It effectively distinguished AD from controls [area under the curve (AUC) > 0.97] and non-AD dementia (AUC > 0.80) and distinguished preclinical (AUC > 0.89) and prodromal AD (AUC > 0.85) from Aß-normal controls. Adjusted or combined with other indicators, higher levels of plasma GFAP displayed predictive value for risk of AD progression (adjusted hazard radio= 4.49, 95%CI, 1.18-16.97, P = 0.027 based on the comparison of those above vs below average at baseline) and cognitive decline (standard-ß=0.34, P = 0.002). Additionally, it strongly correlated with AD-related cerebrospinal fluid (CSF)/neuroimaging markers. CONCLUSIONS: Plasma GFAP effectively distinguished AD dementia from multiple neurodegenerative diseases, gradually increased across the AD continuum, predicted the individual risk of AD progression, and strongly correlated with AD CSF/neuroimaging biomarkers. Plasma GFAP could serve as both a diagnostic and predictive biomarker for AD.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/líquido cefalorraquidiano , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Diagnóstico Diferencial , Biomarcadores , Progressão da Doença , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidianoRESUMO
PURPOSE: Human post mortem studies have described the topographical patterns of tau pathology in progressive supranuclear palsy (PSP). Recent advances in tau PET tracers are expected to herald the next era of PSP investigation for early detection of tau pathology in living brains. This study aimed to investigate whether 18F-Florzolotau PET imaging may capture the distribution patterns and regional vulnerability of tau pathology in PSP, and to devise a novel image-based staging system. METHODS: The study cohort consisted of 148 consecutive patients with PSP who had undergone 18F-Florzolotau PET imaging. The PSP rating scale (PSPrs) was used to measure disease severity. Similarities and differences of tau deposition among different clinical phenotypes were examined at the regional and voxel levels. An 18F-Florzolotau pathological staging system was devised according to the scheme originally developed for post mortem data. In light of conditional probabilities for the sequence of events, an 18F-Florzolotau modified staging system by integrating clusters at the regional level was further developed. The ability of 18F-Florzolotau staging systems to reflect disease severity in terms of PSPrs score was assessed by analysis of variance. RESULTS: The distribution patterns of 18F-Florzolotau accumulation in living brains of PSP showed a remarkable similarity to those reported in post mortem studies, with the binding intensity being markedly higher in Richardson's syndrome. Moreover, 18F-Florzolotau PET imaging allowed detecting regional vulnerability and tracking tau accumulation in an earlier fashion compared with post mortem immunostaining. The 18F-Florzolotau staging systems were positively correlated with clinical severity as reflected by PSPrs scores. CONCLUSIONS: 18F-Florzolotau PET imaging can effectively capture the distribution patterns and regional vulnerability of tau pathology in PSP. The 18F-Florzolotau modified staging system holds promise for early tracking of tau deposition in living brains.
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Paralisia Supranuclear Progressiva , Humanos , Encéfalo/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Proteínas tau/metabolismoRESUMO
BACKGROUND: Development of disease-modifying therapeutic trials of progressive supranuclear palsy (PSP) urges the need for sensitive fluid biomarkers. OBJECTIVES: The objectives of this study were to explore the utility of plasma biomarkers in the diagnosis, differential diagnosis, and assessment of disease severity, brain atrophy, and tau deposition in PSP. METHODS: Plasma biomarkers were measured using a single-molecule array in a cohort composed of patients with PSP, Parkinson's disease (PD), multiple system atrophy with predominant parkinsonism (MSA-P), and healthy controls (HCs). RESULTS: Plasma neurofilament light chain (NfL) outperformed other plasma makers (ie, glial fibrillary acidic protein [GFAP], phosphorylated-tau 181 [p-tau181], amyloid-ß 1-40, amyloid-ß 1-42) in identifying PSP from HC (area under the curve [AUC] = 0.904) and from MSA-P (AUC = 0.711). Plasma GFAP aided in distinguishing PSP from HC (AUC = 0.774) and from MSA-P (AUC = 0.832). It correlated with brainstem atrophy and higher regional tau accumulation. However, plasma p-tau181 neither helped in diagnosis nor was it associated with clinical or neuroimaging measures. CONCLUSIONS: Plasma NfL and GFAP showed different values in differentiating PSP from HC or controls with other forms of neurodegenerative parkinsonism and detecting disease severity, brain atrophy, or tau deposition in PSP. © 2023 International Parkinson and Movement Disorder Society.
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Atrofia de Múltiplos Sistemas , Doença de Parkinson , Transtornos Parkinsonianos , Paralisia Supranuclear Progressiva , Humanos , Biomarcadores , Atrofia de Múltiplos Sistemas/diagnóstico , Doença de Parkinson/diagnóstico , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/patologia , Tomografia por Emissão de Pósitrons/métodos , Paralisia Supranuclear Progressiva/diagnóstico , Proteínas tau/metabolismoRESUMO
BACKGROUND: Frontotemporal lobar degeneration with tauopathy caused by MAPT (microtubule-associated protein tau) mutations is a highly heterogenous disorder. The ability to visualize and longitudinally monitor tau deposits may be beneficial to understand disease pathophysiology and predict clinical trajectories. OBJECTIVE: The aim of this study was to investigate the cross-sectional and longitudinal 18 F-APN-1607 positron emission tomography/computed tomography (PET/CT) imaging findings in MAPT mutation carriers. METHODS: Seven carriers of MAPT mutations (six within exon 10 and one outside of exon 10) and 15 healthy control subjects were included. All participants underwent 18 F-APN-1607 PET/CT at baseline. Three carriers of exon 10 mutations received follow-up 18 F-APN-1607 PET/CT scans. Standardized uptake value ratio (SUVR) maps were obtained using the cerebellar gray matter as the reference region. SUVR values observed in MAPT mutation carriers were normalized to data from healthy control subjects. A regional SUVR z score ≥ 2 was used as the criterion to define positive 18 F-APN-1607 PET/CT findings. RESULTS: Although the seven study patients had heterogenous clinical phenotypes, all showed a significant 18 F-APN-1607 uptake characterized by high-contrast signals. However, the anatomical localization of tau deposits differed in patients with distinct clinical symptoms. Follow-up imaging data, which were available for three patients, demonstrated worsening trends in patterns of tau accumulation over time, which were paralleled by a significant clinical deterioration. CONCLUSIONS: Our data represent a promising step in understanding the usefulness of 18 F-APN-1607 PET/CT imaging for detecting tau accumulation in MAPT mutation carriers. Our preliminary follow-up data also suggest the potential value of 18 F-APN-1607 PET/CT for monitoring the longitudinal trajectories of frontotemporal lobar degeneration caused by MAPT mutations. © 2021 International Parkinson and Movement Disorder Society.
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Doença de Alzheimer , Demência Frontotemporal , Degeneração Lobar Frontotemporal , Estudos Transversais , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Humanos , Mutação/genética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons/métodos , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
BACKGROUND: Previous studies with a limited sample size suggested more severe dopaminergic transporter (DAT) lesions in the striatum of progressive supranuclear palsy (PSP) than those in Parkinson's disease (PD) and multiple system atrophy-parkinsonism (MSA-P). However, few studies had taken various subtypes of PSP into consideration, making the reanalysis of DAT imaging in larger PSP cohort with various subtypes in need. OBJECTIVES: To compare the dopaminergic lesion patterns of PSP with MSA-P and PD, and to explore the specific striatal subregional patterns of different PSP subtypes. METHODS: 11 C-CFT positron emission tomography (PET) imaging was conducted in 83 PSP patients consisting of different subtypes, 61 patients with PD, 41 patients with MSA-P, and 43 healthy volunteers. Demographic and clinical data were compared by the chi-squared test or one-way analysis of variance. A generalized linear model was used to examine intergroup differences in tracer uptake values after adjusting for age, disease duration, and disease severity. Areas under the receiver operating characteristic curve were calculated to assess the diagnostic accuracy of subregional DAT binding patterns. RESULTS: The patients with PSP presented more severe DAT loss in the striatum than in PD and MSA-P, especially in caudate. In PSP, the subregional lesion was still more severe in putamen than in caudate, similar to that in PD and MSA-P. Among detailed subtypes, no significant difference was detected. CONCLUSION: The dopaminergic lesions were more severe in PSP, and no difference was detected among subtypes.
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Atrofia de Múltiplos Sistemas , Doença de Parkinson , Transtornos Parkinsonianos , Paralisia Supranuclear Progressiva , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Humanos , Atrofia de Múltiplos Sistemas/metabolismo , Doença de Parkinson/patologia , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Paralisia Supranuclear Progressiva/patologia , Tomografia Computadorizada de Emissão de Fóton Único/métodosRESUMO
PURPOSE: Striatal asymmetry is a common feature in Parkinson's disease (PD), which changes with the progression of the disease. However, the correlation between the striatal asymmetry and severity of PD remains unclear. The present study aimed to investigate the characteristics of asymmetry in PD, and analyze the correlation between the striatal asymmetry index (SAI) and disease severity. MATERIALS AND METHODS: This retrospective study enrolled 63 patients with idiopathic PD. The severity of PD was classified according to the Hoehn & Yahr (H&Y) staging system. The SAI in the subregions of the striatum was measured using 11C-N-2-carbomethoxy-3-(4-fluorophenyl)-tropane (11C-CFT) positron emission tomography (PET). RESULTS: There was a significant difference in the SAI of the posterior putamen among the three groups (H&Y stage I, H&Y stage II, and H&Y stage III-IV; p = 0.001). However, there was no difference in the SAI of the anterior putamen (p = 0.340) or SAI of the caudate nucleus (p = 0.342) among the three groups. The SAI of the posterior putamen in patients with PD was significantly higher than that in patients with multiple system atrophy or progressive supranuclear palsy (p = 0.008). CONCLUSION: The SAI of the posterior putamen is associated with the severity of PD, and may be correlated to the loss of dopamine cells in the pars compacta of the ventrolateral substantia nigra projecting to the posterior putamen. The SAI may be a potential indicator for evaluating the severity of PD, and distinguishing PD from other degenerative diseases.
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Doença de Parkinson , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Humanos , Doença de Parkinson/diagnóstico por imagem , Putamen/metabolismo , Estudos Retrospectivos , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Swallow tail sign (STS) on MRI is presumed to be an imaging biomarker of nigrosome-1, which may exhibit a similar role as positron emission tomography (PET), indicating dopaminergic degeneration. PURPOSE: To investigate whether an alteration of STS could serve as an alternative screening sign compared with PET in the diagnosis of early-stage Parkinson's disease (esPD). STUDY TYPE: Prospective. POPULATION: Thirty-seven patients with esPD and 27 age- and sex-matched healthy controls (HCs). FIELD STRENGTH/SEQUENCE: Quantitative susceptibility mapping images were collected on 3T MRI and [18 F]9-fluoropropyl-(+)-dihydrotetra-benazine PET images were acquired using a 64 rings PET/CT scanner. ASSESSMENT: Alterations of STS and striatal uptake in each hemisphere were visually rated on a 0-2 points scale. Point 2: normal appearance of STS/normal striatal uptake; Point 1: partial loss of STS/uptake reduction confined to the putamen; Point 0: total loss of STS/uptake reduction extended to the caudate nucleus. The concordance rate of STS rating and ipsilateral striatal binding was calculated at the nuclei level. At the participant level, an evaluation rating was calculated by adding the STS ratings from both hemispheres to distinguish esPD from HCs. STATISTICAL TESTS: The intra- and interobserver agreement were tested using Cohen's kappa and the intraclass correlation coefficient. Hotelling's T-squared test was used to compare the difference of rating points. Receiver operating characteristic analysis was performed to evaluate the diagnostic power. RESULTS: The intra- and interobserver agreement for STS and striatal uptake rating was over 0.75. There was no significant difference of rating point distribution (P = 0.084). The concordance rate was 94.3% for the right side and 91.4% for the left. Using bilateral partial loss of STS as the threshold, the achieved sensitivity and specificity for discriminating esPD from HCs were 94.59% and 92.49%, respectively. DATA CONCLUSION: STS alterations corresponded well with striatal uptake on PET in esPD, and our proposed evaluation scale of STS had satisfactory diagnostic performance in discriminating the disease. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.
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Doença de Parkinson , Humanos , Imageamento por Ressonância Magnética , Doença de Parkinson/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons , Estudos ProspectivosRESUMO
This study aimed to characterize the clinical features and the related cerebral glucose metabolism pattern of cognitive impairments in Parkinson's disease (PD) with positron emission tomography (PET) imaging. We recruited 168 PD patients and 100 age-matched healthy controls of similar education and gender distribution. All of those enrolled underwent clinical assessment including the unified Parkinson's disease rating scale motor score, Hoehn and Yahr scale, and comprehensive neuropsychological tests including domains of executive function, attention, memory, visuospatial function, and language. Demographics and the results of cognitive measures were compared between patients and healthy controls. Cognition status was classified as PD patients with dementia (PD-D), PD patients with mild cognitive impairment (PD-MCI), or PD patients with normal cognition (PD-NC). In 53 PD patients who underwent 18 F-fluorodeoxyglucose (18 F-FDG) PET imaging, correlations between Z-score values of the different cognitive domains and cerebral 18 F-FDG uptake were assessed using statistical parametric mapping (SPM8) corrected for age and motor severity. A total of 23.2% of PD patients were PD-MCI and 8.9% were PD-D. In the group of PD-MCI, 96.3% showed multiple-domain deficits, with executive function and attention impairment most predominantly involved. All the cognitive domain scores with the exception of language correlated with 18 F-FDG metabolisms, primarily in posterior temporo-parieto-occipital association cortical areas. This study found that cognitive impairment in PD particularly encompasses frontal/executive deficits. Posterior cortical areas, containing multiple neurotransmitters and neural circuits, may play an important role in the pathogenesis of cognitive impairment in PD.
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Atenção/fisiologia , Disfunção Cognitiva , Demência , Função Executiva/fisiologia , Doença de Parkinson , Adulto , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Demência/diagnóstico por imagem , Demência/etiologia , Demência/metabolismo , Demência/fisiopatologia , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Tomografia por Emissão de PósitronsRESUMO
Based on the 'AT(N)' system, individuals with normal amyloid biomarkers but abnormal tauopathy or neurodegeneration biomarkers are classified as non-Alzheimer's disease (AD) pathologic change. This study aimed to assess the long-term clinical and cognitive trajectories of individuals with non-AD pathologic change among older adults without dementia, comparing them to those with normal AD biomarkers and AD pathophysiology. Analyzing Alzheimer's Disease Neuroimaging Initiative data, we evaluated clinical outcomes and conversion risk longitudinally using mixed effects models and multivariate Cox proportional hazard models. We found that compared to individuals with A-T-N-, those with abnormal tauopathy or neurodegeneration biomarkers (A-T + N-, A-T-N + , and A-T + N + ) had a faster rate of cognitive decline and disease progression. Individuals with A-T + N + had a faster rate of decline than those with A-T + N-. Additionally, in individuals with the same baseline tauopathy and neurodegeneration biomarker status, the presence of baseline amyloid could accelerate cognitive decline and clinical progression. These findings provide a foundation for future studies on non-AD pathologic change and its comparison with AD pathophysiology.
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Doença de Alzheimer , Disfunção Cognitiva , Tauopatias , Humanos , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Estudos Longitudinais , Peptídeos beta-Amiloides , Disfunção Cognitiva/psicologia , Biomarcadores , Progressão da Doença , Proteínas tauRESUMO
While early-onset Parkinson's disease (EOPD) caused by mutations in the parkin gene (PRKN) tends to have a relatively benign course compared to genetically undetermined (GU)-EOPD, the exact underlying mechanisms remain elusive. We aimed to search for the differences between PRKN-EOPD and GU-EOPD by dopamine transporter (DAT) and glucose metabolism positron-emission-tomography (PET) imaging. Twelve patients with PRKN-EOPD and 16 with GU-EOPD who accepted both 11C-2b-carbomethoxy-3b-(4-trimethylstannylphenyl) tropane (11C-CFT) and 18F-fluorodeoxyglucose PET were enrolled. The 11C-CFT uptake was analyzed on both regional and voxel levels, whereas glucose metabolism was assessed in a voxel-wise fashion. Correlations between DAT and glucose metabolism imaging, DAT imaging and clinical severity, as well as glucose metabolism imaging and clinical severity were explored. Both clinical symptoms and DAT-binding patterns in the posterior putamen were highly symmetrical in patients with PRKN-EOPD, and dopaminergic dysfunction in the ipsilateral putamen was severer in patients with PRKN-EOPD than GU-EOPD. Meanwhile, the DAT binding was associated with the severity of motor dysfunction in patients with GU-EOPD only. Patients with PRKN-EOPD showed increased glucose metabolism in the contralateral medial frontal gyrus (supplementary motor area (SMA)), contralateral substantia nigra, contralateral thalamus, and contralateral cerebellum. Notably, glucose metabolic activity in the contralateral medial frontal gyrus was inversely associated with regional DAT binding in the bilateral putamen. Patients with PRKN-EOPD showed enhanced metabolic connectivity within the bilateral putamen, ipsilateral paracentral and precentral lobules, and the ipsilateral SMA. Collectively, compared to GU-EOPD, PRKN-EOPD is characterized by symmetrical, more severe dopaminergic dysfunction and relative increased glucose metabolism. Meanwhile, SMA with elevated glucose metabolism and enhanced connectivity may act as compensatory mechanisms in PRKN-EOPD. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-022-00077-8.
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Background: According to the new 'AT(N)' system, those with a normal amyloid biomarker but with abnormal tauopathy or biomarkers of neurodegeneration or neuronal injury, have been labeled suspected non-Alzheimer's pathophysiology (SNAP). We aimed to estimate the long-term clinical and cognitive trajectories of SNAP individuals in non-demented elders and its comparison with individual in the Alzheimer's disease (AD) pathophysiology using 'AT(N)' system. Methods: We included individuals with available baseline cerebrospinal fluid (CSF) Aß (A), CSF phosphorylated tau examination (T) and 18F-uorodeoxyglucose PET or volumetric magnetic resonance imaging (N) from the Alzheimer's Disease Neuroimaging Initiative database. Longitudinal change in clinical outcomes are assessed using linear mixed effects models. Conversion risk from cognitively normal (CN) to cognitively impairment, and conversion from mild cognitive impairment (MCI) to dementia are assessed using multivariate Cox proportional hazard models. Results: Totally, 366 SNAP individuals were included (114 A-T-N-, 154 A-T + N-, 54 A-T-N + and 44 A-T + N+) of whom 178 were CN and 188 were MCI. Compared with A-T-N-, CN elders with A-T + N-, A-T-N + and A-T + N + had a faster rate of ADNI-MEM score decline. Moreover, CN older individuals with A-T + N + also had a faster rate of decline in ADNI-MEM score than those with A-T + N- individuals. MCI patients with A-T + N + had a faster rate of ADNI-MEM and ADNI-EF decline and hippocampal volume loss compared with A-T-N- and A-T + N- profiles. CN older individuals with A-T + N + had an increased risk of conversion to cognitive impairment (CDR-GS ≥ 0.5) compared with A-T + N- and A-T-N-. In MCI patients, A-T + N + also had an increased risk of conversion to dementia compared with A-T + N- and A-T-N-. Compared with A-T + N-, CN elders and MCI patients with A + T + N- and A + T + N + had a faster rate of ADNI-MEM score, ADNI-EF score decline, and hippocampal volume loss. CN individuals with A + T + N + had a faster rate of ADNI-EF score decline compare with A-T + N + individuals. Moreover, MCI patients with A + T + N + also had a faster rate of decline in ADNI-MEM score, ADNI-EF score and hippocampal volume loss than those with A-T + N + individuals. Conclusions: The findings from clinical, imaging and biomarker studies on SNAP, and its comparison with AD pathophysiology offered an important foundation for future studies.
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INTRODUCTION: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of autosomal dominantly inherited Parkinson's disease (PD). Recently, a novel pathogenic variant (N1437D; c.4309A > G; NM_98578) in the LRRK2 gene has been identified in three Chinese families with PD. In this study, we describe a Chinese family with autosomal dominant PD that segregated with the N1437D mutation. A detailed clinical and neuroimaging characterization of the affected family members is reported. We also sought to investigate the functional mechanisms by which the detected mutation could cause PD. METHODS: We characterized the clinical and imaging phenotype of a Chinese pedigree with autosomal dominant PD. We searched for a disease-causing mutation by targeted sequencing and multiple ligation-dependent probe amplification. The functional impact of the mutation was investigated in terms of LRRK2 kinase activity, guanosine triphosphate (GTP) binding, and guanosine triphosphatase (GTPase) activity. RESULTS: The disease was found to co-segregate with the LRRK2 N1437D mutation. Patients in the pedigree exhibited typical parkinsonism (age at onset: 54.0 ± 5.9 years). One affected family member - who had evidence of abnormal tau accumulation in the occipital lobe on tau PET imaging - developed PD dementia at follow-up. The mutation markedly increased LRRK2 kinase activity and promoted GTP binding, without affecting GTPase activity. CONCLUSIONS: This study describes the functional impact of a recently identified LRRK2 mutation, N1437D, that causes autosomal dominant PD in the Chinese population. Further research is necessary to investigate the contribution of this mutation to PD in multiple Asian populations.
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Doença de Parkinson , Humanos , População do Leste Asiático , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Guanosina Trifosfato/metabolismo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Mutação/genética , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/genética , Doença de Parkinson/patologiaRESUMO
BACKGROUND: Cognitive dysfunctions have been reported in multiple system atrophy (MSA). However the underlying mechanisms remain to be elucidated. This study aimed to explore the possible cerebral metabolism associated with domain-specific cognitive performances in MSA. METHODS: A total of 84 patients were diagnosed as probable or possible MSA, comprised of 27 patients as MSA with predominant parkinsonism (MSA-P) and 57 patients as MSA with predominant cerebellar ataxia (MSA-C). The comprehensive neuropsychological tests and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) imaging were performed. Z-score was calculated to non-dimensionalize and unify indicators of different tests in the domains of executive function, attention, language, memory, and visuospatial function. Correlations between specific Z-score and cerebral 18F-FDG uptake were analyzed using statistical parametric mapping. The cognition-related metabolic differences between patients with MSA-P and MSA-C were analyzed using the post-hoc test. RESULTS: Z-scores of the domains including attention, executive function, and language correlated positively with the metabolism in the superior/inferior frontal gyrus and cerebellum, but negatively with that in the insula and fusiform gyrus (p < 0.001). No significant differences in neuropsychological performances and frontal metabolism were found between patients with MSA-P and MSA-C. Only lower metabolism in the cerebellum was observed in MSA-C. CONCLUSION: Metabolic changes in the frontal lobe and cerebellum may participate in the cognitive impairments of patients with MSA. Nevertheless, cognitive and corresponding metabolic differences between the two subtypes of MSA still need more exploration.
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Background: Reduced dopamine transporter (DAT) binding in the striatum has been reported in patients with progressive supranuclear palsy (PSP). However, the relationship between striatal dopaminergic lesions and the disease severity of PSP remains to be explored. Objective: To investigate the contributions of striatal dopaminergic lesions to the disease severity of PSP. Methods: One hundred patients with clinically diagnosed PSP were consecutively enrolled in this study. The disease severity was systemically assessed using the PSP rating scale (PSPrs), and the dopaminergic lesions were assessed using the 11C-N-2-carbomethoxy-3-(4-fluorophenyl)-tropane positron emission tomography (11C-CFT PET) imaging. To explore the correlations between striatal DAT bindings and the disease severity, both the region-wise and voxel-wise analysis were adopted. Partial correlations and multiple linear regressions were performed to investigate the contribution of striatal dopaminergic lesions to the disease severity in PSP. Results: Sixty-three patients of PSP with Richardson's syndrome (PSP-RS) and 37 patients with PSP-non-RS were finally included. The disease severity in PSP-RS was much heavier than that in the PSP-non-RS. The DAT bindings in the caudate and anterior putamen correlated significantly with the PSPrs total scores, mainly in the domains of history, mentation, bulbar, and ocular motor symptoms. The striatal DAT bindings (caudate) contributed significantly to the disease severity of PSP, independent of the motor, cognition, emotion and behavioral dysfunctions. Conclusion: Our study highlighted the independent contribution of striatal dopaminergic lesions to the disease severity in PSP.
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BACKGROUND AND OBJECTIVES: To investigate relationship between baseline structural measurements of brain reserve and clinical progression in Parkinson's disease (PD). To further provide a possible underlying mechanism for structural measurements of brain reserve in PD, we combined functional and transcriptional data and investigated its relationship with progression-associated patterns derived from structural measurements and longitudinal clinical scores. METHODS: This longitudinal study collected data from June, 2010, to March, 2019, from two datasets. The Parkinson's progression markers initiative (PPMI) included controls and patients with newly diagnosed PD from 33 participating sites worldwide. Results were confirmed using data from the Huashan dataset (Shanghai, China), which included controls and patients with PD. Clinical symptoms were assessed with MDS-UPDRS scores and Schwab & England ADL. Both datasets were followed up to five years. Linear mixed-effects (LME) models were performed to examine whether changes in clinical scores over time differed as a function of brain structural measurements at baseline. RESULTS: A total of 389 PD patients (n = 346, age 61.3 ± 10.03, 35% female, PPMI dataset; n = 43, age 59.4 ± 7.3, 38.7% female, Huashan dataset) with T1-MRI and follow-up clinical assessments were included in this study. Results of LME models revealed significant interactions between baseline structural measurements of subcortical regions and time on longitudinal deterioration of clinical scores (MDS-UPDRS Part II, absolute ß > 0.27; total MDS-UPDRS scores, absolute ß > 1.05; PIGD score, absolute ß > 0.03; Schwab & England ADL, absolute ß > 0.59; all p < 0.05, FDR corrected). The interaction of baseline structural measurements of subcortical regions and time on longitudinal deterioration of the PIGD score was replicated using data from Huashan Hospital. Furthermore, the ß coefficients of these interactions recapitulated the spatial distribution of dopaminergic, metabolic and structural changes between PD patients and normal controls and the spatial distribution of expression of the α-synuclein gene (SNCA). DISCUSSION: PD patients with greater brain resources (that is, higher DBM values) had greater compensatory capacity, which was associated with slower rates of clinical progression. This knowledge could be used to stratify and monitor patients for clinical trials.
RESUMO
Mutations in Presenilin-1 (PSEN1) have been found to be associated with very early onset Alzheimer's disease (VEOAD). Here, we reported two patients with VEOAD caused by de novo PSEN1 mutations. A 33-year-old man with a de novo p.F177S mutation in PSEN1 presented with progressive decline in memory and daily function. A 37-year-old woman with a de novo PSEN1 p.L381V mutation presented with onset memory impairment, developed cerebellar syndrome, rigidity, and spastic paraparesis. The Amyloid/Tau/Neurodegeneration (ATN) biomarker profiles of both patients were Aâ+âTâ+â(N)+. Our finding increases the genetic knowledge of VEOAD and extends the ethnic distribution of PSEN1 mutations.
Assuntos
Doença de Alzheimer/genética , Mutação , Presenilina-1/genética , Adulto , Idade de Início , Doença de Alzheimer/complicações , Biomarcadores , Doenças Cerebelares/etiologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Paraparesia Espástica/etiologiaRESUMO
ABSTRACT: A correct clinical diagnosis of motor dysfunction accompanied by cognitive impairment remains challenging. Recent advances in molecular imaging biomarkers hold promise to overcome this issue. A 37-year-old woman presenting with parkinsonism and cognitive impairment underwent both multimodal neuroimaging and genetic testing. Her main findings on PET included diffuse tau accumulation in the cerebral cortex and left putamen, increased cerebellar amyloid deposits, asymmetrically reduced dopamine transporter binding, and mild hypermetabolism in the putamen. Genetic analysis revealed the presence of a presenilin-1 mutation (C.1157T>G). These findings suggested a diagnosis of early-onset autosomal dominant Alzheimer disease accompanied by parkinsonism.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Transtornos Parkinsonianos , Adulto , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Feminino , Humanos , Imageamento por Ressonância Magnética , Imagem Multimodal , Mutação , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/genética , Tomografia por Emissão de Pósitrons , Presenilina-1/genéticaRESUMO
A biological research framework to define Alzheimer' disease with dichotomized biomarker measurement was proposed by National Institute on Aging-Alzheimer's Association (NIA-AA). However, it cannot characterize the hierarchy spreading pattern of tau pathology. To reflect in vivo tau progression using biomarker, we constructed a refined topographic 18F-AV-1451 tau PET staging scheme with longitudinal clinical validation. Seven hundred and thirty-four participants with baseline 18F-AV-1451 tau PET (baseline age 73.9 ± 7.7 years, 375 female) were stratified into five stages by a topographic PET staging scheme. Cognitive trajectories and clinical progression were compared across stages with or without further dichotomy of amyloid status, using linear mixed-effect models and Cox proportional hazard models. Significant cognitive decline was first observed in stage 1 when tau levels only increased in transentorhinal regions. Rates of cognitive decline and clinical progression accelerated from stage 2 to stage 3 and stage 4. Higher stages were also associated with greater CSF phosphorylated tau and total tau concentrations from stage 1. Abnormal tau accumulation did not appear with normal ß-amyloid in neocortical regions but prompt cognitive decline by interacting with ß-amyloid in temporal regions. Highly accumulated tau in temporal regions independently led to cognitive deterioration. Topographic PET staging scheme have potentials in early diagnosis, predicting disease progression, and studying disease mechanism. Characteristic tau spreading pattern in Alzheimer's disease could be illustrated with biomarker measurement under NIA-AA framework. Clinical-neuroimaging-neuropathological studies in other cohorts are needed to validate these findings.