RESUMO
Variants in seven genes (LRRK2, GBA1, PRKN, SNCA, PINK1, PARK7 and VPS35) have been formally adjudicated as causal contributors to Parkinson's disease; however, individuals with Parkinson's disease are often unaware of their genetic status since clinical testing is infrequently offered. As a result, genetic information is not incorporated into clinical care, and variant-targeted precision medicine trials struggle to enrol people with Parkinson's disease. Understanding the yield of genetic testing using an established gene panel in a large, geographically diverse North American population would help patients, clinicians, clinical researchers, laboratories and insurers better understand the importance of genetics in approaching Parkinson's disease. PD GENEration is an ongoing multi-centre, observational study (NCT04057794, NCT04994015) offering genetic testing with results disclosure and genetic counselling to those in the US (including Puerto Rico), Canada and the Dominican Republic, through local clinical sites or remotely through self-enrolment. DNA samples are analysed by next-generation sequencing including deletion/duplication analysis (Fulgent Genetics) with targeted testing of seven major Parkinson's disease-related genes. Variants classified as pathogenic/likely pathogenic/risk variants are disclosed to all tested participants by either neurologists or genetic counsellors. Demographic and clinical features are collected at baseline visits. Between September 2019 and June 2023, the study enrolled 10 510 participants across >85 centres, with 8301 having received results. Participants were: 59% male; 86% White, 2% Asian, 4% Black/African American, 9% Hispanic/Latino; mean age 67.4 ± 10.8 years. Reportable genetic variants were observed in 13% of all participants, including 18% of participants with one or more 'high risk factors' for a genetic aetiology: early onset (<50 years), high-risk ancestry (Ashkenazi Jewish/Basque/North African Berber), an affected first-degree relative; and, importantly, in 9.1% of people with none of these risk factors. Reportable variants in GBA1 were identified in 7.7% of all participants; 2.4% in LRRK2; 2.1% in PRKN; 0.1% in SNCA; and 0.2% in PINK1, PARK7 or VPS35 combined. Variants in more than one of the seven genes were identified in 0.4% of participants. Approximately 13% of study participants had a reportable genetic variant, with a 9% yield in people with no high-risk factors. This supports the promotion of universal access to genetic testing for Parkinson's disease, as well as therapeutic trials for GBA1 and LRRK2-related Parkinson's disease.
Assuntos
Testes Genéticos , Glucosilceramidase , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Doença de Parkinson , alfa-Sinucleína , Humanos , Doença de Parkinson/genética , Doença de Parkinson/diagnóstico , Testes Genéticos/métodos , Masculino , Feminino , Glucosilceramidase/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , alfa-Sinucleína/genética , Idoso , Pessoa de Meia-Idade , Ubiquitina-Proteína Ligases/genética , Proteínas Quinases/genética , Proteína Desglicase DJ-1/genética , Proteínas de Transporte Vesicular/genética , América do Norte , Variação Genética/genética , Predisposição Genética para Doença/genética , Adulto , Revelação , Aconselhamento Genético , Canadá , Estados UnidosRESUMO
The olfactory bulb is involved early in the pathophysiology of Parkinson's disease (PD), which is consistent with the early onset of olfactory dysfunction. Identifying the molecular mechanisms through which PD affects the olfactory bulb could lead to a better understanding of the pathophysiology and etiology of olfactory dysfunction in PD. We specifically aimed to assess gene expression changes, affected pathways and co-expression network by whole transcriptomic profiling of the olfactory bulb in subjects with clinicopathologically defined PD. Bulk RNA sequencing was performed on frozen human olfactory bulbs of 20 PD and 20 controls without dementia or any other neurodegenerative disorder, from the Arizona Study of Aging and Neurodegenerative disorders and the Brain and Body Donation Program. Differential expression analysis (19 PD vs 19 controls) revealed 2164 significantly differentially expressed genes (1090 upregulated and 1074 downregulated) in PD. Pathways enriched in downregulated genes included oxidative phosphorylation, olfactory transduction, metabolic pathways, and neurotransmitters synapses while immune and inflammatory responses as well as cellular death related pathways were enriched within upregulated genes. An overrepresentation of microglial and astrocyte-related genes was observed amongst upregulated genes, and excitatory neuron-related genes were overrepresented amongst downregulated genes. Co-expression network analysis revealed significant modules highly correlated with PD and olfactory dysfunction that were found to be involved in the MAPK signaling pathway, cytokine-cytokine receptor interaction, cholinergic synapse, and metabolic pathways. LAIR1 (leukocyte associated immunoglobulin like receptor 1) and PPARA (peroxisome proliferator activated receptor alpha) were identified as hub genes with a high discriminative power between PD and controls reinforcing an important role of neuroinflammation in the olfactory bulb of PD subjects. Olfactory identification test score positively correlated with expression of genes coding for G-coupled protein, glutamatergic, GABAergic, and cholinergic receptor proteins and negatively correlated with genes for proteins expressed in glial olfactory ensheathing cells. In conclusion, this study reveals gene alterations associated with neuroinflammation, neurotransmitter dysfunction, and disruptions of factors involved in the initiation of olfactory transduction signaling that may be involved in PD-related olfactory dysfunction.
Assuntos
Transtornos do Olfato , Bulbo Olfatório , Doença de Parkinson , Análise de Sequência de RNA , Humanos , Bulbo Olfatório/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Masculino , Transtornos do Olfato/genética , Feminino , Idoso , Análise de Sequência de RNA/métodos , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Perfilação da Expressão Gênica/métodos , TranscriptomaRESUMO
BACKGROUND: While preclinical studies have shown that alpha-synuclein can spread through cell-to-cell transmission whether it can be transmitted between humans is unknown. OBJECTIVES: The aim was to assess the presence of a synucleinopathy in autopsied conjugal couples. METHODS: Neuropathological findings in conjugal couples were categorized as Parkinson's disease (PD), dementia with Lewy bodies (DLB), Alzheimer's disease with Lewy bodies (ADLB), incidental Lewy body disease (ILBD), or no Lewy bodies. RESULTS: Ninety conjugal couples were included; the mean age of death was 88.3 years; 32 couples had no Lewy bodies; 42 couples had 1 spouse with a synucleinopathy: 10 PD, 3 DLB, 13 ADLB, and 16 ILBD; 16 couples had both spouses with a synucleinopathy: in 4 couples both spouses had PD, 1 couple had PD and DLB, 4 couples had PD and ADLB, 2 couples had PD and ILBD, 1 couple had DLB and ADLB, in 3 couples both had ADLB, and 1 couple had ADLB and ILBD. No couples had both spouses with ILBD. CONCLUSIONS: This large series of 90 autopsied conjugal couples found 16 conjugal couples with synucleinopathies, suggesting transmission of synucleinopathy between spouses is unlikely. © 2024 International Parkinson and Movement Disorder Society.
Assuntos
Doença por Corpos de Lewy , Doença de Parkinson , Sinucleinopatias , Humanos , Feminino , Masculino , Idoso de 80 Anos ou mais , Doença de Parkinson/patologia , Doença de Parkinson/metabolismo , Doença por Corpos de Lewy/patologia , Doença por Corpos de Lewy/metabolismo , Idoso , Sinucleinopatias/patologia , Autopsia , alfa-Sinucleína/metabolismo , Cônjuges , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Corpos de Lewy/patologiaRESUMO
INTRODUCTION: We examined the progression of extrapyramidal symptoms and signs in autopsy-confirmed dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), and Alzheimer's disease dementia (AD). METHODS: Longitudinal data were obtained from Arizona Study of Aging and Neurodegenerative Disease, with PDD (n = 98), AD (n = 47) and DLB (n = 48) further sub-grouped as with or without parkinsonism (DLB+ and DLB-). Within-group Unified Parkinson's Disease Rating Scale (UPDRS) -II and UPDRS-III trajectories were analyzed using non-linear mixed effects models. RESULTS: In DLB, 65.6% had parkinsonism. Baseline UPDRS-II and III scores (off-stage) were highest (P < 0.001) for PDD (mean ± SD 14.3 ± 7.8 and 27.4 ± 16.3), followed by DLB+ (6.0 ± 8.8 and 17.2 ± 17.1), DLB- (1.1 ± 1.3 and 3.3 ± 5.5) and AD (3.2 ± 6.1 and 8.2 ± 13.6). Compared to PDD, the DLB+ group had faster UPDRS-III progression over 8-years (Cohen's-d range 0.98 to 2.79, P < 0.001), driven by gait (P < 0.001) and limb bradykinesia (P = 0.02) subscales. DISCUSSION: Motor deficits progress faster in DLB+ than PDD, providing insights about expected changes in motor function. HIGHLIGHTS: Dementia with Lewy bodies has faster motor progression than Parkinson's disease dementia Linear and non-linear mixed modeling analysis of longitudinal data was utilized Findings have implications for clinical prognostication and trial design.
Assuntos
Doença de Alzheimer , Demência , Doença por Corpos de Lewy , Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Doença de Parkinson/complicações , AutopsiaRESUMO
BACKGROUND: Hyposmia is characteristic of idiopathic Parkinson's disease (PD) and dementia with Lewy bodies (DLBs), whereas progressive supranuclear palsy (PSP) typically has normal sense of smell. However, there is a lack of pathologically confirmed data. OBJECTIVE: The objective is to study hyposmia in pathologically confirmed PSP patients and compare to PD patients and nondegenerative controls. METHODS: We studied autopsied subjects in the Arizona Study of Aging and Neurodegenerative Disorders who had antemortem olfactory testing and a neuropathological diagnosis of either PD, PSP, or control. RESULTS: This study included 281 cases. Those with neuropathologically confirmed PSP (N = 24) and controls (N = 174) had significantly better sense of smell than those with PD (N = 76). Although most PSP patients had normal olfaction, there were some with hyposmia, resulting in an overall reduced sense of smell in PSP compared to controls. The sensitivity of having PSP pathologically in those presenting with parkinsonism and normosmia was 93.4% with a specificity of 64.7%. Cases with both PSP and PD pathologically had reduced sense of smell similar to PD alone (N = 7). Hyposmic PSP patients had significantly higher Lewy body burden not meeting criteria for additional PD/DLB diagnosis. CONCLUSIONS: Pathologically confirmed PD had reduced olfaction compared with PSP or controls. In the setting of parkinsonism in this sample, the presence of normosmia had high sensitivity for PSP. Hyposmia in PSP suggests the presence of additional Lewy body pathology. © 2021 International Parkinson and Movement Disorder Society.
Assuntos
Doenças Neurodegenerativas , Doença de Parkinson , Transtornos Parkinsonianos , Paralisia Supranuclear Progressiva , Diagnóstico Diferencial , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico , Transtornos Parkinsonianos/diagnóstico , Olfato , Paralisia Supranuclear Progressiva/complicações , Paralisia Supranuclear Progressiva/diagnósticoRESUMO
OBJECTIVE: There are few neuropathological studies on Parkinson's disease with mild cognitive impairment (PD-MCI). Those published reveal coexisting Lewy body and Alzheimer's disease pathology. Our objective is to determine the pathology that underlies PD-MCI. METHODS: We used data from the Arizona Study of Aging and Neurodegenerative Disorders, a longitudinal clinicopathological study. Of 736 autopsied subjects with standardized movement and cognitive assessments, 25 had PD-MCI. Neuropathological findings, including Lewy body and Alzheimer's disease pathology, were compared in PD subjects with amnestic MCI (A-MCI) and nonamnestic MCI (NA-MCI). RESULTS: Significant pathological heterogeneity within PD-MCI was found. This included varying Lewy body stages, Alzheimer's disease pathology, and cerebral amyloid angiopathy. There was a significant increase in the severity of Lewy body pathology (meeting The Unified Staging System for Lewy Body disorders neocortical stage) in nonamnestic MCI (7/1, 63%) when compared with amnestic MCI (3/14, 21%, P = 0.032). CONCLUSION: Although a small study, distinct pathological changes may contribute to PD-MCI phenotype. © 2020 International Parkinson and Movement Disorder Society.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença por Corpos de Lewy , Doença de Parkinson , Disfunção Cognitiva/etiologia , Humanos , Corpos de Lewy , Doença por Corpos de Lewy/complicações , Doença de Parkinson/complicações , Doença de Parkinson/epidemiologiaRESUMO
BACKGROUND: In patients with Parkinson disease (PD), motor symptoms coexist with several nonmotor neuropsychiatric symptoms. Various anxiety subtypes (generalized anxiety disorder, panic disorder, and social anxiety disorder [SAD]) are more prevalent in patients with PD than in the general population. OBJECTIVE: We estimated the prevalence of SAD in early patients with PD and the relationship between severity of SAD and PD symptoms. METHODS: The Liebowitz Social Anxiety Scale (LSAS) and Unified Parkinson's Disease Rating Scale (UPDRS) III, which assess function impairment, were used to grade symptom severity among 41 patients with early PD. Ratings were compared and analyzed in relation to UPDRS subdivisions. RESULTS: UPDRS III and LSAS scores were not significantly correlated (r = 0.23, P = 0.14), but LSAS and UPDRS I, which evaluate nonanxiety psychiatric symptoms, were significantly correlated (r = 0.44; P = 0.004) and were stronger in the group not treated for PD (r = 0.82) but were in the group treated for PD (r = 0.28), although this difference did not reach statistical significance (P = 0.07 using the Fisher r-to-z transformation). LSAS also correlated with total UPDRS and UPDRS II (P ≤ 0.04). CONCLUSIONS: Results suggest that SAD symptoms in patients with PD correlate with PD symptoms as evaluated by the total UPDRS and UPDRS I and II. In our pilot study, this correlation was higher in levodopa-untreated patients with PD but was not statistically significant. Because the UPDRS III and LSAS were not statistically significantly correlated, a direct motor correlation with SAD symptoms cannot be suggested. Further investigation is needed to clarify the relationship of SAD in patients with PD and potential treatment options.
Assuntos
Doença de Parkinson/psicologia , Fobia Social/epidemiologia , Idoso , Depressão/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Prevalência , Escalas de Graduação Psiquiátrica , Qualidade de Vida , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: Identify clinical features predictive of Lewy body pathology in Alzheimer's disease (AD) patients in an ongoing longitudinal clinicopathologic study. MATERIAL AND METHODS: We queried the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) database for dementia cases with AD pathology (1997-2015). Subjects received longitudinal comprehensive clinical evaluations including motor/neuropsychological assessment and Apo-E4 genotyping. All cases were autopsied and had standard neuropathological assessments for AD and Lewy-type synucleinopathy (LTS). Subjects were categorized based on standardized pathological criteria with AD cases that had LTS but did not meet DLB pathologic criteria being categorized as ADLB. We performed pairwise comparison between the different diagnoses and multivariable modelling to identify clinical symptoms that predict the pathological diagnosis. RESULTS: We identified 32 DLB/AD, 54 ADLB, 70 AD only and 41 PDD/AD cases. AD subjects with LTS pathology had higher UPDRS II and III total scores as well as generally higher individual scores compared to AD alone. While depression scales and Trail-making Test A correlated significantly with LTS, other neuropsychological variables were not significantly different. Apo E4 occurrence was similar in all groups (40%-49%). CONCLUSIONS: Our study suggests that the presence (or absence) of LTS influences motor and non-motor clinical findings in AD patients. These findings may lead to biomarkers that allow for more targeted treatment of AD.
Assuntos
Doença de Alzheimer/patologia , Encéfalo/patologia , Corpos de Lewy/patologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Bases de Dados Factuais , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Estudos Prospectivos , Escalas de Graduação PsiquiátricaRESUMO
Progressive gait dysfunction is one of the primary motor symptoms in people with Parkinson's disease (PD). It is generally expressed as reduced step length and gait speed and as increased variability in step time and step length. People with PD also exhibit stooped posture which disrupts gait and impedes social interaction. The gait and posture impairments are usually resistant to the pharmacological treatment, worsen as the disease progresses, increase the likelihood of falls, and result in higher rates of hospitalization and mortality. These impairments may be caused by perceptual deficiencies (poor spatial awareness and loss of temporal rhythmicity) due to the disruptions in processing intrinsic information related to movement initiation and execution which can result in misperceptions of the actual effort required to perform a desired movement and maintain a stable posture. Consequently, people with PD often depend on external cues during execution of motor tasks. Numerous studies involving open-loop cues have shown improvements in gait and freezing of gait (FoG) in people with PD. However, the benefits of cueing may be limited, since cues are provided in a consistent/rhythmic manner irrespective of how well a person follows them. This limitation can be addressed by providing feedback in real-time to the user about performance (closed-loop cueing) which may help to improve movement patterns. Some studies that used closed-loop cueing observed improvements in gait and posture in PD, but the treadmill-based setup in a laboratory would not be accessible outside of a research setting, and the skills learned may not readily and completely transfer to overground locomotion in the community. Technologies suitable for cueing outside of laboratory environments could facilitate movement practice during daily activities at home or in the community and could strongly reinforce movement patterns and improve clinical outcomes. This narrative review presents an overview of cueing paradigms that have been utilized to improve gait and posture in people with PD and recommends development of closed-loop wearable systems that can be used at home or in the community to improve gait and posture in PD.
Assuntos
Transtornos Neurológicos da Marcha/fisiopatologia , Marcha/fisiologia , Doença de Parkinson/fisiopatologia , Postura/fisiologia , Idoso , Cognição/fisiologia , Transtornos Neurológicos da Marcha/reabilitação , Humanos , Doença de Parkinson/reabilitaçãoAssuntos
Doença de Parkinson , Humanos , Doença de Parkinson/diagnóstico , Diagnóstico Precoce , AutopsiaRESUMO
BACKGROUND: The aim of this postmortem study was to compare, in Parkinson's disease subjects with and without bilateral subthalamic nucleus deep brain stimulation (STN-DBS), the loss of pigmented neurons within the substantia nigra and pathological alpha-synuclein density within the SN and other brain regions. METHODS: PD subjects were identified from the Arizona Study of Aging and Neurodegenerative Disorders database (STN-DBS = 11, non-DBS = 156). Pigmented neuron loss scores within the substantia nigra as well as alpha-synuclein density scores within the substantia nigra and 9 other brain regions were compared, the latter individually and in summary as the Lewy body brain load score. RESULTS: DBS subjects had higher alpha-synuclein density scores within the substantia nigra, olfactory bulb, and locus ceruleus, as well as higher total Lewy body brain load scores when compared with non-DBS subjects. No differences in substantia nigra pigmented neuron loss scores were found. CONCLUSIONS: STN-DBS subjects tend to have higher alpha-synuclein density scores, but do not have a differential loss of substantia nigra pigmented neurons. © 2016 International Parkinson and Movement Disorder Society.
Assuntos
Estimulação Encefálica Profunda , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Substância Negra/metabolismo , Substância Negra/patologia , alfa-Sinucleína/metabolismo , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Locus Cerúleo/metabolismo , Locus Cerúleo/patologia , Masculino , Bulbo Olfatório/metabolismo , Bulbo Olfatório/patologia , Doença de Parkinson/terapia , Núcleo SubtalâmicoRESUMO
INTRODUCTION: Quantitative EEG features have been identified as surrogates and predictors of cognitive decline/dementia, a common feature of progressive PD. The biochemical correlates for altered quantitative EEG features are unknown. Our primary objective was to test the hypothesis that quantitative EEG measures correlate with cortical levels of phosphorylated α-synuclein, a modified form of the synaptic protein α-synuclein, in PD cases, in contrast to other pathology-associated proteins. A secondary objective was to explore the same correlations among cellular fractions of these proteins. METHODS: We used posterior cingulate cortex autopsy tissue from 44 PD subjects with various degrees of cognitive decline, who had undergone EEG. In this brain region, which is a major hub of the default mode network, biochemical measurements for levels of phosphorylated α-synuclein, unmodified α-synuclein, amyloid beta peptide, phosphorylated tau, and key synaptic proteins were analyzed and data correlated with spectral EEG measures. RESULTS: Findings revealed significant correlations between background rhythm peak frequency and all bandpower values (highest in delta bandpower) with total phosphorylated α-synuclein, but not any correlation with total α-synuclein, phosphorylated tau protein, amyloid beta peptide, or synaptic proteins. Certain fractions of synaptosomal-associated protein 25 showed correlation with some quantitative EEG measures. CONCLUSIONS: These data show an association between increased phosphorylation of α-synuclein and the abnormal EEG signatures of cognitive decline. Results suggest that quantitative EEG may provide an in vivo approximation of phosphorylated α-synuclein in PD cortex. This adds to previous evidence that quantitative EEG measures can be considered valid biomarkers of PD cognitive decline. © 2016 International Parkinson and Movement Disorder Society.
Assuntos
Ondas Encefálicas/fisiologia , Giro do Cíngulo/metabolismo , Giro do Cíngulo/fisiopatologia , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , alfa-Sinucleína/metabolismo , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , FosforilaçãoRESUMO
BACKGROUND: We evaluated a simplified method for converting Unified Parkinson's Disease Rating Scale Part III Motor Examination total scores (UPDRS III) to the International Parkinson and Movement Disorder Society's (MDS) revised version of the scores. METHODS: PD patients in the Arizona Study of Aging and Neurodegenerative Disorders were assessed with both scales. The accuracy of the predicted scores was assessed using regression modeling, classical intraclass correlation coefficients, and the Bland-Altman method. RESULTS: There was strong correlation between the two scores. Adding 7 points to a UPDRS III total score performed approximately as well as previously published conversion formulas (intraclass correlation: 0.96). The adjusted score is expected to be within 3 points of the MDS-UPDRS III score 50% of the time and within 9 points 95% of the time. CONCLUSIONS: Simply adding 7 points to a UPDRS III total score provides a good approximation of the MDS-UPDRS III total score.
Assuntos
Atividade Motora/fisiologia , Exame Neurológico/métodos , Doença de Parkinson/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Avaliação da Deficiência , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia , Índice de Gravidade de DoençaRESUMO
INTRODUCTION: Rapid eye movement (REM) sleep behavior disorder (RBD) in Parkinson's disease (PD) is associated with differences in clinical phenotype, including dementia, autonomic loss, and gait dysfunction. The pathological basis for this remains unclear. METHODS: Parkinson's disease subjects in a longitudinal clinicopathologic study were screened for probable RBD with the Mayo Sleep Questionnaire. After death, semiquantitative analyses were conducted for synuclein, amyloid, neurofibrillary tangles, and cerebrovascular lesions. RESULTS: Forty cases had probable RBD (PD+RBD), and 41 did not (PD-RBD). Despite similar age at death (â¼80 y) and disease duration (â¼14.5 y), PD+RBD had increased synuclein deposition in all regions examined, with nine of 10 regions significantly different. The Lewy body 10-region total score (scale = 0-40) was 29.5 in PD+RBD versus 24.5 in PD-RBD (Cohen-d effect size = 0.79, P = 0.002). Cerebrovascular lesion burden was slightly higher in PD-RBD. CONCLUSIONS: Although overlap occurs between groups, PD patients with probable RBD may have greater density and range of synuclein pathology on autopsy.
Assuntos
Doença de Parkinson/metabolismo , Transtorno do Comportamento do Sono REM/metabolismo , alfa-Sinucleína/metabolismo , Idoso , Idoso de 80 Anos ou mais , Autopsia , Estudos de Coortes , Feminino , Humanos , Masculino , Doença de Parkinson/complicações , Doença de Parkinson/patologia , Transtorno do Comportamento do Sono REM/etiologia , Transtorno do Comportamento do Sono REM/patologiaRESUMO
BACKGROUND: Although there are studies investigating the pathologic origins of mild cognitive impairment (MCI), they have revolved around comparisons to normal elderly individuals or those with Alzheimer's disease (AD) or other dementias. There are few studies directly comparing the comprehensive neuropathology of amnestic (aMCI) and nonamnestic (naMCI) MCI. METHODS: The database of the Brain and Body Donation Program ( www.brainandbodydonationprogram.org ), a longitudinal clinicopathological study of normal aging and neurodegenerative disorders, was queried for subjects who were carrying a diagnosis of aMCI or naMCI at the time of autopsy. Neuropathological lesions, including neuritic plaques, neurofibrillary tangles (NFTs), Lewy bodies (LBs), infarcts, cerebral white matter rarefaction (CWMR), cerebral amyloid angiopathy (CAA), and concurrent major clinicopathological diagnoses, including Parkinson's disease (PD) were analyzed. RESULTS: Thirty four subjects with aMCI and 15 naMCI met study criteria. Subjects with aMCI were older at death (88 vs. 83 years of age, p = 0.03). Individuals with naMCI had higher densities of LBs within the temporal lobe (p = 0.04) while subjects with aMCI had a propensity for increased NFTs in parietal and temporal lobes (p values = 0.07). After adjusting for age at death, the only significant difference was greater densities of temporal lobe NFTs within the aMCI group. Other regional pathology scores for plaques, NFTs, and LBs were similar between groups. Subjects met clinico-pathological criteria for co-existent PD in 24 % aMCI and 47 % naMCI while neuropathological criteria for AD were met in equal percentages of aMCI and of naMCI cases (53 %); these proportional differences were not significant (p values > 0.35). Furthermore, regardless of amnestic status, there was a greater presence of CAA (71 % of MCI with executive dysfunction vs. 39 % without p = 0.03) and a greater presence of CWMR (81 % of MCI with executive dysfunction and 54 % without p = 0.046) in MCI cases with executive dysfunction. CONCLUSIONS: No single pathologic entity strongly dichotomized MCI groups, perhaps due to the pathologic heterogeneity found within both entities. However, these data suggest the possibility for naMCI to have a propensity for increased LBs and aMCI for increased NFTs in select anatomic regions.
Assuntos
Amnésia/patologia , Encéfalo/patologia , Disfunção Cognitiva/patologia , Corpos de Lewy/patologia , Emaranhados Neurofibrilares/patologia , Placa Amiloide/patologia , Idoso , Idoso de 80 Anos ou mais , Amnésia/complicações , Angiopatia Amiloide Cerebral/complicações , Angiopatia Amiloide Cerebral/patologia , Infarto Cerebral/complicações , Infarto Cerebral/patologia , Disfunção Cognitiva/complicações , Feminino , Humanos , Leucoencefalopatias/complicações , Leucoencefalopatias/patologia , Masculino , Doença de Parkinson/complicações , Doença de Parkinson/patologia , Lobo Temporal/patologiaRESUMO
The Brain and Body Donation Program (BBDP) at Banner Sun Health Research Institute (http://www.brainandbodydonationprogram.org) started in 1987 with brain-only donations and currently has banked more than 1600 brains. More than 430 whole-body donations have been received since this service was commenced in 2005. The collective academic output of the BBDP is now described as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Most BBDP subjects are enrolled as cognitively normal volunteers residing in the retirement communities of metropolitan Phoenix, Arizona. Specific recruitment efforts are also directed at subjects with Alzheimer's disease, Parkinson's disease and cancer. The median age at death is 82. Subjects receive standardized general medical, neurological, neuropsychological and movement disorders assessments during life and more than 90% receive full pathological examinations by medically licensed pathologists after death. The Program has been funded through a combination of internal, federal and state of Arizona grants as well as user fees and pharmaceutical industry collaborations. Subsets of the Program are utilized by the US National Institute on Aging Arizona Alzheimer's Disease Core Center and the US National Institute of Neurological Disorders and Stroke National Brain and Tissue Resource for Parkinson's Disease and Related Disorders. Substantial funding has also been received from the Michael J. Fox Foundation for Parkinson's Research. The Program has made rapid autopsy a priority, with a 3.0-hour median post-mortem interval for the entire collection. The median RNA Integrity Number (RIN) for frozen brain and body tissue is 8.9 and 7.4, respectively. More than 2500 tissue requests have been served and currently about 200 are served annually. These requests have been made by more than 400 investigators located in 32 US states and 15 countries. Tissue from the BBDP has contributed to more than 350 publications and more than 200 grant-funded projects.
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Envelhecimento/patologia , Encéfalo/patologia , Doenças Neurodegenerativas/patologia , Bancos de Tecidos , Obtenção de Tecidos e Órgãos , Idoso de 80 Anos ou mais , Arizona , Autopsia , Biomarcadores , Feminino , Humanos , Masculino , Preservação de Órgãos , Mudanças Depois da Morte , Doadores de Tecidos , Sobrevivência de TecidosRESUMO
Dysphagia is common in Parkinson's disease (PD) and causes significant morbidity and mortality. PD dysphagia has usually been explained as dysfunction of central motor control, much like other motor symptoms that are characteristic of the disease. However, PD dysphagia does not correlate with severity of motor symptoms nor does it respond to motor therapies. It is known that PD patients have sensory deficits in the pharynx, and that impaired sensation may contribute to dysphagia. However, the underlying cause of the pharyngeal sensory deficits in PD is not known. We hypothesized that PD dysphagia with sensory deficits may be due to degeneration of the sensory nerve terminals in the upper aerodigestive tract (UAT). We have previously shown that Lewy-type synucleinopathy (LTS) is present in the main pharyngeal sensory nerves of PD patients, but not in controls. In this study, the sensory terminals in UAT mucosa were studied to discern the presence and distribution of LTS. Whole-mount specimens (tongue-pharynx-larynx-upper esophagus) were obtained from 10 deceased human subjects with clinically diagnosed and neuropathologically confirmed PD (five with dysphagia and five without) and four age-matched healthy controls. Samples were taken from six sites and immunostained for phosphorylated α-synuclein (PAS). The results showed the presence of PAS-immunoreactive (PAS-ir) axons in all the PD subjects and in none of the controls. Notably, PD patients with dysphagia had more PAS-ir axons in the regions that are critical for initiating the swallowing reflex. These findings suggest that Lewy pathology affects mucosal sensory axons in specific regions of the UAT and may be related to PD dysphagia.
Assuntos
Doença de Parkinson/metabolismo , alfa-Sinucleína/biossíntese , Idoso , Idoso de 80 Anos ou mais , Encéfalo/metabolismo , Química Encefálica , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/metabolismo , Feminino , Humanos , Masculino , Mucosa/química , Doença de Parkinson/complicações , Doença de Parkinson/patologia , alfa-Sinucleína/análiseRESUMO
There has been controversy as to whether there is an underlying neurodegenerative process of the cerebellum in essential tremor (ET). The aim of this study was to examine whether ET is associated with Purkinje cell (PC) loss. Prospectively categorized ET and control subjects who were longitudinally examined in the Arizona Study for Aging and Neurodegenerative Disorders and came to autopsy between 1998 and 2013 underwent standardized neuropathological assessment of the brain. PC linear density of the cerebellar hemisphere was calculated in a blinded manner. There were 56 ET cases and 62 age-matched controls free of dementia and other neurodegenerative disorders included in the study. Mean PC linear density was 3.80 ± 0.81 cells per mm for tremor cases and 3.82 ± 0.91 cells per mm for controls (Δ 0.02; 95% confidence interval [CI]: -0.30-0.34). PC counts were not associated with tremor duration (r = 0.06; 95% CI: -0.21-0.32). These data demonstrate that ET is not associated with cerebellar PC loss.
Assuntos
Cerebelo/patologia , Tremor Essencial/patologia , Células de Purkinje/patologia , Envelhecimento/patologia , Autopsia , Contagem de Células , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: Biomarkers based on the underlying pathology of Alzheimer's disease (AD) and Dementia with Lewy Bodies (DLB) have the potential to improve diagnosis and understanding of the substrate for cognitive impairment in these disorders. The objective of this study was to compare the patterns of amyloid and dopamine PET imaging in patients with AD, DLB and Parkinson's disease (PD) using the amyloid imaging agent florbetapir F 18 and 18F-AV-133 (florbenazine), a marker for vesicular monamine type 2 transporters (VMAT2). METHODS: Patients with DLB and AD, Parkinson's disease (PD) and healthy controls (HC) were recruited for this study. On separate days, subjects received intravenous injections of florbetapir, and florbenazine. Amyloid burden and VMAT2 density were assessed quantitatively and by binary clinical interpretation. Imaging results for both tracers were compared across the four individual diagnostic groups and for combined groups based on underlying pathology (AD/DLB vs. PD/HC for amyloid burden and PD/DLB vs. AD/HC for VMAT binding) and correlated with measures of cognition and parkinsonism. RESULTS: 11 DLB, 10 AD, 5 PD, and 5 controls participated in the study. Amyloid binding was significantly higher in the combined AD/DLB patient group (n = 21) compared to the PD/HC groups (n = 10, mean SUVr: 1.42 vs. 1.07; p = 0.0006). VMAT2 density was significantly lower in the PD/DLB group (n = 16) compared to the AD/ HC group (n = 15; 1.83 vs. 2.97; p < 0.0001). Within the DLB group, there was a significant correlation between cognitive performance and striatal florbenazine binding (r = 0.73; p = 0.011). CONCLUSIONS: The results of this study show significant differences in both florbetapir and florbenazine imaging that are consistent with expected pathology. In addition, VMAT density correlated significantly with cognitive impairment in DLB patients (ClinicalTrials.gov identifier: NCT00857506, registered March 5, 2009).
Assuntos
Doença de Alzheimer/diagnóstico por imagem , Amiloide/metabolismo , Compostos de Anilina , Etilenoglicóis , Doença por Corpos de Lewy/diagnóstico por imagem , Placa Amiloide/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Tetrabenazina/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/efeitos adversos , Dopamina/metabolismo , Combinação de Medicamentos , Etilenoglicóis/efeitos adversos , Feminino , Radioisótopos de Flúor/efeitos adversos , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/efeitos adversos , Compostos Radiofarmacêuticos/efeitos adversos , Tetrabenazina/efeitos adversosRESUMO
Progressive supranuclear palsy (PSP) is a neurodegenerative disorder resulting from the deposition of misfolded and neurotoxic forms of tau protein in specific areas of the midbrain, basal ganglia, and cortex. It is one of the most representative forms of tauopathy. PSP presents in several different phenotypic variations and is often accompanied by the development of concurrent neurodegenerative disorders. PSP is universally fatal, and effective disease-modifying therapies for PSP have not yet been identified. Several tau-targeting treatment modalities, including vaccines, monoclonal antibodies, and microtubule-stabilizing agents, have been investigated and have had no efficacy. The need to treat PSP and other tauopathies is critical, and many clinical trials investigating tau-targeted treatments are underway. In this review, the PubMed database was queried to collect information about preclinical and clinical research on PSP treatment. Additionally, the US National Library of Medicine's ClinicalTrials.gov website was queried to identify past and ongoing clinical trials relevant to PSP treatment. This narrative review summarizes our findings regarding these reports, which include potential disease-modifying drug trials, modifiable risk factor management, and symptom treatments.