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1.
Neurobiol Dis ; 168: 105698, 2022 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-35314318

RESUMO

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative cause of dementia, behind Alzheimer's disease (AD). The profile of inflammation in AD has been extensively researched in recent years, with evidence that chronic peripheral inflammation in midlife increases the risk of late-onset AD, and data supporting inflammation being associated with disease progression. In contrast, our understanding of the role of inflammation in DLB is less developed. Most research to date has examined inflammation in related disorders, such as Parkinson's disease, but there is now a growing range of literature examining inflammation in DLB itself. We present a review of the literature in this field, exploring a range of research methodologies including those quantifying markers of inflammation in cerebrospinal fluid, peripheral blood, post-mortem brain tissue, and using neuroimaging and preclinical data. Our review reveals evidence from PET imaging and peripheral blood analysis to support an increase in cerebral and peripheral inflammation in mild or prodromal DLB, that dissipates with disease progression. We present evidence from post-mortem brain tissue and pre-clinical studies that indicate α-synuclein directly promotes inflammation, but that also support the presence of AD co-pathology as an important factor in the profile of neuroinflammation in DLB. We propose that specific markers of inflammation may play a sentinel role in the mild stage of the disease, particularly when combined with AD pathology. We advocate further examination of the profile of inflammation in DLB through robust longitudinal studies, to enhance our understanding of the pathogenesis of the disease. The goal should be to utilise future results to develop a composite biomarker to aid diagnosis of DLB, and to potentially identify novel therapeutic targets.


Assuntos
Doença de Alzheimer , Doença por Corpos de Lewy , Doença de Alzheimer/complicações , Biomarcadores/líquido cefalorraquidiano , Progressão da Doença , Humanos , Inflamação , Corpos de Lewy/patologia , Doença por Corpos de Lewy/patologia
2.
Brain Commun ; 3(3): fcab177, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34485906

RESUMO

While [18F]-AV-1451 was developed as a PET radiotracer with high affinity for hyperphosphorylated tau, it has been proposed that loss of 'off-target' [18F]-AV-1451 binding to neuromelanin in the substantia nigra could be a surrogate marker of Lewy body diseases. [18F]-AV-1451 binding was measured in the substantia nigra of patients with Parkinson's disease (n = 35), dementia with Lewy bodies (n = 10) and separate control groups (n = 37; n = 14). Associations with motor symptoms, cognition and disease duration were evaluated using linear regression models. The dementia with Lewy bodies group had significantly reduced substantia nigra [18F]-AV-1451 binding compared to controls after adjusting for age (P < 0.05). However, there were no significant differences in substantia nigra [18F]-AV-1451 binding between Parkinson's disease and controls. Substantia nigra [18F]-AV-1451 binding was not associated with age, disease duration, Movement Disorders Society-Unified Parkinson's Disease Rating Scale and cognitive scores in dementia with Lewy bodies and Parkinson's disease groups. Despite the reduction of substantia nigra [18F]-AV-1451 binding in dementia with Lewy bodies, these findings suggest that substantia nigra [18F]-AV-1451 binding has no value as a diagnostic marker in early Parkinson's disease. Further investigations in longitudinal cohorts are warranted.

3.
Neurology ; 97(10): e1031-e1040, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34404743

RESUMO

OBJECTIVE: This study aimed to quantify the trajectory and magnitude of change of the key clinical features and corresponding symptom domains of dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD), including global cognition, parkinsonism, recurrent visual hallucinations, cognitive fluctuations, and sleep disturbance. METHODS: One hundred sixteen patients with Lewy body dementia (DLB = 72, PDD = 44) underwent assessment at baseline and 3 and 6 months as part of a prospective multicenter randomized controlled trial. Linear mixed models were constructed for core outcome measures using the Mini-Mental State Examination (MMSE), motor section of the Unified Parkinson's Disease Rating Scale (UPDRS-III), Dementia Cognitive Fluctuations Scale (DCFS), and Neuropsychiatric Inventory (NPI). RESULTS: Within the time frame of our study (6 months), we were able to identify a significant cognitive decline of 1.3 points on the MMSE (p = 0.002) and significant worsening of motor parkinsonism with an increase in UPDRS-III score of 3.2 points (p = 0.018). Fluctuation severity also increased using the DCFS with a 6-month change in score of 1.3 points (p = 0.001). Uniquely, a signal for increased severity of sleep symptoms of 1.2 points (NPI-sleep) was also detectable (p = 0.04). Significant changes in neuropsychiatric symptoms were not detected. There was no difference in rates of change of scores between DLB and PDD. DISCUSSION: Clinically significant rates of change in core clinical features can be detected and quantified in Lewy body dementia over a relatively short period (6 months) using common clinical instruments and thus may be useful as clinical endpoints for therapeutic trials of disease-modifying and symptomatic agents.


Assuntos
Progressão da Doença , Doença por Corpos de Lewy , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/fisiopatologia , Feminino , Humanos , Doença por Corpos de Lewy/fisiopatologia , Estudos Longitudinais , Masculino , Doença de Parkinson/fisiopatologia
4.
Neurobiol Aging ; 101: 172-180, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33631469

RESUMO

Alzheimer's disease (AD) pathology is frequently observed as a comorbidity in people with dementia with Lewy bodies (DLB). Here, we evaluated the in vivo distribution of tau burden and its influence on the clinical phenotype of DLB. Tau deposition was quantified using [18F]-AV1451 positron emission tomography in people with DLB (n = 10), AD (n = 27), and healthy controls (n = 14). A subset of patients with Lewy body diseases (n = 4) also underwent [11C]-PK11195 positron emission tomography to estimate microglial activation. [18F]-AV1451 BPND was lower in DLB than AD across widespread regions. The medial temporal lobe [18F]-AV1451 BPND distinguished people with DLB from AD (AUC = 0.87), and negatively correlated with Addenbrooke's Cognitive Examination-Revised and Mini-Mental State Examination. There was a high degree of colocalization between [18F]-AV1451 and [11C]-PK11195 binding (p < 0.001). Our findings of minimal tau burden in DLB confirm previous studies. Nevertheless, the associations of [18F]-AV1451 binding with cognitive impairment suggest that tau may interact synergistically with other pathologic processes to aggravate disease severity in DLB.


Assuntos
Doença por Corpos de Lewy/diagnóstico por imagem , Doença por Corpos de Lewy/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/metabolismo , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Carbolinas , Feminino , Radioisótopos de Flúor , Humanos , Inflamação , Doença por Corpos de Lewy/genética , Masculino , Microglia/patologia , Pessoa de Meia-Idade , Fenótipo , Radioisótopos , Compostos Radiofarmacêuticos , Índice de Gravidade de Doença
5.
Brain Imaging Behav ; 15(5): 2445-2453, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33511557

RESUMO

The impairment of large-scale brain networks has been observed in dementia with Lewy bodies (DLB) using functional connectivity, but the potential for an analogous effect on structural covariance patterns has not been determined. Twenty-four probable DLB subjects (mean age 74.3 ± 6.7 years, 16.7% female) and 23 similarly aged Controls were included. All participants underwent 3T MRI imaging with high-resolution T1-weighted magnetization-prepared rapid gradient echo (MPRAGE) sequence. Graph theoretical analyses were performed using variation in regional cortical thickness to construct a structural association matrix with pairwise Pearson correlations. Global and nodal graph parameters were computed to assess between-group differences and community structure was studied in order to quantify large-scale brain networks in both groups. In comparison to Controls, DLB subjects had decreased global efficiency, clustering, modularity and small-worldness of structural networks (all p < 0.05). Nodal measures showed that DLB subjects also had decreased clustering in bilateral temporal regions and decreased closeness centrality in extensive areas including right middle frontal, left cingulate and bilateral occipital lobe (all false-discovery rate (FDR)-corrected q < 0.05). Whereas four distinct modules could be clearly identified in Controls, DLB showed extensively disorganized modules, including default-mode network and dorsal attentional network. Our results suggest a marked impairment in large-scale brain structural networks in DLB, mirroring functional connectivity networks disruption.


Assuntos
Doença por Corpos de Lewy , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Feminino , Humanos , Doença por Corpos de Lewy/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Lobo Temporal
6.
Mov Disord ; 36(1): 143-151, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32960456

RESUMO

BACKGROUND: Lewy body dementia, comprising both dementia with Lewy bodies and Parkinson's disease dementia, is challenging to manage because of a complex symptom profile and lack of clear evidence-based management guidelines. OBJECTIVES: We assessed the feasibility of undertaking a cluster randomized study of the introduction of an evidence-based management toolkit for Lewy body dementia, assessing the outcomes for patients and carers as secondary measures. METHODS: We randomized 23 memory/dementia, movement disorder, or nonspecialist secondary care services to the management toolkit or usual care. People with dementia with Lewy bodies or Parkinson's disease dementia underwent assessments of cognition, motor and neuropsychiatric symptoms, and global outcome at baseline and 3 and 6 months. Healthcare, personal and social care costs, and carer-related outcomes of carer stress, depression, and anxiety were also examined. RESULTS: A total of 131 participants were recruited (target 120), for whom 6-month data were available on 108 (83%). There was a benefit of being in the intervention arm for carers (reduced Zarit Burden Scale [P < 0.01], reduced depressive symptoms [P < 0.05]), who also reported less marked patient deterioration on the global outcome measure (P < 0.05). There were no significant differences in other outcomes or in costs between groups. CONCLUSIONS: The introduction of an evidence-based management toolkit for Lewy body dementia was feasible and associated with some benefits, especially for carers. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Doença de Alzheimer , Doença por Corpos de Lewy , Transtornos de Ansiedade , Cuidadores , Cognição , Humanos , Doença por Corpos de Lewy/terapia
7.
Int J Geriatr Psychiatry ; 36(6): 831-838, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33275793

RESUMO

OBJECTIVES: Dementia with Lewy bodies (DLB) is a major cause of degenerative dementia, yet the diagnosis is often missed or mistaken for Alzheimer's disease (AD). We assessed whether the revised Addenbrooke's Cognitive Examination (ACE-R), a brief test for dementia, differentiates DLB from AD. METHODS: We first compared baseline ACE-R performance in 76 individuals with DLB, 40 individuals with AD and 66 healthy controls. We then investigated the diagnostic accuracy of a simple standardised 'memory/visuospatial' ratio calculated from the ACE-R subscores. Finally, as a comparison a logistic regression machine learning algorithm was trained to classify between DLB and AD. RESULTS: Individuals with AD had poorer memory (p = 0.001) and individuals with DLB had poorer visuospatial function (p = 0.005). Receiver operating characteristics curves confirmed that the ACE-R total score could differentiate dementia from non-dementia cases with 98% accuracy, but could not discriminate between dementia types (50%, or chance-level accuracy). However, a 'memory/visuospatial' ratio ≥1.1 differentiated DLB from AD with 82% sensitivity, 68% specificity and 77% mean accuracy. The machine learning classifier did not improve the overall diagnostic accuracy (74%) of the simple ACE-R subscores ratio. CONCLUSIONS: The ACE-R-based 'memory/visuospatial' ratio, but not total score, demonstrates good clinical utility for the differential diagnosis of DLB from AD.


Assuntos
Doença de Alzheimer , Doença por Corpos de Lewy , Doença de Alzheimer/diagnóstico , Cognição , Diagnóstico Diferencial , Humanos , Doença por Corpos de Lewy/diagnóstico , Memória , Testes Neuropsicológicos
8.
BJPsych Open ; 6(4): e61, 2020 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-32539875

RESUMO

BACKGROUND: Lewy body dementia, consisting of both dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), is considerably under-recognised clinically compared with its frequency in autopsy series. AIMS: This study investigated the clinical diagnostic pathways of patients with Lewy body dementia to assess if difficulties in diagnosis may be contributing to these differences. METHOD: We reviewed the medical notes of 74 people with DLB and 72 with non-DLB dementia matched for age, gender and cognitive performance, together with 38 people with PDD and 35 with Parkinson's disease, matched for age and gender, from two geographically distinct UK regions. RESULTS: The cases of individuals with DLB took longer to reach a final diagnosis (1.2 v. 0.6 years, P = 0.017), underwent more scans (1.7 v. 1.2, P = 0.002) and had more alternative prior diagnoses (0.8 v. 0.4, P = 0.002), than the cases of those with non-DLB dementia. Individuals diagnosed in one region of the UK had significantly more core features (2.1 v. 1.5, P = 0.007) than those in the other region, and were less likely to have dopamine transporter imaging (P < 0.001). For patients with PDD, more than 1.4 years prior to receiving a dementia diagnosis: 46% (12 of 26) had documented impaired activities of daily living because of cognitive impairment, 57% (16 of 28) had cognitive impairment in multiple domains, with 38% (6 of 16) having both, and 39% (9 of 23) already receiving anti-dementia drugs. CONCLUSIONS: Our results show the pathway to diagnosis of DLB is longer and more complex than for non-DLB dementia. There were also marked differences between regions in the thresholds clinicians adopt for diagnosing DLB and also in the use of dopamine transporter imaging. For PDD, a diagnosis of dementia was delayed well beyond symptom onset and even treatment.

9.
Neuroimage Clin ; 25: 102200, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32032816

RESUMO

Dementia with Lewy bodies (DLB) is characterized by alpha-synuclein protein deposition with variable degree of concurrent Alzheimer's pathology. Neuroinflammation is also increasingly recognized as a significant contributor to degeneration. We aimed to examine the relationship between microglial activation as measured with [11C]-PK11195 brain PET, MR diffusion tensor imaging (DTI) and grey matter atrophy in DLB. Nineteen clinically probable DLB and 20 similarly aged controls underwent 3T structural MRI (T1-weighted) and diffusion-weighted imaging. Eighteen DLB subjects also underwent [11C]-PK11195 PET imaging and 15 had [11C]-Pittsburgh compound B amyloid PET, resulting in 9/15 being amyloid-positive. We used Computational Anatomy Toolbox (CAT12) for volume-based morphometry (VBM) and Tract-Based Spatial Statistics (TBSS) for DTI to assess group comparisons between DLB and controls and to identify associations of [11C]-PK11195 binding with grey/white matter changes and cognitive score in DLB patients. VBM analyses showed that DLB had extensive reduction of grey matter volume in superior frontal, temporal, parietal and occipital cortices (family-wise error (FWE)-corrected p < 0.05). TBSS showed widespread changes in DLB for all DTI parameters (reduced fractional anisotropy, increased diffusivity), involving the corpus callosum, corona radiata and superior longitudinal fasciculus (FWE-corrected p < 0.05). Higher [11C]-PK11195 binding in parietal cortices correlated with widespread lower mean and radial diffusivity in DLB patients (FWE-corrected p < 0.05). Furthermore, preserved cognition in DLB (higher Addenbrookes Cognitive Evaluation revised score) also correlated with higher [11C]-PK11195 binding in frontal, temporal, and occipital lobes. However, microglial activation was not significantly associated with grey matter changes. Our study suggests that increased microglial activation is associated with a relative preservation of white matter and cognition in DLB, positioning neuroinflammation as a potential early marker of DLB etio-pathogenesis.


Assuntos
Imagem de Tensor de Difusão/métodos , Inflamação , Doença por Corpos de Lewy/imunologia , Doença por Corpos de Lewy/patologia , Microglia , Tomografia por Emissão de Pósitrons/métodos , Substância Branca , Idoso , Idoso de 80 Anos ou mais , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/imunologia , Córtex Cerebral/patologia , Feminino , Humanos , Inflamação/diagnóstico por imagem , Inflamação/imunologia , Inflamação/patologia , Doença por Corpos de Lewy/diagnóstico por imagem , Doença por Corpos de Lewy/fisiopatologia , Masculino , Pessoa de Meia-Idade , Substância Branca/diagnóstico por imagem , Substância Branca/imunologia , Substância Branca/patologia
10.
Ann Clin Transl Neurol ; 6(10): 2133-2136, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31507085

RESUMO

There is evidence of increased microglial activation in Parkinson's disease (PD) as shown by in vivo PET ligand such as 11 C-PK11195. In addition, diffusion tensor imaging (DTI) imaging reveals widespread changes in PD, especially when the associated dementia develops. In the present case series, we studied five subjects with Parkinson's disease dementia (PDD). Our findings suggest that while DTI metrics mirror cognitive severity, higher 11 C-PK11195 binding seems to be associated with a relative preservation of both white matter tracts and cognition. Longitudinal studies are warranted to tackle the complex relationship between microglial activation and structural abnormalities in neurodegenerative conditions.


Assuntos
Amidas , Demência/diagnóstico por imagem , Inflamação/diagnóstico por imagem , Isoquinolinas , Microglia , Doença de Parkinson/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Demência/etiologia , Imagem de Tensor de Difusão , Humanos , Masculino , Doença de Parkinson/complicações , Tomografia por Emissão de Pósitrons
12.
Alzheimers Dement (Amst) ; 10: 678-687, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30426064

RESUMO

INTRODUCTION: The deposition of neurofibrillary tangles in neurodegenerative disorders is associated with neuronal loss on autopsy; however, their in vivo associations with atrophy across the continuum of Alzheimer's disease (AD) remain unclear. METHODS: We estimated cortical thickness, tau ([18F]-AV-1451), and amyloid ß (Aß) status ([11C]-PiB) in 47 subjects who were stratified into Aß- (14 healthy controls and six mild cognitive impairment-Aß-) and Aß+ (14 mild cognitive impairment-Aß+ and 13 AD) groups. RESULTS: Compared with the Aß- group, tau was increased in widespread regions whereas cortical thinning was restricted to the temporal cortices. Increased tau binding was associated with cortical thinning in each Aß group. Locally, regional tau was associated with temporoparietal atrophy. DISCUSSION: These findings position tau as a promising therapeutic target. Further studies are needed to elucidate the casual relationships between tau pathology and trajectories of atrophy in AD.

13.
Brain ; 141(12): 3415-3427, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30403785

RESUMO

Inflammation is increasingly recognized as part of the pathology of neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease, but its role in dementia with Lewy bodies remains unclear. Using multimodal imaging and peripheral cytokine analysis, we therefore investigated central and peripheral inflammation in this common form of dementia. Nineteen participants with probable dementia with Lewy bodies and 16 similarly aged controls underwent 3 T MRI and PET imaging with 11C-PK11195, a marker of microglial activation in vivo. Peripheral blood inflammatory cytokines were also measured in all subjects, as well as in an additional 10 controls, using the Mesoscale Human Cytokine 36 plex panel and additional assays for high sensitivity c-reactive protein, tumour necrosis factor receptor 1, IL-34, YKL-40 (chitinase-3-like protein 1) and colony stimulating factor 1. To test for the presence of in vivo amyloid, 11C-Pittsburgh compound B PET imaging was also performed in 16 of the dementia with Lewy body participants. Microglial activation was elevated in dementia with Lewy bodies subjects with mild disease when compared to those with moderate/severe impairment, where disease severity was indexed by cognitive performance on the revised Addenbrooke's Cognitive Examination. In patients, strong correlations were found between cognitive performance and 11C-PK11195 non-displaceable binding potential in several regions including the caudate nucleus (R = 0.83, P = 0.00008) and cuneus (R = 0.77, P = 0.0005). Several inflammatory cytokines were altered in the patients compared to controls, with elevated macrophage inflammatory protein-3 (P = 0.001), IL-17A (P = 0.008) and IL-2 (P = 0.046) and reduced IL-8 (P = 0.024). There was no correlation between cortical 11C-Pittsburgh compound B standardized uptake value ratio and clinical features, regional 11C-PK11195 binding or peripheral cytokine levels. Nor was there any regional correlation between 11C-PK11195 non-displaceable binding potentials and 11C-Pittsburgh compound B standardized uptake value ratios. Our findings provide evidence for both central and peripheral inflammatory changes in dementia with Lewy bodies, with microglial activation occurring early in the disease in key regions known to be associated with pathology, before declining as cognition declines. Raised peripheral cytokines associated with T cell function further suggest a role for the adaptive immune system in the pathogenesis of the disease.


Assuntos
Encéfalo/imunologia , Citocinas/sangue , Encefalite/imunologia , Inflamação/imunologia , Doença por Corpos de Lewy/imunologia , Microglia/metabolismo , Idoso , Encéfalo/metabolismo , Progressão da Doença , Encefalite/complicações , Encefalite/metabolismo , Feminino , Humanos , Inflamação/complicações , Inflamação/metabolismo , Doença por Corpos de Lewy/complicações , Doença por Corpos de Lewy/metabolismo , Imageamento por Ressonância Magnética , Masculino , Tomografia por Emissão de Pósitrons
14.
Evid Based Ment Health ; 21(2): 61-65, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29602778

RESUMO

Dementia with Lewy bodies (DLB) is a common neurodegenerative dementia in older people; however, the clinical features, particularly cognitive fluctuations and rapid eye movement sleep disorder, are often hard to elicit, leading to difficulty in making the diagnosis clinically. Here we examine the literature for the evidence behind imaging modalities that could assist in making the diagnosis. Dopamine transporter (DAT) imaging remains the best modality for differentiation from dementia of Alzheimer's type with high sensitivity and specificity reported based on pathological diagnoses. 123Iodine-metaiodobenzylguanidine myocardial scintigraphy (MIBG) however is rapidly becoming an alternative imaging modality for the diagnosis of DLB, though studies assessing its accuracy with postmortem verification are still awaited. However, there are suggestions that MIBG may be better in the differentiation of vascular parkinsonism from DLB than DAT scans but may have lower sensitivity for detecting DLB compared with the 80% sensitivity seen in DAT imaging. Structural MRI scans have long been used for the diagnosis of dementia; however, their utility in DLB is limited to revealing the presence of coexisting Alzheimer's disease. Fluorodeoxyglucose (FDG) PET is an alternative biomarker that can also differentiate Alzheimer's disease and DLB but lacks the evidence base of both DAT and MIBG scans.


Assuntos
Doença por Corpos de Lewy/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Imagem de Perfusão do Miocárdio/métodos , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Humanos
15.
Neurology ; 90(22): e1989-e1996, 2018 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-29703774

RESUMO

OBJECTIVE: We tested whether in vivo neuroinflammation relates to the distinctive distributions of pathology in Alzheimer disease (AD) and progressive supranuclear palsy (PSP). METHODS: Sixteen patients with symptomatic AD (including amnestic mild cognitive impairment with amyloid-positive PET scan), 16 patients with PSP-Richardson syndrome, and 13 age-, sex-, and education-matched healthy controls were included in this case-control study. Participants underwent [11C]PK11195 PET scanning, which was used as an in vivo index of neuroinflammation. RESULTS: [11C]PK11195 binding in the medial temporal lobe and occipital, temporal, and parietal cortices was increased in patients with AD, relative both to patients with PSP and to controls. Compared to controls, patients with PSP showed elevated [11C]PK11195 binding in the thalamus, putamen, and pallidum. [11C]PK11195 binding in the cuneus/precuneus correlated with episodic memory impairment in AD, while [11C]PK11195 binding in the pallidum, midbrain, and pons correlated with disease severity in PSP. CONCLUSIONS: Together, our results suggest that neuroinflammation has an important pathogenic role in the 2 very different human neurodegenerative disorders of AD and PSP. The increase and distribution of microglial activation suggest that immunotherapeutic strategies may be useful in slowing the progression of both diseases.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Encefalite/metabolismo , Paralisia Supranuclear Progressiva/metabolismo , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Radioisótopos de Carbono/administração & dosagem , Encefalite/complicações , Encefalite/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Paralisia Supranuclear Progressiva/complicações , Paralisia Supranuclear Progressiva/diagnóstico por imagem
16.
Alzheimers Res Ther ; 10(1): 19, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29448953

RESUMO

BACKGROUND: The prevalence of dementia with Lewy bodies (DLB) and dementia in Parkinson's disease (PDD) in routine clinical practice is unclear. Prevalence rates observed in clinical and population-based cohorts and neuropathological studies vary greatly. Small sample sizes and methodological factors in these studies limit generalisability to clinical practice. METHODS: We investigated prevalence in a case series across nine secondary care services over an 18-month period, to determine how commonly DLB and PDD cases are diagnosed and reviewed within two regions of the UK. RESULTS: Patients with DLB comprised 4.6% (95% CI 4.0-5.2%) of all dementia cases. DLB was represented in a significantly higher proportion of dementia cases in services in the North East (5.6%) than those in East Anglia (3.3%; χ2 = 13.6, p < 0.01). DLB prevalence in individual services ranged from 2.4 to 5.9%. PDD comprised 9.7% (95% CI 8.3-11.1%) of Parkinson's disease cases. No significant variation in PDD prevalence was observed between regions or between services. CONCLUSIONS: We found that the frequency of clinical diagnosis of DLB varied between geographical regions in the UK, and that the prevalence of both DLB and PDD was much lower than would be expected in this case series, suggesting considerable under-diagnosis of both disorders. The significant variation in DLB diagnostic rates between these two regions may reflect true differences in disease prevalence, but more likely differences in diagnostic practice. The systematic introduction of more standardised diagnostic practice could improve the rates of diagnosis of both conditions.


Assuntos
Doença por Corpos de Lewy/epidemiologia , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Incidência , Masculino , Doença de Parkinson/epidemiologia , Prevalência , Reino Unido/epidemiologia
17.
Brain ; 140(3): 781-791, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28122879

RESUMO

The ability to assess the distribution and extent of tau pathology in Alzheimer's disease and progressive supranuclear palsy in vivo would help to develop biomarkers for these tauopathies and clinical trials of disease-modifying therapies. New radioligands for positron emission tomography have generated considerable interest, and controversy, in their potential as tau biomarkers. We assessed the radiotracer 18F-AV-1451 with positron emission tomography imaging to compare the distribution and intensity of tau pathology in 15 patients with Alzheimer's pathology (including amyloid-positive mild cognitive impairment), 19 patients with progressive supranuclear palsy, and 13 age- and sex-matched controls. Regional analysis of variance and a support vector machine were used to compare and discriminate the clinical groups, respectively. We also examined the 18F-AV-1451 autoradiographic binding in post-mortem tissue from patients with Alzheimer's disease, progressive supranuclear palsy, and a control case to assess the 18F-AV-1451 binding specificity to Alzheimer's and non-Alzheimer's tau pathology. There was increased 18F-AV-1451 binding in multiple regions in living patients with Alzheimer's disease and progressive supranuclear palsy relative to controls [main effect of group, F(2,41) = 17.5, P < 0.0001; region of interest × group interaction, F(2,68) = 7.5, P < 0.00001]. More specifically, 18F-AV-1451 binding was significantly increased in patients with Alzheimer's disease, relative to patients with progressive supranuclear palsy and with control subjects, in the hippocampus and in occipital, parietal, temporal, and frontal cortices (t's > 2.2, P's < 0.04). Conversely, in patients with progressive supranuclear palsy, relative to patients with Alzheimer's disease, 18F-AV-1451 binding was elevated in the midbrain (t = 2.1, P < 0.04); while patients with progressive supranuclear palsy showed, relative to controls, increased 18F-AV-1451 uptake in the putamen, pallidum, thalamus, midbrain, and in the dentate nucleus of the cerebellum (t's > 2.7, P's < 0.02). The support vector machine assigned patients' diagnoses with 94% accuracy. The post-mortem autoradiographic data showed that 18F-AV-1451 strongly bound to Alzheimer-related tau pathology, but less specifically in progressive supranuclear palsy. 18F-AV-1451 binding to the basal ganglia was strong in all groups in vivo. Postmortem histochemical staining showed absence of neuromelanin-containing cells in the basal ganglia, indicating that off-target binding to neuromelanin is an insufficient explanation of 18F-AV-1451 positron emission tomography data in vivo, at least in the basal ganglia. Overall, we confirm the potential of 18F-AV-1451 as a heuristic biomarker, but caution is indicated in the neuropathological interpretation of its binding. Off-target binding may contribute to disease profiles of 18F-AV-1451 positron emission tomography, especially in primary tauopathies such as progressive supranuclear palsy. We suggest that 18F-AV-1451 positron emission tomography is a useful biomarker to assess tau pathology in Alzheimer's disease and to distinguish it from other tauopathies with distinct clinical and pathological characteristics such as progressive supranuclear palsy.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Carbolinas/farmacocinética , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Autopsia , Autorradiografia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Estudos de Casos e Controles , Transtornos Cognitivos/diagnóstico por imagem , Transtornos Cognitivos/etiologia , Feminino , Fluordesoxiglucose F18/farmacocinética , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons/métodos , Ligação Proteica/efeitos dos fármacos , Escalas de Graduação Psiquiátrica , Paralisia Supranuclear Progressiva/complicações , Proteínas tau/metabolismo
18.
Int Psychogeriatr ; 29(4): 545-555, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28088928

RESUMO

BACKGROUND: Volumetric atrophy and microstructural alterations in diffusion tensor imaging (DTI) measures of the hippocampus have been reported in people with Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, no study to date has jointly investigated concomitant microstructural and volumetric changes of the hippocampus in dementia with Lewy bodies (DLB). METHODS: A total of 84 subjects (23 MCI, 17 DLB, 14 AD, and 30 healthy controls) were recruited for a multi-modal imaging (3T MRI and DTI) study that included neuropsychological evaluation. Freesurfer was used to segment the total hippocampus and delineate its subfields. The hippocampal segmentations were co-registered to the mean diffusivity (MD) and fractional anisotropy (FA) maps obtained from the DTI images. RESULTS: Both AD and MCI groups showed significantly smaller hippocampal volumes compared to DLB and controls, predominantly in the CA1 and subiculum subfields. Compared to controls, hippocampal MD was elevated in AD, but not in MCI. DLB was characterized by both volumetric and microstructural preservation of the hippocampus. In MCI, higher hippocampal MD was associated with greater atrophy of the hippocampus and CA1 region. Hippocampal volume was a stronger predictor of memory scores compared to MD within the MCI group. CONCLUSIONS: Through a multi-modal integration, we report novel evidence that the hippocampus in DLB is characterized by both macrostructural and microstructural preservation. Contrary to recent suggestions, our findings do not support the view that DTI measurements of the hippocampus are superior to volumetric changes in characterizing group differences, particularly between MCI and controls.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Hipocampo/diagnóstico por imagem , Doença por Corpos de Lewy/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Atrofia/patologia , Estudos de Casos e Controles , Imagem de Tensor de Difusão/métodos , Feminino , Hipocampo/patologia , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Testes Neuropsicológicos , Análise de Regressão , Reino Unido
19.
BMJ Open ; 7(1): e013187, 2017 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-28064175

RESUMO

INTRODUCTION: Inflammation of the central nervous system is increasingly regarded as having a role in cognitive disorders such as dementia and depression, but it is not clear how such inflammation relates to other aspects of neuropathology, structural and functional changes in the brain and symptoms (as assessed via clinical and neuropsychological assessment and MRI). This study will explore these pathophysiological mechanisms using positron emission tomography (PET) which allows in vivo imaging of inflammation, amyloid and τ deposition, together with neuropsychological profiling, MRI and peripheral biomarker analysis. METHODS AND ANALYSIS: Using PET imaging of the ligand [11C]PK11195, we will test for increased neuroinflammation in vivo in patients with Alzheimer's disease, Lewy body dementia, frontotemporal dementia, progressive supranuclear palsy, late-onset depression and mild cognitive impairment, when compared to healthy controls. We will assess whether areas of inflammatory change are associated with amyloid and τ deposition (assessed using 11C-labelled Pittsburgh Compound B ([11C]PiB) and 18F-labelled AV-1451, respectively), as well as structural and connectivity markers found on MRI. Inflammatory biomarker analysis and immune-phenotyping of peripheral blood monocytes will determine the correlation between central inflammation and peripheral inflammation. Finally, we will examine whether central inflammatory markers seen on PET imaging are associated with global and domain specific cognitive impairments or predict cognitive decline over 12 months. ETHICS AND DISSEMINATION: The study protocol was approved by the local ethics committee, East of England-Cambridge Central Research Ethics Committee (reference: 13/EE/0104). The study is also Administration of Radioactive Substances Advisory Committee (ARSAC) approved as part of this process. Data will be disseminated by presentation at national and international conferences and by publication, predominantly in journals of clinical neuroscience, neurology and psychiatry.


Assuntos
Disfunção Cognitiva/diagnóstico por imagem , Demência/diagnóstico por imagem , Depressão/diagnóstico por imagem , Encefalite/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Biomarcadores/sangue , Disfunção Cognitiva/complicações , Disfunção Cognitiva/metabolismo , Estudos de Coortes , Citocinas/sangue , Demência/complicações , Demência/metabolismo , Depressão/complicações , Depressão/metabolismo , Encefalite/complicações , Encefalite/metabolismo , Demência Frontotemporal/complicações , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/metabolismo , Humanos , Transtornos de Início Tardio/complicações , Transtornos de Início Tardio/diagnóstico por imagem , Transtornos de Início Tardio/metabolismo , Doença por Corpos de Lewy/complicações , Doença por Corpos de Lewy/diagnóstico por imagem , Doença por Corpos de Lewy/metabolismo , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Neuroimagem , Testes Neuropsicológicos , Fenótipo , Tomografia por Emissão de Pósitrons/métodos , Projetos de Pesquisa , Paralisia Supranuclear Progressiva/complicações , Paralisia Supranuclear Progressiva/metabolismo , Subpopulações de Linfócitos T , Proteínas tau/metabolismo
20.
Parkinsonism Relat Disord ; 21(12): 1398-406, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26493111

RESUMO

Neuroinflammation is increasingly recognized as a key factor in the pathogenesis of neurodegenerative conditions. However, it remains unclear whether it has a protective or damaging role. Studies of Alzheimer's disease and Parkinson's disease have provided much of the evidence for inflammatory pathology in neurodegeneration. Here we review the evidence for inflammation in dementia with Lewy bodies and Parkinson's disease dementia. Neuroinflammation has been confirmed in vivo using PET imaging, with microglial activation seen in Parkinson's disease dementia and recently in dementia with Lewy bodies. In Parkinson's disease and Parkinson's disease dementia, microglial activation suggests a chronic inflammatory process, although there is also evidence of its association with cognitive ability and neuronal function. Alpha-synuclein in various conformations has also been linked to activation of microglia, with a broad range of components of the innate and adaptive immune systems associated with this interaction. Evidence of neuroinflammation in Lewy body dementia is further supported by pathological and biomarker studies. Genetic and epidemiological studies support a role for inflammation in Parkinson's disease, but have yet to provide the same for Lewy body dementia. This review highlights the need to identify whether the nature and extent of microglial activation in Lewy body dementia can be linked to structural change, progression of domain specific cognitive symptoms and peripheral inflammation as a marker of central microglial pathology. Answers to these questions will enable the evaluation of immunotherapies as potential therapeutic options for prevention or treatment of dementia with Lewy bodies and Parkinson's disease dementia.


Assuntos
Doença por Corpos de Lewy/patologia , Microglia/imunologia , Imunidade Adaptativa , Animais , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Citocinas/fisiologia , Modelos Animais de Doenças , Previsões , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Antígenos HLA-D/imunologia , Humanos , Inflamação , Doença por Corpos de Lewy/epidemiologia , Doença por Corpos de Lewy/genética , Doença por Corpos de Lewy/imunologia , Doença por Corpos de Lewy/metabolismo , Tomografia por Emissão de Pósitrons , alfa-Sinucleína/fisiologia
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