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Acta Neuropathol ; 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34514546


Mutations in glucocerebrosidase (GBA) are the most prevalent genetic risk factor for Lewy body disorders (LBD)-collectively Parkinson's disease, Parkinson's disease dementia and dementia with Lewy bodies. Despite this genetic association, it remains unclear how GBA mutations increase susceptibility to develop LBD. We investigated relationships between LBD-specific glucocerebrosidase deficits, GBA-related pathways, and α-synuclein levels in brain tissue from LBD and controls, with and without GBA mutations. We show that LBD is characterised by altered sphingolipid metabolism with prominent elevation of ceramide species, regardless of GBA mutations. Since extracellular vesicles (EV) could be involved in LBD pathogenesis by spreading disease-linked lipids and proteins, we investigated EV derived from post-mortem cerebrospinal fluid (CSF) and brain tissue from GBA mutation carriers and non-carriers. EV purified from LBD CSF and frontal cortex were heavily loaded with ceramides and neurodegeneration-linked proteins including alpha-synuclein and tau. Our in vitro studies demonstrate that LBD EV constitute a "pathological package" capable of inducing aggregation of wild-type alpha-synuclein, mediated through a combination of alpha-synuclein-ceramide interaction and the presence of pathological forms of alpha-synuclein. Together, our findings indicate that abnormalities in ceramide metabolism are a feature of LBD, constituting a promising source of biomarkers, and that GBA mutations likely accelerate the pathological process occurring in sporadic LBD through endolysosomal deficiency.

Bone Joint J ; 103-B(9): 1514-1525, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34465156


AIMS: The aims of this study were to investigate the ability to kneel after total knee arthroplasty (TKA) without patellar resurfacing, and its effect on patient-reported outcome measures (PROMs). Secondary aims included identifying which kneeling positions were most important to patients, and the influence of radiological parameters on the ability to kneel before and after TKA. METHODS: This prospective longitudinal study involved 209 patients who underwent single radius cruciate-retaining TKA without patellar resurfacing. Preoperative EuroQol five-dimension questionnaire (EQ-5D), Oxford Knee Score (OKS), and the ability to achieve four kneeling positions were assessed including a single leg kneel, a double leg kneel, a high-flexion kneel, and a praying position. The severity of radiological osteoarthritis (OA) was graded and the pattern of OA was recorded intraoperatively. The flexion of the femoral component, posterior condylar offset, and anterior femoral offset were measured radiologically. At two to four years postoperatively, 151 patients with a mean age of 70.0 years (SD 9.44) were included. Their mean BMI was 30.4 kg/m2 (SD 5.36) and 60 were male (40%). They completed EQ-5D, OKS, and Kujala scores, assessments of the ability to kneel, and a visual analogue scale for anterior knee pain and satisfaction. RESULTS: The ability to kneel in the four positions improved in between 29 (19%) and 53 patients (35%) after TKA, but declined in between 35 (23%) and 46 patients (30%). Single-leg kneeling was most important to patients. After TKA, 62 patients (41%) were unable to achieve a single-leg kneel, 76 (50%) were unable to achieve a double-leg kneel, 102 (68%) were unable to achieve a high-flexion kneel and 61 (40%) were unable to achieve a praying position. Posterolateral cartilage loss significantly affected preoperative deep flexion kneeling (p = 0.019). A postoperative inability to kneel was significantly associated with worse OKS, Kujala scores, and satisfaction (p < 0.05). Multivariable regression analysis identified significant independent associations with the ability to kneel after TKA (p < 0.05): better preoperative EQ-5D and flexion of the femoral component for single-leg kneeling; the ability to achieve it preoperatively and flexion of the femoral component for double-leg kneeling; male sex for high-flexion kneeling; and the ability to achieve it preoperatively, anterior femoral offset, and patellar cartilage loss for the praying position. CONCLUSION: The ability to kneel was important to patients and significantly influenced knee-specific PROMs, but was poorly restored by TKA with equal chances of improvement or decline. Cite this article: Bone Joint J 2021;103-B(9):1514-1525.

Artroplastia do Joelho , Articulação do Joelho/fisiopatologia , Articulação do Joelho/cirurgia , Idoso , Fenômenos Biomecânicos , Feminino , Humanos , Articulação do Joelho/diagnóstico por imagem , Estudos Longitudinais , Masculino , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/cirurgia , Medição da Dor , Dor Pós-Operatória/diagnóstico , Articulação Patelofemoral/diagnóstico por imagem , Articulação Patelofemoral/fisiopatologia , Articulação Patelofemoral/cirurgia , Medidas de Resultados Relatados pelo Paciente , Estudos Prospectivos , Amplitude de Movimento Articular/fisiologia , Inquéritos e Questionários
Knee ; 28: 194-201, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33418395


BACKGROUND: The aim of this study was to compare the outcomes and cost economics of TKA without patella resurfacing in patients with and without patellar cartilage loss. METHODS: Prospective case control study of 209 consecutive patients undergoing TKA without patella resurfacing. Patella cartilage status was documented intra-operatively: 108 patients had patella cartilage loss (mean age 70 ± 9.7, mean BMI 31 ± 6.2, 72 (67%) female) and 101 control patients did not (age 68 ± 9.2, BMI 31 ± 5.6, 52 (51%) female). The primary outcome measure was Oxford Knee Score (OKS) improvement at one year. Secondary outcomes included OKS, EQ-5D, anterior knee pain (AKP), Kujala scores and reoperation at 2-4 years. The cost to prevent secondary patella resurfacing was calculated. RESULTS: There were more women in the patella cartilage loss group (67% Vs 51%, p = 0.037), but no other preoperative characteristics differed. There was no difference in OKS improvement between those with and without patella cartilage loss at 1 year (mean difference -1.03, -3.68 to 1.62 95%CI, p = 0.446) or 2-4 years (mean difference 1.52, -1.43 to 4.45 95%CI, p = 0.310). At 2-4 years there was no difference in AKP (14/87 with vs 17/80 without, p = 0.430) nor Kujala score (mean difference 2.66, -3.82 to 9.13 95%CI, p = 0.418). Routine patella resurfacing would have cost £58,311 to prevent one secondary resurfacing. CONCLUSION: There was no difference in OKS, anterior knee pain, reoperation or Kujala scores up to 2-4 years between patients with and without patellar cartilage loss following TKA without patella resurfacing. Resurfacing for this indication would not have been a cost effective intervention.

Artroplastia do Joelho , Cartilagem Articular/fisiopatologia , Articulação do Joelho/fisiopatologia , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Medidas de Resultados Relatados pelo Paciente , Estudos Prospectivos , Reoperação