The molecular mechanisms underlying the association between mutations in GBA1 and risk of developing the ‘synucleinopathy’ disorders Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) remain elusive. To better understand the precise molecular cascade that connects GBA1 mutations with α-synuclein dysregulation, a modified lipid extraction and HPTLC protocol was optimized to detect changes in levels of neutral sphingolipids (SLs) from neural cells and tissue expressing wild-type (WT) GBA1, mutant GBA1, or both. We demonstrate that mutant GBA1 does not confer a dominant-negative effect on WT GBA1-mediated activity; however, bona fide loss-of-enzymatic function mutation events led to the accumulation of lipid substrates in neural cells and tissue, and enhance α- synuclein/ubiquitin reactivity in brain tissue of mutant gba1 mice. Our HPLC-MS/MS data are consistent with other studies demonstrating that heterozygous GBA1 mutations do not lead to lipid accumulation, but may alter α-synuclein degradation through a yet-to-be defined novel gain-of-toxic function event.

Parkinson disease (PD) is the second most common neurodegenerative disease worldwide, with estimates suggesting that PD prevalence and incidence will increase with aging populations. Therapeutic options and clinical guidelines for PD have significantly changed over the past 15 years; however, pharmacoepidemiology data in PD are lacking, especially regarding adverse effects of non-ergot dopamine agonists (DAs) and outcomes associated with anticholinergic burden. The objectives of this doctoral research are threefold: 1) examine patterns of antiparkinson drug use in relation to clinical guideline publication, drug availability, and emerging safety concerns; 2) determine whether PD patients treated with non-ergot DAs are at increased risk of adverse cardiovascular or cerebrovascular outcomes; and 3) determine whether anticholinergic burden is associated with adverse outcomes in PD. Specific research questions were investigated using epidemiological methods and electronic health data from Cerner Health Facts®, an electronic medical record database that stores time-stamped patient records for more than 300 Cerner subscribing facilities across the United States. Findings from this work are reported in a series of manuscripts, all of which have been published. Key findings include: 1) DA use began declining in 2007, from 34% to 27% in 2012. The decline followed publication of the American Academy of Neurology’s practice parameter refuting levodopa toxicity, pergolide withdrawal, and pramipexole label revisions; 2) heart failure was the only adverse cardiovascular or cerebrovascular outcome that demonstrated a significant association with non-ergot DA use, mainly pramipexole; and 3) anticholinergic burden in PD was associated with the diagnosis of fracture and delirium, and significantly increased the risk of emergency department visit and readmission post inpatient discharge. Reported antiparkinson prescribing trends suggest that safety and best practice information may be communicated effectively in PD. Although findings warrant replication, individuals with PD and independent risk factors for or a history of heart failure may benefit from limited use of pramipexole. Similarly, individuals with PD may benefit from substituting non-PD medications with anticholinergic effects for equally effective non-anticholinergic agents. Additional pharmacovigilance studies are needed to better understand health risks and the impact of population health interventions in PD.

Previous controlled studies have shown that severe daytime restriction of dietary protein improves the efficacy of L-dopa and reduces response fluctuations in some Parkinson's disease in-patients. The main purpose of the present study was to investigate the nutritional adequacy of the restricted protein diet. Other objectives were to assess the patients' acceptance of the diet and to identify the practical difficulties encountered in following the diet at home. The effect of the restricted protein diet on the subjects' response to levodopa was also examined. Subjects were 11 free-living, otherwise healthy Parkinson's disease patients who suffered from unpredictable response fluctuations to Sinemet (L-dopa containing medicine). This condition is also described as the "on-off" phenomenon. They were counselled to consume a daytime restricted protein diet for 6 weeks (mean ± s.d. protein intake before evening meal 12 ± 2 g for females and 14 ± 3 g for males). Food intake was unrestricted from dinner until bedtime, and subjects were encouraged to consume nutrient-dense foods during this period. The subjects were required to complete a series of three 6-day food records and "on-off" charts (pre-diet, diet week 2, diet week 6). The "on-off" charts indicated the daily number of hours spent in the "on" state (when medication is effective and parkinsonian symptoms are controlled) and in the "off" state (when medication is not effective and symptoms are not well controlled). Hemoglobin, plasma albumin, prealbumin and ferritin were measured before and after the 6-week diet period. Subjective evaluation questionnaires were completed by all participants and their spouses or caregivers. Results from dietary record analysis showed that the restricted protein diet was associated with significant decreases in total intakes of protein, calcium, iron, magnesium, phosphorus, niacin, riboflavin, vitamin B6 and pantothenate, in comparison to "usual" intakes. Intake of energy, carbohydrates, lipids, potassium, thiamin, folacin, and vitamins A, C and B12 did not change significantly. While on the restricted protein diet, only calcium intake was substantially less than the RNI. Biochemical measures of nutritional status were not significantly reduced. Mean body weight tended to decrease (p=.054) over the first 2 weeks and then stabilized until the end of the study period. The results of the "on-off" charts showed that three of the eleven subjects significantly increased their daily time "on" while on the restricted protein diet. Subjectively, six individuals noted an improvement in daytime mobility and indicated that they would maintain the diet for an indefinite period of time. Problems identified by the subjects included hunger prior-'to the evening meal and a lack of variety in food choices. These results show that otherwise healthy and motivated patients with Parkinson's disease can maintain an adequate intake of energy, protein, and most nutrients while on the daytime restricted protein diet. The diet appeared to be relatively well tolerated by patients who obtained a subjective benefit. It is suggested that in patients whose regular diets are marginally adequate, the restricted protein diet might compromise nutrient intakes. Counselling by a registered dietitian is recommended for all patients who undertake this type of diet. / Land and Food Systems, Faculty of / Graduate

Orientador: Fabio Augusto Barbieri / Banca: Carolina Rodrigues Alves Silveira / Banca: Paula Favaro Polastri Zago / Resumo: Uma tarefa cognitiva concomitante prejudica a locomoção de idosos com doença de Parkinson (DP). Apesar de uma tarefa dupla cognitiva mais complexa afetar mais a locomoção desta população, pouco é conhecido sobre o nível de dificuldade de tarefa dupla cognitiva ou qual tipo de tarefa cognitiva que sobrecarrega esta capacidade cognitiva, prejudicando os parâmetros espaço-temporais do andar em idosos com DP. O objetivo geral deste estudo foi investigar os efeitos da complexidade da tarefa dupla concomitante nos parâmetros espaço-temporais do andar em idosos com DP. Para responder essa pergunta foi realizado dois estudos, no primeiro estudo, idosos com DP e seus pares neurologicamente sadios realizaram uma série de condições de andar com tarefa cognitiva concomitante com demanda de memória de trabalho com diferentes níveis de dificuldade. No segundo estudo, foi investigado a influência do tipo da demanda cognitiva exigida pela tarefa concomitante na locomoção de idosos com DP e idosos neurologicamente sadios. Para isso, os participantes realizarão condições do andar com tarefas cognitivas concomitante com diferentes demandas cognitivas (flexibilidade mental, resposta a inibição e memória de trabalho). Os parâmetros espaço-temporais foram coletados através de um sistema de câmeras VICON (200 Hz). Sendo calculados, separadamente para cada estudo, os principais parâmetros da marcha (comprimento, velocidade, largura, duração e tempo de duplo suporte). Além disso, foi analisado o cust... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: A concomitant cognitive task impairs the mobility of elderly people with Parkinson's disease (PD). Although a more complex cognitive dual task affects the locomotion of this population more, little is known about the difficulty level of cognitive double task or what type of cognitive task that overloads this cognitive capacity, impairing the spatiotemporal parameters of walking in elderly with DP. The general objective of this study was to investigate the effects of the concomitant dual task complexity on spatiotemporal gait parameters in elderly with PD. To answer this question, two studies were conducted. In the first study, elderly people with PD and their neurologically healthy peers performed a series of walking conditions with cognitive task concomitant with working memory demand with different levels of difficulty. In the second study, the influence of the type of cognitive demand required by the concomitant task on the mobility of elderly with PD and neurologically healthy elderly was investigated. For this, participants will perform walking conditions with cognitive tasks concomitant with different cognitive demands (mental flexibility, inhibition response and working memory). The spatiotemporal parameters were collected through a VICON (200 Hz) camera system. Being calculated separately for each study, the main gait parameters (length, speed, width, duration and time of double support). In addition, the cost and variability for these parameters were analyzed. Our re... (Complete abstract click electronic access below) / Mestre

Bakgrund: Parkinsons sjukdom (PS) är en kronisk sjukdom med progressivt förlopp där nedsatt balans och ökad fallrisk tidigt blir ett problem. På senare tid har alternativa träningsformer som bland annat innefattar stegstrategier anpassats till personer med PS, dock är det vetenskapliga underlaget rörande dess effektivitet oklart. Syfte: Att granska kunskapsläget avseende alternativa träningsformer såsom tai chi, dans och boxning som behandling för att motverka nedsatt balans hos personer med PS. Resultatet presenterar relevanta studiers effekt på balans, samt gradering av evidensens kvalitet. Metod: Litteraturstudie valdes som design. Datainsamling gjordes genom sökning i databaserna PubMed och PEDro. Författarna  kvalitetsgranskade inkluderade studierna med granskningsmallen TESTEX, därefter  granskades studiernas resultat och slutligen sammanvägd tillförlitlighet med GRADEstud.  Resultat: Nio studier med totalt 608 deltagare inkluderades i studien. Studiernas kvalitet varierade mellan 8-12 poäng vid kvalitetsgranskning med TESTEX. Fyra studier fann signifikant förbättring i balans jämfört med kontroll. En inkluderad studie undersökte boxning, utan att skillnad mellan grupperna identifierades. Det samlade evidensläget för tai chi respektive dans som behandling vid nedsatt balans vid PS bedöms vara lågt, detta främst på grund av heterogenitet i studierna. Boxning bedöms ha otillräckligt underlag för sammanvägning av resultat. Konklusion: Med den granskade evidensen kan vi i dagsläget inte säga om träningsmodaliteterna är effektiva för att förbättra balans vid PS, men det fanns indikation på att samtliga interventioner har en positiv inverkan på balans. Mer forskning med hög metodologisk kvalitet och större urvalsgrupper behövs. / Background: Parkinson’s Disease (PD) is a chronic disease with a progressive course, where impaired balance and increased risk of falls becomes a problem. In recent times alternative forms of training, which include compensatory stepping responses among other things, have been adopted for people with PD. However, the scientific evidence about its efficacy is unclear. Purpose: To systematically review the evidence surrounding alternative training methods such as tai chi, dance and boxing as a treatment for imparied balance in people with Parkinson's disease. The result presents relevant effects on balance, as well as a grading of the quality of the evidence. Method: The search for literature was carried out on the databases PubMed and PEDro. The authors reviewed the quality of the included studies with the assessment tool TESTEX. After that the results of the studies were reviewed, and lastly the reliability was assessed with GRADEstud. Results: Nine studies with a total of 608 participants were included in the study. Studies ranged from 8-12 points in the quality assessment. Four studies found significant improvement in balance in comparison to control. One of the included studies examined boxing, the study found no difference between groups. The reliability of evidence for tai chi and dance as treatment for impaired balance was assessed to be low, mainly because of heterogeneity in the studies. Boxing did not meet the requirements for an assessment of the reliability. Conclusion: The result does not provide us with enough knowledge to determine whether these training methods are effective for improving balance in PS, but there were indications of a positive impact on balance caused by the interventions. More research with high methodological quality and larger sample groups is needed.

Parkinson disease(PD) is a degenerative neurological disorder that impacts a great number of individuals in the United States and often results in significant changes to speech and voice, as well as increased reliance on informal caregivers. Relevant literature has shown that caring for a person with PD can have a negative impact on caregivers but has not explored the relationship between perceived impact of life events or relationship satisfaction and caregiver quality of life(CGQOL), or the impact that therapy delivery paradigm can have on these psychosocial factors and on caregivers of people with PD. The current study examined the psychosocial factors associated with caring for someone who has PD and the effect of therapy delivery paradigm on these factors through regression and mediation analyses. Results indicated that caregiver burden, caregiver depression, and perceived impact of life events (PILES), were significantly associated with CGQOL post-treatment, but quality of life pre-treatment and treatment modality were not significant. Although no evidence of mediation was found in this study, change in PILES scores from pre-to post-treatment was significantly associated with caregivers’ ratings of patient self-efficacy for communication post-treatment, while caregiver burden pre-treatment and self-efficacy for people with disabilities pre-treatment were significantly associated with caregivers’ rating of self-efficacy for people with disabilities post-treatment. Collectively, results from this study suggest that focusing on the psychosocial impact of caregiving is an integral part of the treatment process for any provider working with people with PD. Ensuring that caregivers receive the support and education needed to effectively manage the psychosocial factors associated with caregiving will lead to higher quality of care for the patient, as well as better patient outcomes in therapy, and in their daily lives.

The MAPT gene has been shown to be associated with several neurodegenerative disorders, including forms of parkinsonism and Parkinson disease (PD), but the results reveal population differences. We investigated the association of 10 single-nucleotide polymorphisms (SNPs) in the region of MAPT on chromosome 17q21 with PD and age at onset, by using 443 discordant sib pairs in PD from a public dataset (Mayo-Perlegen LEAPS Collaboration). Association with PD was assessed by the FBAT using generalized estimating equations (FBAT-GEE), while the association with age at onset as a quantitative trait was evaluated using the FBAT-logrank statistic. Five SNPs were significantly associated with PD (P < 0.05) in an additive model, and 9 SNPs were associated with PD (P < 0.05) in dominant and recessive models. Interestingly, 8 PD-associated SNPs were also associated with age at onset of PD (P < 0.05) in dominant and recessive models. The SNP most significantly associated with PD and age at onset was rs17649641 (P = 0.015 and 0.021, respectively). Two-SNP haplotypes inferred from rs17563965 and rs17649641 also showed association with PD (P = 0.018) and age at onset (P = 0.026). These results provide further support for the role of MAPT in development of PD.

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13220号 / 論医博第2167号 / 新制||医||1033(附属図書館) / (主査)教授 高橋 淳, 教授 宮本 享, 教授 伊佐 正 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24786号 / 医博第4978号 / 新制||医||1066(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 花川 隆, 教授 村井 俊哉, 教授 高橋 淳 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM