Parkinson's through a cultural lens: Diversity in disease expression and care.

IntroductionPrevious studies have assessed antipsychotic use after Parkinson's disease (PD) diagnosis, but incident antipsychotic use before PD diagnosis is unknown. The objective is to study the incidence of antipsychotic use among community-dwelling persons with and without PD 10 years before and after the PD diagnosis. MethodsThe study was based on the nationwide register-based FINPARK-study including 20,994 persons with PD (diagnosed 1996–2015) and 142,944 comparison persons who had not used antipsychotics during one-year washout before the follow-up. PD was diagnosed according to the United Kingdom's Parkinson's disease Society Brain Bank's criteria. Antipsychotic initiations in six-month time-windows was assessed. Results26.9% (n = 5,654) of people with PD initiated antipsychotics in comparison to 9.7% (n = 13,887) of people without PD during the entire follow-up. The incidence rate increased in people with PD approximately four years before the PD diagnosis. The most commonly initiated antipsychotic was quetiapine (n = 3,642, 64.4%) in persons with PD and risperidone (n = 5,232, 37.7%) in comparison persons. The initiation rates were higher in persons with PD before (6.5 and 3.0/1000 person-years for persons with and without PD, respectively, incidence rate ratio 2.18, 95%CI 2.03–2.33) and after the index date (43.3 and 11.7/1000 person-years for persons with and without PD, respectively, IRR 3.70, 95%CI 3.57–3.83). ConclusionPersons with PD have symptoms treated with antipsychotics both before and after diagnosis. Psychotic symptoms may be challenging to recognize as prodromal symptoms since they can occur years before the motor symptoms and thus, they cannot be clinically associated with the diagnosis of PD.

Culturally Competent Nursing Care

Parkinson's disease (PD) and Parkinson plus syndromes (PPS) are neurodegenerative movement disorders caused by loss of dopamine in the basal ganglia. The diagnosis of both PD and PPS is complex as it is made solely on the basis of clinical features, with no established imaging modality to aid in the diagnosis. Technetium-99m-labeled tropane derivative (Tc-TRODAT-1) binds to the dopamine transporters present in the presynaptic membrane of the dopaminergic nerve terminal. The aim of this prospective study was to investigate the potential usefulness of Tc-TRODAT-1 imaging in the diagnosis of PD and PPS. Fifty-eight patients with a clinical diagnosis of idiopathic PD or PPS were recruited. The severity of the disease was assessed using the Hoehn and Yahr scale. Patients in stage I and II were considered as cases of Early PD. Twenty-five apparently healthy volunteers served as controls. Brain single-photon emission computed tomography/computed tomography in all the participants was performed 3-4 h after an injection of Tc-TRODAT-1. Specific uptake ratios (SURs) of striatum were calculated for both the left and right striatum, and the values were compared between PD, PPS, and healthy volunteers. A significant lower uptake of tracer activity was found in either of the striatum in PD and PPS cases compared with the control group, which showed a symmetrical comma-shaped striatal uptake. This was also reflected in the SUR values, which were significantly higher in the control group in comparison with the PD and PPS patients (P<0.001). A significant difference was also found in the SUR values between the cases of early PD and control group (P<0.001).No significant difference was noted among the SUR values in different Hoehn and Yahr stages. For clinical practice, both the visual analysis and the quantitative parameters of Tc-TRODAT-1 single-photon emission computed tomography/computed tomography showed usefulness in distinguishing cases of PD and PPS from the healthy individuals.

Studies on real-world treatment patterns and long-term economic burden of Parkinson's disease (PD) have been limited. To assess treatment patterns, healthcare resource utilization (HRU), and costs associated with PD symptoms and treatment-related adverse events (AEs) among Medicare beneficiaries in the United States. A 100% Medicare Fee-For-Service data (2006-2020) of patients with PD were analyzed. PD treatment patterns were described for the subset of patients who had no previously observed PD treatments or diagnoses (ie, the incident cohort). HRU and healthcare costs associated with PD symptoms were assessed for all patients with PD (ie, the overall cohort) and that associated with treatment-related AEs were assessed for the subset of patients who received PD treatments after PD diagnosis (ie, the active treatment cohort), using longitudinal models with repeated measures. Overall, 318,582 patients were included (mean age at PD diagnosis: 77.4 years; 53.3% female). Among patients in the incident cohort (N=214,829), 51.1% initiated levodopa monotherapy and 5.9% initiated dopamine agonists (DAs) monotherapy as first-line treatment. The proportion of incident patients treated with DAs and other PD therapies generally increased from post-diagnosis years 1 to 10. The median time from diagnosis to PD treatment initiation was 2.0 months; the median time to treatment discontinuation was the longest with levodopa (18.7 months), followed by DAs (9.5 months). In the overall cohort, PD symptoms, especially motor symptoms and severe motor symptoms, were associated with significantly higher rates of HRU and costs. In the active treatment cohort (N=234,298), treatment-related AEs were associated with significantly higher rates of HRU and medical costs. While levodopa is still the mainstay of PD management, considerable heterogeneity exists in real-world treatment patterns. Overall, PD symptoms and AEs were associated with significantly higher HRU and healthcare costs, suggesting unmet medical needs for PD treatments with better tolerability profiles.

Neurodegeneration diseases such as Parkinson's disease (PD) dampen cognitive function severely in aged population. The neuropathological mechanisms underlying PD included progressive loss of midbrain dopamine neurons, due to the activation of oxidative stress pathways, for instance. The post-mortem characteristics of the brains from PD patients were described by the formation of Lewy bodies, through the pathological accumulation of the protein alpha-synuclein. In recent years, different loci and genes were identified to be associated with familial (with family history) PD, such as PARK1-15 and associated genes. In addition, there are genes such as LRRK2, SNCA, MAPT, and GBA that are associated with sporadic (without family history) PD 1. Epigenetic modulation represents a newly identified mechanism to regulate gene expression or cellular phenotype without the alteration of genome DNA sequences. The common epigenetic modulation approaches include DNA methylation, chromatin remodeling, and the gene expression regulation via small noncoding RNAs. In recent years, the epigenetic changes have been well recognized and documented in brain development, plastic changes, as well as different brain diseases, including the PD. With an animal model (overexpression of α-synuclein in fly) of PD, the histone deacetylase (HDAC) inhibitor was firstly found to inhibit synuclein toxicity to the dopamine neuron 2, followed by a series of studies that established the importance of histone acetylation in pathogenesis of PD 3. In a recent paper appearing on CNS Neuroscience & Therapeutics, Zhu et al. 4, the authors found that the application of HDAC inhibitor is able to block the mitochondrial fragmentation, which is an early event during MPP+ induced neuronal apoptosis. HDAC inhibitors therefore could provide potential therapeutic agents for neuroprotection in different neurodegeneration diseases. Dysregulation of DNA methylation in PD was well documented as well. For instance, post-mortem brain analyses revealed decreased methylation of α-synuclein (SNCA) in dopaminergic brain regions 5, 6, which might be responsible for the increased protein expression and therefore the PD progression. In addition, the methylation of several other genes such as PARK16/1q32, GPNMB, and STX1B was found to be dysregulated in PD brains 7. Last but not least, different miRNAs were reported to be downregulated or losing the binding site in PD animal models, as well as the brains from PD patients 8, 9. These studies established the roles of epigenetic regulation in pathogenesis and development of PD (Table 1). Present investigations on epigenetic changes of PD patients largely rely on post-mortem brain analyses, therefore lacking evidences of progressive changes, and it is hard to differentiate if the changes are resulted from the previous therapeutic treatments. One recent study on epigenetics examined the genome-wide DNA methylation status from both brain and peripheral blood samples of PD patients, and the authors found concordant methylations in both brain and blood samples 10, suggesting for a new route of PD prognosis and drug discovery for epigenetics. In this study, the authors obtained fresh post-mortem brain and blood samples from PD patients and aged-matched healthy subjects. They found that the two sources of samples exhibited high similarity in DNA methylation status. Their results confirmed the utility of blood samples in surrogate of brain samples, especially for human subjects. The similarity or concordant changes persist in PD patients, suggesting that blood samples from PD patients could act as important substrate of both genetic and epigenetic studies. Finally, the authors identified lists of genes with either increased or decreased DNA methylation in PD patients from brain and blood samples, showing highly correlated variations in both samples. Notably, with blood samples, it is possible to separate PD patients from healthy subjects simply based on epigenetic analyses, suggesting for a novel approach in PD prognosis and diagnosis. It will also be possible to track the efficiency of therapeutic treatments along the clinical management of patients as well. The epigenetic changes in the blood DNA could act as important drug target in screening new therapeutic molecules, in both animal models and human subjects, in addition to the neurological assessment. The sensitivity and specificity are yet to be improved with increased number of subjects recruited. Conceivably, the epigenetic changes occur in prior to protein accumulation as well as the neurological impairment, therefore might act as early biomarkers in evaluating PD progression. In summary, epigenetic changes represent important characteristics in PD diagnosis and treatment. The HDAC inhibitors provide intriguing possibilities in clinical management of PD, while blood-cells based detection of epigenetic changes would offer new possibilities in biomarker discovery. C-L.S. received funding from Jiangsu Provincial Natural Science Foundation (No. BK2011850), Six Talents Peak Project of Jiangsu Province (No. 2012100), and Fund of Jiangsu Province Health Development Project with Science and Education. All authors were supported by their institutes. The authors declare no conflict of interest.

Background Multiple system atrophy (MSA) and Parkinson's disease (PD) are characterized by abnormal changes in the extrapyramidal system and autonomic nervous system. The two diseases are consistent in some clinical manifestations and few objective indicators for preclinical prediction. Method The value of anal sphincter electromyography (EAS-EMG) in the diagnosis of MSA has been recognized by researchers, while the bulbocavernosus reflex (BCR) has been found to be of great significance in the diagnosis of PD and MSA. In this study, the diagnostic value of BCR combined with EAS-EMG in patients with MSA and PD was further discussed. Results Forty-three patients with MSA, 120 patients with PD and 40 normal controls were recruited, and the BCR and EAS-EMG were evaluated. The average duration, average amplitude, percentage of polyphasic waves, satellite potential, phase pattern and amplitude of strong contraction were observed. The results showed that the abnormal rate of BCR in the control group was 0%, and the abnormal rate of EAS-EMG was 2.5%; these differences were statistically significant compared with the MSA group (BCR 90.9%, EAS-EMG 93.9%). For patients with PD, there were some significant differences in BCR and EAS-EMG between the control group and the PD group. Conclusion Our study revealed that BCR combined with EAS-EMG detection can provide an objective electrophysiological basis for the diagnosis of MSA and PD, which is beneficial for the early treatment of disease.

Background: Parkinson's Disease (PD) affects over 10 million people worldwide. Many PD patients experience comorbid anxiety disorders, which have been correlated with reduced quality of life and can manifest at any time during the course of PD, including prior to motor symptom onset. Purpose: Prior work has demonstrated that patients diagnosed with depression following a PD diagnosis are less likely to receive depression treatment, but no such study has been conducted for anxiety. Research Design: A cross-sectional analysis of secondary electronhic health record data was conducted. Study Sample: Data was obtained through Optum® de-identified Electronic Health Record dataset, using ICD-9 and ICD-10 diagnosis codes to determine PD status and comparing index date of anxiety and PD diagnoses to classify patients by relative time of diagnosis. Data Analysis: Multivariate logistic regression was performed to assess factors associated with receipt of mental health treatment. Results: Of PD patients with anxiety, 52% documented a diagnosis of anxiety prior to PD. Overall, 69% documented some treatment, with 79% of those diagnosed with anxiety prior to PD receiving some treatment compared to 59% of those diagnosed with anxiety on or after PD (P < 0.001). Conclusion: Patients with PD and subsequent anxiety diagnoses are less likely to receive treatment. Further study could explore reasons for variations in mental health care within the context of an existing PD diagnosis.

Substantia nigra hyperechogenicity (SN+) detected by transcranial ultrasound (TUS) is useful for Parkinson's disease (PD) diagnosis. Approximately 15% false negative results of unknown significance are reported. However, most TUS studies are transversal, and diagnosis of PD may change during follow-up. Analysis of our prospective registry of TUS in clinical practice, selecting patients with sufficient bone window, to whom TUS was performed because of suspected PD, and a minimum of 3-year follow-up. Subjects were classified regarding SN echogenicity (SN+/SN-). 172 patients (122 SN+, 50 SN-), mean age 71years (25-90), were included. At the end of follow-up, PD diagnosis was retained by 91% SN+ vs. 54% SN- subjects (p < 0.0001), while final diagnosis of atypical parkinsonism (3%SN+ vs. 16%SN-, p:0.0059) was more frequent in SN-. Dopaminergic therapy response was associated with SN+ (88% SN+ vs. 50% SN-, p < 0.0001), as were abnormal DaTSCANs (90%SN+ vs. 56%SN-, p 0.0027). SN echogenicity had 80% sensitivity and 68% specificity for PD diagnosis, while SPECT had 91% and 73%, respectively. SN+ was the only baseline predictor of keeping PD diagnosis at the end of follow-up, with an odds ratio of 12 (95% CI 3-42) (p < 0.001). In our sample of patients with suspected PD, SN hyperechogenicity predicted PD diagnosis in the long term with a high odds ratio. Conversely, a baseline normal SN echogenicity was associated with a poorer response to PD therapy and change to a different diagnosis from PD. Normal SN appears to be a caveat for clinicians to check for atypical parkinsonism features during follow-up.

Parkinson's disease (PD) diagnosis relies primarily on clinical evaluation due to lack of validated tests and biomarkers. DaTscan imaging has been used to distinguish psychogenic and drug-induced parkinsonism from idiopathic PD. Some clinically diagnosed PD patients show scans without evidence of dopaminergic deficit (SWEDD), including some that respond to dopaminergic treatment. Some SWEDD patients present abnormal scans consistent with PD many years later and it is unknown if these patients developed PD in between scans or presented PD with low dopaminergic degeneration. α-Synuclein seed amplification assays (αS-SAAs) detect α-synuclein (αSyn) aggregates in the cerebrospinal fluid (CSF) of PD, dementia with Lewy bodies (DLB), and isolated rapid eye movement (REM) sleep behavior disorder (iRBD) patients with high sensitivity and specificity.1-4 We used an optimized high-throughput αS-SAA (based on a previously described α-Syn protein misfolding cyclic amplification (PMCA) assay)2, 5, 6 that detects αSyn aggregates in CSF, to evaluate 140 blinded samples from the Parkinson's Progression Markers Initiative (PPMI). Samples included baseline (BL) and 3-year follow-up (V08) from 30 PD and 30 healthy controls (HC), and BL samples from 20 SWEDD patients. PD-BL samples were collected within 2 years from diagnosis and presented abnormal DaTscans, while SWEDD patients presented normal DaTscans. PPMI classified enrollees as PD or SWEDD based on visual inspection of their baseline DaTscans. Figure 1A shows the assay results. The assay performed with 96.2% sensitivity (95% CI: 80.4%–99.9%) and 96.7% specificity (95% CI: 82.8%–99.9%) for PD versus HC at BL, and 96.4% sensitivity (95% CI: 81.7%–99.9%) and 93.8% specificity (95% CI: 79.2%–99.2%) at V08. After αS-SAA analysis, PPMI reclassified two of the three αS-SAA-negative subjects in the PD cohort as non-PD, therefore they were excluded from the above calculation. There were three false-positive samples: #3112-V08 and both samples from patient #3264. The latter was found to be a probable RBD case based on their RBD questionnaire score. Unfortunately, confirmatory polysomnography is not available and both samples from this patient were considered to be false-positives. Two BL-PD samples were inconclusive. Retest was not possible due to lack of sample and they were excluded from analysis. Of the 20 BL-SWEDD samples, we found 4 positive, 15 negative, and 1 inconclusive. Second DaTscans available at V10 (4 years from BL) of the negatives were normal. Interestingly, two of the four αS-SAA-positive SWEDD subjects (#3050 and #3101) showed a substantial increase in dopaminergic degeneration by DaTscans at 42 and 46 months after enrollment, with substantial putamen deficits consistent with a PD diagnosis (Fig. 1B). After αS-SAA analysis and after reviewing all longitudinal, clinical, and imaging data, the PPMI analytic cohort consensus committee decided to change the enrollment diagnosis of #3050 and #3101 from SWEDD to PD. Our results indicate that the optimized αS-SAA is highly accurate compared to the gold standard (longitudinal, clinical, and imaging data). The potential value of unbiased αS-SAA results in a clinical setting can be appreciated in cases with disputable diagnosis, such as the two αS-SAA-negative clinical PD patients (reclassified as non-PD) and the two αS-SAA-positive SWEDD cases (reclassified as PD). The αS-SAA-positive HC with probable RBD is in agreement with recent reports showing prodromal PD diagnosis.4, 7 Detailed introduction, results, methods, comparison to the original assay,2, 5 and discussion are included as Appendix S1. We thank the sample donors and their families for supporting this research by participating in the PPMI study. We also want to thank The Michael J. Fox Foundation for their assistance in accessing CSF samples and online information of the cohort. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. L.C.-M.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B C.M.F.: 1B, 1C, 2C, 3B B.H.: 1C, 3B Y.M.: 1C, 3B J.S.: 1C, 3B M.J.R.: 2A, 2B, 2C, 3B U.J.K.: 2A, 2B, 2C, 3B S.H.: 1B, 3B K.M.: 3B M.S.: 3B C.S.: 1A, 2C, 3B Dr. Soto, Dr. Concha, Ms. Farris, Mr. Ma, and Mr. Holguin are inventors on several patents related to the SAA (PMCA) technology and are affiliated to Amprion Inc., a biotech company focusing on the commercial utilization of SAA (PMCA) for diagnosis. Dr. Shahnawaz is also an inventor on several patents related to SAA (PMCA) technology but he is not associated with Amprion. Dr. Kang is on the advisory board of Amprion. All data presented in this letter is available at the PPMI database (https://ida.loni.usc.edu/login.jsp). AppendixS1. Supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Type 2 diabetes and Parkinson's disease

Brain magnetic resonance (MR) imaging offers the potential for objective criteria in the differential diagnosis of multiple system atrophy with predominant parkinsonism (MSA-P) and Parkinson disease (PD), since it frequently shows characteristic abnormalities in patients with MSA-P and is believed to be normal in patients with PD. To determine concordance between clinical and MR imaging-based diagnoses of MSA-P and PD. Two neuroradiologists identified and rated striatal and infratentorial abnormalities in 39 brain MR images and assigned a diagnosis of PD, MSA-P, or MSA with additional marked cerebellar ataxia (MSA-C). Academic medical center. Thirty-nine patients with parkinsonism, including 21 with a clinical diagnosis of PD, 14 with MSA-P, and 4 with MSA-C. All patients with MSA and 14 (67%) of 21 patients with PD had some abnormality on brain MR imaging. Brainstem atrophy was seen in patients with MSA-P and MSA-C. Putaminal atrophy was seen only in MSA-P. Putaminal hypointensity and lateral slitlike hyperintensity were seen in both PD and MSA-P but were always mild in PD. Cerebellar abnormalities, seen in all patients with MSA-C and 11 patients with MSA-P, were also identified in 6 patients with PD, albeit always rated as mild. Nonconcordance between clinical and radiological diagnosis occurred in 2 patients with PD, 5 with MSA-P, and 1 with MSA-C. Since several features on brain MR imaging are seen only in MSA-P, a simple diagnostic algorithm may improve the MR imaging diagnosis of MSA-P and PD.

Parkinson's disease (PD) is a prevalent, disabling neurodegenerative disorder. Early diagnosis and treatment of PD remains challenging due to the absence of definitive diagnostic tests and the non-specificity of its clinical manifestations. Initial consultations for PD symptoms often involve specialists who are not specifically trained in PD. Consequently, it is imperative to assess the general knowledge regarding PD among these specialists to develop optimal educational strategies and enhance early recognition and diagnosis of PD. We developed a questionnaire covering motor symptoms, non-motor symptoms, prodromal symptoms, risk factors and antiparkinsonian medications based on published guidelines, and conducted the web-based survey via Wenjuan xing (https://www.wjx.cn/) among physicians not specializing in PD in Guangdong Province, China. A total of 312 respondents, working in 28 diverse departments across 64 hospitals of three different categories, were eligible for data analysis. Notably, 95.2% of the respondents were aware of rest tremor as a motor symptom, yet only 76.9% recognized bradykinesia as a motor symptom. Regarding non-motor symptoms, erectile dysfunction, urinary dysfunction, restless legs, olfactory loss, orthostatic hypotension, rapid eye movement behavior disorder (RBD), lower back pain and diaphoresis, were recognized by less than 50% of the respondents. Additionally, with the exception of subthreshold parkinsonism or abnormal quantitative motor testing, prodromal symptoms such as excessive daytime somnolence, depression (± anxiety), olfactory loss, urinary dysfunction, RBD, and constipation were recognized by 36.5-48.7% of the respondents. First-degree relatives with PD received recognition from 86.5% of the respondents, whereas the remaining risk factors were recognized by 50-60% of the participants. Concerning protective factors for PD, recognition was limited to no more than 23%. Levodopa and dopamine releasers were the most widely recognized antiparkinsonian medications, while the recognition of other medications was below 70%. Variables such as medical degrees, professional titles, hospital categories, and education subjects contributed to statistical differences in PD knowledge. Among non-PD specialists in south China, current knowledge regarding PD, including non-motor symptoms, prodromal symptoms, risk and protective factors, and antiparkinsonian medications, is relatively inadequate. This necessitates targeted education and training to improve their understanding and recognition of PD.

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