Parkinson's disease multimodal complex treatment (PD-MCT)

Parkinson's disease Multimodal Complex Treatment (PD-MCT) is a multidisciplinary inpatient treatment approach that has been demonstrated to improve motor function and quality of life in patients with Parkinson's disease (PD). In this study, we assessed the efficacy of PD-MCT and calculated predictors for improvement. We performed a prospective analysis in a non-randomized, open-label observational patient cohort. Study examinations were done at baseline (BL), at discharge after two-weeks of inpatient treatment (DC) and at a six-week follow-up examination (FU). Besides Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III as a primary outcome, motor performance was measured by the Timed Up-and-Go (TUG), the Berg Balance Scale (BBS) and the Perdue Pegboard Test (PPT). Until DC, motor performance improved significantly in several parameters and was largely maintained until FU (MDS-UPDRS III BL-to-DC: −4.7 $\pm$ 1.2 (SE) $\it p$ = 0.0012, BL-to-FU: −6.1 $\pm$ 1.3 $\it p$ = 0.0001; TUG BL-to-DC: −2.5 $\pm$ 0.9 $\it p$ = 0.015, BL-to-FU: 2.4 $\pm$ 0.9 $\it p$ = 0.027; $\it BBS$ BL-to-DC: 2.4 $\pm$ 0.7 $\it p$ = 0.003, BL-to-FU: 1.3 $\pm$ 0.7 $\it p$ = 0.176, PPT BL-to-DC: 3.0 $\pm$ 0.5 $\it p$ = 0.000004, BL-to-FU: 1.7 $\pm$ 0.7 $\it p$ = 0.059). Overall, nontremor items were more therapy responsive than tremor items. Motor complications evaluated with MDS-UPDRS IV occurred significantly less frequent at DC (−1.8 $\pm$ 0.5 $\it p$ = 0.002). Predictor analyses revealed an influence of initial motor impairment and disease severity on the treatment response in different motor aspects. In summary, we demonstrate a significant positive treatment effect of PD-MCT on motor function of PD patients which can be maintained in several parameters for an extended time period of six weeks and identify predictors for an improvement of motor function

Propionic acid and fasudil as treatment against rotenone toxicity in an in vitro model of Parkinson's disease

Parkinson's disease (PD) is a multifactorial neurodegenerative disease. In recent years, several studies demonstrated that the gastroenteric system and intestinal microbiome influence central nervous system function. The pathological mechanisms triggered thereby change neuronal function in neurodegenerative diseases including dopaminergic neurons in Parkinson's disease. In this study, we employed a model system for PD of cultured primary mesencephalic cells and used the pesticide rotenone to model dopaminergic cell damage. We examined neuroprotective effects of the Rho kinase inhibitor Fasudil and the short chain fatty acid (SCFA) propionic acid on primary neurons in cell morphological assays, cell survival, gene and protein expression. Fasudil application resulted in significantly enhanced neuritic outgrowth and increased cell survival of dopaminergic cells. The application of propionic acid primarily promoted cell survival of dopaminergic cells against rotenone toxicity and increased neurite outgrowth to a moderate extent. Interestingly, Fasudil augmented gene expression of synaptophysin whereas gene expression levels of tyrosine hydroxylase (TH) were substantially increased by propionic acid. Concerning protein expression propionic acid treatment increased STAT3 levels but did not lead to an increased phosphorylation indicative of pathway activation. Our findings indicate that both Fasudil and propionic acid treatment show beneficial potential in rotenone-lesioned primary mesencephalic cells

Brainstem raphe alterations in TCS

Depression and apathy can both be present in patients with Parkinson's disease (PD) while e. g., essential tremor (ET) patients mostly only report depressive symptoms. In PD, depression has been linked with brainstem raphe (BR) signal alterations in transcranial sonography (TCS) but apathy has not been evaluated in such terms as a putative biomarker. Furthermore, the BR has only been investigated using a singular axial TCS examination plane, although coronal TCS examination allows a much more accurate evaluation of the craniocaudal formation of serotonergic raphe structures in the midbrain area. The objective of this study was to investigate the value of coronal TCS examination for the detection of BR signal alterations and clinically correlate it to apathy in patients with PD, ET and healthy controls (HC). We prospectively included PD patients ($\it {n}$ = 31), ET patients ($\it {n}$ = 16), and HC ($\it {n}$ = 16). All were examined by TCS in the axial and coronal plane with focus on BR signal alterations. LARS and BDI-II scores were conducted to assess apathic and depressive symptoms in the study population. In a detailed analysis we found that the correlation of coronal and axial TCS alterations of BR was very high (rho = 0.950, $\it {p}$ < 0.001). BR signal alterations were more frequent in PD patients than in ET patients and HC, while it was not different between ET patients and HC. In the PD patient group, BDI-II and LARS scores were negatively correlated to BR signal changes in TCS in a significant manner (BDI-II and axial BR: $\it {p}$ = 0.019; BDI-II and coronal BR: $\it {p}$ = 0.011; LARS and axial BR: $\it {p}$ = 0.017; LARS and coronal BR: $\it {p}$ = 0.023). Together in this brainstem ultrasound study we find a significant association of BR signal alterations with clinically evident apathy and depression in patients with PD. Therefore, TCS might enable the identification of a subgroup of PD patients which are at higher risk to suffer from or to develop depression or apathy

Brainstem raphe alterations in TCS

Depression and apathy can both be present in patients with Parkinson's disease (PD) while e. g., essential tremor (ET) patients mostly only report depressive symptoms. In PD, depression has been linked with brainstem raphe (BR) signal alterations in transcranial sonography (TCS) but apathy has not been evaluated in such terms as a putative biomarker. Furthermore, the BR has only been investigated using a singular axial TCS examination plane, although coronal TCS examination allows a much more accurate evaluation of the craniocaudal formation of serotonergic raphe structures in the midbrain area. The objective of this study was to investigate the value of coronal TCS examination for the detection of BR signal alterations and clinically correlate it to apathy in patients with PD, ET and healthy controls (HC). We prospectively included PD patients ($\it n$ = 31), ET patients ($\it n$ = 16), and HC ($\it n$ = 16). All were examined by TCS in the axial and coronal plane with focus on BR signal alterations. LARS and BDI-II scores were conducted to assess apathic and depressive symptoms in the study population. In a detailed analysis we found that the correlation of coronal and axial TCS alterations of BR was very high (rho = 0.950, p < 0.001). BR signal alterations were more frequent in PD patients than in ET patients and HC, while it was not different between ET patients and HC. In the PD patient group, BDI-II and LARS scores were negatively correlated to BR signal changes in TCS in a significant manner (BDI-II and axial BR: $\it p$ = 0.019; BDI-II and coronal BR: $\it p$ = 0.011; LARS and axial BR: $\it p$ = 0.017; LARS and coronal BR: $\it p$ = 0.023). Together in this brainstem ultrasound study we find a significant association of BR signal alterations with clinically evident apathy and depression in patients with PD. Therefore, TCS might enable the identification of a subgroup of PD patients which are at higher risk to suffer from or to develop depression or apathy

Brainstem encephalitis with low-titer acetylcholine receptor antibodies mimicking myasthenia gravis

$\textbf {Objective:}$ To report a rare case of brainstem encephalitis with low-titer acetylcholine receptor antibodies mimicking myasthenia gravis. $\textbf {Methods:}$ The patient was investigated with repeated brain MRI, CSF examination, repetitive nerve stimulation, thoracic CT, and serologic screening. Our patient passed away and finally autopsy revealed a definitive diagnosis. Written informed consent was obtained from the relatives of the patient for access to clinical files for research purposes and publication. $\textbf {Results:}$ We present a young woman with a subacute bulbar syndrome, who was initially diagnosed with myasthenia gravis based on clinical finding and elevated acetylcholine receptor antibodies. Episodes of numbness in the pharynx and tongue and moderate saccadic horizontal and vertical pursuits were atypical. Despite initial stabilization with intravenous immunoglobulins she developed acute asphyxia after regurgitation of food and had to be resuscitated with ultimately lethal outcome. Autopsy revealed an autoimmune T-cell mediated brainstem encephalitis. Serological screening revealed positive GAD and Ma2 autoantibodies, indicating its probable paraneoplastic nature. $\textbf {Conclusions:}$ Brainstem encephalitis is an important differential diagnosis even in seropositive bulbar myasthenia gravis, as several autoimmune processes often co-occur. Sudden unexpected death must be taken into account in brainstem encephalitis, requiring prolonged monitoring of the patients

Novel immunotherapeutic approaches to target alpha-synuclein and related neuroinflammation in Parkinson’s disease

The etiology of Parkinson’s disease (PD) is significantly influenced by disease-causing changes in the protein alpha-Synuclein (aSyn). It can trigger and promote intracellular stress and thereby impair the function of dopaminergic neurons. However, these damage mechanisms do not only extend to neuronal cells, but also affect most glial cell populations, such as astroglia and microglia, but also T lymphocytes, which can no longer maintain the homeostatic CNS milieu because they produce neuroinflammatory responses to aSyn pathology. Through precise neuropathological examination, molecular characterization of biomaterials, and the use of PET technology, it has been clearly demonstrated that neuroinflammation is involved in human PD. In this review, we provide an in-depth overview of the pathomechanisms that aSyn elicits in models of disease and focus on the affected glial cell and lymphocyte populations and their interaction with pathogenic aSyn species. The interplay between aSyn and glial cells is analyzed both in the basic research setting and in the context of human neuropathology. Ultimately, a strong rationale builds up to therapeutically reduce the burden of pathological aSyn in the CNS. The current antibody-based approaches to lower the amount of aSyn and thereby alleviate neuroinflammatory responses is finally discussed as novel therapeutic strategies for PD

Lentiform nucleus hyperechogenicity in Parkinsonian syndromes

The hyperechogenicity of the substania nigra (SN) has been established as a valid finding in patients with Parkinson’s disease (PD), probably caused by an increased tissue iron concentration in the SN. The application of transcranial sonography (TCS) has been investigated for further echogenic basal ganglia alterations in patients with extrapyramidal movement disorders. Compared to PD, a hyperechogenic nucleus lentiformis (LN) has been reported to appear more frequently in atypical parkinsonian syndromes (aPS) such as the parkinsonian phenotype of multiple system atrophy (MSA-P) or the progressive supranuclear palsy (PSP). As the evidence providing study sizes are small, we conduct the first meta-analysis of the prevalence of LN hyperechogenicity in PD and aPS. We search for available studies providing prevalence of LN hyperechogenicity in patients with PD and aPS (MSA-P and PSP) detected by TCS in MEDLINE and SCOPUS databases. We calculate the prevalence rates of LN hyperechogenicity detection in patients with clinical diagnosis of PD vs. aPS under the random-effects model. We include a total of 1330 patients, 1091 PD and 239 aPS (MSA-P and PSP). We find a significantly higher prevalence of LN hyperechogenicity in aPS (76%, 95% CI: 0.62-0.88) compared to PD (16%, 95% CI: 0.10-0.23). After proving a higher prevalence of LN hyperechogenicity in aPS compared to PD, its histopathological cause needs to be investigated. Furthermore, its full diagnostic accuracy and the qualification to serve as a risk factor for MSA-P and PSP should also be questioned in future studies

Dynamics of Parkinson’s disease multimodal complex treatment in Germany from 2010–2016

Parkinson’s disease (PD) is currently the world’s fastest-growing neurological disorder. It is characterized by motor and non-motor symptoms which progressively lead to significant clinical impairment, causing a high burden of disease. In addition to pharmacological therapies, various non-pharmacological treatment options are available. A well established and frequently used multiprofessional inpatient treatment concept in Germany is "Parkinson’s disease multimodal complex treatment" (PD-MCT) which involves physiotherapists, occupational therapists, speech therapists, and other specializations for the optimization of treatment in PD (ICD G20) and other Parkinsonian syndromes (ICD G21 and G23). In this study we analyze the PD-MCT characteristics of 55,141 PD inpatients who have been integrated into this therapy concept in Germany in the years 2010–2016. We demonstrate that PD-MCT is increasingly applied over this time period. Predominately, PD patients with advanced disease stage and motor fluctuations in age groups between 45 and 69 years were hospitalized. In terms of gender, more male than female patients were treated. PD-MCT is provided primarily in specialized hospitals with high patient numbers but a minor part of all therapies is performed in a rather large number of hospitals with each one treating only a few patients. Access to PD-MCT differs widely across regions, leading to significant migration of patients from underserved areas to PD-MCT centers – a development that should be considered when implementing such therapies in other countries. Furthermore, our data imply that despite the overall increase in PD-MCT treatments during the observational period, the restricted treatment accessibility may not adequately satisfy current patient’s need

Hospitalization rates and comorbidities in patients with progressive supranuclear palsy in Germany from 2010 to 2017

Progressive supranuclear palsy (PSP) belongs to the disease spectrum of Parkinsonian syndromes. Due to the chronic and progressive neurodegenerative course of the disease, PSP patients often have to be hospitalized to undergo diagnostic and therapeutic measures. The dynamics and characteristics of PSP inpatient treatment in Germany have not been investigated thus far. The current study analyzed trends of inpatient treatment in Germany for the years 2010–2017 based on the German DRG statistics ("diagnostic-related groups") in the category G23.- (other degenerative diseases of the basal ganglia) and with special focus on PSP (G23.1). Inpatient case numbers of the G23.- category comprised a total of 21,196 patients from 2010–2017, whereas the PSP subcategory (G23.1) amounted to 10,663 cases. In the analyzed time period, PSP patient numbers constantly increased from 963 in 2010 to 1780 in 2017 with yearly growth rates of up to 20%. Similar trends were observed for other Parkinsonian syndromes such as multiple system atrophy (MSA). Differentiating PSP inpatients by gender demonstrated a higher proportion of males (55–60%) in comparison to female patients for the entire observation period. The average age of hospitalized PSP patients over these years was between 72.3 and 73.4 years without relevant differences for gender. The most common comorbidities consisted of cardiovascular, neurological, muscular and urological disorders. In summary, the analysis demonstrates that PSP patients are increasingly hospitalized in Germany and the current concepts of stationary care have to differentiate standard practices for Parkinson’s disease (PD) to also address the needs of patients with PSP and other Parkinsonian syndromes

Interventional influence of the intestinal microbiome through dietary intervention and bowel cleansing might improve motor symptoms in Parkinson's disease

The impact of the gut microbiome is being increasingly appreciated in health and in various chronic diseases, among them neurodegenerative disorders such as Parkinson’s disease (PD). In the pathogenesis of PD, the role of the gut has been previously established. In conjunction with a better understanding of the intestinal microbiome, a link to the misfolding and spread of alpha-synuclein via inflammatory processes within the gut is discussed. In a case-control study, we assessed the gut microbiome of 54 PD patients and 32 healthy controls (HC). Additionally, we tested in this proof-of-concept study whether dietary intervention alone or additional physical colon cleaning may lead to changes of the gut microbiome in PD. 16 PD patients underwent a well-controlled balanced, ovo-lacto vegetarian diet intervention including short fatty acids for 14 days. 10 of those patients received additional treatment with daily fecal enema over 8 days. Stool samples were collected before and after 14 days of intervention. In comparison to HC, we could confirm previously reported PD associated microbiome changes. The UDPRS III significantly improved and the levodopa-equivalent daily dose decreased after vegetarian diet and fecal enema in a one-year follow-up. Additionally, we observed a significant association between the gut microbiome diversity and the UPDRS III and the abundance of $\it Ruminococcaceae$. Additionally, the abundance of $\it Clostridiaceae$ was significantly reduced after enema. Dietary intervention and bowel cleansing may provide an additional non-pharmacologic therapeutic option for PD patients