Comparison of autonomic dysfunction in patients with Parkinson's Disease, progressive supranuclear palsy, and multiple system atrophy.

AIM OF THE STUDY: To assess and compare autonomic nervous system (ANS) dysfunction, especially cardiovascular dysautonomia, in Parkinson's Disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and healthy controls. CLINICAL RATIONALE FOR THE STUDY: Assessment of ANS can be useful in differential diagnosis. Dysautonomia affects quality of life and can lead to potentially life-threatening complications. There is very little literature data regarding dysautonomia in PSP in relation to other parkinsonian syndromes. This study expands the knowledge about ANS dysfunction in parkinsonisms, especially PSP. MATERIAL AND METHODS: Patients with PD, MSA and PSP were prospectively recruited to our study. Demographic data and information about clinical and neuropsychological assessment, medication and comorbidities was collected. SCOPA-AUT questionnaire, 5-minute tilt test, and 5-minute heart rate variability (HRV) analysis in time and frequency domains were used to assess ANS. Analysis was also performed in patients with PSP-RS and PSP-P phenotypes, and in a subgroup with eliminated confounding factors, including age and disease duration. RESULTS: 76 PD, 25 PSP, and 12 MSA patients, and 20 controls, were included. Symptoms of dysautonomia revealed by a SCOPA-AUT questionnaire were present in all groups of patients. Urinary dysfunction was more pronounced in atypical parkinsonisms, and cardiovascular symptoms in α-synucleinopathies. HRV was disrupted in all groups of patients. However, when PSP-P and PSP-RS phenotypes were considered, HRV was diminished in PSP-RS, but there were no differences in HRV parameters between PSP-P and controls. Neurogenic orthostatic hypotension was present in 25% of PD and 58% of MSA patients, but it was absent in PSP patients and the control group. 13 PD and nine PSP patients and 16 controls were included in subanalysis. This revealed that PSP, but not PD, patients had significantly more symptoms of dysautonomia and lower HRV indices compared to controls, and that orthostatic hypotension was even more common in PD than in controls. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our study suggests that dysautonomia is common in PD, MSA and PSP, even though it has different profiles in the different diseases. NOH is present in PD and MSA, but not in PSP.

Are 5-2-1 Delphi criteria and MANAGE-PD useful screening tools for general neurologists for qualification to device-aided therapies in advanced Parkinson's Disease?

AIM OF STUDY: We sought to compare MANAGE-PD and 5-2-1 Delphi criteria which are two commonly used and approved screening tools in Parkinson's Disease, in order to highlight their strengths and limitations. CLINICAL RATIONALE FOR STUDY: Timely intervention with device-aided therapies is vital as it enables improving motor symptoms, lowering the dosage and side-effects of dopaminergic treatment, and improving patients' and caregivers' quality of life. Various screening tools have been created to help clinicians find the best candidates for device-aided therapies (DAT) for advanced Parkinson's Disease. In this study, we aimed to compare the 5-2-1 Delphi criteria to MANAGE-PD to determine how they could be used specifically to maximise their potential. MATERIAL AND METHODS: All of the patients (260) included in this study were DAT-naive, > 18 years of age, diagnosed with Parkinson's Disease, and had been referred to the Department of Neurology for qualification for advanced therapies over a 4-year period (2019-2022). They were subjected to both 5-2-1 Delphi criteria and MANAGE-PD tools and divided into subgroups based on the results of the screening. The data of patients was then statistically analysed. RESULTS: In the study group, 51 patients (19.5%) met all three of the 5-2-1 criteria, and 123 (47.1%) patients were categorised as '3' in MANAGE-PD, meaning that they may benefit from DAT. Finally, at the local centre level, 64 (24.5%) patients were qualified for DAT. 22 (34.4%) patients who were qualified for DAT by a clinician did not meet the 5-2-1 criteria. CONCLUSIONS: The 5-2-1 scheme based on the data from this study was characterised by a 92.5% specificity level and 65.1% sensitivity level compared to 69.5% specificity and 98.4% sensitivity level of MANAGE-PD. CLINICAL IMPLICATIONS: We found that MANAGE-PD has a better screening potential of DAT admission than 5-2-1 criteria. While both tools are reliable and valuable in daily practice, our study suggests that some patients may be omitted when using only less complicated tools such as 5-2-1 during the assessment.

Analysis of seroconversion following COVID-19 vaccination among multiple sclerosis patients treated with disease-modifying therapies in Poland.

CLINICAL RATIONALE FOR THE STUDY: The rapid spread of SARS-CoV-2 throughout the world has highlighted the importance of vaccinations to control the pandemic and to protect people at risk for severe disease courses. Disease-modifying therapies (DMT) in multiple sclerosis (MS), whether immunomodulatory or immunosuppressive, may affect the immune response. Therefore, the question arose as to whether these vaccinations would be effective. AIM OF THE STUDY: We planned a study to assess the immune response to SARS-CoV-2 vaccines by type of therapy. MATERIAL AND METHODS: Participants were recruited from 14 Polish MS centres. The data was obtained by neurologists using a questionnaire. We collected data on 353 MS patients (269 females, 84 males) who received complete primary SARS-CoV-2 vaccination. All persons with MS (PwMS) were treated with disease-modifying therapies. RESULTS: 305 out of 353 PwMS (86.4%) were positive for IgG Abs against SARS-CoV-2 S domain S1 Ag after vaccination. A strong immune response was noted in 129 PwMS (36.5%). The rate of seroconversion after SARS-CoV-2 vaccination in PwMS who received immunomodulatory DMTs (interferon beta, glatiramer acetate, teriflunomide, dimethyl fumarate, natalizumab) was 91.5%, in PwMS receiving immune reconstruction therapy (alemtuzumab, cladribine) was 92%, and in immunosuppressive DMTs (fingolimod, ocrelizumab), the seroconversion rate was 59%. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our study shows that, in PwMS receiving immunomodulatory therapy, the immune response to vaccination is generally excellent. Even in immunosuppressive patients, seroconversion is satisfactory.

Impulse Control Disorders in the Polish Population of Patients with Parkinson's Disease.

Background and Objectives: Parkinson's disease (PD) is one of the most common neurodegenerative diseases in the world. It is characterized by the presence of not only typical motor symptoms but also several less known and aware non-motor symptoms (NMS). The group of disorders included in the NMS is Impulse Control Disorders (ICDs). ICDs are a group of disorders in which patients are unable to resist temptations and feel a strong, pressing desire for specific activities such as gambling, hypersexuality, binge eating, and compulsive buying. The occurrence of ICDs is believed to be associated primarily with dopaminergic treatment, with the use of dopamine agonists (DA), and to a lesser extent with high doses of L-dopa. The aim of our study was to develop a profile of Polish ICDs patients and assess the frequency of occurrence of ICDs, as well as determine the risk factors associated with these disorders against the background of the PD population from other countries. Materials and Methods: Our prospective study included 135 patients with idiopathic PD who were hospitalized between 2020 and 2022 at the Neurological Department of University Central Hospital in Katowice. In the assessment of ICDs, we used the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP). Other scales with which we assessed patients with PD were as follows: MDS-UPDRS part III and modified Hoehn-Yahr staging. Clinical data on age, gender, disease duration and onset, motor complications, and medications were collected from electronic records. Results: ICDs were detected in 27.41% of PD patients (binge eating in 12.59%, hypersexuality in 11.11%, compulsive buying in 10.37%, and pathological gambling occurred in only 5.19% of patients. In total, 8.89% had two or more ICDs). The major finding was that ICDs were more common in patients taking DA than in those who did not use medication from this group (83.78% vs. 54.07%, respectively; p = 0.0015). Patients with ICDs had longer disease duration, the presence of motor complications, and sleep disorders. An important finding was also a very low detection of ICDs in a routine medical examination; only 13.51% of all patients with ICDs had a positive medical history of this disorder. Conclusions: ICDs are relatively common in the population of Polish PD patients. The risk factors for developing ICDs include longer duration of the disease, presence of motor complications, sleep disorders, and use of DA and L-dopa. Due to the low detectability of ICDs in routine medical history, it is essential for physicians to pay more attention to the possibility of the occurrence of these symptoms, especially in patients with several risk factors. Further prospective studies on a larger group of PD patients are needed to establish a full profile of Polish PD patients with ICDs.

Risk factors for dementia in Parkinson's Disease - the overuse of anticholinergic drugs.

AIM OF THE STUDY: To determine the risk factors for dementia in a group of patients with Parkinson's Disease (PD), especially the effect of the anticholinergic burden assessed according to the Anticholinergic Cognitive Burden scale (ACB) and the CRIDECO Anticholinergic Load Scale (CALS). CLINICAL RATIONALE FOR THE STUDY: To provide information about factors associated with Parkinson's Disease dementia (PDD), especially the anticholinergic burden and testing the effect of both scales in an assessment of the anticholinergic burden in this group of patients. MATERIAL AND METHODS: A retrospective and cross-sectional analysis of medical records of patients with Parkinson's Disease admitted to the Neurology Department of the Medical University of Silesia, Katowice, Poland between 2019 and 2021 was performed. We found 418 patients with a diagnosis of PD, but 80 were excluded due to lack of a cognitive function assessment. Based on MMSE score, the remaining 338 patients were divided into two groups of patients with, and without, PDD. Next, demographic and clinical data was collected. The anticholinergic burden was assessed using the ACB and the CALS scales. According to the authors of these scales, : if a scale score is of three or more points, this should be considered as a significant anticholinergic burden. Multiple logistic regression with backward elimination was used to assess factors significantly related to the presence of dementia, and two different models were used for both scales assessing the anticholinergic burden. RESULTS: 62 (18.3%) patients were diagnosed with PDD. Overall significant anticholinergic burden (≥ 3 points) was found in 31.95% of patients using CALS and in 18.93% using ACB. Anticholinergic burden was higher in patients with dementia (CALS 50 vs. 27.90%, p < 0.001, ACB 43.5 vs. 13.41%, p < 0.001). According to both models, the factors significantly related to dementia were: age (ACB OR 1,114 (1.062-1.170), p < 0.001, CALS OR 1.123 (1.070-1.178), p < 0.001), significant anticholinergic burden (ACB OR 3.433 (1.746-6.750), p < 0.001, CALS OR 2.166 (1.157-4.055), p = 0.016) disease severity in the Hoehn-Yahr scale (ACB OR 1.752 (1.197-2.565), p = 0.004, CALS OR 1.831 (1.256-2.670), p = 0.002) and atrial fibrillation (ACB OR 5.593 (1.417-22.083), p = 0.014, CALS OR 5.159 (1.314-20.254), p = 0.016). CONCLUSIONS AND CLINICAL IMPLICATIONS: The anticholinergic burden is larger in PDD patients compared to PD patients without dementia. CALS or ACB scales are helpful in this risk assessment and might be crucial to avoid the development of PDD, especially in older PD patients with multimorbidities.

Cathepsin B p.Gly284Val Variant in Parkinson's Disease Pathogenesis.

Parkinson's disease (PD) is generally considered a sporadic disorder, but a strong genetic background is often found. The aim of this study was to identify the underlying genetic cause of PD in two affected siblings and to subsequently assess the role of mutations in Cathepsin B (CTSB) in susceptibility to PD. A typical PD family was identified and whole-exome sequencing was performed in two affected siblings. Variants of interest were validated using Sanger sequencing. CTSB p.Gly284Val was genotyped in 2077 PD patients and 615 unrelated healthy controls from the Czech Republic, Ireland, Poland, Ukraine, and the USA. The gene burden analysis was conducted for the CTSB gene in an additional 769 PD probands from Mayo Clinic Florida familial PD cohort. CTSB expression and activity in patient-derived fibroblasts and controls were evaluated by qRT-PCR, western blot, immunocytochemistry, and enzymatic assay. The CTSB p.Gly284Val candidate variant was only identified in affected family members. Functional analysis of CTSB patient-derived fibroblasts under basal conditions did not reveal overt changes in endogenous expression, subcellular localization, or enzymatic activity in the heterozygous carrier of the CTSB variant. The identification of the CTSB p.Gly284Val may support the hypothesis that the CTSB locus harbors variants with differing penetrance that can determine the disease risk.

The Influence of Serum Uric Acid Level on Non-Motor Symptoms Occurrence and Severity in Patients with Idiopathic Parkinson's Disease and Atypical Parkinsonisms-A Systematic Review.

Background and Objectives: A growing number of studies correlated higher levels of serum uric acid (UA) with both: lower risk of Parkinson's Disease (PD) occurrence and slower progression of the disease. Similar conclusions were made where studies correlated UA with atypical Parkinsonisms (AP) progression. A few researchers have studied the issue of the influence of serum UA on the occurrence of non-motor symptoms (NMS) in PD and AP. Our systematic review is the first review completely dedicated to this matter. Materials and Methods: A comprehensive evaluation of the literature was performed to review the relationship between UA and NMS in PD and AP. The systematic review was conducted according to PRISMA Statement guidelines. The following databases were searched starting in April 2021: MEDLINE via PubMed, Embase, and Scopus. During the research, the following filters were used: >2010, articles in English, concerning humans. The study was not registered and received no external funding. Results: Seven articles meeting all inclusion criteria were included in this study. Collectively, data on 1104 patients were analyzed. A correlation between serum UA concentration and a few NMS types has been provided by the analyzed studies. In four papers, sleep disorders and fatigue were related to UA for both advanced and early PD. Other commonly appearing NMS domains were Attention/memory (4 studies), Depression/anxiety (3 studies), Cardiovascular (3 studies), Gastrointestinal (1 study), Perceptual (1 study), and Miscellaneous (1 study). For AP, no significant correlation between UA and worsening of NMS has been found. Conclusions: Based on the analyzed studies, a correlation between serum UA level and the occurrence and worsening of NMS in PD and APs cannot be definitively determined. Large-scale studies with a more diverse patient population and with more accurate methods of NMS assessment in Parkinsonism are needed.

Alzheimer's disease and type 2 diabetes mellitus: similarities in pathomechanisms lead to therapeutic opportunities.

INTRODUCTION: Type 2 diabetes mellitus is a metabolic disease the development of which depends on both environmental and genetic factors. The rapid increase in the number of cases observed in recent decades has been associated with the lifestyle predominant in the West, characterised by a high-calorie diet rich in carbohydrates and saturated fatty acids as well as little physical activity and chronic stress. Another disease with growing morbidity is Alzheimer's disease, a neurodegenerative disorder characterised by progressive dementia. STATE OF THE ART: The results of numerous studies indicate many similarities between these two diseases in terms of their pathomechanisms, especially changes in the activity of enzymatic pathways, accumulation of peptides with altered structure, and chronic inflammation. Amyloid ß, hyperphosphorylated tau protein, amylin, and apolipoprotein J are involved in both pathologies. The reasons for their excessive accumulation are not fully understood, but cellular metabolism disorders associated with insulin resistance and diabetes mellitus may play a key role in this process. It is highly probable that the changes observed at cellular level, which translate into the clinical state of patients, are caused by many abnormalities common to both diseases. CLINICAL IMPLICATIONS: The discovery of pathophysiological similarities has resulted in attempts to use antidiabetic drugs in Alzheimer's disease therapy. While animal studies have revealed the potential benefits of oral antidiabetic drugs, studies on humans have not provided clear data regarding their effectiveness. Most clinical trial results are promising, but there have also been studies that have shown no significant, or even adverse, effects of these drugs on Alzheimer's disease course. FUTURE DIRECTIONS: Undoubtedly, further research is needed to better understand the mechanisms by which the medications used in diabetes treatment affect the nervous system, and further clinical trials to compare the effectiveness of this therapy in patients presenting different clinical conditions at different stages of Alzheimer's disease.

Validation of the Polish version of the Unified Dyskinesia Rating Scale (UDysRS).

BACKGROUND: In 2008, the Movement Disorders Society published the Unified Dyskinesia Rating Scale (UDysRS). This has become the established tool for assessing the severity and disability associated with dyskinesia in patients with Parkinson's Disease (PD). We translated and validated the Polish version of the UDysRS, explored its dimensionality, and compared it to the Spanish version, which is the Reference Standard for UDysRS translations. MATERIAL AND METHODS: The UDysRS was translated into Polish by a team led by JS and GO. The back-translation, completed by colleagues fluent in both Polish and English who were not involved in the original translation, was reviewed and approved by the Executive Committee of the MDS Rating Scales Programme. Then the translated version of the UDysRS underwent cognitive pretesting, and the translation was modified based on the results. The approved version was considered to be the Official Working Document of the Polish UDysRS and was tested on 250 Polish PD patients recruited at movement disorder centres. Data was compared to the Reference Standard used for validating UDysRS translations. RESULTS: The overall factor structure of the Polish version was consistent with that of the Reference Standard version, as evidenced by the high Confirmatory Fit Index score (CFI = 0.98). The Polish UDysRS was thus confirmed to share a common factor structure with the Reference Standard. CONCLUSIONS: The Official Polish UDysRS translation is recommended for use in clinical and research settings. Worldwide use of uniform rating measures offers a common ground to study similarities and differences in disease manifestations and progression across cultures.

Affective Disorder and Functional Status as well as Selected Sociodemographic Characteristics in Patients with Multiple Sclerosis, Parkinson's Disease and History of Stroke.

The main arguments in support of researching anxiety and depression in patients with chronic somatic diseases are the prevalence of affective disorders in the population, somatic conditions as risk factors of affective disorders and the search for effective preventative and therapeutic strategies. The aim of the study was to determine the association between the functional status, selected sociodemographic characteristics and prevalence as well as severity of anxiety and depression in patients with multiple sclerosis (MS), Parkinson's disease (PD) and history of stroke (S). Material and methods: Eighty participants (44 women and 36 men) with MS (n = 22), PD (n = 31) and history of stroke (n = 27) were enrolled. All participants completed a questionnaire consisting of metrics, the Katz Index of Independence in Activities of Daily Living and the Hospital Anxiety and Depression Scale (HADS). Results: Fifty-five per cent of all participants did not present with anxiety or depression, 20% scored above the diagnostic threshold on the anxiety scale and 26% scored above the diagnostic threshold on the depression scale. Subgroup analysis revealed that anxiety and depression sufferers were 13.64% and 13.64% of MS patients, respectively; 22.58% and 35.48% of PD patients, respectively; and 22.22% and 25.93% of stroke survivors, respectively. There was a significant correlation between depression and independence level in the entire group and between depression and marital status in stroke survivors. Conclusions: Although depression and anxiety are highly prevalent in patients with neurological conditions, the disorder has a very individual nature and is not associated with the patient's age, duration of a condition or concomitant diseases. Screening for depression and anxiety as a part of comprehensive approach may increase treatment efficacy in neurological patients.

Validation of the Polish version of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS).

BACKGROUND: In 2008, the Movement Disorders Society (MDS) published a new Unified Parkinson's Disease Rating Scale (MDS-UPDRS) as the official benchmark scale for Parkinson's Disease (PD). We have translated and validated the Polish version of the MDS-UPDRS, explored its dimensionality, and compared it to the original English one. METHODS: The MDS-UPDRS was translated into Polish by a team of Polish investigators led by JS and GO. The back-translation was completed by colleagues fluent in both languages (Polish and English) who were not involved in the original translation, and was reviewed by members of the MDS Rating Scales Programme. Then the translated version of the MDS-UPDRS underwent cognitive pretesting, and the translation was modified based on the results. The final translation was approved as the Official Working Document of the MDS-UPDRS Polish version, and was tested on 355 Polish PD patients recruited at movement disorders centres all over Poland (at Katowice, Gdansk, Lódz, Warsaw, Wroclaw, and Kraków). Confirmatory and explanatory factor analyses were applied to determine whether the factor structure of the English version could be confirmed in the Polish version. RESULTS: The Polish version of the MDS-UPDRS showed satisfactory clinimetric properties. The internal consistency of the Polish version was satisfactory. In the confirmatory factor analysis, all four parts had greater than 0.90 comparative fit index (CFI) compared to the original English MDS-UPDRS. Explanatory factor analysis suggested that the Polish version differed from the English version only within an acceptable range. CONCLUSIONS AND CLINICAL IMPLICATIONS: The Polish version of the MDS-UPDRS meets the requirements to be designated as the Official Polish Version of the MDS-UPDRS, and is available on the MDS web page. We strongly recommend using the MDS-UPDRS instead of the UPDRS for research purposes and in everyday clinical practice.

Identification of genetic modifiers of age-at-onset for familial Parkinson's disease.

Parkinson's disease (PD) is the most common cause of neurodegenerative movement disorder and the second most common cause of dementia. Genes are thought to have a stronger effect on age-at-onset of PD than on risk, yet there has been a phenomenal success in identifying risk loci but not age-at-onset modifiers. We conducted a genome-wide study for age-at-onset. We analysed familial and non-familial PD separately, per prior evidence for strong genetic effect on age-at-onset in familial PD. GWAS was conducted in 431 unrelated PD individuals with at least one affected relative (familial PD) and 1544 non-familial PD from the NeuroGenetics Research Consortium (NGRC); an additional 737 familial PD and 2363 non-familial PD were used for replication. In familial PD, two signals were detected and replicated robustly: one mapped to LHFPL2 on 5q14.1 (PNGRC = 3E-8, PReplication = 2E-5, PNGRC + Replication = 1E-11), the second mapped to TPM1 on 15q22.2 (PNGRC = 8E-9, PReplication = 2E-4, PNGRC + Replication = 9E-11). The variants that were associated with accelerated onset had low frequencies (<0.02). The LHFPL2 variant was associated with earlier onset by 12.33 [95% CI: 6.2; 18.45] years in NGRC, 8.03 [2.95; 13.11] years in replication, and 9.79 [5.88; 13.70] years in the combined data. The TPM1 variant was associated with earlier onset by 15.30 [8.10; 22.49] years in NGRC, 9.29 [1.79; 16.79] years in replication, and 12.42 [7.23; 17.61] years in the combined data. Neither LHFPL2 nor TPM1 was associated with age-at-onset in non-familial PD. LHFPL2 (function unknown) is overexpressed in brain tumours. TPM1 encodes a highly conserved protein that regulates muscle contraction, and is a tumour-suppressor gene.

Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism.

SEE GANDHI AND PLUN-FAVREAU DOI101093/AWW320 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: It has been postulated that heterozygous mutations in recessive Parkinson's genes may increase the risk of developing the disease. In particular, the PTEN-induced putative kinase 1 (PINK1) p.G411S (c.1231G>A, rs45478900) mutation has been reported in families with dominant inheritance patterns of Parkinson's disease, suggesting that it might confer a sizeable disease risk when present on only one allele. We examined families with PINK1 p.G411S and conducted a genetic association study with 2560 patients with Parkinson's disease and 2145 control subjects. Heterozygous PINK1 p.G411S mutations markedly increased Parkinson's disease risk (odds ratio = 2.92, P = 0.032); significance remained when supplementing with results from previous studies on 4437 additional subjects (odds ratio = 2.89, P = 0.027). We analysed primary human skin fibroblasts and induced neurons from heterozygous PINK1 p.G411S carriers compared to PINK1 p.Q456X heterozygotes and PINK1 wild-type controls under endogenous conditions. While cells from PINK1 p.Q456X heterozygotes showed reduced levels of PINK1 protein and decreased initial kinase activity upon mitochondrial damage, stress-response was largely unaffected over time, as expected for a recessive loss-of-function mutation. By contrast, PINK1 p.G411S heterozygotes showed no decrease of PINK1 protein levels but a sustained, significant reduction in kinase activity. Molecular modelling and dynamics simulations as well as multiple functional assays revealed that the p.G411S mutation interferes with ubiquitin phosphorylation by wild-type PINK1 in a heterodimeric complex. This impairs the protective functions of the PINK1/parkin-mediated mitochondrial quality control. Based on genetic and clinical evaluation as well as functional and structural characterization, we established p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a partial dominant-negative function phenotype.

(Patho-)physiological relevance of PINK1-dependent ubiquitin phosphorylation.

Mutations in PINK1 and PARKIN cause recessive, early-onset Parkinson's disease (PD). Together, these two proteins orchestrate a protective mitophagic response that ensures the safe disposal of damaged mitochondria. The kinase PINK1 phosphorylates ubiquitin (Ub) at the conserved residue S65, in addition to modifying the E3 ubiquitin ligase Parkin. The structural and functional consequences of Ub phosphorylation (pS65-Ub) have already been suggested from in vitro experiments, but its (patho-)physiological significance remains unknown. We have generated novel antibodies and assessed pS65-Ub signals in vitro and in cells, including primary neurons, under endogenous conditions. pS65-Ub is dependent on PINK1 kinase activity as confirmed in patient fibroblasts and postmortem brain samples harboring pathogenic mutations. We show that pS65-Ub is reversible and barely detectable under basal conditions, but rapidly induced upon mitochondrial stress in cells and amplified in the presence of functional Parkin. pS65-Ub accumulates in human brain during aging and disease in the form of cytoplasmic granules that partially overlap with mitochondrial, lysosomal, and total Ub markers. Additional studies are now warranted to further elucidate pS65-Ub functions and fully explore its potential for biomarker or therapeutic development.

A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression.

INTRODUCTION: We hypothesized that common Alzheimer's disease (AD)-associated variants within the triggering receptor expressed on myeloid (TREM) gene cluster influence disease through gene expression. METHODS: Expression microarrays on temporal cortex and cerebellum from ∼400 neuropathologically diagnosed subjects and two independent RNAseq replication cohorts were used for expression quantitative trait locus analysis. RESULTS: A variant within a DNase hypersensitive site 5' of TREM2, rs9357347-C, associates with reduced AD risk and increased TREML1 and TREM2 levels (uncorrected P = 6.3 × 10-3 and 4.6 × 10-2, respectively). Meta-analysis on expression quantitative trait locus results from three independent data sets (n = 1006) confirmed these associations (uncorrected P = 3.4 × 10-2 and 3.5 × 10-3, Bonferroni-corrected P = 6.7 × 10-2 and 7.1 × 10-3, respectively). DISCUSSION: Our findings point to rs9357347 as a functional regulatory variant that contributes to a protective effect observed at the TREM locus in the International Genomics of Alzheimer's Project genome-wide association study meta-analysis and suggest concomitant increase in TREML1 and TREM2 brain levels as a potential mechanism for protection from AD.

Cognitive impairment and BDNF serum levels.

BACKGROUND/AIMS: To investigate the alterations of brain-derived neurotrophic factor (BNDF) serum levels in subjects with different intensity of cognitive impairment and different neurodegenerative processes. MATERIAL AND METHODS: Serum BDNF levels were analyzed by ELISA kit in 378 subjects: 134 Alzheimer's disease (AD) patients, 115 amnestic mild cognitive impairment (MCI) patients, and 129 controls divided into two groups: neurodegenerative control group (ND), consisting of 49 Parkinson's disease patients without any cognitive complaints, and cognitively normal control group (CN), consisting of 80 subjects without any neurological disorders. RESULTS: AD patients had significantly lower (p<0.001) BDNF serum levels compared to MCI, CN and ND controls. Age and education had significant influence on BDNF serum levels regardless the diagnosis or group assignment. We have found no influence of depression on BDNF serum levels either in our group as a whole, or in each group assessed separately. We found significant correlation between BDNF serum levels and cognitive impairments. After multiple comparisons between the groups, we found that, after adjustment for confounding factors (age, gender, education, depression, cognitive impairment), BDNF serum levels were the lowest in AD group (p=0.05). CONCLUSIONS: Advanced age and low educational level are associated with decreased BDNF serum levels. Decreased BDNF serum levels correspond to the severity of cognitive impairment. There is no correlation between BDNF serum levels and depressive symptoms.

Genetics of Parkinson's disease: a review of SNCA and LRRK2.

Parkinson's disease (PD) is a common neurodegenerative disorder that usually affects the elderly. Resting tremor, rigidity, bradykinesia, and postural instability are the main symptoms of PD. The loss of dopaminergic neurons in the substantia nigra and Lewy bodies in remaining neurons are pathological characteristics of PD. To combat these symptoms, dopaminergic therapy can benefit PD patients; however, it is only symptomatic therapy. Although the pathogenesis of PD has yet to be elucidated, approximately 10% of PD patients have familial history of PD. Since the first discovery of a causative gene of PD, SNCA, in 1997, 18 other genes have been identified in familial PD. These discoveries make it possible to begin to understand the pathogenesis of PD and can lead to the development of curative therapies. Here, we describe the clinical and pathological features of PD caused by mutations in two major PD-associated genes, SNCA and LRRK2. Mutations in SNCA revealed the pathological association between α-synuclein and PD, while LRRK2 is the most common genetic cause of PD. The patients with LRRK2 mutations present with relatively typical PD phenotypes, but heterogeneous pathologies including α-synuclein, tau, and occasionaly transactive response DNA-binding protein 43.

ALS-FTD complex disorder due to C9ORF72 gene mutation: description of first Polish family.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are complex neurodegenerative disorders that can be either sporadic or familial and can overlap clinically and pathologically. We present the first Central-Eastern European family with ALS-FTD syndrome due to a C9ORF72 repeat expansion. METHODS: We studied a family consisting of 37 family members, 6 of whom were genetically evaluated for C9ORF72 expansions. Family members were evaluated clinically, by history, and by chart review. RESULTS: Overall, 5 generations of the family were studied, and 6 affected family members were identified. All affected members were females and had a different clinical presentation, which was ALS, FTD or both. Among the genetically evaluated subjects, 5 carried a C9ORF72 expansion; 4 of these individuals remain clinically unaffected. CONCLUSION: Our report reveals that the hexanucleotide repeat expansion of C9ORF72, which is the most common genetic cause of ALS-FTD complex disorder, is also present in Central-Eastern Europe. Further studies are needed to assess the frequency of this expansion in the Polish population with familial as well as sporadic ALS, FTD and the ALS-FTD complex disorder.

Evaluation of Cardiovascular Autonomic Nervous System in Essential Tremor and Tremor Dominant Parkinson's Disease.

(1) Background: The differential diagnosis of essential tremor (ET) and tremor-dominant Parkinson's disease (TDPD) can be challenging. Only a few studies have investigated the autonomic nervous system (ANS) in ET. However, some of these suggested that heart rate variability (HRV) might be useful in the differential diagnosis. (2) Methods: Demographic and clinical data, including medications and comorbidities, were collected from 15 TDPD patients, 19 ET patients, and 20 healthy controls. Assessment with the SCOPA-AUT questionnaire, 5 min HRV analysis in time and frequency domains, and evaluation of orthostatic hypotension (OH) with tilt test were performed. (3) Results: There were no significant differences between all groups on the SCOPA-AUT questionnaire. PD patients had OH more frequently and a larger drop in systolic blood pressure (SBP) during the tilt test than ET patients and controls. HRV was affected in PD, but not in ET and controls. Power in the low frequency band, the standard deviation of all normal RR intervals and SBP drop were potentially useful in differential diagnosis with AUCs of 0.83, 0.78, and 0.83, respectively. (4) Conclusions: Cardiovascular ANS dysfunction was present in TDPD, but not in ET and controls. HRV analysis and assessment of SBP drop may be potentially useful in the differential diagnosis of ET and TDPD.