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BACKGROUND: Multiple system atrophy (MSA), an atypical parkinsonian syndrome, is a rapidly progressive neurodegenerative disease with currently no established fluid biomarkers available. MSA is characterized by an oligodendroglial α-synucleinopathy, progressive neuronal cell loss and concomitant astrocytosis. Here, we investigate glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) as fluid biomarkers for differential diagnosis, assessment of clinical disease severity and prediction of disease progression in MSA. METHODS: GFAP and NfL levels were analyzed in plasma and CSF samples of 47 MSA patients as well as 24 Parkinson's disease (PD) and 25 healthy controls (HC) as reference cohorts. In MSA, biomarker levels were correlated to baseline and longitudinal clinical disease severity (UMSARS scores). RESULTS: In MSA, GFAP levels in CSF and plasma predicted baseline clinical disease severity as indicated by UMSARS scores, while NfL levels predicted clinical disease progression as indicated by longitudinal changes in UMSARS scores. Cross-sectionally, NfL levels in CSF and plasma were significantly elevated in MSA compared to both PD and HC. Receiver operating curves (ROC) indicated high diagnostic accuracy of NfL for distinguishing MSA from PD (CSF: AUC = 0.97, 95% CI 0.90-1.00; plasma: AUC = 0.90, 95% CI 0.81-1.00). DISCUSSION: In MSA, GFAP shows promise as novel biomarker for assessing current clinical disease severity, while NfL might serve as biomarker for prediction of disease progression and differential diagnosis of MSA against PD.

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Background: Anticholinergic adverse effects pose a relevant threat to patients, in particular elderly and cognitively impaired patients. Patients with Parkinsonian syndromes are especially at risk from anticholinergic adverse effects due to the often-required complex drug therapy. Aims: The aim of this study was to evaluate the potential effect of the anticholinergic burden on motor and non-motor symptoms in Parkinson's disease and atypical Parkinsonian syndromes. Methods: This cross-sectional, monocentric retrospective data analysis included 151 patients with Parkinson's disease (PD), 63 with progressive supranuclear palsy (PSP), and 36 with multiple system atrophy (MSA). The anticholinergic burden of patients' medications was determined using two established scores: the Anticholinergic Drug Scale (ADS) and the German Anticholinergic Burden Scale (GABS). These scores were compared between the different diseases and correlated with several disease-specific scores. Results: Anticholinergic burden was higher in patients with PD, in particular, compared to PSP. In the PD group, anticholinergic burden showed a weak correlation with almost all analyzed clinical scores and the number of administered drugs. The UMSARS I and II showed a significant correlation with the anticholinergic burden in MSA patients. In general, the GABS-measured anticholinergic burden was significantly higher compared to the ADS-measured. Conclusions: The calculated anticholinergic burden affected motor and non-motor symptoms in patients with various Parkinsonian syndromes poorly. Since the GABS also contains basic anti-parkinsonian drugs, this score tended to overestimate the anticholinergic burden in patients with Parkinsonian syndromes and, therefore, seemed less appropriate for this application.

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BACKGROUND: Diagnostic criteria for progressive supranuclear palsy (PSP) include midbrain atrophy in MRI and hypometabolism in [18F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) as supportive features. Due to limited data regarding their relative and sequential value, there is no recommendation for an algorithm to combine both modalities to increase diagnostic accuracy. This study evaluated the added value of sequential imaging using state-of-the-art methods to analyse the images regarding PSP features. METHODS: The retrospective study included 41 PSP patients, 21 with Richardson's syndrome (PSP-RS), 20 with variant PSP phenotypes (vPSP) and 46 sex- and age-matched healthy controls. A pretrained support vector machine (SVM) for the classification of atrophy profiles from automatic MRI volumetry was used to analyse T1w-MRI (output: MRI-SVM-PSP score). Covariance pattern analysis was applied to compute the expression of a predefined PSP-related pattern in FDG-PET (output: PET-PSPRP expression score). RESULTS: The area under the receiver operating characteristic curve for the detection of PSP did not differ between MRI-SVM-PSP and PET-PSPRP expression score (p≥0.63): about 0.90, 0.95 and 0.85 for detection of all PSP, PSP-RS and vPSP. The MRI-SVM-PSP score achieved about 13% higher specificity and about 15% lower sensitivity than the PET-PSPRP expression score. Decision tree models selected the MRI-SVM-PSP score for the first branching and the PET-PSPRP expression score for a second split of the subgroup with normal MRI-SVM-PSP score, both in the whole sample and when restricted to PSP-RS or vPSP. CONCLUSIONS: FDG-PET provides added value for PSP-suspected patients with normal/inconclusive T1w-MRI, regardless of PSP phenotype and the methods to analyse the images for PSP-typical features.

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OBJECTIVE: The Progressive Supranuclear Palsy quality of life scale (PSP-QoL) has been shown to be a useful tool for capturing health-related quality of life of patients in "everyday life" and in progressive supranuclear palsy (PSP) research. However, at 45 items in length, the questionnaire can take a long time, exhausting PSP patients, in particular if cognitive impaired, which can have a negative impact on the assessment. The aim of this study was to establish a condensed version of the PSP-QoL for research and routine clinical care. METHODS: In this retrospective study, data originating from a German cohort of PSP patients was analyzed. Data from 245 PSP patients were included in this study. The short PSP-QoL questionnaire was created using a two-factor solution and item-total and inter-item correlations for mental and physical aspects of daily living of the PSP-QoL followed by confirmatory factor analysis. RESULTS: The final scale included 12 items representing mental (five items) and physical symptoms (seven items). The specified two-factor model displayed an excellent fit in the confirmatory factor analysis. The short Progressive Supranuclear Palsy Quality of Life scale (PSP-ShoQoL) correlated moderately with the PSP Rating Scale (r [243] = 0.514, P < 0.001) and Geriatric depression scale (r [231] = 0.548, P < 0.001). Sensitivity to change confirmed a significant decrease in QoL after 12 months. DISCUSSION: In this study, we created a 12-item PSP-ShoQoL designed to "facilitate" daily clinical work that correlated strongly with the PSP-QoL and was sensitive to change. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Amyotrophic lateral sclerosis (ALS) leads to death within 2-5 yr. Currently, available drugs only slightly prolong survival. We present novel insights into the pathophysiology of Superoxide Dismutase 1 (SOD1)- and in particular Fused In Sarcoma (FUS)-ALS by revealing a supposedly central role of glycolic acid (GA) and D-lactic acid (DL)-both putative products of the Parkinson's disease associated glyoxylase DJ-1. Combined, not single, treatment with GA/DL restored axonal organelle phenotypes of mitochondria and lysosomes in FUS- and SOD1-ALS patient-derived motoneurons (MNs). This was not only accompanied by restoration of mitochondrial membrane potential but even dependent on it. Despite presenting an axonal transport deficiency as well, TDP43 patient-derived MNs did not share mitochondrial depolarization and did not respond to GA/DL treatment. GA and DL also restored cytoplasmic mislocalization of FUS and FUS recruitment to DNA damage sites, recently reported being upstream of the mitochondrial phenotypes in FUS-ALS. Whereas these data point towards the necessity of individualized (gene-) specific therapy stratification, it also suggests common therapeutic targets across different neurodegenerative diseases characterized by mitochondrial depolarization.

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The new lithium arsenidotetrelates Li8SiAs4, Li8GeAs4, Li14SiAs6, Li14GeAs6 and Li14SnAs6 were synthesized via ball milling and structurally characterized by Rietveld analysis of X-ray powder diffraction data. The aliovalent substitution of lithium in hexagonal Li3As by introducing a tetravalent tetrel cation stabilizes cubic structures for Li8TtAs4 (Tt = Si, Ge) in the space group Pa3̄ and for the lithium richer compound Li14TtAs6 (Tt = Si, Ge, Sn) in the higher symmetrical space group Fm3̄m (no. 225). Thermal properties of the arsenidotetrelates were investigated via high temperature powder diffraction and differential thermal analysis revealing a decomposition process of the lithium richer arsenidotetrelate (Li14TtAs6 → Li8TtAs4 + 2Li3As) into the lithium poorer arsenidotetrelates and lithium arsenide at moderate temperatures. Impedance spectroscopy shows moderate to good lithium ion conductivity for the lithium arsenidotetrelates.

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BACKGROUND: Multiple system atrophy (MSA) is a complex and fatal neurodegenerative movement disorder. Understanding the comorbidities and drug therapy is crucial for MSA patients' safety and management. OBJECTIVES: To investigate the pattern of comorbidities and aspects of drug therapy in MSA patients. METHODS: Cross-sectional data of MSA patients according to Gilman et al. (2008) diagnostic criteria and control patients without neurodegenerative diseases (non-ND) were collected from German, multicenter cohorts. The prevalence of comorbidities according to WHO ICD-10 classification and drugs administered according to WHO ATC system were analyzed. Potential drug-drug interactions were identified using AiDKlinik®. RESULTS: The analysis included 254 MSA and 363 age- and sex-matched non-ND control patients. MSA patients exhibited a significantly higher burden of comorbidities, in particular diseases of the genitourinary system. Also, more medications were prescribed MSA patients, resulting in a higher prevalence of polypharmacy. Importantly, the risk of potential drug-drug interactions, including severe interactions and contraindicated combinations, was elevated in MSA patients. When comparing MSA-P and MSA-C subtypes, MSA-P patients suffered more frequently from diseases of the genitourinary system and diseases of the musculoskeletal system and connective tissue. CONCLUSIONS: MSA patients face a substantial burden of comorbidities, notably in the genitourinary system. This, coupled with increased polypharmacy and potential drug interactions, highlights the complexity of managing MSA patients. Clinicians should carefully consider these factors when devising treatment strategies for MSA patients.

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Severe acute respiratory coronavirus 2 (SARS-CoV-2) causes neurological disease in the peripheral and central nervous system (PNS and CNS, respectively) of some patients. It is not clear whether SARS-CoV-2 infection or the subsequent immune response are the key factors that cause neurological disease. Here, we addressed this question by infecting human induced pluripotent stem cell-derived CNS and PNS neurons with SARS-CoV-2. SARS-CoV-2 infected a low number of CNS neurons and did not elicit a robust innate immune response. On the contrary, SARS-CoV-2 infected a higher number of PNS neurons. This resulted in expression of interferon (IFN) λ1, several IFN-stimulated genes and proinflammatory cytokines. The PNS neurons also displayed alterations characteristic of neuronal damage, as increased levels of sterile alpha and Toll/interleukin receptor motif-containing protein 1, amyloid precursor protein and α-synuclein, and lower levels of cytoskeletal proteins. Interestingly, blockade of the Janus kinase and signal transducer and activator of transcription pathway by Ruxolitinib did not increase SARS-CoV-2 infection, but reduced neuronal damage, suggesting that an exacerbated neuronal innate immune response contributes to pathogenesis in the PNS. Our results provide a basis to study coronavirus disease 2019 (COVID-19) related neuronal pathology and to test future preventive or therapeutic strategies.

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BACKGROUND: Progressive supranuclear palsy (PSP) is usually diagnosed in elderly. Currently, little is known about comorbidities and the co-medication in these patients. OBJECTIVES: To explore the pattern of comorbidities and co-medication in PSP patients according to the known different phenotypes and in comparison with patients without neurodegenerative disease. METHODS: Cross-sectional data of PSP and patients without neurodegenerative diseases (non-ND) were collected from three German multicenter observational studies (DescribePSP, ProPSP and DANCER). The prevalence of comorbidities according to WHO ICD-10 classification and the prevalence of drugs administered according to WHO ATC system were analyzed. Potential drug-drug interactions were evaluated using AiDKlinik®. RESULTS: In total, 335 PSP and 275 non-ND patients were included in this analysis. The prevalence of diseases of the circulatory and the nervous system was higher in PSP at first level of ICD-10. Dorsopathies, diabetes mellitus, other nutritional deficiencies and polyneuropathies were more frequent in PSP at second level of ICD-10. In particular, the summed prevalence of cardiovascular and cerebrovascular diseases was higher in PSP patients. More drugs were administered in the PSP group leading to a greater percentage of patients with polypharmacy. Accordingly, the prevalence of potential drug-drug interactions was higher in PSP patients, especially severe and moderate interactions. CONCLUSIONS: PSP patients possess a characteristic profile of comorbidities, particularly diabetes and cardiovascular diseases. The eminent burden of comorbidities and resulting polypharmacy should be carefully considered when treating PSP patients.

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Tau seed amplification assays (SAAs) directly measure the seeding activity of tau and would therefore be ideal biomarkers for clinical trials targeting seeding-competent tau in Alzheimer's disease (AD). However, the precise relationship between tau seeding measured by SAA and the levels of pathological forms of tau in the AD brain remains unknown. We developed a new tau SAA based on full-length 0N3R tau with sensitivity in the low fg/ml range and used it to characterize 103 brain samples from three independent cohorts. Tau seeding clearly discriminated between AD and control brain samples. Interestingly, seeding was absent in Progressive Supranuclear Palsy (PSP) putamen, suggesting that our tau SAA did not amplify 4R tau aggregates from PSP brain. The specificity of our tau SAA for AD brain was further supported by analysis of matched hippocampus and cerebellum samples. While seeding was detected in hippocampus from Braak stages I-II, no seeding was present in AD cerebellum that is devoid of tau inclusions. Analysis of 40 middle frontal gyrus samples encompassing all Braak stages showed that tau SAA seeding activity gradually increased with Braak stage. This relationship between seeding activity and the presence of tau inclusions in AD brain was further supported by robust correlations between tau SAA results and the levels of phosphorylated tau212/214, phosphorylated tau181, aggregated tau, and sarkosyl-insoluble tau. Strikingly, we detected tau seeding in the middle frontal gyrus already at Braak stage II-III, suggesting that tau SAA can detect tau pathology earlier than conventional immunohistochemical staining. In conclusion, our data suggest a quantitative relationship between tau seeding activity and pathological forms of tau in the human brain and provides an important basis for further development of tau SAA for accessible human samples.

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BACKGROUND: To date, studies on positron emission tomography (PET) with 18 F-fluorodeoxyglucose (FDG) in progressive supranuclear palsy (PSP) usually included PSP cohorts overrepresenting patients with Richardson's syndrome (PSP-RS). OBJECTIVES: To evaluate FDG-PET in a patient sample representing the broad phenotypic PSP spectrum typically encountered in routine clinical practice. METHODS: This retrospective, multicenter study included 41 PSP patients, 21 (51%) with RS and 20 (49%) with non-RS variants of PSP (vPSP), and 46 age-matched healthy controls. Two state-of-the art methods for the interpretation of FDG-PET were compared: visual analysis supported by voxel-based statistical testing (five readers) and automatic covariance pattern analysis using a predefined PSP-related pattern. RESULTS: Sensitivity and specificity of the majority visual read for the detection of PSP in the whole cohort were 74% and 72%, respectively. The percentage of false-negative cases was 10% in the PSP-RS subsample and 43% in the vPSP subsample. Automatic covariance pattern analysis provided sensitivity and specificity of 93% and 83% in the whole cohort. The percentage of false-negative cases was 0% in the PSP-RS subsample and 15% in the vPSP subsample. CONCLUSIONS: Visual interpretation of FDG-PET supported by voxel-based testing provides good accuracy for the detection of PSP-RS, but only fair sensitivity for vPSP. Automatic covariance pattern analysis outperforms visual interpretation in the detection of PSP-RS, provides clinically useful sensitivity for vPSP, and reduces the rate of false-positive findings. Thus, pattern expression analysis is clinically useful to complement visual reading and voxel-based testing of FDG-PET in suspected PSP. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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BACKGROUND: Brain magnetic resonance imaging (MRI) is used to support the diagnosis of progressive supranuclear palsy (PSP). However, the value of visual descriptive, manual planimetric, automatic volumetric MRI markers and fully automatic categorization is unclear, particularly regarding PSP predominance types other than Richardson's syndrome (RS). OBJECTIVES: To compare different visual reading strategies and automatic classification of T1-weighted MRI for detection of PSP in a typical clinical cohort including PSP-RS and (non-RS) variant PSP (vPSP) patients. METHODS: Forty-one patients (21 RS, 20 vPSP) and 46 healthy controls were included. Three readers using three strategies performed MRI analysis: exclusively visual reading using descriptive signs (hummingbird, morning-glory, Mickey-Mouse), visual reading supported by manual planimetry measures, and visual reading supported by automatic volumetry. Fully automatic classification was performed using a pre-trained support vector machine (SVM) on the results of atlas-based volumetry. RESULTS: All tested methods achieved higher specificity than sensitivity. Limited sensitivity was driven to large extent by false negative vPSP cases. Support by automatic volumetry resulted in the highest accuracy (75.1% ± 3.5%) among the visual strategies, but performed not better than the midbrain area (75.9%), the best single planimetric measure. Automatic classification by SVM clearly outperformed all other methods (accuracy, 87.4%), representing the only method to provide clinically useful sensitivity also in vPSP (70.0%). CONCLUSIONS: Fully automatic classification of volumetric MRI measures using machine learning methods outperforms visual MRI analysis without and with planimetry or volumetry support, particularly regarding diagnosis of vPSP, suggesting the use in settings with a broad phenotypic PSP spectrum. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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BACKGROUND: Progressive supranuclear palsy (PSP) is an atypical Parkinsonian syndrome characterized by supranuclear gaze palsy, early postural instability, and a frontal dysexecutive syndrome. Contrary to normal brain magnetic resonance imaging in Parkinson's disease (PD), PSP shows specific cerebral atrophy patterns and alterations, but these findings are not present in every patient, and it is still unclear if these signs are also detectable in early disease stages. OBJECTIVE: The aim of the present study was to analyze the metabolic profile of patients with clinically diagnosed PSP in comparison with matched healthy volunteers and PD patients using whole-brain magnetic resonance spectroscopic imaging (wbMRSI). METHODS: Thirty-nine healthy controls (HCs), 29 PD, and 22 PSP patients underwent wbMRSI. PSP and PD patients were matched for age and handedness with HCs. Clinical characterization was performed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale, PSP rating scale, and DemTect (test for cognitive assessment). RESULTS: In PSP patients a significant reduction in N-acetyl-aspartate (NAA) was detected in all brain lobes. Fractional volume of the cerebrospinal fluid significantly increased in PSP patients compared to PD and healthy volunteers. CONCLUSIONS: In PSP much more neuronal degeneration and cerebral atrophy have been detected compared with PD. The most relevant alteration is the decrease in NAA in all lobes of the brain, which also showed a partial correlation with clinical symptoms. However, more studies are needed to confirm the additional value of wbMRSI in clinical practice. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Multiple system atrophy of the parkinsonian type (MSA-P) is a rare, fatal neurodegenerative disease with sporadic onset. It is still unknown if MSA-P is a primary oligodendropathy or caused by neuronal pathophysiology leading to severe, α-synuclein-associated neurodegeneration, mainly in the striatum. In this study, we generated and differentiated induced pluripotent stem cells (iPSCs) from patients with the clinical diagnosis of probable MSA-P (n = 3) and from three matched healthy controls into GABAergic striatal medium spiny neurons (MSNs). We found a significantly elevated release and neuronal distribution for α-synuclein, as well as hypoexcitability in the MSNs derived from the MSA-P patients compared to the healthy controls. These data suggest that the striatal hypoexcitable neurons of MSA-P patients contribute to a pathological α-synuclein burden which is likely to spread to neighboring cells and projection targets, facilitating disease progression.

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Pathogenic variants in the Parkin-gene (PRKN) are among the most common genetic causes of early onset Parkinson's disease (EOPD). Patients with EOPD can present with atypical clinical features and misdiagnosis is frequent. Here, we report a clinical phenotype with atypical signs and symptoms of a 35-year-old male patient with EOPD caused by a compound heterozygous PRKN-gene deletion of exons 2 and 4. After the initial diagnosis of stiff person syndrome, the patient was admitted to our department for a second opinion after 8 years of untreated disease progression. The patient presented with prominent spastic paraparesis pronounced on the right side and hyperreflexia as well as Parkinsonism with rigidity predominantly affecting the upper limbs, bradykinesia, and resting tremor. In the diagnostic assessment, magnetic evoked potentials to the anterior tibial muscles showed a low amplitude on the right side, compatible with pyramidal tract disturbance. However, an MRI of the head and the spine did not show any pathologies or atrophy. A [123I] FP-CIT SPECT scan revealed profoundly and left-pronounced reduced striatal uptake suggesting a neurodegenerative Parkinson's syndrome. Even though an acute levodopa challenge did not show marked improvement of symptoms, the chronic levodopa challenge with up to 450 mg/day significantly reduced the rigidity and bradykinesia. Surprisingly, spastic paraparesis and hyperreflexia diminished under dopaminergic treatment. Finally, genetic analysis by next-generation sequencing via copy number variant analysis (CNV) and multiplex ligation-dependent probe amplification (MLPA) confirmed compound heterozygous deletions of exons 2 and 4 in the PRKN-gene. As presented in this case, the awareness of atypical clinical symptoms of EOPD is essential to prevent misdiagnosis in young patients.

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A major proportion of people with Parkinson's disease (PwP) in Germany has written an advance directive (AD). Unfortunately, these ADs are unclear for PD-specific endpoints. We previously established consensus-based recommendations for disease-specific content of an AD in PwP. However, the implementation of those recommendations and the consulting of AD creation and modification in PwP remains to be evaluated. This study aimed to investigate the practical use of PD-specific recommendations for ADs in outpatient settings. A total of 87 physicians (45 general practitioners (GPs) and 42 neurologists, 10% response rate) answered a self-constructed semiquantitative questionnaire. The participants were asked to evaluate the suggested PD-specific recommendations for ADs and the supply of palliative care in the outpatient setting. Overall, the vast majority of treating physicians agreed on the usefulness of the newly constructed PD-specific recommendations. Consultations to discuss information about PD-specific ADs were scarce with short durations. Only 24% of participating physicians implemented the PD-specific recommendations in their daily practice. GPs and neurologists agreed on the benefit of disease-specific recommendations for ADs. In future, a more general integration of these recommendations in routine care might improve specific AD creation of PwP and advanced care planning.

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Little is known about the early pathogenic events by which mutant superoxide dismutase 1 (SOD1) causes amyotrophic lateral sclerosis (ALS). This lack of mechanistic understanding is a major barrier to the development and evaluation of efficient therapies. Although protein aggregation is known to be involved, it is not understood how mutant SOD1 causes degeneration of motoneurons (MNs). Previous research has relied heavily on the overexpression of mutant SOD1, but the clinical relevance of SOD1 overexpression models remains questionable. We used a human induced pluripotent stem cell (iPSC) model of spinal MNs and three different endogenous ALS-associated SOD1 mutations (D90Ahom, R115Ghet or A4Vhet) to investigate early cellular disturbances in MNs. Although enhanced misfolding and aggregation of SOD1 was induced by proteasome inhibition, it was not affected by activation of the stress granule pathway. Interestingly, we identified loss of mitochondrial, but not lysosomal, integrity as the earliest common pathological phenotype, which preceded elevated levels of insoluble, aggregated SOD1. A super-elongated mitochondrial morphology with impaired inner mitochondrial membrane potential was a unifying feature in mutant SOD1 iPSC-derived MNs. Impaired mitochondrial integrity was most prominent in mutant D90Ahom MNs, whereas both soluble disordered and detergent-resistant misfolded SOD1 was more prominent in R115Ghet and A4Vhet mutant lines. Taking advantage of patient-specific models of SOD1-ALS in vitro, our data suggest that mitochondrial dysfunction is one of the first crucial steps in the pathogenic cascade that leads to SOD1-ALS and also highlights the need for individualized medical approaches for SOD1-ALS.

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Parkinson's disease (PD) is a progressive neurodegenerative disorder resulting in reduced health-related quality of life (HR-QoL) of people with PD (PwP) and their caregivers. Furthermore, there is an accumulating burden on caregivers of patients in advanced stages of the disease. In previous studies, motor- and non-motor-symptoms of PwP have been identified to contribute to reduced HR-QoL and an increased caregiver burden. This cross-sectional observational study aimed to study the influence of neuropsychiatric symptoms measured with the Scale for Evaluation of Neuropsychiatric Disorders in Parkinson's Disease (SEND-PD) questionnaire on the HR-QoL of PwP, as well as the caregiver burden. Analyses revealed a significant association between SEND-PD subscale mood/apathy and reduced HR-QoL in PwP, measured by the Parkinson's disease quality of life questionnaire (PDQ-8) (p < 0.001). Furthermore, mood/apathy was significantly correlated with caregiver burden (p = 0.001) in the multiple linear regression analysis. Hence, neuropsychiatric symptoms were found to have a profound impact on the HR-QoL of PwP, as well as on caregiver burden. Since neuropsychiatric symptoms were one of the main predictors for caregiver burden, physicians of PwP should treat these symptoms to stabilize caregiver burden, as well as HR-QoL in PwP and their caregivers.