Dulski, Jarosław

Abstract Biallelic colony‐stimulating factor 1 receptor ( CSF1R ) variants are a major cause of early‐onset CSF1R ‐related disorder (CSF1R‐RD), although fewer than 30 cases have been reported and genotype–phenotype correlations remain unclear. The aim of this study was to characterize the clinical, radiological, and genetic features of patients with brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS). Six patients with biallelic CSF1R variants underwent detailed clinical, neurological, and magnetic resonance imaging evaluation. Three siblings with a homozygous p.Gly585Val variant showed marked phenotypic variability, ranging from severe childhood‐onset neurodegeneration to an asymptomatic presentation, all with white matter abnormalities. Three unrelated patients carried different biallelic CSF1R variants and presented with congenital skeletal abnormalities or early‐onset neurological disease of variable severity. These cases broaden the phenotypic spectrum of biallelic CSF1R‐RD and demonstrate that disease severity cannot be predicted solely by genotype, suggesting an important role for genetic or environmental modifiers.

Abstract Background Spinocerebellar ataxia type 3 (SCA3), the most common autosomal dominant ataxia, is driven by the accumulation of polyglutamine‐expanded (polyQ) ATXN3 proteins. While promising as biomarkers, their longitudinal trajectories across multiple biofluids remain poorly defined. Objectives To quantify polyQ ATXN3 levels in cerebrospinal fluid (CSF), plasma, and urine within a comprehensive cohort, utilizing serial measurements to map protein dynamics. Methods We employed a validated immunoassay to quantify polyQ ATXN3 in 97 symptomatic and 13 presymptomatic SCA3 patients, correlating levels with clinical features, ancestry, disease status, and longitudinal progression. Results Asian participants exhibited lower plasma but elevated urinary polyQ ATXN3 levels relative to other ancestries. While CSF levels were higher in symptomatic patients at baseline, they showed a significant longitudinal decline. Conclusions PolyQ ATXN3 is a viable multi‐biofluid biomarker. Declining CSF levels likely reflect neurodegeneration, supporting its role in tracking progression and emphasizing the need for ancestry‐based adjustment in trials. © 2026 International Parkinson and Movement Disorder Society.

Introduction Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB) are progressive neurodegenerative disorders characterized by alpha-synuclein pathology. As current therapies largely target symptoms, there is a clear need for disease-modifying treatments. Emerging evidence links these disorders to glucose metabolism dysregulation, suggesting antidiabetic agents may hold therapeutic potential. Methods This was a prospective, randomized, double-blind pilot study involving 12 subjects with PD or DLB to evaluate the tolerability and preliminary effects of a dipeptidyl peptidase 4 (DPP4) inhibitor (sitagliptin 100 mg) vs. sodium glucose like transporter 2 (SGLT2) inhibitor (dapagliflozin 10 mg) over a 4-week period, compared to a placebo. We assessed changes in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores, cognitive function, and autonomic biomarkers. Both sitagliptin and dapagliflozin were well-tolerated, with no adverse events. While no significant changes were observed in cognitive scores, a significant difference was found in the change from baseline for MDS-UPDRS part 1 ( P = 0.008), part 2 ( P = 0.020), and total scores ( P = 0.047) when comparing the three groups. Discussion The dapagliflozin group showed more favorable trends in MDS-UPDRS scores. Limitations include small study size and duration as well as all participants had PD except one subject in the DPP4 inhibitor group with DLB. This pilot study suggests that these inhibitors are safe in PD and DLB patients. The preliminary findings, particularly the trends in the dapagliflozin group, provide a basis for larger-scale, long-term studies to confirm these potential symptomatic benefits and explore disease-modifying effects. Clinical trial registration https://clinicaltrials.gov/study/NCT06263673 , identifier: NCT06263673.

Spinocerebellar ataxia type 7 (SCA7), a rare form of ataxia, possesses a wide phenotypic spectrum ranging from classic ataxic symptoms to blindness, multiorgan failure, cardiomyopathy, and early death among younger age groups. Biomarkers associated with disease progression and severity could aid in disease prognostication. We evaluated the utility of glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) in distinguishing patients with SCA7 from healthy controls and estimating patient prognosis. GFAP and NfL levels were measured in 23 plasma and 20 cerebrospinal fluid (CSF) samples from asymptomatic (N = 3) and symptomatic SCA7 participants (N = 10) and from healthy controls (N = 8). GFAP concentrations were elevated in the plasma (82.7 pg/mL) and CSF (9318 pg/mL) of patients with SCA7 compared to controls (plasma: 48.0 pg/mL; CSF: 89,056 pg/mL). Similarly, NfL plasma (21.6 pg/mL) and CSF (2615.0 pg/mL) levels were also significantly upregulated in SCA7 compared to controls (plasma: 8.2 pg/mL; CSF: 414.6 pg/mL). Higher levels of NfL, but not of GFAP, significantly discriminated symptomatic SCA7 patients from controls (area under de curve, AUC: 0.898, p = 0.0059, in plasma, and AUC: 1.0, p = 0.0012, in CSF). The levels of both biomarkers increased overtime, with plasma NfL levels strongly associated with a worse score in the scale for the assessment and rating of ataxia (SARA) (Spearman r: 0.8354, p = 0.0007; regression analysis: β: 0.021, 95% CI: 0.008–0.035, p = 0.0048). These findings suggest that NfL could serve as a valuable biomarker for monitoring disease progression and prognosis in SCA7 patients.

Abstract KIF5A (Kinesin family member 5A) is a motor protein that functions as a key component of the axonal transport machinery. Variants in KIF5A are linked to several neurodegenerative diseases, mainly spastic paraplegia type 10 (SPG10), Charcot-Marie-Tooth disease type 2 (CMT2), and amyotrophic lateral sclerosis (ALS). These diseases share motor neuron involvement but vary significantly in clinical presentation, severity, and progression. KIF5A variants are mainly categorized into N-terminal variants associated with SPG10/CMT2 and C-terminal variants linked to ALS. This study utilized a novel multiplex NULISA targeted platform to analyze plasma proteome from KIF5A -linked SPG10, ALS patients and compared to healthy controls. Our results revealed distinct proteomic signatures, with significant alterations in proteins related to synaptic function, and inflammation. Notably, neurofilament light polypeptide, a biomarker for neurodegenerative diseases, was elevated in KIF5A ALS but not in SPG10 patients. Moreover, these findings can now be taken forward to gain mechanistic understanding of axonopathies linking to N- vs C-terminal KIF5A variants affecting both central and peripheral nervous systems.

Abstract Background Perry syndrome (PS) is a rare and fatal hereditary autosomal dominant neurodegenerative disorder caused by mutations in dynactin ( DCTN1 ). PS brains accumulate inclusions positive for ubiquitin, transactive‐response DNA‐binding protein of 43 kDa (TDP‐43), and to a lesser extent dynactin. Objectives Little is known regarding the contributions of TDP‐43, an RNA binding protein that represses cryptic exon inclusion, in PS. Therefore, we sought to identify the degree of TDP‐43 dysfunction in two regions of PS brains. Methods We evaluated the levels of insoluble pTDP‐43 and TDP‐43‐regulated cryptic RNAs and protein in the caudate nucleus and substantia nigra of 7 PS cases, 12 cases of frontotemporal lobar degeneration (FTLD) with TDP‐43 pathology, and 11 cognitively healthy controls without TDP‐43 pathology. Results Insoluble pTDP‐43 protein levels were detected in PS brains to a similar extent in the caudate nucleus and substantia nigra but lower than those in FTLD brains. The caudate nucleus of PS showed accumulation of eight TDP‐43‐regulated cryptic RNAs ( ACTL6B , CAMK2B , STMN2 , UNC13A , KCNQ2 , ATG4B , GPSM2 , and HDGFL2 ) and cryptic protein (HDGFL2) characteristic of FTLD. Conversely, only one cryptic target, UNC13A , reached significance in the substantia nigra despite similar pTDP‐43 levels. Conclusion We detected TDP‐43 cryptic RNAs and protein in PS caudate nucleus. Given the importance of cryptic exon biology in the development of biomarkers, and the identification of novel targets for therapeutic intervention, it is imperative we understand the consequences of TDP‐43 dysfunction across different brain regions and determine the targets that are specific and common to TDP‐43 proteinopathies. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder characterized by decreased or undetectable serum levels of immunoglobulin G (IgG), decreased levels of IgA isotypes, and poor specific antibody production in response to vaccines and pathogens. Owing to hypogammaglobulinemia, patients have increased susceptibility to infections and a higher risk of malignancies. Here we present a case study of patient with a diagnosis of CVID, who refused immunoglobulin replacement therapy despite plenty of complications. Patient suffered from recurrent respiratory and digestive tract infections, diarrhea, malnutrition, infection of the central nervous system, and autoimmune complications. The complications of untreated hypogammaglobulinemia eventually led to the death of the patient at the age of 63 years. Patients with CVID have an increased susceptibility to chronic infections and subsequent complications; hence, proper treatment with immunoglobulin replacement therapy should be administered. Owing to the increased risk of autoimmunity and malignancy, regular surveillance should be conducted in patients with CVID. Understanding the natural history of untreated hypogammaglobulinemia emphasizes the need for early diagnosis, appropriate treatment, and vigilant follow-up in patients with CVID.

Spinocerebellar ataxia type 3 (SCA3) is the most common type of disease related to poly-glutamine (polyQ) repeats. Its hallmark pathology is related to the abnormal accumulation of ataxin 3 with a longer polyQ tract (polyQ-ATXN3). However, there are other mechanisms related to SCA3 progression that require identifying trait and state biomarkers for a more accurate diagnosis and prognosis. Moreover, the identification of potential pharmacodynamic targets and assessment of therapeutic efficacy necessitates valid biomarker profiles. The aim of this review was to identify potential trait and state biomarkers and their potential value in clinical trials. Our results show that, in SCA3, there are different fluid biomarkers involved in neurodegeneration, oxidative stress, metabolism, miRNA and novel genes. However, neurofilament light chain NfL and polyQ-ATXN3 stand out as the most prevalent in body fluids and SCA3 stages. A heterogeneity analysis of NfL revealed that it may be a valuable state biomarker, particularly when measured in plasma. Nonetheless, since it could be a more beneficial approach to tracking SCA3 progression and clinical trial efficacy, it is more convenient to perform a biomarker profile evaluation than to rely on only one.