Neurobiology of Disease

A critical challenge in endocrine neurosurgery is intraoperative discrimination between normal pituitary tissue and pituitary neuroendocrine tumors (PitNETs). Suggesting the universal persistence of near-infrared autofluorescence (NIRAF) in endocrine organs and inspired by routine clinical use of NIRAF for parathyroid gland identification, we discovered that pituitary NIRAF can be employed for label-free transsphenoidal surgery guidance. Ex vivo confocal spectral imaging of 33 specimens identified secretory granules as the dominant long-wavelength fluorescence source and showed that normal pituitary had higher granule content than PitNETs. For the first time, we made use of the pituitary NIRAF during surgery and assessed its performance for pituitary/adenoma separation in vivo for 27 surgeries and showed near-perfect separability between pituitary and non-pituitary measurement sites with ROC-AUC of 0.98. The obtained results clearly demonstrate that the suggested method, based on the solid microscopic background, has the potential for clinical translation and paves the way for enhanced gland preservation during resection.

The human cerebral microvasculature is both essential for brain function and highly vulnerable, yet its in-vivo structure and local hemodynamics remain largely unexplored due to the lack of imaging techniques capable of resolving deep microvascular flow in humans. This limitation not only constrains fundamental neurovascular research, but poses life-altering risks during neurosurgery, where damage to small perforating arteries can have devastating neurological consequences. Specifically, the deep cerebral perforators, branching from the major trunks of the Circle of Willis, supply essential regions of the cerebral central core but remain beyond the resolution of current intraoperative imaging modalities. Here, we report a first in-human cohort study (10 patients) demonstrating the use of 4-dimensional ultrasound localization microscopy (4D-ULM) for the intraoperative visualization of cerebral microvascular anatomy and hemodynamics. In eight patients, 4D-ULM enabled volumetric mapping of deep perforators with sub-millimeter spatial resolution ([~]140 {micro}m) at depths reaching 7 cm. This approach revealed detailed flow patterns within the previously inaccessible deep vascular networks of the human brain. Our results open new opportunities for studying microvascular physiology and could enhance intraoperative decision-making by providing high-resolution hemodynamic data, paving the way for improved microsurgical precision in neurosurgical procedures.

IntroductionVentriculoperitoneal (VP) and Lumboperitoneal (LP) shunts are the most common treatments for Idiopathic Normal Pressure Hydrocephalus (iNPH). Shunt procedure choice is generally based on surgeon on preference rather than evidence. We performed a systematic review and meta-analysis to address this gap for evidence-based shunt selection in iNPH treatment. MethodsPublications on post-operative outcomes for LP and VP shunts in iNPH were identified in MEDLINE and EMBASE. Papers were selected based on pre-specified inclusion and exclusion criteria and meta-analysis was conducted for outcome measures after shunt procedure. Results17 papers were included. LP Shunt patients showed greater cognitive improvement with an average increase of 2.00 points (95% CI: 1.08; 2.93, p < 0.0001) on their MMSE score post-operatively compared to VP shunt patients who improved on average by 1.30 points (95% CI: 0.81; 1.79, p < 0.0001). The LP group had considerable heterogeneity (I2 = 66.42%, p = 0.0003) whereas the VP shunt group had minimal heterogeneity (I2 = 0.00%, p = 0.8447) reflecting more uniformity across its included studies. For overall symptomatic improvement measured by the iNPHGS, VP shunts patients demonstrated a larger reduction in overall symptom scores with an average decrease of 2.91 points (95% CI: -3.78; -2.05, p < 0.0001) but with a high heterogeneity (I2 = 79.12%, p = 0.0012) compared to LP shunt patients with an average reduction of 1.91 points (95% CI: -2.31; -1.51, p < 0.0001) with no detected heterogeneity (I2 = 0.00%, p = 0.8454). ConclusionsOur findings demonstrate that LP and VP shunts show differing patterns of improvement across the cognitive domain and the broader iNPH triad, with LP shunting showing greater cognitive improvement and VP shunting showing greater overall symptomatic improvement. These differences represent a signal warranting further investigation, specifically whether symptom profiles should inform shunt selection.

ObjectiveBrain branks preserve extensive material relevant to neurodegenerative disease research. As these collections age, tissue becomes archival, raising the question of whether long-term fixed and stored human brain tissue remains suitable for contemporary immunohistochemical analyses. Materials and MethodsForty-one autopsy brains collected between 1946 to 1980 were examined. For each case, midbrain and hippocampus were available both as original paraffin-embedded blocks and as tissue stored long term in fixative. New paraffin blocks were prepared from the long-term fixated tissue. Sections from original and newly prepared blocks were immunohistochemically stained for -synuclein, hyperphosphorylated tau and amyloid-{beta}. Immunoreactivity was assessed using semi-quantitative scoring. ResultsOriginal blocks consistently showed good staining intensity and morphological preservation for each protein pathology. Newly prepared blocks showed slightly lower semi-quantitative scores for Lewy-related pathology, without statistically significant differences, except for astrocytic -synuclein in the substantia nigra in cases from the 1960s. Tau pathology displayed modestly reduced labelling, particularly of the neuropil threads and neurofibrillary tangles, most evident in cases from the 1950s. Amyloid-{beta}-positive senile plaques showed similar or slightly higher scores in newly prepared blocks, with no significant differences across regions. ConclusionHuman brain tissue preserved as paraffin-embedded blocks or stored in fixative for up to 78 years remains suitable for immunohistochemical analyses. Adequate-to-good detection of aggregated of -synuclein, hyperphosphorylated tau and amyloid-{beta} is achievable, indicating preserved pathological hallmarks of Lewy Body Disease and Alzheimers Disease in archival tissue.

Mitochondrial single-nucleotide variants (mtSNVs) can dysregulate cellular bioenergetics and have been increasingly implicated in susceptibility to Parkinsons disease (PD). These variants may impair oxidative metabolism and respiratory chain efficiency, thus contributing to neuronal dysfunction and degeneration. In peripheral blood, mtSNVs may also reflect systemic immunometabolic alterations associated with PD; however, this aspect remains poorly explored, particularly in admixed populations with significant indigenous ancestry. In this study, we analyzed the complete mtDNA of peripheral blood samples from 179 admixed individuals (104 with PD and 75 controls) from the Brazilian Amazon. Associations between mtSNVs and PD were assessed using adjusted logistic regression models, and functional annotation was performed using the Variant Effect Predictor. Furthermore, we proposed and calculated a heteroplasmy-weighted mitochondrial polygenic risk score (mtPRS). We observed a higher mtSNV burden in PD patients, predominantly in RNR2 gene and genes of Complexes I and IV. In total, 536 unique mitochondrial SNVs were identified (214 exclusive to PD, 321 shared between PD and controls, and one exclusive to controls). Four mitochondrial SNVs were associated with PD, including three novel variants (COX1: m.6630G>A, COX2: m.7613C>T, and RNR2: m.1996C>T) and one previously reported variant (ND4: m.12112C>T). Notably, the mitochondrial polygenic risk score (mtPRS) showed a strong association with increased PD risk (OR = 3.64; FDR = 1.12 x 10-_). Taken together, these results suggest that mtSNVs may contribute to PD susceptibility in admixed Amazonian population, highlighting the relevance of mitochondrial genetic architecture in PD and emphasizing the importance of including underrepresented populations in genomic research.

ImportanceSome individuals are capable of tolerating Alzheimer disease neuropathological changes (ADNC) without manifesting clinical symptoms. Elucidating the neuropathological, and molecular mediators may facilitate the identification of more accurate in vivo biomarkers and inform the development of targeted therapeutic strategies. ObjectiveTo investigate cellular distribution of tau pathology, microglial responses, and gene expression profiles associated with divergent clinical outcomes (dementia vs. no dementia) in individuals exhibiting comparable ADNC. Design, Setting and ParticipantsWe analyzed postmortem brain tissue from 97 participants from the ROSMAP study:49 with high likelihood of AD (25 demented [demented AD] and 24 cognitively normal [resilient]), and 48 with low likelihood (22 demented [impaired-other (IMP-O)] and 26 cognitively normal [control]). Cases were matched for age, gender, and co-pathologies. Main outcomes and measuresAmyloid-{beta} plaques, phospho-tau pathology (tangles and tau-positive neurites), tau oligomers in synaptic-fractions, tau seeding activity, neurons, synapse density, and astrocyte and microglia activation were quantified. The relationships with bulk and microglia-specific RNA-sequencing were also examined. Statistical analyses employed ANOVA with Tukeys HSD/Bonferroni corrections for pathological and clinical variables, and the Wald test for differential gene expression ResultsDemented AD and resilient brains exhibited comparable tau tangle and amyloid-{beta} plaques; however, demented AD showed higher total pTau burden (tangles and tau-positive neurites) (Mean[SD], 27.39%[21.89%] vs. 10.60%[14.71%]; p= 0.0004) and elevated pTau oligomer levels in synaptic-enriched fractions (0.48[0.52] vs. 0.16[0.19]; p=0.0010). Both demented AD (0.21x107[0.14x107]; p<0.0001) and IMP-O (0.62x107 [0.42x107]; p<0.0001) showed greater synaptic loss than resilient (1.54x107[0.55x107]; p=0.0008) and controls (2.92x107[1.13x107]). CD68+ microglia burden was increased in demented (1.14%[0.27%]; p<0.0001) and IMP-O (0.97%[0.36%]; p<0.0001) but not in resilient (0.72% [0.17%]; p=0.2835) compared to controls (0.59%[0.17%]). Synaptic pTau oligomers and CD68+ microglia were the strongest correlates with antemortem cognition. Resilient brains exhibited downregulation of neuroinflammation-related genes and possessed a distinct microglial subpopulation supporting resilience, characterized by overexpression of CD83, DUSP1, and NAMPT. Conclusion and relevanceOur findings suggest that aberrant accumulation of tau in neurites and synapses, rather than tangles within neuronal soma, may trigger a microglial pro-inflammatory activation linked to synaptic loss and impaired cognition. Cell-specific transcriptomic analysis identified a distinct microglial cell subpopulation associated with resilience to ADNC.

Parkinsons disease (PD) is a progressive movement disorder that affects over ten million individuals worldwide. While the involvement of genetically-driven cellular mechanisms in PD pathogenesis is well-established, there is increasing evidence that epigenetic dysregulation also plays a key role. We profiled genome-wide DNA methylation in isolated neuronal, oligodendrocyte and other glial nuclei populations from the prefrontal cortex of 71 PD and 56 control individuals. We identified seven significant differentially methylated positions in neuronal nuclei associated with PD. All these sites were hypermethylated in PD, with five of the differentially methylated positions located in the following genes: ROBO4, SSBP2, PDE4B, NPHP1, and HSD17B12. No differentially methylated positions were observed in oligodendrocyte or other glial nuclei, highlighting the neuronal specificity of PD-associated methylation changes. Comparison with a large bulk brain meta-analysis of Lewy body pathology confirmed concordant directionality for [~]79% of neuronal differentially methylated positions, indicating that bulk tissue signals primarily reflect neuronal alterations. Together, these findings provide the first cell type-resolved map of DNA methylation changes in the PD cortex, revealing neuronal-specific hypermethylation at novel loci and emphasizing the importance of cell type-specific analyses in disentangling the molecular heterogeneity of PD. This study lays the groundwork for future multi-omics and region-specific studies aimed at uncovering mechanisms underlying disease vulnerability and progression at the cellular level.

BackgroundParkinsons disease (PD) is characterized by widespread neurodegeneration across neuromodulatory systems, profoundly affecting cortico-basal ganglia-thalamic loops. The resulting cortical alterations can be detected with electroencephalography (EEG). Emerging evidence shows that aperiodic EEG components provide biologically meaningful information that complements the periodic features traditionally examined. Therefore, dissociating periodic and aperiodic components may yield sensitive and specific pathophysiological markers of PD. ObjectivesTo characterize aperiodic and periodic EEG signatures in PD during OFF-medication resting-state and examine their relationships with age, disease duration, and levodopa-induced dyskinesias. MethodsResting-state EEG was recorded from forty patients with PD OFF-medication and twenty-six age- and sex-matched healthy controls. Twenty-five patients and ten controls returned for a second visit. Power spectra were parametrized to extract aperiodic exponent, offset and power in the alpha and beta frequency bands. Bayesian ANCOVAs were used to assess between-group differences and associations with clinical and demographic variables. ResultsAperiodic offset and alpha power were higher in patients than controls across all channels (BF10=72.41; BF10=20.45) and when restricting analysis to pericentral sensorimotor channels (BF10=63.01; BF10=12.06). These differences were expressed in patients with and without levodopa-induced dyskinesias and replicated at follow-up. In patients, aperiodic offset and exponent, but not periodic alpha or beta power, scaled positively with age and disease duration (BF10=2.16-9.76). ConclusionsPD is associated with changes in resting-state brain activity, reflected in both aperiodic and periodic EEG activity. The finding that aperiodic parameters scale with age and disease duration suggests that aperiodic EEG features may serve as markers of disease progression, complementing traditional periodic measures.

Acellular Adipose Tissue (AAT) is an off-the-shelf, cadaveric adipose-derived ECM-based biomaterial for soft tissue reconstruction. AAT has been validated preclinically to promote angiogenesis and adipogenesis and demonstrated safety, biocompatibility, and tolerability in a Phase I study. In this study we report the findings for the first ten patients in the Phase II study for permanent reconstruction of modest soft tissue defects. AAT promoted macrophages, CD3+ T cells, and CD34+ progenitor activity. Multiplex immunofluorescence staining using the PhenoCycler (formerly CODEX) imaging platform found that AAT can induce tertiary lymphoid structures (TLS). Nanostring GEOMx spatial transcriptional data analysis found significant differential gene expression between neighboring tissues with EGR1, MCL1, and NR4A1 upregulated in AAT. These genes have roles in angiogenesis, anti-apoptotic processes, and promotion of anti-inflammatory genes, respectively. AAT promoted anti-fibrotic CD74+ adipose-derived stromal cells, confirmed by immunofluorescence staining. Our findings demonstrate that AAT promotes angiogenesis, adipogenesis, and anti-fibrotic remodeling.

BackgroundThe SLC25A46 gene encodes a mitochondrial carrier protein previously implicated in neuropathy and optic atrophy. Biallelic variants in SLC25A46 have been described in patients with Parkinsons disease (PD) with optic atrophy, but the evidence supporting a role in PD remains limited. ObjectiveTo assess whether SLC25A46 variants contribute to PD, REM sleep behavior disorder (RBD), or Dementia with Lewy Bodies (DLB). MethodsWe examined common variants using four representative PD genome-wide association studies (GWAS) and an RBD GWAS and applied Summary-data-based Mendelian Randomization (SMR) to evaluate whether genetically regulated expression of SLC25A46 shows a causal association with the risk of PD or RBD. Rare variant analyses were conducted in four cohorts of European descent: Accelerated Medicines Partnership: Parkinsons Disease (AMP-PD) PD (3,051 PD, 3,667 controls), UK Biobank (3,267 PD, 14,939 proxy, 54,800 controls), RBD (1,376 RBD, 2,580 controls), and AMP-PD DLB (2,605 DLB, 1,894 controls). Optimal Sequence Kernel Association test (SKAT-O) and meta-analysis were used to assess rare variants. ResultsNo associations were observed between SLC25A46 variants and PD, RBD, or DLB. SMR analyses revealed no evidence supporting a causal relationship between SLC25A46 expression and PD or RBD risk. Rare variant burden analyses did not identify significant associations after multiple-testing correction across cohorts or meta-analyses. ConclusionSLC25A46 variants showed no evidence of association, suggesting the gene does not play a major role in PD, RBD, or DLB risk.

X chromosome-wide association studies (XWAS) have successfully identified risk loci on the X chromosome associated with Parkinsons disease (PD) susceptibility. However, only three such studies have been completed to date. Here, we present the first XWAS using an African cohort, comprising 690 PD cases and 826 controls. We applied an established XWAS workflow to perform male- and female-stratified analyses, as well as a combined meta-analysis. The male-stratified analysis identified five significant variants, including one lead locus (rs200539602), while the female-stratified analysis revealed 29 significant variants and two lead loci (rs2499550 and rs58045540), where rs2499550 is an upstream variant of the protein-coding gene FAAH2. The remaining female-stratified significant variants are expression quantitative trait loci for SPIN2A, SPIN2B, and SPIN3, which are highly expressed in the brain and nerve tissues, making them strong candidates for further investigation. One previously reported PD XWAS locus (rs28602900) was also replicated at a significance threshold of 0.05. The meta-analysis identified five variants surpassing chromosome-wide significance, including two lead loci (rs140715059 and rs141026964), the latter has no significant expression quantitative trait locus information but lies closest to the protein-coding gene MAGEC2, which may warrant further follow-up. None of the meta-analysis signals replicated in prior neurodegenerative disease XWAS. Overall, this study provides novel insights into the contribution of the X chromosome to PD susceptibility and represents the first PD XWAS to include participants of African ancestry, highlighting the importance of extending genetic studies to diverse populations.

SORL1, the gene encoding the SORLA protein, has arisen as a potential therapeutic target for Alzheimers disease (AD). Studies suggest that restoring SORLA function or its trafficking pathways, particularly the SORLA-retromer recycling system, may offer a promising strategy to slow or halt AD progression. While both rare and common SORL1 variants have been associated with increased AD risk, recent evidence suggests a potential involvement of SORL1 in other neurodegenerative conditions. This study assessed the contribution of SORL1 genetic variation to the risk of AD, related dementias (RD), and Parkinsons disease (PD) using data from six large-scale biobanks, comprising 15,043 AD, 9,943 RD, and 42,763 PD cases, along with 111,969 controls across 11 ancestries. We identified 53 potentially disease-related SORL1 variants (CADD score > 20, MAC [&ge;] 2, annotated as protein-altering or splicing, and with the mutated allele present only in cases), including 41 novel and 12 previously reported variants. Three were found across multiple ancestries. Overall, 13 variants were found in AD-related cohorts, 5 in RD cohorts, and 35 in PD cohorts. Association analysis identified 10 nominally significant variants associated with AD and 5 with PD. The replication of multiple SORL1 variants across neurodegenerative diseases and ancestrally diverse populations underscores its potential broad genetic contribution to neurodegeneration and reinforces its relevance across distinct clinical phenotypes. Gene-based burden analysis did not reveal any significant cumulative effect of SORL1 variants in the populations tested. A family-based analysis identified a rare predicted-damaging variant in two East Asian families (11:121478242:G:A, p.R176Q) and two variants in two families of European ancestry (11:121514222:A:C, p.N371T; 11:121545392:G:A, p.V672M) that show some evidence of segregation in PD families. Although these variants were slightly more frequent in unrelated PD cases vs. controls, none of them showed statistically significant enrichment in PD, likely due to their very low frequency. Overall, our results extend the understanding of SORL1 beyond AD, suggesting a broader role in neurodegeneration and emphasizing the need for diverse population studies when evaluating genetic risk.

BackgroundThe causes of neuropsychiatric symptoms in Parkinsons disease (PD) remain ill-defined. Disruptions in dopamine-dependent reward learning, a consequence of midbrain dopamine loss, potentially represent a mechanism that could underlie the neuropsychiatric symptoms of apathy, depression, and impulsivity, all of which have been proposed to reflect aberrant goal-directed behaviour. However no large-scale investigation that jointly considers these symptoms in PD has ever been undertaken. We aimed to determine if reward learning is associated with apathy, depression and impulsivity symptom in two samples of PD patients. MethodsTwo samples of PD patients (nsample1=81, nsample2=90), tested in their medicated state, completed two widely used reward learning tasks (probabilistic stimulus selection task, probabilistic reward task) from which we derived five summary measures of performance. Apathy, depression, and impulsivity were evaluated using validated self-report questionnaires. ResultsOverall, there was poor consistency in the relationship between reward learning and neuropsychiatric symptom severity. Greater depressive symptom severity was associated with slower reward learning performance in sample 1, but with both slower and faster reward learning performance in sample 2. Greater impulsivity symptom severity was associated with slower reward learning performance in sample 1 but not in sample 2. There were no associations between apathy and reward learning. ConclusionsWe found inconsistent relationships between symptoms of apathy, depression, and impulsivity and reward learning performance across two samples of PD patients. While this doesnt rule out the possibility that reward learning impairments contribute to these symptoms, it suggests any effect is likely to be small and overshadowed by other non-measured factors.

2- AbstractO_ST_ABSOBJECTIVEC_ST_ABSTo compare, in a Brazilian population, the clinical efficacy and quality-of-life (QoL) impact of one-stage bilateral thoracic sympathectomy (BTS) versus unilateral sympathectomy on the dominant side (UniS), with additional analysis of patients who later underwent contralateral surgery (two-stage bilateral, 2stS). METHODSProspective, randomized, controlled, multicenter trial (11 centers) including 163 adults with primary palmar hyperhidrosis. Participants were randomized 1:1 to BTS or UniS. From 6 months onward, UniS patients could elect contralateral sympathectomy (2stS). Sweating severity was assessed using the Hyperhidrosis Disease Severity Scale (HDSS) across 18 anatomical sites at each visit. Compensatory sweating (CS) was defined as new sweating in previously unaffected areas (preoperative HDSS = 1) and graded by the magnitude of HDSS increase. QoL was measured with two complementary validated instruments: HidroQOL and the Horn questionnaire. RESULTSBaseline characteristics were similar between groups, with most participants presenting severe preoperative disease. Improvement in the operated (dominant) hand was comparable after BTS and UniS, whereas control of the non-operated hand favored BTS. In the UniS group, spontaneous contralateral improvement occurred in approximately one-seventh of untreated hands. The proportion of patients without CS was similar in both groups ([~]25%), but severe CS was more frequent after BTS (40.4% vs 21.0%, p = 0.0344). QoL improved in both groups, with larger and more sustained reductions in Horn and HidroQOL scores after BTS (p < 0.001). In the 2stS subgroup, contralateral surgery produced a consistent HDSS decrease and marked QoL improvement, with predominantly mild additional CS. CONCLUSIONSBTS provides more complete symptom control and greater QoL improvement, but at the cost of more severe CS. UniS offers excellent control on the treated side, may reduce severe CS, and supports a staged strategy in which some patients avoid a second procedure (requested by 22.5% in this study); when needed, contralateral completion tends to restore additional clinical and QoL gains.

Olfactory decline is a well-established aspect of Parkinsons disease (PD) and is considered one of its earliest signs, often preceding motor symptoms by years to decades. However, because olfactory impairment is also common in healthy aging and other medical conditions, current olfactory tests that score performance (odor detection, discrimination, and identification) lack disease specificity. In contrast to performance scores, olfactory perceptual fingerprints are derived from odor ratings and sniffing behavior, and provide a stable measure of how the world smells to an individual. To test the hypothesis that olfactory perceptual fingerprints may provide a disease-specific marker, we obtained them in three cohorts: Individuals with PD (n=33), healthy age-matched controls (n=33), and critically, in participants with non-PD olfactory dysfunction (n=28). Consistent with previous results, a standard clinical olfactory test detected impairment in both PD and non-PD olfactory dysfunction, but failed to distinguish between these two groups. In contrast, olfactory perceptual fingerprints detected impairment, and distinguished PD from non-PD olfactory dysfunction at 88% accuracy (SVM classification, leave-one-out cross validation, 90% sensitivity, 85% specificity, P=3.2x10-4), or 94% accuracy after matching age and sex (SVM classification, leave-one-out cross-validation, 100% sensitivity, 88% specificity, P=0.0047). The difference between PD related and unrelated olfactory decline was particularly evident in sniffing behavior: Whereas both healthy participants and non-PD olfactory decline groups decreased sniff duration in response to unpleasant odors (-12.5% and -11.36% respectively), individuals with PD paradoxically increased sniff duration (+1.69%; P=4.5x10-5). Thus, PD was marked not by loss of olfactory performance, but by a distinct shift in olfactory perception. These findings imply that olfactory perceptual fingerprints provide for a disease-specific marker in PD.

Parkinsons disease (PD) is a complex neurodegenerative disorder with a substantial genetic influence. To better characterize the genetic landscape of PD in South Africa, we conducted the largest genetic screening to date for pathogenic single nucleotide and copy number variations (CNVs) using genotyping array data from 689 PD probands. We identified 16 unique missense variants, confirming 15 with Sanger sequencing, in 47 individuals across seven well-established PD genes, with GBA1 and PRKN being most frequent. Also in known PD genes, 18 variants of unknown significance were found. Additionally, CNV analysis using CNV-Finder revealed seven novel CNVs, five in PRKN and two in SNCA, of which, six were validated with Multiplex Ligation-dependent Probe Amplification. The findings highlight the contribution of both rare variants and structural rearrangements to PD in this underrepresented population. This study underscores the importance of expanding genetic research in African cohorts to improve global understanding of PD etiology.

Essential tremor is a disabling and highly prevalent movement disorder. Deep brain stimulation of the ventral intermediate nucleus provides substantial symptom relief; however, many patients experience diminishing benefit over time. The underlying causes range from natural disease progression and worsening ataxia to, less commonly, habituation or tolerance. We performed a retrospective longitudinal analysis of 86 individuals with essential tremor who underwent unilateral ventral intermediate nucleus deep brain stimulation and had three or more follow-up visits (mean follow-up duration 5.2 years; maximum 15.4 years; >470 total visits). This approach provided a unique opportunity to assess contralateral limbs in addition to long term effects of stimulation. Tremor severity was quantified using the Fahn-Tolosa-Marin Tremor Rating Scale total score and subscores, with particular focus on contralateral and ipsilateral upper-extremity tremor. Longitudinal trajectories were assessed across limbs and stimulation states at both the population and individual levels. Comparison of tremor between the non-stimulated side and the stimulated side were conducted in the stimulation off condition and served as an intrinsic control to disentangle natural disease progression from tolerance to deep brain stimulation. Contralateral and ipsilateral upper-extremity tremor assessed with stimulation off showed slow, bilateral progression over time. Tremor in the ipsilateral limb followed the same trajectory as the unstimulated contralateral limb, consistent with natural disease progression. Stimulation exerted no measurable cross-hemispheric influence, as ipsilateral tremor progressed similarly with stimulation on and off. During chronic stimulation, tremor progression in the stimulated limb closely tracked that of the ipsilateral limb, with most patients showing no meaningful difference between sides. Progression in the stimulated limb was also similar during stimulation on and off conditions, suggesting that habituation, stimulation-induced maladaptation, or deep brain stimulation-accelerated decline was not observed in this cohort. Long-term symptoms of worsening tremor in essential tremor patients with unilateral ventral intermediate nucleus deep brain stimulation were primarily driven by natural disease progression, not by deep brain stimulation-related causes. While tolerance may rarely emerge, the dominant effect of worsening is disease progression. In this cohort, the stimulation programming parameters were individually optimised over time, likely minimizing the influence of suboptimal programming or stimulation-related decline. These findings underscore the importance of extended comprehensive outcome assessment in essential tremor, incorporating objective measures to distinguish disease progression from treatment-related effects. Follow-up studies are needed to better characterise the relative contributions of tremor and ataxia to long-term disability.

ANO6 (TMEM16F), a Ca2{square}-activated lipid scramblase and ion channel, has been implicated in -synuclein secretion and propagation, a hallmark of Parkinsons disease (PD). To evaluate whether genetic variation in ANO6 contributes to PD risk, we analyzed common and rare variants across large-scale datasets. Relying on genome-wide association study (GWAS) summary statistics from 63,555 PD cases, 17,700 proxy cases, and 1.7 million controls, we identified seven noncoding common variants within ANO6 that reached genome-wide significance, but these signals were driven by linkage disequilibrium (LD) with the nearby LRRK2 p.G2019S variant. We further tested rare variant burden in 4,879 PD cases and 65,279 controls. Rare variant burden analysis showed significant enrichment only when all rare variants were aggregated (meta-analysis PFDR = 0.02), with no signal detected in functional categories. Overall, human genetic data does not support an important role for ANO6 in PD.

BackgroundDNAJC13 was initially linked to autosomal dominant (AD) Parkinsons disease (PD) in a European Mennonite family carrying the p.N855S variant. However, imperfect segregation and conflicting reports of pathogenicity raised uncertainty of DNAJC13s role in the disease. ObjectivesExplore the association between common and rare variants in DNAJC13 and Parkinsons disease. MethodsWe leveraged the largest available PD genetics data from the Accelerating Medicines Partnership - Parkinson Disease (AMP-PD) and the diverse ancestry available through the Global Parkinsons Genetics Program (GP2), consisting of 2,471 patients and 3,098 controls, and 44,186 patients and 27,066 controls, respectively, to perform burden tests and association tests for rare and common variants, respectively. ResultsBurden analysis showed no association between rare variants in DNAJC13 and PD. However, association analysis within common non-synonymous variants nominated 5 variants within DNAJC13. Nevertheless, these associations require further validation since the analyses are still underpowered. DiscussionOur analysis did not find further evidence supporting DNAJC13 involvement in PD. However, studies of even larger cohorts and AD-PD families may bring definite answers about DNAJC13s role in PD.

BackgroundParkinsons disease (PD) and schizophrenia (SZ), while clinically distinct, exhibit overlapping symptoms and neurobiological features. Emerging genetic evidence suggests a shared heritable component between the two disorders. In this study, we aim to identify novel genetic loci common to both PD and SZ and to further investigate the convergent molecular mechanisms that may underlie their shared pathophysiology. MethodsWe analyzed large-scale genome-wide association studies (GWAS) on SZ (55,193 cases, 74,132 controls, 7,659,767 SNPs) and PD (56,306 cases, 1,417,791 controls, 7,200,892 SNPs) using a proxy-phenotype method combined with a Bayesian statistical approach to evaluate overlap in common genetic variants and enhance statistical power for genetic discovery. To elucidate the biological mechanisms underlying newly identified shared genetic loci associated with PD, we leveraged single-cell RNA sequencing (scRNA-seq) data from induced pluripotent stem cell (iPSC)-derived dopaminergic neurons generated by the FOUNDIN-PD consortium (416,216 high-quality single-cells from PD patients). We performed differential gene expression analysis, and gene ontology (GO) enrichment analysis to systematically investigate the functional relevance of these loci in a disease-relevant cellular context. ResultsWe identified thirteen SNPs with concordant effect directions and one SNP with a discordant direction shared between PD and SZ. Of these fourteen SNPs, eleven SNPs were in linkage disequilibrium with previous PD GWAS hits. Further, we identified another three shared novel SNPs (rs2240921, rs11649804, and rs9607782) associated with PD and SZ. In addition, a missense variant in RAI1 (rs11649804) was identified as a shared genetic signal associated with both PD and SZ. Notably, differential expression analysis of RAI1 demonstrated distinct genotype-dependent expression patterns (CC/CA/AA) in both idiopathic PD (iPD) and PD patients carrying GBA1 mutation (GBA1-PD) cohorts. Gene ontology (GO) enrichment analysis further implicated RAI1 in mitochondrial dysfunction-related biological processes, highlighting its potential role in PD pathogenesis. ConclusionIn summary, our study provides novel insights into the shared genetic architecture of PD and SZ, highlighting previously unrecognized loci with potential cross-disorder relevance. The functional characterization of these loci suggests that inflammation and mitochondrial dysfunction may represent convergent biological mechanisms underlying both neurodegenerative and psychiatric pathologies. These findings advance our understanding of the molecular interplay between PD and SZ and open new avenues for exploring shared therapeutic targets.