Faster Progression Research Articles

Neuroanatomical heterogeneity drives divergent cognitive and motor trajectories in Parkinson's disease subtypes

IntroductionCognitive symptoms of Parkinson's disease (PD) may initially present subtly, often overshadowed by more noticeable motor symptoms. However, as PD progresses, predicting which individuals will experience significant cognitive decline becomes challenging due to variability, suggesting distinct PD subtypes with varying cognitive trajectories. This study aimed to identify early PD subtypes based on patterns of gray matter atrophy in brain regions associated with cognition and assess their distinct patterns of cognitive change over time. Recognizing PD primarily as a movement disorder, we also evaluated their motor symptoms. MethodsWe analyzed T1-weighted MRI data, cognitive, and motor scores from 114 de novo PD patients and 120 healthy controls. Multivariate gray matter volumetric distances (MGMV) across frontal, subcortical, parietal, temporal, and occipital regions were computed, and K-means clustering was used to identify PD subtypes. Subsequently, cognitive assessments were compared between subtypes at baseline and 48 months using linear mixed-effects models and reliable change indices. Motor-symptom changes were assessed using linear mixed-effects models. ResultsTwo PD subtypes were identified from baseline MRI. Subtype 1 showed significantly higher MGMV in frontal (p < 0.001) and subcortical (p < 0.001) regions, indicating atrophy. At 48 months, subtype 1 had poorer global cognitive performance than subtype 2 (p = 0.005) and faster progression of postural instability and gait disturbance (p = 0.04). ConclusionsPD subtypes identified early by distinct frontal and subcortical atrophy patterns exhibited divergent trajectories of cognitive decline and worsening motor symptoms over time, underscoring the neuroanatomical heterogeneity that drives clinical variability in PD.

Systematic study on vulnerabilities, countermeasures and security analysis tools for cryptocurrencies and post quantum cryptographic approach to design quantum resistant blockchains

Blockchain and other Distributed Ledger Technologies (DLTs) have evolved significantly in the last years and their use has been suggested for numerous applications due to their ability to provide transparency, redundancy and accountability. Public key cryptography and hash functions provide security to blockchains, smart contracts and cryptocurrencies. Fast progress in Quantum computing presents significant threats to blockchain systems as it has leveraged possibility of attacking cryptosecurity systems in near future forcing re-design of blockchains to withstand quantum attacks and vulnerabilities. This article studies different types of vulnerabilities to blockchains, existing countermeasures for attacks and investigates causes and preventive mechanisms to make quantum resistant or quantum proof blockchains. Thus, this article seeks to provide a broad view on security analysis tools, quantum-based cryptosystems, signature schemes and algorithms on Post-Quantum Blockchain (PQB) security to future blockchain researchers and developers.

Genetic basis of early onset and progression of type 2 diabetes in South Asians.

South Asians develop type 2 diabetes (T2D) early in life and often with normal body mass index (BMI). However, reasons for this are poorly understood because genetic research is largely focused on European ancestry groups. We used recently derived multi-ancestry partitioned polygenic scores (pPSs) to elucidate underlying etiological pathways British Pakistani and British Bangladeshi individuals with T2D (n = 11,678) and gestational diabetes mellitus (GDM) (n = 1,965) in the Genes & Health study (n = 50,556). Beta cell 2 (insulin deficiency) and Lipodystrophy 1 (unfavorable fat distribution) pPSs were most strongly associated with T2D, GDM and younger age at T2D diagnosis. Individuals at high genetic risk of both insulin deficiency and lipodystrophy were diagnosed with T2D 8.2 years earlier with BMI 3 kg m-2 lower compared to those at low genetic risk. The insulin deficiency pPS was associated with poorer HbA1c response to SGLT2 inhibitors. Insulin deficiency and lipodystrophy pPSs were associated with faster progression to insulin dependence and microvascular complications. South Asians had a greater genetic burden from both of these pPSs than white Europeans in the UK Biobank. In conclusion, genetic predisposition to insulin deficiency and lipodystrophy in British Pakistani and British Bangladeshi individuals is associated with earlier onset of T2D, faster progression to complications, insulin dependence and poorer response to medication.

Hypometabolic mismatch with atrophy and tau pathology in mixed Alzheimer and Lewy body disease.

Polypathology is a major driver of heterogeneity in clinical presentation and extent of neurodegeneration (N) in patients with Alzheimer Disease (AD). Beyond amyloid (A) and tau (T) pathologies, over half of patients with AD have concomitant pathology such as α-synuclein (S) in mixed AD with Lewy Body Disease (LBD). Patients with Mixed Etiology Dementia (MED) such as AD+LBD have faster progression and potentially differential responses to targeted treatments, though the diagnosis of AD+LBD can be challenging given overlapping clinical and imaging features. Development and validation of improved in vivo biomarkers are required to study relationships between N and S and identify imaging patterns reflecting mixed AD+LBD pathologies. We hypothesize that individual proteinopathies, such as T and S, are associated with commensurate levels of N. Thus, we assessed biomarkers of A, T, N and S with positron emission tomography (PET), magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) seeding amplification assay (SAA) data to determine molecular presentations of mixed A+S+ vs. A+S- cognitively impaired patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We found A+S+ patients had parieto-occipital 18F-Fluorodeoxyglucose hypometabolism (a measure of N) disproportionate to the degree of regional atrophy or T burden, highlighting worse hypometabolism associated with S+ SAA. Following up on this hypometabolic mismatch with CSF metabolite and proteome analyses, we found that A+S+ patients exhibited lower CSF levels of dopamine metabolites and synaptic markers like neuronal pentraxin-2 (NPTX2), suggesting that altered neurotransmission and neuron integrity contribute to this dissociation between metabolic PET and MRI. Potential confounders exist when studying relations between N, AD and LBD pathologies, including neuroinflammation and other non-Alzheimer pathologies in MED, though our findings imply posterior hypometabolic mismatch is related more to S than vascular or TDP-43 pathology. A+S+ patients had posterior mismatch with excessive 18F-Fluorodeoxyglucose hypometabolism relative to atrophy or T load, possibly reflecting impaired neuron integrity. Further research must disentangle the impact of multiple proteinopathies and clinicopathologic factors on hypometabolism and atrophy. Cumulatively, patients with mixed AD+LBD etiologies harbor a unique metabolic PET mismatch signature.

Cardiometabolic risk factors and coronary atherosclerosis progression in patients with metabolic dysfunction-associated steatotic liver disease: the influential role of quantity over type.

Individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) who are at an increased risk of cardiovascular disease (CVD) are critical to identify and manage. We aimed to assess whether the risk of CVD in patients with MASLD differed according to the type or number of cardiometabolic risk factors. This longitudinal cohort study involved 5674 adults who underwent at least two health checkups between 2004 and 2021. Steatotic liver disease (SLD) was assessed using ultrasonography and participants with SLD were classified as having either non-MASLD or MASLD. CVD risk was evaluated using coronary artery calcium (CAC) progression as measured using multidetector computed tomography scans. Over an average 5.8-year follow-up period, patients with MASLD exhibited faster CAC progression than those with non-MASLD (18% vs 11%, P<0.01). MASLD with any cardiometabolic risk factor exacerbated CAC progression; however, the degree of CAC progression was similar among the different risk components. The adjusted ratios (95% CI) of CAC progression rates comparing non-MASLD with MASLD with one, two, three, four, and five cardiometabolic risk factors were 1.02 (0.99, 1.06), 1.04 (1.01, 1.08), 1.07 (1.03, 1.10), 1.08 (1.05, 1.11), and 1.11 (1.07, 1.15), respectively. In individuals with MASLD, all cardiometabolic risk factors contributed to the deterioration of coronary atherosclerosis, with no specific factor exerting a dominant influence. Coronary atherosclerosis progression is directly associated with the cumulative number of cardiometabolic risk factors. Therefore, identifying and managing an increasing number of these factors is imperative in clinical practice, even when MASLD is diagnosed based on only one risk factor.

Sleep deprivation in dementia comorbidities: focus on cardiovascular disease, diabetes, anxiety/depression and thyroid disorders.

Sleep disturbances are a significant concern in individuals with dementia, affecting their overall health and quality of life, as well as that of their family members and caregivers. Dementia, a progressive neurodegenerative condition marked by cognitive decline, often coexists with various comorbidities such as cardiovascular disease, diabetes, obesity, anxiety/depression and thyroid disorders. These comorbidities can further impair cognitive function and complicate the clinical management of dementia, making it essential to address them in a holistic manner. This review critically examines the complex interplay between dementia and its associated comorbidities, with a special focus on the prevalence and impact of sleep disturbances. Sleep problems in dementia patients are not only common but also contribute to a faster progression of cognitive decline and increased burden on caregivers. The article explores the mechanisms by which these comorbidities, including cardiovascular conditions and metabolic disorders, exacerbate sleep disturbances and cognitive impairment in dementia patients. By synthesizing recent research findings, the review highlights the importance of identifying and managing modifiable risk factors for sleep disturbances in dementia. Integrated treatment approaches that address both cognitive and sleep-related challenges are essential for improving patient outcomes. The review also underscores the need for further research to develop targeted interventions that can effectively manage sleep disturbances in dementia, thereby enhancing the quality of life for both patients and caregivers. Understanding the relationship between dementia, comorbidities, and sleep disturbances is crucial for the development of comprehensive care strategies. This review aims to inform healthcare professionals about the current state of knowledge and encourage the implementation of evidence-based practices in dementia care.

Why protein-energy wasting leads to faster progression of chronic kidney disease.

Protein-energy wasting (PEW) is increasingly more prevalent as chronic kidney disease (CKD) progresses to more advanced stages. There is a global recognition of the importance of preventing and mitigating PEW in the CKD population not on dialysis given the goal of extending dialysis-free time and delaying dialysis initiation and growing evidence of the clinical consequences of PEW which include the risk of death, hospitalization and clinical conditions such as infections. We reviewed the association of PEW and the malnutrition characteristics indicative of PEW on CKD progression. Studies show the association between low serum albumin levels, low BMI, and diets with inadequate dietary energy and protein intake and CKD progression. Limited studies suggest low muscle mass impacts CKD progression. Optimizing nutrition by dietary management, including a moderately low protein (0.6-0.8 g/kg/day) and plant-based (>50% of protein source, known as PLADO) diet and as needed with supplementation [e.g. during acute kidney injury (AKI) event] administrated orally, enterally, or parenterally are the basis for the prevention and treatment of PEW in CKD and delaying CKD progression. Furthermore, other therapeutic methods such as treating or avoiding comorbidities and AKI, ensuring appropriate exercise and incremental transition to dialysis treatment may help ameliorate and prevent PEW development in CKD patients. Using tailored precision nutrition approaches and nutritional supplementation with or without other beneficial strategies may help prevent and treat PEW and its consequent occurrence of CKD progression.

Neuroinflammation and glycosylation-related cerebrospinal fluid proteins for predicting functional decline in amyotrophic lateral sclerosis: a proteomic study.

The rate of disease progression varies widely among patients with amyotrophic lateral sclerosis (ALS). Prognostic assessment using biomarkers is highly anticipated to improve clinical trial design. We aimed to explore the cerebrospinal fluid (CSF) for prognostic biomarkers to predict future functional decline in patients with ALS. We collected CSF samples from 64 patients with ALS and 25 disease controls. The prospective progression rate was calculated using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) at CSF collection and in 6 months. The ALS patients were classified into slow, intermediate, and fast progression groups. We performed comprehensive proteomic analyses of the CSF samples. Factors with significant changes between slow and fast progression groups were investigated via receiver operating characteristic curve analyses. Moreover, the correlation of the CSF factors with progression rate was evaluated by multiple regression analyses. In total, 26 proteins changed significantly (p < 0.05 and q < 0.10), with levels varying within a large dynamic range (fold change of >1.5 or < 0.5). A receiver operating characteristic curve analyses showed that the following proteins showed high discrimination power between slow and fast progression groups: glycoprotein non-metastatic melanoma protein B (GPNMB; area under the curve [AUC], 0.88), glial fibrillary acidic protein (AUC, 0.81), glypican-1 (GPC1; AUC, 0.79), alpha-1,6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase (AUC, 0.74), and chitinase-3-like protein 2 (CHI3L2; AUC, 0.73). Of these, GPNMB, GPC1, and CHI3L2 were significantly correlated to prognostic progression rate. This study demonstrated that CSF levels of neuroinflammation and glycosylation-related proteins were significantly correlated with prospective progression rates in patients with ALS. These proteins could be useful prognostic biomarkers for ALS.

Cerebral Infarct Growth: Pathophysiology, Pragmatic Assessment, and Clinical Implications.

Cerebral ischemic injury occurs when blood flow drops below a critical level, resulting in an energy failure. The progressive transformation of hypoperfused viable tissue, the ischemic penumbra, into infarction is a mechanism shared by patients with ischemic stroke if timely reperfusion is not achieved. Yet, the pace at which this transformation occurs, known as the infarct growth rate (IGR), exhibits remarkable heterogeneity among patients, brain regions, and over time, reflecting differences in compensatory collateral flow and ischemic tolerance. We review (1) the pathophysiology of infarct growth, (2) the advantages and pitfalls of different approaches of IGR measurement, (3) research gaps for future studies, and (4) the clinical implications of stroke progressor phenotypes. The estimated average IGR in patients with acute large vessel occlusion stroke is 5.4 mL/h although there is wide variability based on ischemic stroke subtype, occlusion location, presence of collaterals, and patient baseline status. The IGR can be calculated using various pragmatic strategies, mostly either quantifying the extension of the infarct at a particular time and dividing this measure by the time that elapsed from symptom onset to imaging assessment or by using collateral blood flow status as a radiological surrogate marker. The IGR defines a spectrum of clinical stroke phenotypes, often dichotomized into fast and slow progressors. An IGR ≥10 mL/h and the perfusion metric hypoperfusion intensity ratio ≥0.5 are commonly used definitions of fast progressors. A nuanced understanding of the IGR and stroke progressor phenotypes could have clinical implications, including informing prognostication, acute decision-making in peripheral-to-comprehensive transfer patients eligible for thrombectomy, and selection for adjuvant neuroprotective agents.

Offline supervisory control synthesis: taxonomy and recent developments

AbstractThis paper surveys recent advances in supervisory control theory since its 30th anniversary in 2017. We performed a systematic literature search and selected 272 relevant papers, with a focus on automata-based approaches. These were fitted into coherent narratives, based in part on a taxonomy of supervisor synthesis methods. The obtained papers show the fast and vast progress of the field, where recent research covers a wide range of new synthesis optimization techniques, different aspects such as fault tolerance, security, and timing, and new and diverse application domains. This survey refrains from in-depth descriptions of techniques, instead focusing on high-level contributions of recent works, how they relate to each other, and future directions for research.

Alcohol Consumption and Risk of Age-Related Macular Degeneration and Geographic Atrophy Progression: AREDS2 Report 34

PurposeTo examine potential relationships between alcohol consumption and age-related macular degeneration (AMD) progression, including progression to late AMD and geographic atrophy (GA) enlargement rate. DesignPost hoc analysis of cohorts within the Age-Related Eye Diseases Study 2 (AREDS2). Participants6670 eyes (of 3673 participants) with no late AMD at baseline; 1143 eyes (of 841 participants) with GA at ≥2 consecutive visits. MethodsColor fundus photographs were collected at annual study visits and graded centrally for late AMD, GA area, and GA proximity. Alcohol consumption was calculated by food frequency questionnaire. Regression analyses of disease progression were performed according to alcohol consumption.Main outcome measures:Progression to late AMD and its subtypes; GA area-based progression; GA proximity-based progression. ResultsOver mean follow-up of 3.8 years, 40.2% of eyes progressed to late AMD. In men, with alcohol tertile 1 (no regular consumption) as reference, hazard ratios for progression to late AMD were 0.69 (95% CI 0.55-0.87, p=0.0015) for tertile 2 and 0.85 (0.71-1.02, p=0.079) for tertile 3. In women, hazard ratios were 1.12 (0.95-1.31, p=0.17) and 0.85 (0.72-1.00, p=0.046), respectively. Over mean follow-up of 3.1 years, GA area-based progression was significantly faster in women than men, at 0.295 (95% CI 0.278-0.311) and 0.260 mm/year (0.241-0.279), respectively (p=0.007). In men, area-based progression differed significantly by alcohol tertile (p=0.0001), at 0.275 (0.248-0.303), 0.183 (0.143-0.223), and 0.280 mm/year (0.254-0.306) in tertiles 1-3, respectively. In women, the area-based rate did not differ significantly by alcohol tertile (p=0.11). In men only, CDC-defined heavy drinking was associated with faster progression (p=0.024), at 0.306 (0.262-0.349) vs 0.252 mm/year (0.233-0.270). In 808 eyes with non-central GA, GA proximity-based progression did not differ significantly by alcohol tertile (p=0.55). ConclusionsModerate alcohol consumption is associated with decreased risk of progression to late AMD in men. GA progression is faster in women, but its relationship with alcohol consumption is much stronger in men. In men, moderate consumption is associated with slower GA progression and higher consumption with faster progression. Although some of these associations may also relate to confounding, they might suggest that individuals with GA should avoid high alcohol consumption.

Long-Term Blood Pressure Variability and Visual Field Progression in Glaucoma

Long-term variability of blood pressure may be associated with visual field (VF) progression in patients with glaucoma. To investigate the association between blood pressure parameters and VF progression over time in patients with glaucoma. This retrospective cohort study of longitudinal data included patients with suspected or confirmed glaucoma who were selected from the Diagnostic Innovations in Glaucoma Study and the African Descent and Glaucoma Evaluation Study. Patients underwent blood pressure and VF testing from November 2000 to December 2022, and data were analyzed in October 2023. Suspected or confirmed glaucoma. Mean and SD values of blood pressure variables were calculated for systolic and diastolic arterial pressures. These parameters were incorporated into multivariable mixed-effect models to investigate the association between blood pressure parameters and mean intraocular pressure with rates of VF mean deviation loss. Interaction terms between blood pressure parameters and mean intraocular pressure were also included in the models. A total of 1674 eyes from 985 patients were assessed (mean [SD] age, 61.2 [0.4] years; 563 female [57.2%]). The mean rate of VF mean deviation change was -0.13 (95% CI, -0.16 to -0.10) dB/y over a mean follow-up of 8.0 (95% CI, 7.7-8.2) years. The interaction terms of higher mean blood pressure and higher SD of blood pressure were associated with faster annual mean deviation changes for both mean arterial pressure (0.02 [95% CI, 0.01-0.04] dB/y per 1-mm Hg higher; P = .001) and diastolic arterial pressure (0.02 [95% CI, 0.01-0.03] dB/y per 1-mm Hg higher; P < .001). The interaction term of higher SD of blood pressure and higher mean intraocular pressure was associated with faster annual mean deviation changes for both mean arterial pressure (0.01 [95% CI, 0.00-0.02] μm per 1-mm Hg higher; P = .003) and diastolic arterial pressure (0.01 [95% CI, 0.00-0.01] μm per 1-mm Hg higher; P = .001). In this cohort study, higher mean blood pressure and higher SD of blood pressure were associated with faster VF progression. These findings suggest that long-term variability of blood pressure may be a modifier of the association between intraocular pressure and VF progression in glaucoma.

Abstract 4138306: Impact of Early Menopause and Hormonal Replacement Therapy on Aortic Stenosis Progressio

Background: Early menopause is associated with an increased risk of cardiovascular disease and mortality in women. The present study aimed to examine the impact of early menopause and hormonal replacement therapy (HRT) on the progression of aortic stenosis (AS). Methods: Thirty-three postmenopausal women (mean age 65 ± 10 years) with mild or moderate AS prospectively recruited in the PROGRESSA study (NCT01679431) were included in this sub-analysis. All patients underwent multidetector computed tomography and Doppler-echocardiography at least twice during follow-up to assess both anatomic and hemodynamic AS severity, based on aortic valve calcification (AVC), mean pressure gradient (MG), and aortic valve area indexed to body surface area (AVA). Annualized changes in AVC, MG and AVAi were calculated between baseline and the last follow-up. Results: Over a median follow-up of 2 [1-4] years, early menopausal women had a faster progression rate of AVC, MG, and AVAi compared to other women: (100[58-130] vs. 23[2-71] AU/year, p=0.03); (2.37[0.82-3.61] vs. 0.31[0.01-1.78] mmHg/year, p=0.04); and (-0.12[-0.23-0.002] vs. -0.004[-0.07-0.08] cm 2 /m 2 /year, p=0.08) respectively. In multivariate analysis adjusted for age, AS severity at baseline, and comorbidities, early menopause remained significantly associated with faster AVC progression (p=0.003). Moreover, after comprehensive adjustment, women who received HRT (45%) had a slower progression rate of AVC (20[10-42] AU/year vs. 62[2-100], adjusted p=0.04). Conclusion: Early menopause is associated with faster progression of AS, both anatomically and hemodynamically. However, the use of HRT is associated with slower progression of AS. Integrating female-specific risk factors, particularly menopausal history and hormonal therapy status, into the clinical management of AS could enhance patient care.

Type 2 diabetes pathway-specific polygenic risk scores elucidate heterogeneity in clinical presentation, disease progression and diabetic complications in 18,217 Chinese individuals with type 2 diabetes.

Type 2 diabetes is a complex and heterogeneous disease and the aetiological components underlying the heterogeneity remain unclear in the Chinese and East Asian population. Therefore, we aimed to investigate whether specific pathophysiological pathways drive the clinical heterogeneity in type 2 diabetes. We employed newly developed type 2 diabetes hard-clustering and soft-clustering pathway-specific polygenic risk scores (psPRSs) to characterise individual genetic susceptibility to pathophysiological pathways implicated in type 2 diabetes in 18,217 Chinese patients from Hong Kong. The 'total' type 2 diabetes polygenic risk score (PRS) was summed by genome-wide significant type 2 diabetes signals (n=1289). We examined the associations between psPRSs and cardiometabolic profile, age of onset, two glycaemic deterioration outcomes (clinical requirement of insulin treatment, defined by two consecutive HbA1c values ≥69 mmol/mol [8.5%] more than 3 months apart during treatment with two or more oral glucose-lowering drugs, and insulin initiation), three renal (albuminuria, end-stage renal disease and chronic kidney disease) outcomes and five cardiovascular outcomes. Although most psPRSs and total type 2 diabetes PRS were associated with an earlier and younger onset of type 2 diabetes, the psPRSs showed distinct associations with clinical outcomes. In particular, individuals with normal weight showed higher psPRSs for beta cell dysfunction and lipodystrophy than those who were overweight. The psPRSs for obesity were associated with faster progression to clinical requirement of insulin treatment (adjusted HR [95% CI] 1.09 [1.05, 1.13], p<0.0001), end-stage renal disease (1.10 [1.04, 1.16], p=0.0007) and CVD (1.10 [1.05, 1.16], p<0.0001) while the psPRSs for beta cell dysfunction were associated with reduced incident end-stage renal disease (0.90 [0.85, 0.95], p=0.0001) and heart failure (0.83 [0.73, 0.93], p=0.0011). Major findings remained significant after adjusting for a set of clinical variables. Beta cell dysfunction and lipodystrophy could be the driving pathological pathways in type 2 diabetes in individuals with normal weight. Genetic risks of beta cell dysfunction and obesity represent two major genetic drivers of type 2 diabetes heterogeneity in disease progression and diabetic complications, which are shared across ancestry groups. Type 2 diabetes psPRSs may help inform patient stratification according to aetiology and guide precision diabetes care.

Brain neurovascular coupling in amyotrophic lateral sclerosis: Correlations with disease progression and cognitive impairment.

'Neurovascular coupling' (NVC) alterations, assessing the interplay between local cerebral perfusion and neural activity within a given brain region or network, may reflect neurovascular unit impairment in amyotrophic lateral sclerosis (ALS). The aim was to explore NVC as a correlation between the functional connectivity and cerebral blood flow within the large-scale resting-state functional magnetic resonance imaging brain networks in a sample of ALS patients compared to healthy controls (HCs). Forty-eight ALS patients (30 males; mean age 60.64 ± 9.62 years) and 32 HC subjects (14 males; mean age 55.06 ± 16 years) were enrolled and underwent 3 T magnetic resonance imaging. ALS patients were screened by clinical and neuropsychological scales and were retrospectively classified as very fast progressors (VFPs), fast progressors and slow progressors (SPs). Neurovascular coupling reduction within the default mode network (DMN) (p = 0.005) was revealed in ALS patients compared to HCs, observing, for this network, significant NVC differences between VFP and SP groups. Receiver operating characteristic curve analysis showed that impaired NVC in the DMN at baseline best discriminated VFPs and SPs (area under the curve 75%). Significant correlations were found between NVC and the executive (r = 0.40, p = 0.01), memory (r = 0.32, p = 0.04), visuospatial ability (r = 0.40, p = 0.01) and non-ALS-specific (r = 0.40, p = 0.01) subscores of the Edinburgh Cognitive and Behavioural ALS Screen. The reduction of brain NVC in the DMN may reflect largely distributed abnormalities of the neurovascular unit. NVC alterations in the DMN could play a role in anticipating a faster clinical progression in ALS patients, aiding patient selection and monitoring during clinical trials.

NIMG-21. EARLY-STAGE GLIOBLASTOMA AND MOLECULAR ANALYSIS REVEAL THE RADIOLOGICAL INITIATION OF IDH WILDTYPE GLIOBLASTOMA

Abstract Glioblastoma (GB), IDH wildtype, is an aggressive and malignant tumor that necessitate early surgical intervention upon radiological suspicion. Consequently, the natural growth dynamics of GB remain not fully understood. Previous studies have examined GB growth using multiple MRIs between initial radiological diagnosis of GB and preoperative MRI, but these studies have short-term intervals between MRIs (defined as shortGB-cohort). Unless GB growth is a constant phenomenon, shortGB cannot estimate radiological initiation. In this study, we focused on early-stage GB (eGB), characterized by small, nonspecific lesions on MRI that eventually progress to classic GB findings. We compared three cohorts: 49 cases of eGB. 68 cases of shortGBt, and 23 cases of eGB from previous publications (other-eGB). Molecular analyses revealed that TERT promoter mutations, EGFR amplification/gain, CDKN2A hemi/homozygous deletion, and PTEN hemi/homozygous deletion were consistent between eGB and shortGB. Our analysis indicated that the radiological initiation of GB in eGB was -0.84 years (95% confidence interval (CI): -1.09 to -0.68), compared to -0.35 years (95%CI: -0.46 to -0.28) in shortGB. In eGB, factors such as age &amp;lt; 65, MIB1 &amp;gt; 30%, TERTp mutation, and the presence of copy-number alterations (CNA) in EGFR/PTEN/CDKN2A, with or without TERTp mutation, correlated with faster tumor progression. In cases without these alterations, the estimated radiological initiation was -2.31 years (95%CI: -100 to -0.80), indicating slower progression. The ShortGB-cohort did not show any significant changes based on these factors, suggesting it does not actually reflect tumor origin. The other-eGB cohort presented radiological initiation between -0.92 and -0.15 year, consistent with our eGB-cohort. This study investigates the radiological origin of GB using extremely rare cases of eGB, providing insights into the radiological pathophysiology and its association with molecular alterations in IDH-wildtype GB.

Parkinson's Disease Mild Cognitive Impairment with MRI evidence of Cholinergic Nucleus 4 Degeneration: A New Subtype?

Subtyping Parkinson's disease with mild cognitive impairment (PD-MCI) could improve clinical trial design and personalized treatments. Cholinergic nucleus 4 (Ch4) volume has been linked to cognitive impairment severity and future decline in PD. This study investigates whether PD-MCI patients with MRI evidence of Ch4 degeneration have distinct clinical profiles and cognitive trajectories. Baseline MRI scans of 148 PD-MCI participants from the Parkinson's Progression Markers Initiative (PPMI) were analyzed. Patients with low Ch4 grey matter density (GMD) had worse motor, autonomic, and olfactory symptoms, and were more likely to belong to the diffuse malignant PD subtype (51.6% vs. 23.4%; P < 0.01). They also had faster progression to cognitive milestones (P = 0.0046). These findings identify PD-MCI with low Ch4 as a distinct subtype with more severe symptoms and faster cognitive decline, highlighting the importance of considering this group in PD-MCI clinical trials, particularly for cholinergic therapies.

CTIM-17. INDIVIDUALIZED MULTIMODAL IMMUNOTHERAPY (IMI) FOR ADULTS WITH DIFFUSE MIDLINE GLIOMA OR DIFFUSE HEMISPHERIC GLIOMA

Abstract Diffuse Midline Glioma (DMG, H3K27 mutant) and Diffuse Hemispheric Glioma (DHG, H3G34 mutant) are rare malignant CNS tumors with dismal prognosis. We retrospectively searched in our database for adults (&amp;gt;18y) with molecularly define DMG/DHG, treated between May 2015 and 2024 with IMI as part of first-line treatment. Amongst 157 IMI-treated malignant glioma patients, four patients fit these restrictions, pointing to scarce experience of IMI for DMG/DHG adult patients. HM (M, 29y) was diagnosed with a DMG in the pons. He received radiochemotherapy, and continued after 2x TMZm with BRAF-MEK-inhibition therapy. He received one IO-Vac® dendritic cell vaccine but showed fast progression thereafter. He died 9 months after diagnosis. GJE (F, 28y) had a DMG at the corpus callosum. She received radiochemotherapy and 6x TMZm, followed by 2x IO-Vac® and 3x maintenance immunogenic cell death (ICD) immunotherapy (NDV injections, sessions of modulated electrohyperthermia), combined with WT1 and H3K27M long-peptide vaccines. She progressed after 20 months, for which a new IO-Vac® and an H3K27M short- and long-peptide vaccine were given. She died 5 months later. Overall Survival (OS) was 26 months after initial diagnosis. JD (F, 27y) was diagnosed with a DMG in C2-C6. She received radiochemotherapy followed by IMI alone, including 2x IO-Vac®, one ICD immunotherapy, and four doses of anti-PD1. She died 17 months later, making OS 27 months after diagnosis. VJ (F, 21y) had a DHG in the left cerebrum. She received radiochemotherapy and 12 cycles of maintenance TMZ (TMZm), between which ICD immunotherapy was inserted each time. Afterwards, she received two IO-Vac®. Finally, she received ICD immunotherapy (6x) combined with checkpoint inhibitors (4x anti-CTLA4, 10x anti-PD1). Thirty months after diagnosis, she is in remission with a stable Health Utility Index of 0.72. IMI might have contributed to a better OS in three out of four DMG/DHG patients, and should be explored further as part of the treatment for these patients.

Fasciculation potentials are related to the prognosis of amyotrophic lateral sclerosis.

Some prognostic biomarkers of amyotrophic lateral sclerosis (ALS) have been described; however, they are inadequate for satisfactorily predicting individual patient outcomes. Fasciculation potentials (FPs) on electromyography (EMG) are useful for the early diagnosis of ALS, and complex FPs are associated with shorter survival in ALS. In this study, we investigated the relationship between the proportion of muscles with FPs, biochemical markers, and the prognosis of ALS. 89 Patients with ALS were retrospectively classified into three groups based on the interval from onset to death or tracheostomy (less than 1 year: fast progression; from 1 year to less than 3 years: average progression; 3 years or more: slow progression). We performed statistical analysis of the electrophysiological findings, including the percentage of examined muscles with FPs, and biochemical markers evaluated on admission. Patients with fast ALS progression had a higher percentage of muscles with FPs (93.1% vs. 37.9%, P<0.001) and lower uric acid (UA) levels (male: 4.19 mg/dl vs 5.55 mg/dl, P<0.001; female: 3.71 mg/dl vs 5.41 mg/dl, P<0.001) than patients with slow progression. Survival curves demonstrated a relationship between these factors and the survival time in patients with ALS. Furthermore, UA levels were correlated with the percentage of muscles with FPs. Our electrophysiological findings suggest that ALS presents with multisystem neurological manifestations, and these manifestations differed among the groups classified by disease progression. The percentage of muscles with FPs on EMG and serum UA levels were especially associated with the prognosis of ALS.

Metabolomic Profiling of Open-Angle Glaucoma Etiologic Endotypes: Tohoku Multi-Omics Glaucoma Study.

The purpose of this study was to investigate biologically meaningful endotypes of open-angle glaucoma (OAG) by applying unsupervised machine learning to plasma metabolites. This retrospective longitudinal cohort study enrolled consecutive patients aged ≥20 years with OAG at Tohoku University Hospital from January 2017 to January 2020. OAG was confirmed based on comprehensive ophthalmic examinations. Among the 523 patients with OAG with available clinical metabolomic data, 173 patients were longitudinally followed up for ≥2 years, with available data from ≥5 reliable visual field (VF) tests without glaucoma surgery. We collected fasting blood samples and clinical data at enrollment and nuclear magnetic resonance spectroscopy to profile 45 plasma metabolites in a targeted approach. After computing a distance matrix of preprocessed metabolites with Pearson distance, gap statistics determined the optimal number of OAG endotypes. Its risk factors, clinical presentations, metabolomic profiles, and progression rate of sector-based VF loss were compared across endotypes. Five distinct OAG endotypes were identified. The highest-risk endotype (endotype B) showed a significant faster progression of central VF loss (P = 0.007). Compared with patients with other endotypes, those with endotype B were more likely to have a high prevalence of dyslipidemia, cold extremities, oxidative stress, and low OAG genetic risk scores. Pathway analysis of metabolomic profiles implicated altered fatty acid and ketone body metabolism in this endotype, with 34 differentially enriched pathways (false discovery rate [FDR] < 0.05). Integrated metabolomic profiles identified five distinct etiologic endotypes of OAG, suggesting pathological mechanisms related with a high-risk group of central vision loss progression in the Japanese population.