Association of Family History and Polygenic Risk Score With Longitudinal Prognosis in Parkinson Disease
Having a family history of PD predicts slower progression of cognitive decline and caudate dopaminergic degeneration, and less FOG compared with those without a family history independent of PRS. Taken together, information on family history could be used as a proxy for the clinical heterogeneity of PD.
KEY FINDINGS: Having a family history of PD predicts slower progression of cognitive decline and caudate dopaminergic degeneration, and less FOG compared with those without a family history independent of PRS. Taken together, information on family history could be used as a proxy for the clinical heterogeneity of PD.
BACKGROUND: Evidence suggests that either family history or polygenic risk score (PRS) is associated with developing Parkinson disease (PD). However, little is known about the longitudinal prognosis of PD according to family history and higher PRS.
DETAILS: From the Parkinson's Progression Markers Initiative database, 395 patients with PD who followed up for more than 2 years were grouped into those with family history within first-degree, second-degree, and third-degree relatives (N = 127 [32.2%]) vs those without (N = 268 [67.8%]). The PRS of 386 patients was computed using whole-genome sequencing data. Longitudinal assessment of motor, cognition, and imaging based on dopaminergic degeneration was conducted during the regular follow-up period. Effects of family history, PRS, or both on longitudinal changes of cognition, motor severity, and nigrostriatal degeneration were tested using a linear mixed model. The risk of freezing of gait (FOG) according to family history was assessed using the Kaplan-Meier analysis and Cox regression models. During a median follow-up of 9.1 years, PD with positive family history showed a slower decline of caudate dopamine transporter uptake (ß estimate of family history x time = 0.02, 95% CI = 0.002-0.036, p = 0.027). Family history of PD and higher PRS were independently associated with a slower decline of Montreal Cognitive Assessment (ß estimate of family history x time = 0.12, 95% CI = 0.02-0.22, p = 0.017; ß estimate of PRS x time = 0.09, 95% CI = 0.03-0.16, p = 0.006). In those 364 patients without FOG at baseline, PD with positive family history had a lower risk of FOG (hazard ratio of family history = 0.57, 95% CI = 0.38-0.84, p = 0.005).
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Source: Park, M. and Lee, Y. (2025). Association of Family History and Polygenic Risk Score With Longitudinal Prognosis in Parkinson Disease. Neurology Genetics. 2025; Published: October, 2025. DOI: 10.1212/NXG.0000000000200115.
Next-Generation Phenotyping May Strengthen Variant Interpretation in Mowat-Wilson Syndrome
In a proof-of-concept study, GestaltMatcher ranked Mowat-Wilson syndrome as the leading diagnosis in a 4-year-old child with a de novo ZEB2 variant. Three of 4 facial images met the PP4 moderate threshold and 1 met the supporting threshold. Integration of facial, HPO, and molecular data through PEDIA ranked ZEB2 as the most likely disease-causing gene. The findings suggest that AI-assisted phenotyping may provide quantitative support for variant interpretation while complementing expert clinical genetics assessment.
KEY FINDINGS: Computational facial phenotyping using GestaltMatcher identified MWS as the leading diagnosis in a child with a suspected de novo ZEB2 variant and provided quantitative evidence that supported variant interpretation. Three of 4 facial images reached the PP4 moderate threshold, while 1 reached the supporting threshold. Integration of facial phenotype, HPO information, and molecular data through PEDIA ranked ZEB2 first and contributed to classification of the variant as likely pathogenic. The findings provide a proof of concept for incorporating NGP into rare-disease diagnostic and variant-interpretation workflows, although larger, multicenter studies are needed to establish reproducibility and generalizability.
BACKGROUND: Mowat-Wilson syndrome (MWS) is a rare neurodevelopmental disorder caused by pathogenic variants in the ZEB2 gene and characterized by developmental impairment, epilepsy, congenital anomalies, and distinctive craniofacial features. Although next-generation phenotyping (NGP) tools such as GestaltMatcher can assist in recognizing rare genetic disorders, their use as quantitative evidence for variant interpretation within the American College of Medical Genetics and Genomics (ACMG) framework remains less established. This study evaluated whether computational facial phenotyping and multimodal clinical data could support variant prioritization and the ACMG PP4 phenotype-specificity criterion in MWS.
DETAILS: The investigators applied GestaltMatcher to a 4-year-old child with an undiagnosed neurodevelopmental disorder, suspected MWS, and a de novo ZEB2 variant. Facial photographs were analyzed alongside Human Phenotype Ontology (HPO) terms and simulated exome data using the PEDIA framework. Bayesian likelihood modeling was used to establish Gestalt score thresholds corresponding to supporting, moderate, strong, and very strong PP4 evidence. Brain MRI was also analyzed for structural abnormalities associated with MWS. The GestaltMatcher model had been trained using 9,671 images from 7,294 patients representing 275 disorders. For the MWS analysis, the dataset included 11 individuals with MWS and 14 age-matched controls.
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GestaltMatcher ranked MWS as the leading diagnosis, while integration through PEDIA also ranked ZEB2 as the most likely disease-causing gene. Across the 4 facial images from the proband, 3 achieved the PP4 moderate threshold and 1 achieved the PP4 supporting threshold. The established Gestalt score thresholds were 0.5111 for supporting, 0.5672 for moderate, 0.6609 for strong, and 0.7632 for very strong evidence.
Using the NGP-derived PP4 moderate evidence together with the original ACMG evidence, the ZEB2 variant was classified as likely pathogenic. Brain MRI demonstrated subtle thinning of the corpus callosum, a finding consistent with previously reported MWS-associated neuroimaging abnormalities. MRI-derived features also differentiated individuals with MWS from age-matched controls in exploratory analysis.
An additional exploratory case involving an infant with molecularly confirmed MWS showed that GestaltMatcher could prioritize MWS based solely on infant facial characteristics. The authors emphasize that NGP is intended to complement, rather than replace, expert clinical genetic assessment.
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Source: Hsieh, T. C., Todd, D., Warner, T., et al. Leveraging Next-Generation Phenotyping in Dysmorphology to Support Variant Interpretation in Mowat-Wilson Syndrome. Neurology Genetics. 2026; 12(4): e200384. Published: July 1, 2026. DOI: 10.1212/NXG.0000000000200384
Somatic Diseases May Affect the Brain Primarily Through Vascular Injury and Neuronal Loss
A narrative review found that common age-related somatic diseases were consistently associated with brain atrophy, neuronal loss, and cerebrovascular lesions. Evidence linking these diseases to amyloid and tau pathology was limited and inconsistent. The findings suggest that systemic diseases may contribute to dementia primarily through non-Alzheimer's mechanisms, particularly vascular injury and neuronal loss. The review underscores the importance of recognizing mixed dementia and considering systemic health in the assessment of cognitive decline.
KEY FINDINGS: Common age-related somatic diseases appear to be more consistently associated with cerebrovascular injury, brain atrophy, and neuronal loss than with amyloid or tau pathology. These findings suggest that the relationship between systemic disease and dementia may involve multiple non-AD pathways rather than a direct effect on classical AD pathology. The review highlights the importance of recognizing mixed dementia and considering systemic health when evaluating brain aging and cognitive decline.
BACKGROUND: Several common age-related somatic diseases are associated with an increased risk of dementia, but the neuropathological pathways underlying these associations remain incompletely understood. This narrative review examined evidence linking heart disease, type 2 diabetes, kidney disease, liver disease, lung disease, and anemia with brain pathology, including Alzheimer's disease (AD)-related amyloid and tau pathology and non-AD changes such as neuronal loss, brain atrophy, cerebrovascular lesions, neuroinflammation, and non-AD proteinopathies.
DETAILS: The authors conducted a PubMed search for human studies investigating associations between somatic diseases and brain pathology using postmortem examinations, brain imaging, or cerebrospinal fluid biomarkers. The available evidence was qualitatively synthesized and graded according to its strength. The review specifically evaluated whether common systemic diseases were associated with AD-related pathology or with other forms of brain injury that may contribute to cognitive impairment and dementia.
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Across the conditions examined, the strongest and most consistent associations were between somatic diseases and global neuronal loss or brain atrophy, as well as cerebrovascular lesions. In contrast, associations between somatic diseases and amyloid or tau deposition were limited and inconsistent. The review found no systematic studies examining neuroinflammation or non-AD proteinopathies in relation to somatic diseases.
Overall, the available evidence suggests that systemic diseases may contribute to brain damage predominantly through non-AD mechanisms, particularly cerebrovascular injury and diffuse neuronal loss, rather than by directly driving the characteristic amyloid and tau pathology of AD. The authors emphasize that these processes may contribute to the complex combination of pathologies frequently underlying dementia in older adults.
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Source: Grande, G., Valletta, M., Gasparini, F., et al. Brain pathology in relation to somatic diseases: Exploring the body–brain crosstalk. Journal of Internal Medicine. 2026; 300(3): 223–237. Published: June 2, 2026. DOI: 10.1111/joim.70119.
Hyponatremia Treatment Guidelines: Maintain Cautious Correction to Prevent Osmotic Demyelination
Current hyponatremia correction safeguards should be maintained. For chronic hyponatremia with sodium 120 mmol/L or lower, correction should generally remain within 10-12 mmol/L in 24 hours and 18 mmol/L in 48 hours; high-risk patients require a stricter limit of 8 mmol/L in 24 hours. Frequent monitoring and desmopressin may prevent overcorrection.
KEY FINDINGS: Current safeguards for severe hyponatremia remain warranted despite recent evidence questioning restrictive correction limits. Correction should be particularly cautious in patients with sodium ≤105 mmol/L or other ODS risk factors. Frequent serum sodium measurement and urine-output monitoring are essential because spontaneous water diuresis can cause rapid sodium increases. Desmopressin may help prevent or reverse excessive correction.
BACKGROUND: Severe hyponatremia can cause life-threatening neurologic complications, while overly rapid correction can result in osmotic demyelination syndrome (ODS). Recent retrospective evidence has questioned whether existing correction limits are overly restrictive. This review reassesses the evidence supporting current treatment safeguards and emphasizes continued caution when correcting severe hyponatremia.
DETAILS: The review examines the evidence underlying international recommendations for limiting the rate of serum sodium correction, with particular attention to patients with severe or chronic hyponatremia. The authors discuss evidence linking rapid correction with ODS and review data that have challenged the need for conservative correction limits.
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For chronically hyponatremic patients with serum sodium ≤120 mmol/L who are at normal risk for ODS, the US/Irish expert panel recommends limiting correction to 10–12 mmol/L during any 24-hour period and 18 mmol/L during any 48-hour period, with a minimum correction of 4–8 mmol/L. Patients at increased risk of ODS—including those with sodium ≤105 mmol/L, alcohol use disorder, hypokalemia, malnutrition, or advanced liver disease—should have correction limited to 8 mmol/L in any 24-hour period, with a minimum daily correction goal of 4–6 mmol/L.
For patients with severe symptoms, European and US/Irish recommendations support bolus administration of hypertonic saline to increase serum sodium by approximately 5 mmol/L or 4–6 mmol/L, respectively, within a few hours. The review notes that this initial increase can substantially reduce intracranial pressure and may reverse impending brain herniation.
The review concludes that current safeguards for treating severe hyponatremia should not be abandoned. Excessive increases in serum sodium can occur because of sudden elimination of dilute urine rather than excessive saline administration. Water diuresis may increase serum sodium by more than 2 mmol/L per hour, emphasizing the need for frequent serum sodium measurements and close monitoring of urine output in patients with sodium ≤120 mmol/L.
Desmopressin can be used to prevent or reverse inadvertent overcorrection. A strategy involving scheduled desmopressin with controlled hypertonic saline administration, termed the "DDAVP clamp"", has been reported to help achieve correction targets, although comparative evidence remains limited.
The review highlights that patients with sodium ≤105 mmol/L and additional risk factors for ODS are particularly vulnerable. If correction exceeds 8 mmol/L in less than 24 hours in these high-risk patients, relowering the serum sodium should be considered.
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Source: Sterns, R. H., Rondon-Berrios, H., Adrogué, H. J., et al. Treatment Guidelines for Hyponatremia: Stay the Course. Clinical Journal of the American Society of Nephrology. 2026; 19(1): 129-135. Published: January, 2024. DOI: 10.2215/CJN.0000000000000244.
Paternal Valproate Use During Spermatogenesis Not Linked to Neurodevelopmental Disorders in Offspring
A large Swedish-Norwegian cohort found no significant association between paternal valproate use during spermatogenesis and neurodevelopmental disorders in offspring compared with paternal lamotrigine or levetiracetam use. Findings were consistent across dose-response analyses and among fathers with epilepsy, supporting reassessment of paternal valproate restrictions.
Summary
A population-based cohort study in Sweden and Norway.
[Posted 17/Aug/2026]
AUDIENCE: Neurology, Psychiatry
KEY FINDINGS: In this large Nordic population-based cohort, paternal valproate monotherapy during spermatogenesis was not significantly associated with neurodevelopmental disorders in offspring compared with paternal lamotrigine or levetiracetam monotherapy. Findings were consistent across dose-response analyses and among fathers with epilepsy. The results do not support an increased neurodevelopmental risk from paternal valproate exposure, although limitations inherent to registry-based observational research remain.
BACKGROUND: Valproate is an effective antiseizure medication, but its established teratogenic effects with maternal exposure have led to regulatory restrictions for women of reproductive potential. Concerns about possible paternal effects on offspring neurodevelopment have also prompted precautionary recommendations for men. This study evaluated whether paternal valproate use during spermatogenesis was associated with neurodevelopmental disorders (NDDs) in offspring.
DETAILS: This population-based cohort study used nationwide Swedish and Norwegian health registries. It included singleton live births at >=22 completed gestational weeks between 1 January 2007 and 31 December 2020 in Sweden and between 1 January 2010 and 31 December 2018 in Norway. After exclusions, 4681 children in Sweden and 1572 children in Norway were included for analysis.
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The analysis compared children whose fathers received valproate monotherapy during spermatogenesis with children whose fathers received lamotrigine or levetiracetam monotherapy. Outcomes included NDDs, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), intellectual disability (ID), and disorders of psychological development. Analyses were adjusted for relevant parental and child characteristics, including parental age, psychiatric diagnoses, psychotropic medication use, epilepsy diagnosis, and, in Sweden, parental education and maternal cohabitation/marital status.
The study specifically examined paternal antiseizure medication exposure during spermatogenesis, corresponding to the approximately 3 months before conception. Dose-response analyses and analyses restricted to fathers with epilepsy were also conducted.
Among the children included in the primary comparison, 2051 were born to fathers who used valproate monotherapy during spermatogenesis. No significant association was identified between paternal valproate exposure and NDDs compared with paternal lamotrigine or levetiracetam exposure. The findings remained consistent in dose-response analyses and when the analysis was restricted to fathers with epilepsy.
During follow-up in Sweden, 406 children were diagnosed with an NDD, including 287 with ADHD, 140 with ASD, 55 with ID, and 79 with disorders of psychological development. In Norway, 60 children were diagnosed with an NDD, including 35 with ADHD, 13 with ASD, 5 with ID, and 26 with disorders of psychological development.
For ASD, the pooled adjusted hazard ratio was 1.29 (95% CI 0.89 to 1.85). The study authors noted that point estimates were slightly above 1.0 in some analyses but did not reach statistical significance.
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Source: Razaz, N., Soderling, J., Tomson, T., et al. Risk of Neurodevelopmental Disorders Associated With Paternal Use of Valproate During Spermatogenesis. Journal of Neurology, Neurosurgery & Psychiatry. 2026; 97-8: 671-679. Published: August, 2026. DOI: 10.1136/jnnp-2025-337441.
Suicide Risk Peaks During the First Year After Dementia Diagnosis in Older Adults
Among 2,667,987 older adults with newly diagnosed dementia, suicide risk during the first year was significantly higher than in the general population (SMR 1.53), peaking within 90 days of diagnosis. Adults aged 65–74 years, patients with frontotemporal dementia, and those with mental illness, substance use disorders, or chronic pain had the greatest risk.
KEY FINDINGS: Older adults experience a significantly elevated risk of suicide during the first year after receiving a dementia diagnosis, particularly within the first 90 days. Individuals aged 65-74 years and those diagnosed with frontotemporal dementia represent the highest-risk groups. Coexisting mental illness, substance use disorders, chronic pain, rural residence, and recent mental health service utilization further increase suicide risk. These findings support routine suicide risk assessment, early psychiatric evaluation when appropriate, caregiver support, and discussions regarding restriction of access to lethal means immediately after a dementia diagnosis.
BACKGROUND: A new diagnosis of Alzheimer's disease or related dementias (ADRD) can be psychologically distressing and may increase vulnerability to suicidal behavior. Previous studies have reported inconsistent findings regarding suicide risk after dementia diagnosis. This nationwide U.S. cohort study evaluated suicide mortality and non-fatal suicidal events during the first year following a new ADRD diagnosis and identified patient characteristics associated with increased risk.
DETAILS: This retrospective cohort study included 2,667,987 Medicare fee-for-service beneficiaries aged >=65 years with newly diagnosed ADRD identified between 2012 and 2015. Patients were followed for up to 12 months after the initial dementia diagnosis or until death. Suicide deaths were identified through linkage with the National Death Index, while non-fatal suicidal events were captured using hospital claims. Standardized mortality ratios (SMRs) compared suicide risk with that of the general U.S. older adult population. Adjusted hazard ratios (AHRs) were calculated after controlling for age, sex, and race/ethnicity. During the first year after diagnosis, 705 suicide deaths occurred, corresponding to a suicide rate of 26.42 per 100,000 person-years, with an overall SMR of 1.53 (95% CI 1.42-1.65) compared with the general older adult population. The highest relative risk was observed among adults aged 65-74 years (SMR 3.40; 95% CI 2.94-3.86), and approximately half of all suicides occurred within the first 90 days after diagnosis. Patients with frontotemporal dementia had the highest suicide rate (124.63 per 100,000 person-years) and a significantly increased risk of suicide compared with unspecified dementia (AHR 2.91; 95% CI 1.67-5.05). Rural residence, recent mental health disorders, substance use disorders, chronic pain, and recent mental health-related healthcare utilization were independently associated with higher suicide risk. Non-fatal suicidal events were more frequent among patients with vascular dementia, personality disorders, bipolar disorder, anxiety disorders, substance use disorders, and chronic pain.
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