Clinical-Genetic Features Influencing Disability in Spastic Paraplegia Type 4

The SPAST-HSP phenotypic spectrum in Italian patients confirms a predominantly pure form of HSP with mild-to-moderate disability in 75% of cases, and slight prevalence of men, who appeared more severely affected.

source: Neuro Genetics

Summary

A Cross-sectional Study by the Italian DAISY Network

[Posted 18/May/2022]

AUDIENCE: Neurology, Internal Medicine

KEY FINDINGS: The SPAST-HSP phenotypic spectrum in Italian patients confirms a predominantly pure form of HSP with mild-to-moderate disability in 75% of cases, and slight prevalence of men, who appeared more severely affected. Early-onset cases with intellectual disability were more frequent among patients carrying missense SPAST variants, whereas patients with truncating variants showed a more complicated disease. Both longer DD and altered MEPs are associated with worse disability.

BACKGROUND: Hereditary spastic paraplegias (HSPs) are a group of inherited rare neurologic disorders characterized by length-dependent degeneration of the corticospinal tracts and dorsal columns, whose prominent clinical feature is represented by spastic gait. Spastic paraplegia type 4 (SPG4, SPAST-HSP) is the most common form. We present both clinical and molecular findings of a large cohort of patients, with the aim of (1) defining the clinical spectrum of SPAST-HSP in Italy; (2) describing their molecular features; and (3) assessing genotype-phenotype correlations to identify features associated with worse disability.

DETAILS: A cross-sectional retrospective study with molecular and clinical data collected in an anonymized database was performed. A total of 723 Italian patients with SPAST-HSP (58% men) from 316 families, with a median age at onset of 35 years, were included. Penetrance was 97.8%, with men showing higher Spastic Paraplegia Rating Scale (SPRS) scores (19.67 ± 12.58 vs 16.15 ± 12.61, p = 0.009). In 26.6% of patients with SPAST-HSP, we observed a complicated phenotype, mainly including intellectual disability (8%), polyneuropathy (6.7%), and cognitive decline (6.5%). Late-onset cases seemed to progress more rapidly, and patients with a longer disease course displayed a more severe neurologic disability, with higher SPATAX (3.61 ± 1.46 vs 2.71 ± 1.20, p < 0.001) and SPRS scores (22.63 ± 11.81 vs 12.40 ± 8.83, p < 0.001). Overall, 186 different variants in the SPAST gene were recorded, of which 48 were novel. Patients with SPAST-HSP harboring missense variants displayed intellectual disability (14.5% vs 4.4%, p < 0.001) more frequently, whereas patients with truncating variants presented more commonly cognitive decline (9.7% vs 2.6%, p = 0.001), cerebral atrophy (11.2% vs 3.4%, p = 0.003), lower limb spasticity (61.5% vs 44.5%), urinary symptoms (50.0% vs 31.3%, p < 0.001), and sensorimotor polyneuropathy (11.1% vs 1.1%, p < 0.001). Increasing disease duration (DD) and abnormal motor evoked potentials (MEPs) were also associated with increased likelihood of worse disability (SPATAX score>3).

Our Most Popular Resources

Copyright © American Academy of Neurology. All Rights Reserved.

Source: Rossi, S., Rubegni, A., Riso, V., et al. (2022). Clinical-Genetic Features Influencing Disability in Spastic Paraplegia Type 4: A Cross-sectional Study by the Italian DAISY Network. Neuro Genetics. 2022; 8(2): e664. Published: April, 2022. DOI: 10.1212/NXG.0000000000000664.



Maternal Serotonergic Antidepressant Use in Pregnancy and Risk of Seizures in Children

Found no support for the concern that maternal SSRI/SNRI use in pregnancy increases children's risk for neonatal seizures or epilepsy.

source: Neurology

Summary

[Posted 8/Jun/2022]

AUDIENCE: Neurology, Pediatric

KEY FINDINGS: Found no support for the concern that maternal SSRI/SNRI use in pregnancy increases children's risk for neonatal seizures or epilepsy.

BACKGROUND: Purpose of this study was to evaluate whether children born to women who use serotonergic antidepressants during pregnancy have higher risk of neonatal seizures and epilepsy.

DETAILS: Swedish register-based data was used to examine associations between maternal reported use of selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) in pregnancy and diagnosis of neonatal seizures or epilepsy in >1.2 million children. To account for systematic differences between exposed and unexposed children, adjusted for a wide range of measured confounders. After first evaluating the role of maternal indication for SSRI/SNRI use (i.e., depression or anxiety) and parental epilepsy, adjusted for remaining parental background factors (e.g., age, comorbidities, education, and family socioeconomic indices) and pregnancy-specific characteristics (e.g., maternal use of other psychotropic medications and tobacco smoking in early pregnancy). Compared with all other children, children of women who reported use of SSRI/SNRI in pregnancy had an elevated risk of neonatal seizures and epilepsy (risk ratio [RR] 1.41, 95% CI 1.03-1.94; hazard ratio [HR] 1.21, 95% CI 1.03-1.43, respectively). The estimates of association were attenuated by adjustment for maternal indications for SSRI/SNRI use (RR 1.30, 95% CI 0.94-1.80; HR 1.13, 95% CI 0.95-1.33), but not by additional adjustment for parental history of epilepsy. Full adjustment for all measured parental and pregnancy-specific factors resulted in substantial attenuation of the remaining associations (RR 1.10, 95% CI 0.79-1.53; HR 0.96, 95% CI 0.81-1.14).

Our Most Popular Resources

Copyright © American Academy of Neurology. All Rights Reserved.

Source: Wiggs, K. K., Sujan, A. C., Rickert, M. E., et al. (2022). Maternal Serotonergic Antidepressant Use in Pregnancy and Risk of Seizures in Children. Neurology. 2022, 98(23): e2329-e2336. Published: May 6, 2022. DOI: 10.1212/WNL.0000000000200516.



Neurobiological Correlates of Change in Adaptive Behavior in Autism

The findings suggest that patients who die by suicide by violent means their behavioral outcome may be less dependent on genetic risk for conventional psychiatric disorders.

source: Am J Psychiatry

Summary

[Posted 24/May/2022]

AUDIENCE: Psychiatry, Neurology, Family Medicine

KEY FINDINGS: This study demonstrates, for the first time, that variation in clinical (adaptive) outcome is associated with both group- and individual-level variation in anatomy of brain regions enriched for genes relevant to ASD. This may facilitate the move toward better targeted/precision medicine approaches.

BACKGROUND: Autism spectrum disorder (ASD) is a lifelong neurodevelopmental condition that is associated with significant difficulties in adaptive behavior and variation in clinical outcomes across the life span. Some individuals with ASD improve, whereas others may not change significantly, or regress. Hence, the development of "personalized medicine" approaches is essential. However, this requires an understanding of the biological processes underpinning differences in clinical outcome, at both the individual and subgroup levels, across the lifespan.

DETAILS: The authors conducted a longitudinal follow-up study of 483 individuals (204 with ASD and 279 neurotypical individuals, ages 6-30 years), with assessment time points separated by ~12-24 months. Data collected included behavioral data (Vineland Adaptive Behavior Scale-II), neuroanatomical data (structural MRI), and genetic data (DNA). Individuals with ASD were grouped into clinically meaningful "increasers," "no-changers," and "decreasers" in adaptive behavior. First, the authors compared neuroanatomy between outcome groups. Next, they examined whether deviations from the neurotypical neuroanatomical profile were associated with outcome at the individual level. Finally, they explored the observed neuroanatomical differences’ potential genetic underpinnings. Outcome groups differed in neuroanatomical features (cortical volume and thickness, surface area), including in "social brain" regions previously implicated in ASD. Also, deviations of neuroanatomical features from the neurotypical profile predicted outcome at the individual level. Moreover, neuroanatomical differences were associated with genetic processes relevant to neuroanatomical phenotypes (e.g., synaptic development).

Our Most Popular Resources

Copyright © American Psychiatric Association. All rights reserved.

Source: Pretzsch, C. M., Schafer, T., Lombardo, M. V., et al. (2022). Neurobiological Correlates of Change in Adaptive Behavior in Autism. Am J Psychiatry. 2022; 179(5): 336-349. Published: May, 2022. DOI: 10.1176/appi.ajp.21070711.



Association of Traumatic Brain Injury With the Risk of Developing Chronic Cardiovascular, Endocrine, Neurological, and Psychiatric Disorders

Findings suggest that patients with TBI in all age groups may benefit from a proactive targeted screening program for chronic multisystem diseases, particularly cardiometabolic diseases, after injury.

source: JAMA Netw Open

Summary

[Posted 2/May/2022]

AUDIENCE: Cardiology, Emergency Medicine

KEY FINDINGS: These findings suggest that TBI of any severity was associated with a higher risk of chronic cardiovascular, endocrine, and neurological comorbidities in patients without baseline diagnoses. Medical comorbidities were observed in relatively young patients with TBI. Comorbidities occurring after TBI were associated with higher mortality. These findings suggest the need for a targeted screening program for multisystem diseases after TBI, particularly chronic cardiometabolic diseases.

BACKGROUND: Aim of the study is to assess the incidence of cardiovascular, endocrine, neurological, and psychiatric comorbidities in patients with mild TBI (mTBI) or moderate to severe TBI (msTBI) and analyze associations between post-TBI comorbidities and mortality. Increased risk of neurological and psychiatric conditions after traumatic brain injury (TBI) is well-defined. However, cardiovascular and endocrine comorbidity risk after TBI in individuals without these comorbidities and associations with post-TBI mortality have received little attention.

DETAILS: This prospective longitudinal cohort study used hospital-based patient registry data from a tertiary academic medical center to select patients without any prior clinical comorbidities who experienced TBI from 2000 to 2015. Using the same data registry, individuals without head injuries, the unexposed group, and without target comorbidities were selected and age-, sex-, and race-frequency-matched to TBI subgroups. Patients were followed-up for up to 10 years. Data were analyzed in 2021. Cardiovascular, endocrine, neurologic, and psychiatric conditions were defined based on International Classification of Diseases, Ninth Revision (ICD-9) or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10). Associations between TBI and comorbidities, as well as associations between the comorbidities and mortality, were analyzed. A total of 4351 patients with mTBI (median [IQR] age, 45 [29-57] years), 4351 patients with msTBI (median [IQR] age, 47 [30-58] years), and 4351 unexposed individuals (median [IQR] age, 46 [30-58] years) were included in analyses. In each group, 45% of participants were women. mTBI and msTBI were significantly associated with higher risks of cardiovascular, endocrine, neurologic, and psychiatric disorders compared with unexposed individuals. In particular, hypertension risk was increased in both mTBI (HR, 2.5; 95% CI, 2.1-2.9) and msTBI (HR, 2.4; 95% CI, 2.0-2.9) groups. Diabetes risk was increased in both mTBI (HR, 1.9; 95% CI, 1.4-2.7) and msTBI (HR, 1.9; 95% CI, 1.4-2.6) groups, and risk of ischemic stroke or transient ischemic attack was also increased in mTBI (HR, 2.2; 95% CI, 1.4-3.3) and msTBI (HR, 3.6; 95% CI, 2.4-5.3) groups. All comorbidities in the TBI subgroups emerged within a median (IQR) of 3.49 (1.76-5.96) years after injury. Risks for post-TBI comorbidities were also higher in patients aged 18 to 40 years compared with age-matched unexposed individuals: hypertension risk was increased in the mTBI (HR, 5.9; 95% CI, 3.9-9.1) and msTBI (HR, 3.9; 95% CI, 2.5-6.1) groups, while hyperlipidemia (HR, 2.3; 95% CI, 1.5-3.4) and diabetes (HR, 4.6; 95% CI, 2.1-9.9) were increased in the mTBI group. Individuals with msTBI, compared with unexposed patients, had higher risk of mortality (432 deaths [9.9%] vs 250 deaths [5.7%]; P < .001); postinjury hypertension (HR, 1.3; 95% CI, 1.1-1.7), coronary artery disease (HR, 2.2; 95% CI, 1.6-3.0), and adrenal insufficiency (HR, 6.2; 95% CI, 2.8-13.0) were also associated with higher mortality.

Our Most Popular Resources

Copyright © American Medical Association. All Rights Reserved.

Source: Izzy, S., Chen, P. M., Tahir, Z., et al. (2022). Association of Traumatic Brain Injury With the Risk of Developing Chronic Cardiovascular, Endocrine, Neurological, and Psychiatric Disorders. JAMA Netw Open. 2022; 5(4): e229478. Published: April 1, 2022. DOI: 10.1001/jamanetworkopen.2022.9478.



Long-term Cognitive Outcomes and Socioprofessional Attainment

This study underscores how cognitive reserve may partially mitigate the negative effects of brain damage, highlighting the critical importance of intellectual enrichment early during the disease course.

source: Neurology

Summary

Long-term Cognitive Outcomes and Socioprofessional Attainment in People With Multiple Sclerosis With Childhood Onset

[Posted 26/Apr/2022]

AUDIENCE: Neurology, Internal Medicine

KEY FINDINGS: The longitudinal cognitive trajectory in pediatric-onset MS has a heterogeneous course over time, with a decline in the first years followed by a partial recovery over the long term. However, at the last follow-up evaluation, the proportion of impaired patients was more than double compared with baseline, with a negative impact on the individual’s socioprofessional attainment in adulthood. This study underscores how cognitive reserve may partially mitigate the negative effects of brain damage, highlighting the critical importance of intellectual enrichment early during the disease course.

BACKGROUND: Patients with pediatric-onset multiple sclerosis (MS) can be especially vulnerable to cognitive impairment (CI) due to the onset of MS during a critical period for CNS development and maturation. The objective of this longitudinal study was to assess long-term cognitive functioning and socioprofessional attainment in the Italian pediatric MS cohort, previously assessed at baseline and 2 and 5 years.

DETAILS: The 48 patients evaluated at the 5-year assessment were screened for inclusion. All participants were assessed with a cognitive test battery exploring 4 different cognitive abilities. Depression, fatigue, and socioprofessional attainment were also assessed. Mean cognitive z scores were calculated for the whole cohort, and their evolution over time was analyzed with an analysis of variance for repeated measurements test. Predictors of cognitive worsening or improvement were assessed with a linear mixed-model analysis. Thirty-three participants were included (mean follow-up 12.8 ± 0.8 years). The global cognitive performance worsened at year 2 and improved at year 5, although the z score remained significantly lower than at baseline (-0.9 ± 1.2 vs -0.3 ± 0.9, p = 0.002). There was no significant variation between years 5 and 12 (-0.7 ± 1.1, p = 0.452). Higher IQ (>90) at baseline (effect 0.3, 95% CI 0.1–0.5, p = 0.017) and lower number of relapses in the 2 years before baseline (effect -0.1, 95% CI -0.1 to 0.1, p = 0.025) predicted better cognitive performances. Eighteen (54.5%) patients failed at least 2 tests compared with healthy controls and were defined as cognitively impaired. The presence of CI predicted worse socioprofessional attainment (ß = 4.8, 95% CI 1.4–8.2, p = 0.008).

Our Most Popular Resources

Copyright © American Academy of Neurology. All Rights Reserved.

Source: Portaccio, E., Bellinivia, A., Razzolini, L., et al. (2022). Long-term Cognitive Outcomes and Socioprofessional Attainment in People With Multiple Sclerosis With Childhood Onset. Neurology. 2022; 98(16): e1626-e1636. Published: April 19, 2022. DOI: 10.1212/WNL.0000000000200115.



Subjective Cognitive Decline - Association of CSF, Plasma, and Imaging Markers of Neurodegeneration

In cognitively unimpaired older adults, correlations between different N biomarkers were only moderate, indicating they reflect different aspects of neurodegeneration and should not be used interchangeably.

source: Neurology

Summary

Association of CSF, Plasma, and Imaging Markers of Neurodegeneration With Clinical Progression in People With Subjective Cognitive Decline

[Posted 6/Apr/2022]

AUDIENCE: Neurology, Internal Medicine

KEY FINDINGS: In cognitively unimpaired older adults, correlations between different N biomarkers were only moderate, indicating they reflect different aspects of neurodegeneration and should not be used interchangeably. T-tau was strongly associated with p-tau (T), which makes it less desirable to use as a measure for N. HV, NfL, and GFAP predicted clinical progression beyond A and T. The results do not allow to choose one most suitable biomarker for N, but illustrate the added prognostic value of N beyond A and T.

BACKGROUND: Multiple biomarkers have been suggested to measure neurodegeneration (N) in the AT(N) framework, leading to inconsistencies between studies. The association of 5 N biomarkers with clinical progression and cognitive decline in individuals with subjective cognitive decline (SCD) was investigated.

DETAILS: Included individuals with SCD from the Amsterdam Dementia Cohort and SCIENCe project, a longitudinal cohort study (follow-up 4±3 years). Used the following N biomarkers: CSF total tau (t-tau), medial temporal atrophy visual rating on MRI, hippocampal volume (HV), serum neurofilament light (NfL), and serum glial fibrillary acidic protein (GFAP).Correlations between biomarkers were determine. Assessed associations between N biomarkers and clinical progression to mild cognitive impairment or dementia (Cox regression) and Mini-Mental State Examination (MMSE) over time (linear mixed models). Models included age, sex, CSF ß-amyloid (Aß) (A), and CSF p-tau (T) as covariates, in addition to the N biomarker. Included 401 individuals (61±9 years, 42% female, MMSE 28 ± 2, vascular comorbidities 8%-19%). N biomarkers were modestly to moderately correlated (range r -0.28 -0.58). Serum NfL and GFAP correlated most strongly (r 0.58, p < 0.01). T-tau was strongly correlated with p-tau (r 0.89, p < 0.01), although these biomarkers supposedly represent separate biomarker groups. All N biomarkers individually predicted clinical progression, but only HV, NfL, and GFAP added predictive value beyond Aß and p-tau (hazard ratio 1.52 [95% CI 1.11-2.09]; 1.51 [1.05-2.17]; 1.50 [1.04-2.15]). T-tau, HV, and GFAP individually predicted MMSE slope (range ß -0.17 to -0.11, p 0.05), but only HV remained associated beyond Aß and p-tau (ß -0.13 [SE 0.04]; p 0.05).

Our Most Popular Resources

Copyright © American Academy of Neurology. All Rights Reserved.

Source: Ebenau, J. L., Pelkmans, W., Verberk, I. M. W., et al. (2022). Association of CSF, Plasma, and Imaging Markers of Neurodegeneration With Clinical Progression in People With Subjective Cognitive Decline. Neurology. 2022; 98(13): e1315-e1326. Published: March 29, 2022. DOI: 10.1212/WNL.0000000000200035.



Specialty: 

Breaking Medical News Cardiology Emergency Medicine Endocrinology Family Medicine Gastroenterology General Interests General Surgery Hematology/Oncology Infectious Disease Internal Medicine Nephrology Neurology Nursing Ob/Gyn Ophthalmology Pediatrics Pharmacy Psychiatry