A Systematic Review and Meta-analysis

[Posted 16/Aug/2022]

AUDIENCE: Neurology, Pediatric, Internal Medicine

KEY FINDINGS: Temporal trends in stroke incidence are diverging by age in high-income countries, with less favorable trends at younger vs older ages, highlighting the urgent need to better understand etiology and prevention of stroke at younger ages.

BACKGROUND: Overall stroke incidence is falling in high-income countries, but data on time trends in incidence of young stroke (ie, stroke in individuals younger than 55 years) are conflicting. An age-specific divergence in incidence, with less favorable trends at younger vs older ages, might be a more consistent underlying finding across studies. Purpose of this study was to compare temporal trends in incidence of stroke at younger vs older ages in high-income countries.

DETAILS: For all retrieved studies, 2 authors independently reviewed the full text against the inclusion criteria to establish their eligibility. Meta-analysis was performed with the inverse variance-weighted random-effects model. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. The main outcome was age-specific divergence (55 vs >=55 years) in temporal trends in stroke incidence (relative temporal rate ratio [RTTR]) in studies extending to at least 2000. RTTRs were calculated for each study and pooled by random-effects meta-analysis, with stratification by administrative vs prospective population-based methodology, sex, stroke subtype (ischemic vs intracerebral hemorrhage vs subarachnoid hemorrhage) and geographical region. Among 50 studies in 20 countries, 26 (13 prospective population-based and 13 administrative studies) reported data allowing calculation of the RTTR for stroke incidence at younger vs older ages across 2 or more periods, the latest extending beyond 2000. Reported trends in absolute incidence of young individuals with stroke were heterogeneous, but all studies showed a less favorable trend in incidence at younger vs older ages (pooled RTTR = 1.57 [95% CI, 1.42-1.74]). The overall RTTR was consistent by stroke subtype (ischemic, 1.62 [95% CI, 1.44-1.83]; intracerebral hemorrhage, 1.32 [95% CI, 0.91-1.92]; subarachnoid hemorrhage, 1.54 [95% CI, 1.00-2.35]); and by sex (men, 1.46 [95% CI, 1.34-1.60]; women, 1.41 [95% CI, 1.28-1.55]) but was greater in studies reporting trends solely after 2000 (1.51 [95% CI, 1.30-1.70]) vs solely before (1.18 [95% CI, 1.12-1.24]) and was highest in population-based studies in which the most recent reported period of ascertainment started after 2010 (1.87 [95% CI, 1.55-2.27]).

Copyright © American Medical Association. All Rights Reserved.

Source: Scott, C. A., Li, L., Rothwell, P. M. (2022). Diverging Temporal Trends in Stroke Incidence in Younger vs Older People: A Systematic Review and Meta-analysis. JAMA Neurology. Published: August 9, 2022. DOI: 10.1001/jamaneurol.2022.1520.

[Posted 26/Jul/2022]

AUDIENCE: Endocrinology, Neurology, Family Medicine

KEY FINDINGS: Middle-aged and older adults with T1DM showed brain volume loss and increased vascular injury in comparison with control subjects without diabetes, equivalent to 4-9 years of brain aging.

BACKGROUND: Individuals with type 1 diabetes mellitus (T1DM) are living to ages when neuropathological changes are increasingly evident. Hypothesized that middle-aged and older adults with long-standing T1DM will show abnormal brain structure in comparison with control subjects without diabetes.

DETAILS: MRI was used to compare brain structure among 416 T1DM participants in the Epidemiology of Diabetes Interventions and Complications (EDIC) study with that of 99 demographically similar control subjects without diabetes at 26 U.S. and Canadian sites. Assessments included total brain (TBV) (primary outcome), gray matter (GMV), white matter (WMV), ventricle, and white matter hyperintensity (WMH) volumes and total white matter mean fractional anisotropy (FA). Biomedical assessments included HbA1c and lipid levels, blood pressure, and cognitive assessments of memory and psychomotor and mental efficiency (PME). Among EDIC participants, HbA1c, severe hypoglycemia history, and vascular complications were measured longitudinally. Mean age of EDIC participants and control subjects was 60 years. T1DM participants showed significantly smaller TBV (least squares mean ± SE 1,206 ± 1.7 vs. 1,229 ± 3.5 cm3, P < 0.0001), GMV, and WMV and greater ventricle and WMH volumes but no differences in total white matter mean FA versus control subjects. Structural MRI measures in T1DM were equivalent to those of control subjects who were 4-9 years older. Lower PME scores were associated with altered brain structure on all MRI measures in T1DM participants.

Copyright © American Diabetes Association. All rights reserved.

Source: Jacobson, A. M., Braffett, B. H., Erus, G., et al. (2022). Brain Structure Among Middle-aged and Older Adults With Long-standing Type 1 Diabetes in the DCCT/EDIC Study. Diabetes Care. 2022; 45(8): 1779-1787. Published: July 26, 2022. DOI: 10.2337/dc21-2438.

[Posted 25/Jul/2022]

AUDIENCE: Psychiatry, Pediatric, Family Medicine

KEY FINDINGS: The connectivity strength of the VS within the reward network showed distinct patterns of association with depressive disorders and anhedonia from mid to late adolescence, suggesting that the role of this circuitry in depression changes with age. This study replicates, in an independent sample, the association between the VS and depression previously reported in younger adolescents. The findings suggest a role of VS connectivity_rw in anhedonia but not in low mood.

BACKGROUND: Research in adolescent depression has found aberrant intrinsic functional connectivity (iFC) among the ventral striatum (VS) and several brain regions implicated in reward processing. The present study probes this question by taking advantage of the availability of data from a large youth cohort, the IMAGEN Consortium.

DETAILS: iFC data from 303 adolescents (48% of them female) were used to examine associations of VS connectivity at baseline (at age 14) with depressive disorders at baseline and at 2-year (N=250) and 4-year (N=219) follow-ups. Eleven regions of interest, key nodes of the reward system, were used to probe the reward network and calculate the connectivity strength of the VS within this network (VS connectivity_rw). The main analyses assessed associations of VS connectivity_rw with depressive disorders, anhedonia, and low mood using logistic regression. Autoregressive models accounting for carryover effects over time were conducted to further evaluate these brain-behavior associations. Higher right VS connectivity_rw was associated with higher probability of depressive disorders at baseline (odds ratio=2.65, 95% CI=1.40, 5.05). This finding was confirmed in the autoregressive model, adjusting for carryover effects of the depressive disorders across the three time points. VS connectivity_rw was not predictive of depressive disorders at follow-up assessments. Longitudinal associations between VS connectivity_rw and anhedonia emerged in the structural equation model: left VS connectivity_rw was associated with anhedonia at 2 years (odds ratio=2.20, 95% CI=1.54, 3.14), and right VS connectivity_rw was linked to anhedonia at 4 years (odds ratio=1.87, 95% CI=1.09, 3.21). VS connectivity_rw did not predict low mood at any time point in the structural equation model.

Copyright © American Psychiatric Association. All rights reserved.

Source: Pan, P. M., Sato, J. R., Martinot, M. P.,, et al. (2022). Longitudinal Trajectory of the Link Between Ventral Striatum and Depression in Adolescence. Am J Psychiatry. 2022; 179(7): 470-481. Published: July, 2022. DOI: 10.1176/appi.ajp.20081180.

[Posted 19/Jul/2022]

AUDIENCE: Neurology, Psychiatry, Internal Medicine

KEY FINDINGS: Patients with CAA show more subcortical cerebellar atrophy than HC or patients with AD and more cortical cerebellar atrophy than HCs. Reduced pCbll-ScV correlated with lower gait velocity in regression models including other relevant variables. Overall, this study suggests that CAA causes cerebellar injury, which might contribute to gait disturbance.

BACKGROUND: Recent data suggest that cerebral amyloid angiopathy (CAA) causes haemorrhagic lesions in cerebellar cortex as well as subcortical cerebral atrophy. However, the potential effect of CAA on cerebellar tissue loss and its clinical implications have not been investigated.

DETAILS: The study included 70 non-demented patients with probable CAA, 70 age-matched healthy controls (HCs) and 70 age-matched patients with Alzheimer's disease (AD). The cerebellum was segmented into percent of cerebellar subcortical volume (pCbll-ScV) and percent of cerebellar cortical volume (pCbll-CV) represented as percent (p) of estimated total intracranial volume. We compared pCbll-ScV and pCbll-CV between patients with CAA, HCs and those with AD. Gait velocity (metres/second) was used to investigate gait function in patients with CAA. Patients with CAA had significantly lower pCbll-ScV compared with both HC (1.49±0.1 vs 1.73±0.2, p<0.001) and AD (1.49±0.1 vs 1.66 ± 0.24, p<0.001) and lower pCbll-CV compared with HCs (6.03±0.5 vs 6.23±0.6, p=0.028). Diagnosis of CAA was independently associated with lower pCbll-ScV compared with HCs (p<0.001) and patients with AD (p<0.001) in separate linear regression models adjusted for age, sex and presence of hypertension. Lower pCbll-ScV was independently associated with worse gait velocity (ß=0.736, 95% CI 0.28 to 1.19, p=0.002) in a stepwise linear regression analysis including pCbll-CV along with other relevant variables.

Copyright © BMJ Publishing Group Ltd. All rights reserved.

Source: Horn, M. J., Gokcal, E., Becker, A. J., et al. (2022). Cerebellar Atrophy and Its Implications On Gait In Cerebral Amyloid Angiopathy. Journal of Neurology, Neurosurgery & Psychiatry. 2022; 93(8): 802-807. Published: August, 2022. DOI: 10.1136/jnnp-2021-328553.

[Posted 6/Jul/2022]

AUDIENCE: Neurology, Internal Medicine

KEY FINDINGS: The data suggest that there is a ceiling effect on the clinical consequences of GAA-TR length in FRDA, as would be predicted by variegated silencing. Patients with GAA-TRs of >700 triplets represent a subgroup in which the severity of clinical manifestations based on GAA-TR length have reached maximal levels and therefore display limited clinical variability in disease progression.

BACKGROUND: Friedreich ataxia (FRDA) is a neurodegenerative disease caused by a GAA triplet repeat (GAA-TR) expansion in intron 1 of the FXN gene. Patients have 100–1,300 GAA triplets compared with less than 30 in healthy controls. The GAA-TR expansion leads to FXN silencing, and consequent frataxin protein deficiency results in progressive ataxia, scoliosis, cardiomyopathy, and diabetes. The overt heterogeneity in age at onset and disease severity is explained partly by the length of the GAA-TR, in which shorter repeats correlate with milder disease. Evidence of variegated silencing in FRDA suggests that patients with shorter repeats retain a significant proportion of cells with FXN genes that have escaped GAA-TR expansion–induced silencing, explaining the less severe frataxin deficiency in this subpopulation. In ex vivo experiments, the proportion of spared cells negatively correlates with GAA-TR length until it plateaus at 500 triplets, an indication that the maximal number of silenced cells has been reached. In this study, we assessed whether an analogous ceiling effect occurs in severity of clinical features of FRDA by analyzing clinical outcome data.

DETAILS: The FRDA Clinical Outcome Measures Study database was used for a cross-sectional analysis of 1,000 patients with FRDA. Frataxin levels were determined by lateral flow immunoassays. The length of the GAA-TR in our cohort predicted frataxin level (R2 = 0.38, p < 0.0001) and age at onset (R2 = 0.46, p < 0.0001) but only with GAA-TRs with <= 700 triplets. Age and disease duration predicted performance on clinical outcome measures, and such predictions in linear regression models statistically improved in the subcohort of patients with >700 GAA triplets. The prevalence of cardiomyopathy and scoliosis increased as GAA-TR length increased up to 700 GAA triplets where prevalence plateaued.

Copyright © American Academy of Neurology. All Rights Reserved.

Source: Rodden, L. N., Rummey, C., Dong, Y. N., et al. (2022). 2022; 8(3): e683. Clinical Evidence for Variegated Silencing in Patients With Friedreich Ataxia. Neuro Genetics. Published: June, 2022. DOI: 10.1212/NXG.0000000000000683.

[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).

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.