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]).

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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 2/Oct/2026]

AUDIENCE: Psychiatry, Neurology

KEY FINDINGS: In this 12-month randomized trial, a smartphone intervention providing personalized circadian rhythm stabilization feedback was associated with fewer recurrent mood episodes and fewer days spent in recurrent episodes among adults with MDD or BD. The findings support further evaluation of personalized digital chronotherapy as an adjunct to standard psychiatric care. The study was conducted in a relatively small sample, and additional research will be important to assess effectiveness across broader and more diverse patient populations.

BACKGROUND: Recurrence of depressive and bipolar mood episodes remains a major challenge in long-term psychiatric care. Because disruptions in circadian rhythms are associated with mood instability, researchers developed the Circadian Rhythm for Mood (CRM) smartphone app to provide individualized mood forecasts and personalized feedback aimed at stabilizing circadian patterns. This randomized clinical trial evaluated whether the intervention could reduce recurrent mood episodes in adults with major depressive disorder or bipolar disorder.

DETAILS: This multicenter, double-blind, sham-controlled randomized clinical trial included 93 adults with MDD or BD. Participants were randomly assigned to an active CRM app group (47 participants) or a sham-app group (46 participants) for 12 months. The CRM app used passive sensor data and machine-learning algorithms to generate individualized 3-day mood forecasts and personalized circadian rhythm stabilization feedback. The sham app had an identical interface but provided nonactionable feedback generated by a dummy algorithm. The primary outcome was the number of recurrent mood episodes during follow-up.

The modified intention-to-treat analysis included 80 participants, with 38 in the active CRM group and 42 in the sham group. The sham group had a significantly higher rate of recurrent mood episodes than the active CRM group, with an incidence rate ratio of 3.39 (95% CI, 1.86-6.17). Cumulative recurrent episode-days per person-year were also greater with the sham intervention, with a duration rate ratio of 2.76 (95% CI, 1.19-6.40). Time to recurrence differed between groups, with a hazard ratio of 3.03 (95% CI, 1.58-5.81). No significant adverse effects were observed.

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Source: Yeom, J. W., Jeong, J., Moon, E., et al. Circadian Rhythm Stabilization App to Prevent Mood Episode Recurrence in Patients With Mood Disorders: A Multicenter, Double-Blind, Sham-Controlled, Randomized Clinical Trial. American Journal of Psychiatry. 2026; 183(9): 657-667. Published: September, 2026. DOI: 10.1176/appi.ajp.20251008.

[Posted 24/Sep/2026]

AUDIENCE: Neurology, Psychiatry

KEY FINDINGS: People with CAA in this study had substantially more depressive symptoms and poorer cognitive performance than cognitively normal controls. Depressive symptoms explained a small but significant portion of the association between CAA and impairment in episodic memory and executive function, suggesting that mood symptoms may contribute to cognitive difficulties in CAA. Greater depressive symptom severity was also associated with MRI markers of cortical and small-vessel brain injury. Because the study was cross-sectional, the findings do not establish whether CAA-related brain injury causes depression or whether depressive symptoms contribute to subsequent cognitive decline.

BACKGROUND: Cerebral amyloid angiopathy (CAA), a small-vessel disease characterized by β-amyloid deposition in cerebral vessel walls, is associated with cognitive impairment and dementia. Depression can independently affect memory and executive function, but the relationship between depressive symptoms, CAA-related brain injury, and cognition has been less clearly defined. This study examined whether depressive symptoms were associated with cognitive performance in people with CAA and whether depression helped explain the relationship between CAA and cognitive impairment.

DETAILS: Researchers analyzed baseline data from a prospective longitudinal cohort recruited through memory and stroke-prevention clinics at two Canadian centers. The analysis included adults aged ≥55 years with probable CAA and cognitively normal controls. Cognitive performance was evaluated across episodic memory, executive function, and processing speed, while depressive symptoms were assessed using the 15-item Geriatric Depression Scale (GDS-15). A score ≥5 was classified as "possible depression." The primary analysis included 168 participants: 85 with CAA and 83 cognitively normal controls. The mean age was 73.5 years among participants with CAA and 68.8 years among controls. Additional analyses exam-ined relationships between depressive symptoms and CAA-related MRI markers in 81 participants with CAA.

Participants with CAA had substantially higher odds of possible depression than controls, with an odds ratio of 15.71 (95% CI, 4.26-80.05; P<0.001). Their GDS-15 scores were also 2.71 times higher than those of controls (95% CI, 2.10-3.51; P<0.001). Possible depression was associated with poorer performance across all three cognitive domains. After adjustment for age, sex, and education, associations were observed for episodic memory (β=-1.03; 95% CI, -1.53 to -0.53; P<0.001), executive function (β=-1.11; 95% CI, -1.65 to -0.58; P<0.001), and processing speed (β=-0.73; 95% CI, -1.24 to -0.21; P=0.006). Mediation analysis suggested that depressive symptoms accounted for 11% of the association between CAA and episodic memory and 9% of the association between CAA and executive function. No significant mediation was observed for processing speed, where depression accounted for approximately 2% of the association.

Among participants with CAA, greater depressive symptom severity was also associated with lower mean cortical thickness, cortical superficial siderosis, and a higher CAA-related small-vessel disease burden. Specifically, the count ratio was 1.33 (95% CI, 1.09-1.62; P=0.005) per SD decrease in cortical thickness, 2.04 (95% CI, 1.35-3.09; P<0.001) for cortical superficial siderosis, and 1.16 (95% CI, 1.00-1.35; P=0.047) for higher CAA small-vessel disease score.

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Source: Nukala, N., Muir, R. T., Beaudin, A. E., et al. Associations Between Cerebral Amyloid Angiopathy, Cognitive Impairment, and Depressive Symptoms. Neurology. 2026; 107(5): e218354. Published: September, 2026. DOI: 10.1212/WNL.0000000000218354.

[Posted 22/Sep/2026]

AUDIENCE: Ophthalmology, Endocrinology, Internal Medicine

KEY FINDINGS: The development of NVG was associated with additional long-term systemic morbidity and mortality beyond the underlying PDR or CRVO in this large retrospective cohort. The strongest associations included mortality and ESRD among patients with PDR and mortality and stroke among those with CRVO. The findings suggest that development of NVG may identify patients with substantial systemic vascular risk and support closer coordination between ophthalmic and other medical specialties. Because the study was retrospective and based on electronic health records, the observed associations should not be interpreted as evidence that NVG itself directly causes these systemic outcomes.

BACKGROUND: Neovascular glaucoma (NVG) is a serious ocular complication of retinal vascular disease, including proliferative diabetic retinopathy (PDR) and central retinal vein occlusion (CRVO). Although NVG is primarily recognized for its effects on vision and intraocular pressure, less is known about whether its development is associated with additional long-term systemic health risks. This multicenter retrospective cohort study evaluated mortality and major systemic outcomes among adults with PDR or CRVO who did or did not subsequently develop NVG.

DETAILS: The investigators used the TriNetX Research Network, a deidentified electronic health record database containing information from more than 177 million patients across more than 150 healthcare organizations worldwide. Adults older than 40 years with PDR or CRVO were identified and compared according to whether NVG subsequently developed. Patients were propensity-score matched 1:1 based on demographic characteristics and comorbidities. Outcomes were assessed at 1, 5, and 10 years and included all-cause mortality, stroke, myocardial infarction (MI), end-stage renal disease (ESRD), and deep-vein thrombosis (DVT). A total of 1,278 patients with PDR and NVG were matched with 1,278 patients with PDR without NVG. The study also evaluated patients with CRVO and NVG compared with matched CRVO patients without NVG, as well as an NVG cohort compared with a cataract control cohort.

Among patients with PDR, development of NVG was associated with higher 10-year mortality (HR, 1.34; 95% CI, 1.14-1.57) and ESRD (HR, 1.43; 95% CI, 1.23-1.67) compared with PDR without NVG. Ten-year survival was 60.4% in the PDR + NVG group compared with 68.4% in the PDR without NVG group. Among patients with CRVO, those who developed NVG had higher 10-year mortality (HR, 1.61; 95% CI, 1.17-2.20) and stroke risk (HR, 1.86; 95% CI, 1.19-2.90). Differences in MI and ESRD were not statistically significant in this comparison, and DVT risk was also not significantly different. When PDR + NVG was compared directly with CRVO + NVG, the PDR + NVG group had higher 10-year risks of mortality (HR, 1.56; 95% CI, 1.17-2.07), MI (HR, 1.94; 95% CI, 1.13-3.32), and ESRD (HR, 4.04; 95% CI, 2.43-6.73). Compared with the cataract control cohort, NVG was associated at 10 years with higher risks of mortality (HR, 2.66; 95% CI, 2.40-2.94), stroke (HR, 2.17; 95% CI, 1.85-2.54), MI (HR, 1.89; 95% CI, 1.60-2.23), and ESRD (HR, 3.34; 95% CI, 2.89-3.88).

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Source: Margolis, R., Vasu, P., and Dorairaj, S. K. Long-Term Risk of Mortality and Systemic Morbidity in Neovascular Glaucoma: A Multicenter Retrospective Cohort Study. Ophthalmology Glaucoma. 2026; 9(5): 517-526. Published: September-October, 2026. DOI: 10.1016/j.ogla.2026.01.017.

[Posted 10/Sep/2026]

AUDIENCE: Psychiatry, Neurology

KEY FINDINGS: The findings indicate that brain regions associated with improvement in nicotine addiction through TMS and lesions converge on a common functional brain circuit. Rather than relying solely on stimulation of an individual anatomical region, connectivity with this circuit may help guide selection of TMS targets for nicotine addiction. The identified circuit provides a testable framework for future neuromodulation studies. However, the study demonstrates an association between TMS-site connectivity and withdrawal improvement and does not establish that targeting these regions will improve long-term smoking cessation outcomes.

BACKGROUND: Transcranial magnetic stimulation (TMS) is an established neuromodulation approach for smoking cessation, but the optimal brain region to target for nicotine addiction remains uncertain. Previous lesion-mapping research identified a brain circuit associated with remission of nicotine addiction. This study investigated whether TMS sites connected to that lesion-derived circuit were also associated with greater improvement in nicotine withdrawal symptoms.

DETAILS: The study included 72 participants with tobacco use disorder who abstained from smoking for at least 12 hours before TMS assessment. TMS was delivered to four left-hemisphere regions-the dorsolateral prefrontal cortex, superior frontal gyrus, posterior parietal cortex, and visual cortex-across separate sessions, producing a total of 243 stimulation sites.

Nicotine withdrawal was assessed before and after each TMS session using the Shiffman-Jarvik Withdrawal Scale. The investigators used a normative functional-connectivity dataset derived from 1,000 healthy individuals to determine how strongly each stimulation site was connected with the previously identified lesion-based nicotine-addiction remission circuit. They then examined whether this connectivity predicted improvement in withdrawal symptoms.

Greater connectivity between the TMS stimulation site and the lesion-derived addiction-remission circuit was significantly associated with greater improvement in nicotine withdrawal symptoms. The association remained significant after adjustment for sex, baseline nicotine dependence, or both factors simultaneously.

A data-driven TMS circuit associated with withdrawal improvement showed substantial correspondence with the lesion-based remission circuit, with a Pearson correlation of r=-0.74. Combining the lesion and TMS findings identified potential therapeutic targets involving the frontopolar cortex, posterior parietal cortex, lateral temporal lobe, and superior frontal gyrus.

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Source: Khosravani, S., Drew, W., Apostol, M. R., et al. Convergence of TMS Sites and Lesion Locations Associated With Nicotine Addiction Improvement on a Common Brain Circuit.. American Journal of Psychiatry. 2026; 183(9): 646-656. Published: September, 2026. DOI: 10.1176/appi.ajp.20250855.

[Posted 4/Sep/2026]

AUDIENCE: Ob/Gyn, Family Medicine

KEY FINDINGS: In 203 nulliparous women assessed at 35+0 to 36+6 weeks, higher sFlt-1/PlGF ratios were associated with higher OA-PSV ratios, lower OA-PI, and higher MAP. An OA-PSV ratio 0.61 identified women with an sFlt-1/PlGF ratio <38 with 90.5% accuracy at a 15% false-positive rate. The findings suggest that OA Doppler, particularly the PSV ratio, may provide a noninvasive and accessible surrogate for angiogenic imbalance near term. Further validation is needed before OA Doppler can replace biochemical assessment in clinical practice.

BACKGROUND: Angiogenic imbalance, reflected by an elevated soluble fms-like tyrosine kinase-1 to placental growth factor (sFlt-1/PlGF) ratio, is associated with the pathophysiology of pre-eclampsia. Although the sFlt-1/PlGF ratio can help identify angiogenic imbalance, its use may be limited by cost and availability. This study evaluated whether ophthalmic artery (OA) Doppler parameters are associated with the sFlt-1/PlGF ratio and whether OA Doppler could help identify or exclude angiogenic imbalance in near-term pregnancy.

DETAILS: This cross-sectional cohort study was nested within the PE37 randomized controlled trial and included nulliparous women recruited between January 2023 and January 2025. Women underwent sFlt-1/PlGF measurement between 35+0 and 36+6 weeks' gestation. A subsample underwent OA Doppler assessment, including the OA peak systolic velocity (PSV) ratio and pulsatility index (PI), together with measurement of mean arterial pressure (MAP) and mean uterine artery PI. The Doppler operator was blinded to the sFlt-1/PlGF results. The analysis included 203 women, distributed across the lowest, middle, and highest sFlt-1/PlGF ratio tertiles as 62, 71, and 70 women, respectively.

Increasing sFlt-1/PlGF ratio was associated with progressive changes in OA Doppler measurements. The median OA-PSV ratio increased from 0.45 (IQR, 0.39–0.53) in the lowest tertile to 0.48 (IQR, 0.41–0.58) in the middle tertile and 0.59 (IQR, 0.50–0.66) in the highest tertile (adjusted P<0.001). Conversely, median OA-PI decreased from 2.20 (IQR, 1.92–2.61) to 2.13 (IQR, 1.86–2.37) and 1.86 (IQR, 1.60–2.26), respectively (adjusted P=0.031).

MAP also increased across the sFlt-1/PlGF tertiles, from 87.0 (IQR, 82.7–92.0) mmHg to 88.7 (IQR, 83.7–93.7) mmHg and 94.7 (IQR, 89.3–100.0) mmHg (adjusted P<0.001). In contrast, mean uterine artery PI did not demonstrate a significant trend across the sFlt-1/PlGF tertiles.

For identifying an sFlt-1/PlGF ratio <38, an OA-PSV ratio <0.61 correctly identified 90.5% of women at a 15% false-positive rate. The authors therefore identified OA Doppler, particularly the PSV ratio, as a potentially useful surrogate measure for angiogenic imbalance and a promising approach for ruling out abnormal angiogenic status.

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Source: Tinajero, M. F., Faraci, C., Cuenca, M., et al. Ophthalmic artery Doppler as potential surrogate marker of angiogenic imbalance in near-term pregnancy. Ultrasound in Obstetrics & Gynecology. 2026; 68(2):211–219. Published: August, 2026. DOI: 10.1002/uog.70270.