Smaller Brain Volume, Greater WMH Lead to Cognitive Decline After Intracerebral Hemorrhage

Smaller brain volume and greater white matter hyperintensity (WMH) volumes, which indicate vascular damage, are strongly associated with poor cognitive function after intracerebral hemorrhage.1

These data, a substudy of the Triple Therapy Prevention of Recurrent Intracerebral Disease EveNts Trial (TRIDENT), were presented at the World Stroke Congress (WSC) 2026 in Seoul, South Korea, by Katie Harris, PhD, a senior research fellow in the professorial unit at the George Institute for Global Health.1

“Of course, when someone’s survived an ICH, they have to consider physical recovery and potential disabilities, which are clearly very important, as well as the concern of a recurrent stroke,” Harris told HCPLive in an exclusive interview. “But now, we need to look further ahead, maybe 5, 10 years post-ICH, and see whether cognitive impairment and ultimately dementia may occur.”

The original TRIDENT study was a multinational, double-blind, randomized, placebo-controlled trial evaluating the effects of blood pressure reduction on patients with a history of intracerebral hemorrhage. Patients were eligible for inclusion if they had a systolic blood pressure (SBP) of 130-160 mmHg at baseline and were in clinically stable condition. After a 2-week active run-in phase in which patients were given a once-daily pill of 3 antihypertensive agents at low doses (namely telmisartan 20 mg, amlodipine 2.5 mg, and indapamide 1.25 mg), these patients were randomly assigned to either continue with the triple pill or move to matching placebo.2

A total of 1670 patients were enrolled in the TRIDENT study, of whom 833 were assigned to the triple pill and 837 to placebo. At a median follow-up of 2.5 years, 38 patients in the treatment arm and 62 in the placebo arm saw recurrent strokes (HR, 0.61; 95% CI, 0.41-0.92; P = .02). Mean SBP was 127 mmHg and 138 mmHg during follow-up, respectively, and serious adverse events occurred in 23.2% of patients in the treatment arm and 26% in the placebo arm.2

Harris and colleagues conducted the present substudy at either the penultimate or final study visit. Cognitive function was assessed at regular intervals in the study using the Montreal Cognitive Assessment (MoCA), and the primary MRI marker was WMH, the volume and number of whole-brain T2 lesions. The team modeled associations of WMH and whole brain volume on end of study MoCA and dementia using linear and logistic regression models, respectively, adjusted for randomized treatment, country, baseline age, baseline SBP, and follow-up duration.1

A total of 714 patients participated in the MRI substudy and had good quality MRI measures and end-of-study cognitive assessment. Among these patients, Harris and colleagues saw that larger volumes of WMH were associated with poorer cognition via lower MoCA score (P <.0001). However, the team also noted that the number of T2 lesions was not associated with cognition based on their analyses (P = .71). Smaller brain volumes were also associated with poorer cognition (P <.0001). For each standard deviation increase in brain volume, the team found a 51% lower risk of dementia (odds ratio, 0.49; 95% CI, 0.31-0.79; P = .003).1

Ultimately, Harris and colleagues concluded that, as existing literature suggests, these results support the role of vascular pathology as a central contributor and driver of cognitive impairments following ICH.1

“Blood pressure management is an important factor for stroke prevention and recurrent stroke prevention, so that’s obviously a key target,” Harris said. “But so are all of the major risk factors, such as smoking, diet, physical activity, managing diabetes and cholesterol measures. So, we need a very holistic approach, with blood pressure of course being an important primary factor as well.”

Editors’ Note: Harris reports no relevant disclosures.

References

1. Harris K. Role of Cerebral Small Vessel Disease in Cognitive Decline After Intracerebral Hemorrhage: TRIDENT MRI Substudy. Presented at the World Stroke Congress (WSC) 2026, Seoul, South Korea. October 21-23, 2026.

2. Anderson C, Chow C, de Silva A, et al. Three low-dose antihypertensive agents in a single pill after intracerebral hemorrhage. NEJM. 2026;394(16):1571-1582. doi:10.1056/nejmoa2515043