Stroke Severity, Recurrence Increase Dementia Risk

Stroke raises a person’s likelihood of developing dementia. Does a severe stroke or having multiple strokes further increase risk? Yes, according to researchers led by Silvia Koton and Josef Coresh, Johns Hopkins University, Baltimore, and Rebecca Gottesman of the National Institute of Neurological Disorders and Stroke, Bethesda, Maryland. In the January 24 JAMA Neurology, they reported that dementia risk rose 1.7-fold after one mild ischemic stroke and tripled after one major or multiple minor strokes. People’s risk jumped nearly sevenfold if they had several major strokes. This is one of the first studies assessing the effect of stroke recurrence on the risk of dementia.

  • One minor-to-mild stroke increased dementia risk 1.8-fold.
  • Risk jumped 3.5 times higher after a moderate-to-severe stroke.
  • All increases were independent of vascular risk factors.

“The data on stroke recurrence is important because it is rare and hard to capture,” Jason Hinman, University of California, Los Angeles, told Alzforum. Martin Dichgans, Ludwig-Maximilians University, Munich, agreed and noted that these findings reinforce the importance of vascular brain health on dementia. “Vascular pathology contributes to at least 40 percent of dementia cases, so stroke prevention is dementia prevention,” he told Alzforum (Hachinski et al., 2019). 

A person’s risk for dementia rises up to fourfold after stroke (De Ronchi et al., 2007). However, data on how the severity or number of strokes affect dementia risk remain scarce.

To investigate, first author Koton, now at Tel Aviv University, analyzed medical records from 15,379 adults in the Atherosclerosis Risk in Communities study when she was at JHU. The mean age at baseline was 54 years. One-quarter were black, and 55 percent were women. Over an average of 25.5 years, 1,155 participants had an ischemic stroke, and 182 had at least one more. The severity of 999 strokes were classified using the National Institutes of Health Stroke Scale, which assesses the patient’s consciousness, language, and visual and motor function. Of the rated strokes, 647 and 208 were minor and mild, respectively, with only 73 being moderate, and 71 severe.

ARIC researchers diagnosed 2,860 participants with dementia using in-person and telephone memory tests, caregiver interviews, hospitalization records, or death certificates. Because stroke can also affect cognition for months afterwards, Koton only used data from the 269 participants who were diagnosed with dementia at least one year after they had a stroke. Of those, 52 had multiple strokes. Only 234 were NIHSS rated, classifying 165 and 45 as minor or mild, respectively, with just 17 as moderate, and seven as severe.

While stroke-free participants reached an average age of 90 before developing dementia, one minor to mild stroke brought on dementia an average of nine years sooner, and a moderate to severe stroke hastened diagnosis by 16 years (see image below).

Stroke and Dementia. Compared to healthy individuals (black line), people who had a minor to mild stroke (yellow line) or moderate to severe stroke (blue line) developed dementia sooner. [Courtesy of Koton et al., JAMA Neurology, 2022.]

The scientists adjusted dementia risk for sociodemographics, APOE genotype, baseline global cognition, and vascular risk factors, including blood pressure, total cholesterol, and body mass index. They also adjusted for changes in smoking habits, diabetes, atrial fibrillation, and antihypertension drug use over time. This helped account for the dramatic improvements in public health and medications for hypertension and diabetes that could have contributed to lower stroke risk over the decades of the study, noted Sandra Black, University of Toronto.

Despite these corrections, Lawrence Honig, Columbia University, New York, was not convinced the link between strokes and dementia is causative. He noted the significant demographic and risk factor differences between the healthy and stroke groups, and how very early stages of dementia may have gone undiagnosed before the strokes happened. “The demonstration of graded responses of stroke numbers or stroke severity to ‘risk of dementia’ does not obviate the reasonable hypothesis that it is not the stroke(s) but rather the underlying status of these individuals that is responsible for the apparent dementia risk,” Honig wrote to Alzforum (full comment below).

Still, dementia risk rose 1.7-fold after a minor to mild stroke and 3.5-fold after a moderate to severe one. This agrees with data from the community-based Oxford Vascular Study in the U.K., suggesting people who had had a severe stroke were four times likelier to be diagnosed with dementia than those who had a minor one (Pendlebury et al., 2019). 

Notably, black participants had a significantly higher risk of dementia after a moderate to severe stroke than their white counterparts. Deborah Levine, University of Michigan, Ann Arbor, thought that this heightened potency needs to be better understood, but praised the findings as robust and generalizable because the researchers accounted for pre-stroke cognition and included a diverse population (full comment below).

What about people who had multiple strokes? Compared to healthy participants, those who had two or more minor or mild strokes were 3.5 times likelier to be diagnosed with dementia, whereas those who had multiple major strokes had a whopping 6.7-fold higher risk. “The additive effect of recurrent strokes is concerning,” Hinman said. He wondered whether it is due only to structural damage from the stroke, or if that synergizes with amyloid and tau pathology.

Gottesman and colleagues aim to answer this with the Determinants of Incident Stroke Cognitive Outcomes and Vascular Effects on Recovery (DISCOVERY) study. In older adults hospitalized with stroke, the researchers will collect structural MRIs, amyloid and tau PET scans, and fluid biomarkers to track dementia-related changes that occur post-stroke.—Chelsea Weidman Burke

Comments

    • User Profile Image Lawrence Honig
      Columbia University College of Physicians & Surgeons
    • Posted:

    This paper examines the risk of dementia from strokes in the large epidemiologic ARIC study of ~15,000 individuals. It is generally appreciated that stroke and degenerative dementia can provide additive injury to the brain. This paper purports to show increased risk of dementia after stroke(s) “independent of risk factors,” but it does not address the nature of this additivity.

    Particular limitations of this study are: (a) the diagnosis of dementia was made by various fashions, including by telephone interviews and chart and billing code reviews, and there are no biomarkers; (b) the timing of the dementia state is often unclear—i.e., there may have been MCI or mild dementia before stroke, and development of more frank dementia, unsurprisingly, after stroke; (c) the stroke and non-stroke populations differed markedly in a number of ways, including gender, ethnicity, education, tobacco use, BMI, hypertension, diabetes, and hyperlipidemia.

    As in any epidemiologic study, the question is whether the statistical adjustment for these marked confounds is enough to be able to conclude that the dementia was independent of underlying variables that might predispose to both stroke and dementia (including unmentioned variables such as diet, drug use, alcohol use, occupation, or genetics). The demonstration of graded responses of stroke numbers or stroke severity to “risk of dementia” does not obviate the reasonable hypothesis that it is not the “stroke(s)” but rather the underlying status in these individuals that is responsible for the apparent dementia risk.

    No data is provided on the characteristics of the persons with dementia without stroke vs. dementia with stroke (e.g., APOE, test scores, method of dementia diagnosis). The data of this paper contribute to the large body of evidence that having strokes is unfavorable to brain function. And in a similar vein, while all would agree that stroke prevention is a worthy aim, this association data, at its best, does not allow the conclusion that preventing strokes, per se, would affect incidence of dementia.

    View all comments by Lawrence Honig

  2. The main takeaway message of Dr. Koton’s rigorous study is that stroke doubles your risk of dementia. The findings suggest that preventing stroke by controlling vascular risk factors, such as high blood pressure, and maintaining healthy lifestyles is a potential strategy for reducing dementia risk. The results also suggest that clinicians should monitor stroke survivors closely for cognitive decline and dementia over the years after the stroke event.

    One surprise of the study is that vascular risk factors before and after stroke did not explain the risk of post-stroke dementia. One hypothesis is that shared risk factors between stroke and dementia contribute to post-stroke dementia. Another surprise is that black adults had a higher risk of dementia after moderate to severe stroke than did white adults. Black adults have a higher stroke risk than white adults. So, we need to understand better why a stroke is a more potent cause of dementia in black adults.

    Many previous studies of post-stroke dementia risk had mostly white populations and did not control for pre-stroke cognition. Dr. Koton's study findings are robust and generalizable because the study included black and white adults and accounted for pre-stroke cognition.

    View all comments by Deborah Levine

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References

Paper Citations

  1. Hachinski V, Einhäupl K, Ganten D, Alladi S, Brayne C, Stephan BC, Sweeney MD, Zlokovic B, Iturria-Medina Y, Iadecola C, Nishimura N, Schaffer CB, Whitehead SN, Black SE, Østergaard L, Wardlaw J, Greenberg S, Friberg L, Norrving B, Rowe B, Joanette Y, Hacke W, Kuller L, Dichgans M, Endres M, Khachaturian ZS. Preventing dementia by preventing stroke: The Berlin Manifesto. Alzheimers Dement. 2019 Jul;15(7):961-984. PubMed.
  2. De Ronchi D, Palmer K, Pioggiosi P, Atti AR, Berardi D, Ferrari B, Dalmonte E, Fratiglioni L. The combined effect of age, education, and stroke on dementia and cognitive impairment no dementia in the elderly. Dement Geriatr Cogn Disord. 2007;24(4):266-73. Epub 2007 Aug 14 PubMed.
  3. Pendlebury ST, Rothwell PM, Oxford Vascular Study. Incidence and prevalence of dementia associated with transient ischaemic attack and stroke: analysis of the population-based Oxford Vascular Study. Lancet Neurol. 2019 Mar;18(3):248-258. Epub 2019 Feb 12 PubMed.

External Citations

  1. Atherosclerosis Risk in Communities
  2. National Institutes of Health Stroke Scale
  3. Determinants of Incident Stroke Cognitive Outcomes and Vascular Effects on Recovery

Further Reading

Papers

  1. Mijajlović MD, Pavlović A, Brainin M, Heiss WD, Quinn TJ, Ihle-Hansen HB, Hermann DM, Assayag EB, Richard E, Thiel A, Kliper E, Shin YI, Kim YH, Choi S, Jung S, Lee YB, Sinanović O, Levine DA, Schlesinger I, Mead G, Milošević V, Leys D, Hagberg G, Ursin MH, Teuschl Y, Prokopenko S, Mozheyko E, Bezdenezhnykh A, Matz K, Aleksić V, Muresanu D, Korczyn AD, Bornstein NM. Post-stroke dementia - a comprehensive review. BMC Med. 2017 Jan 18;15(1):11. PubMed.
  2. Levine DA, Galecki AT, Langa KM, Unverzagt FW, Kabeto MU, Giordani B, Wadley VG. Trajectory of Cognitive Decline After Incident Stroke. JAMA. 2015 Jul 7;314(1):41-51. PubMed.

Primary Papers

  1. Koton S, Pike JR, Johansen M, Knopman DS, Lakshminarayan K, Mosley T, Patole S, Rosamond WD, Schneider AL, Sharrett AR, Wruck L, Coresh J, Gottesman RF. Association of Ischemic Stroke Incidence, Severity, and Recurrence With Dementia in the Atherosclerosis Risk in Communities Cohort Study. JAMA Neurol. 2022 Mar 1;79(3):271-280. PubMed.

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