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Parental stroke has been related to an increased risk of stroke in the offspring. This study examines whether parental stroke is also associated with increased vascular brain injury and poorer cognitive performance among offspring free of clinical stroke.
Multivariable regression analyses were used to relate parental stroke to cross-sectional and change in brain magnetic resonance imaging measures and cognitive function among the offspring, with and without adjustment for vascular risk factors.
Stroke- and dementia-free Framingham Offspring (n=1,297, age:61±9 years, 54% women) were studied. Parental stroke by age 65 years was associated with a higher baseline white matter hyperintensity volume (WMHV;β=0.17±0.08; p=0.027), and with lower visual memory performance (β =−0.80±0.34; p=0.017). During a 6 year follow-up, parental stroke was also associated with increase in WMHV (odds ratio [OR] = 1.87;95%CI:1.03–3.38) and decline in executive function (Trails B–A; OR=1.81;95%CI:1.06–3.09). The associations with WMHV and visual memory attenuated after additional adjustment for concomitant vascular risk factors.
Parental stroke by age 65 years is associated with increased vascular brain injury and lower memory in offspring equivalent to 3 and 7 years of brain aging, respectively. This may be partly attributed to inheritance of vascular risk factors.
There is a substantial heritable component to the risk of stroke1 and genes that may play a role in this hereditary propensity have been discovered.2 We have previously shown that documented parental stroke by age 65 years is associated with a significantly increased risk of offspring stroke, and that this association is unlikely to be due to shared environmental factors alone.3 In turn, people with high stroke risk are also more prone to brain injury and cognitive impairment.4 In the current study, we relate prospectively verified parental stroke by age 65 years to volumetric brain magnetic resonance imaging (MRI) measures and cognitive function in middle-aged and older offspring who are free of clinical stroke and dementia, and examine the role of offspring vascular risk factors in mediating these associations.
Framingham Offspring participants, who survived until the seventh examination (1998 – 2001) and attended at least one of the examinations between the fifth and the seventh, were invited to undergo the first cognitive evaluation battery and volumetric brain MRI (1999 – 2005). We selected a subset of tests from the cognitive battery as follows: The delayed recall component of the Logical Memory test (LM-d), the delayed recall component of the Visual Reproductions test (VR-d), the delayed recall component of the Paired Associate Learning test (PAR), the Similarities test (SIM), the difference in the time taken by an individual to complete the Trails B versus the Trails A tasks (TrB-A) (we transformed TrB-A so that higher scores reflected better performance as was true for the other tests) and the Hooper test. The brain MRI measures assessed were total cerebral brain volume (TCBV), the regional brain volume of the hippocampus (HPV) and white matter hyperintensity volume (WMHV). HPV at the second MRI examination was available only in a small subset of participants at this time, therefore change in hippocampal size was approximated using change in temporal horn volume of the lateral ventricles (THV).5
We included only those who were free of dementia and stroke at baseline. A subset of this sample also underwent a second cognitive and brain MRI examination (2005–2007). Data was obtained under a protocol approved by the Institutional Review Board of the Boston University Medical Center and informed consent was obtained from all participants.
Inclusion and exclusion criteria, definition of parental stroke and details of methodology of cognitive testing and brain MRI, are provided in the online-only Data Supplement. The definition of parental stroke was restricted to strokes occurring before the age of 65 years since early occurring strokes are more likely to have a genetic component.6
Multivariable general linear and logistic regression models were used to relate parental stroke status to cognitive performance and MRI phenotypes. For the longitudinal analyses, odds ratios of being in the highest quintile of change were compared for participants with parental stroke versus those without parental stroke (changes in cognitive and MRI measures are listed in table S4). All analyses were adjusted for age, sex and education and in additional separate models, for vascular risk factors and for white matter hyperintensity volume (WMHV), a measure of subclinical vascular injury on brain MRI. The longitudinal analysis was also repeated excluding interval strokes.
Participants with parental stroke (N=128) were less educated and were more likely to have hypertension and diabetes at baseline compared to participants without parental stroke (table 1).
Parental stroke was significantly associated with a higher baseline WMHV and with poorer performance on a test of visual memory (equivalent to 2.8 and 7 years of brain aging, respectively). These associations attenuated and were not significant at p<0.05 after adjusting for vascular risk factors, however the effect size for WMHV diminished only slightly (table 2). Over the follow-up period, there was a greater increase in WMHV among individuals with parental stroke compared to others (table 3). This association also attenuated after additional adjustment for vascular risk factors and after excluding 18 persons who developed interval strokes. In addition, parental history of stroke by age 65 years was associated with a decline in performance on an executive function test (Trails B-A). These results remained significant after adjustment for vascular risk factors (table 3) or excluding interval strokes, but attenuated after including WMHV in the model (table 3). Our findings did not differ by maternal or paternal stroke.
The present study explores, for the first time to our knowledge, the relationship between occurrence of stroke in the parents and measures of brain injury and cognitive performance in the offspring. Our findings show that persons in late middle-age who have at least one parent who suffered a stroke by age 65 years demonstrate subclinical brain injury and cognitive impairment compared to their peers without parental stroke. The associations were independent of age, sex and education, but the associations with WMHV and visual memory could be partly explained by a familial clustering of vascular risk factors and therefore strongly support the use of preventive strategies in persons whose parent had a stroke before the age of 65 years. On the other hand, our data show that the risk of accelerated decline in executive function associated with parental stroke could not be attributed to the familial clustering of vascular risk factors alone, nor to the occurrence of offspring strokes during the follow-up period and hence a hereditary propensity is suggested. This is supported by a previous study in which we have demonstrated a strong relationship between parental occurrence of stroke by age 65 years and an increased risk of incident stroke in the offspring, which was independent of vascular risk factors.3
Previously, large WMHV has been shown to be related specifically to poorer executive function,7 since WMH is most extensive in the frontal lobes and executive function reflects the integrity of the subcortical frontal system. Our observation that WMHV (and not vascular risk factors) mediates the association between parental stroke and decline in executive function suggests that the increase in WMHV in persons with a parental stroke has functional consequences.
Poor performances on memory and executive function tasks and large WMHV have each been associated with both vascular injury and an increased risk of incident AD.8–10 It is possible that the young age of our study sample limited our power to detect differences in other brain MRI and cognitive measures (such as total brain and hippocampal volume and verbal memory performance) that are more specifically associated with AD pathology, particularly since AD is a late-life condition and the changes preceding it might be delayed till the 8th and subsequent decades.11 In addition, the overwhelmingly European origin of the study sample limits the generalizability of our results. We consider this study exploratory requiring validation in other samples, and thus a post-hoc correction for multiple comparisons was not performed. However, the consistent pattern of associations with MRI measures and cognitive tests that have been more often associated with vascular and metabolic stroke risk factors suggests that the observed associations are more likely to be real. The strengths of this study are its population based setting and the prospective verification of parental stroke status. Further, the follow-up study design enabled us to examine both cross-sectional data and longitudinal change.
Overall, our findings imply that a higher burden of vascular risk factors and presumably a greater genetic propensity to vascular brain injury exists among offspring of parents with a history of stroke by age 65 years that in turn, leads to cognitive decline. A history of parental stroke may serve as a simple, clinically useful tool to assess the risk of cognitive impairment.
This work was supported by the dedication of the Framingham Heart Study participants, the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and by grants from the National Institute of Neurological Disorders and Stroke (NS17950), the National Heart, Lung and Blood Association (HL93029, U01HL 096917) and the National Institute of Aging (AG08122, AG16495, AG033193, AG031287, P30AG013846). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke, the National Heart Lung and Blood Institute, the National Institute of Aging or the National Institutes of Health.
Sources of funding: This study was supported by National Institute of Neurological Disorders and Stroke (NS17950), the National Heart, Lung and Blood Association (HL93029, U01HL 096917) and the National Institute of Aging (AG08122, AG16495, AG033193, AG031287, P30AG013846).
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Disclosures: None of the authors has a financial conflict of interest to disclose.