CT indicates computed tomography; ICH, intracerebral hemorrhage; and MRI, magnetic resonance imaging.
Cumulative incidence of delayed post-ICH dementia as percentages of total study population. Rates were computed among all study participants who were free of dementia at 6 months. Number of patients alive and being followed up at each time point is listed at the bottom.
eTable 1. Multivariable Analyses of Risk Factors for Early vs Delayed Dementia Incidence After Intracerebral Hemorrhage, Excluding Patients who Developed Recurrent Intracerebral Hemorrhage During Follow-up
eTable 2. Multivariable Analyses of Factors Associated with Cognitive Decline Rates Before vs After 6 months Post-Intracerebral Hemorrhage
eFigure 1. Overall Study Design
eFigure 2. Incident Dementia Cases During Post-Intracerebral Hemorrhage Follow-up
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Biffi A, Bailey D, Anderson CD, et al. Risk Factors Associated With Early vs Delayed Dementia After Intracerebral Hemorrhage. JAMA Neurol. 2016;73(8):969–976. doi:10.1001/jamaneurol.2016.0955
Patients who have experienced intracerebral hemorrhage (ICH) appear to develop cognitive impairment at high rates, both early after ICH and over the long term.
To identify and compare risk factors for early and delayed dementia after ICH.
Design, Setting, and Participants
A longitudinal study enrolled patients who had experienced ICH from January 1, 2006, to December 31, 2013. A total of 738 participants 18 years or older, without pre-ICH dementia, who presented to a tertiary care academic institution with primary ICH were included in the analyses of early post-ICH dementia (EPID). After accounting for incident dementia and mortality at 6 months, 435 participants were included in the analyses of delayed post-ICH dementia (DPID).
Main Outcomes and Measures
Cognitive performance was captured using the modified Telephone Interview for Cognitive Status test. Outcomes included EPID, diagnosed within 6 months after ICH, and DPID, diagnosed beyond 6 months after ICH.
Among 738 patients who had experienced ICH (mean [SD] age, 74.3 [12.1] years; 384 men [52.0%]), 140 (19.0%) developed dementia within 6 months. A total of 435 patients without dementia at 6 months were followed up longitudinally (median follow-up, 47.4 months; interquartile range, 43.4-52.1 months), with an estimated yearly incidence of dementia of 5.8% (95% CI, 5.1%-7.0%). Larger hematoma size (hazard ratio [HR], 1.47 per 10-mL increase; 95% CI, 1.09-1.97; P < .001 for heterogeneity) and lobar location of ICH (HR, 2.04; 95% CI, 1.06-3.91; P = .02 for heterogeneity) were associated with EPID but not with DPID. Educational level (HR, 0.60; 95% CI, 0.40-0.89; P < .001 for heterogeneity), incident mood symptoms (HR, 1.29; 95% CI, 1.02-1.63; P = .01 for heterogeneity), and white matter disease as defined via computed tomography (HR, 1.70; 95% CI, 1.07-2.71; P = .04 for heterogeneity) were associated with DPID but not EPID.
Conclusions and Relevance
Incident dementia early after ICH is strongly associated with hematoma size and location. Delayed incident dementia is frequent among patients who have experienced ICH and is not prominently associated with acute characteristics of ICH. These findings suggest the existence of heterogeneous biological mechanisms accounting for early vs delayed cognitive decline among patients who have experienced ICH.
Intracerebral hemorrhage (ICH) accounts for 15% of all strokes and approximately 50% of stroke-related mortality and disability worldwide.1,2 Patients who have experienced ICH are at high risk for several negative outcomes, including rebleeding, ischemic stroke, and progressive cognitive impairment. These findings likely reflect the detrimental effect of underlying cerebral small-vessel disease (CSVD), which is presumed to be the etiologic factor responsible for both primary ICH and the associated conditions listed above.3 Patients who have experienced ICH demonstrate a higher prevalence of genetic and neuroimaging markers of underlying CSVD than do the general elderly population.4-6
Although progressive cognitive decline (including incident dementia) is frequent after ICH, we possess limited understanding of its associated risk factors. Prior studies reported high rates of dementia after ICH but were unable to fully describe its predictors.7-10 In particular, the studies did not investigate whether early and delayed dementias after ICH demonstrate comparable or distinct risk factor profiles.
We hypothesized that the extent of central nervous system injury associated with acute hematoma formation would be strongly associated with early post-ICH dementia (EPID) but confer limited risk for delayed post-ICH dementia (DPID). We sought to test this hypothesis in an ongoing longitudinal study enrolling patients who experienced primary ICH by means of 2 separate analyses focused on the risk of developing dementia within 6 months after acute ICH (EPID) and the risk of developing dementia 6 months after acute ICH and beyond (DPID). Risk factors associated with either outcome were tested to clarify whether they conferred risk for cognitive decline only in the early or delayed time frame.
Question Are risk factors for dementia following intracerebral hemorrhage (ICH) different for early vs delayed cognitive impairment?
Findings In this longitudinal study enrolling 738 patients who experienced ICH, 140 developed dementia within 6 months of initial cerebral bleeding, and 139 did so after 6 months. Larger hematoma size and lobar location of ICH were associated with risk of post-ICH dementia within 6 months, whereas educational level, incident mood symptoms, and severity of white matter disease were associated with dementia risk after 6 months.
Meaning Different risk factors are associated with early vs delayed cognitive impairment among patients who have experienced ICH.
To investigate whether risk factors for post-ICH dementia differ based on temporal association with acute bleeding, we designed a 2-stage study format (eFigure 1 in the Supplement), including separate analyses for risk of EPID (onset ≤6 months after ICH) and risk of DPID (onset >6 months after ICH). We restricted the analyses to individuals surviving beyond 3 months after ICH to limit the effect on cognitive status of unrelated medical and neurologic comorbidities leading to early death. We therefore selected the next available follow-up time point in our study (6 months) to separate EPID from DPID. Participants were first included in the analyses of early dementia. Within this group, patients who survived and remained free of dementia at 6 months were then included in the analyses of delayed dementia risk. Visual inspection of incidence rates of dementia supported our study design format by identifying a substantial decrease in cases of incident dementia beyond 6 months from index ICH (eFigure 2 in the Supplement).
Participating individuals were enrolled in an ongoing, single-center, longitudinal cohort study of ICH as previously described.4,11,12 Participants were selected among consecutive patients 18 years or older admitted to Massachusetts General Hospital from January 1, 2006, to December 31, 2013, with primary ICH (ie, not related to trauma, conversion of an ischemic infarct, rupture of a vascular malformation or aneurysm, or a brain tumor) (Figure 1).
All preenrollment data were collected via review of existing medical records and billing information, combined with a structured, standardized in-person interview. As the primary goal of this study was to investigate incident cognitive decline after ICH, all participants diagnosed with dementia before index were excluded. Pre-ICH dementia was identified by administering the 16-item (short) version of the Informant Questionnaire on Cognitive Decline in the Elderly to reliable informants.13 As per reported normative data, any patient with a mean score of more than 3.3 was diagnosed with pre-ICH dementia. In light of known ethnic and racial variations in outcomes after ICH,14 participants were asked at enrollment to self-identify race and ethnicity, choosing from the options recommended for use in research studies by the Office for Management and Budget and the National Institutes of Health. All participants underwent an index ICH admission computed tomography (CT) scan within 24 hours of onset of symptoms.
The study protocol was approved by the Massachusetts General Hospital Institutional Review Board. Written informed consent was obtained from all study participants or their surrogates.
APOE (OMIM 107741) genotype was determined according to previously published methods4,11 for patients who consented to have their blood drawn to determine the number of copies of ε2, ε3, or ε4 alleles. Location of ICH was assigned based on consensus review of results of index ICH CT scans by study staff as previously described.4,11 Computed tomography–defined white matter disease (CT-WMD) was quantified using a previously validated 4-point scale, separately grading severity of anterior and posterior WMD as none or mild (grade 0), moderate (grade 1), or severe (grade 2).4,15,16 Magnetic resonance imaging (MRI) with axial gradient-echo images was performed in a subset of patients within 90 days of onset of symptoms according to previously described methods.4 On available MRI scans, we quantified volume of MRI-defined white matter hyperintensity17 and burden and location (lobar vs nonlobar) of cerebral microbleeds (CMBs).4 All imaging analyses were performed and results recorded by study investigators without knowledge of participants’ clinical and/or genetic information.
Patients who experienced ICH and/or their caregivers were contacted and interviewed by dedicated study staff at 3 and 6 months after index ICH, and every 6 months thereafter, per established protocols.4,11,12 Investigators inquired about and collected medical records pertaining to recurrence of ICH, death, functional status, and medication regimens according to previously published methods.12 Cognitive testing was performed at all follow-up times using the modified Telephone Interview for Cognitive Status (TICS-m),18-22 which is a validated, telephone-based, global cognitive assessment tool that measures overall cognitive performance, with scores ranging from 0 (worst performance) to 39 (best performance).19 We supplemented telephone-based collection of follow-up data with semiautomated review of longitudinal electronic medical records as previously described.4,11,12 Patients who were missing 1 or more cognitive measurement were excluded based on prespecified criteria (Figure 1). Patients’ data were censored in cases of diagnosis of incident dementia, death, or loss to follow-up.
Age at index ICH was analyzed as a continuous variable. Race/ethnicity was analyzed as a categorical variable, with European American patients as the reference group owing to their numerical preponderance. Educational level was dichotomized using a cutoff of 10 or more years of education.4APOE genotype was analyzed using 2 categorical variables indicating presence of any ε2 or ε4 alleles.4 Computed tomography–defined volumes for index ICH (and intraventricular component, if any) were analyzed as continuous variables. Computed tomography–defined WMD was analyzed as an ordinal variable indicating increasing burden.4 Cerebral microbleeds were analyzed using previously used cutoff values of 0, 1, 2 to 4, or 5 or more microbleeds, with separate variables created for lobar and nonlobar CMBs.4 Volumes of MRI-defined white matter hyperintensity were log transformed and analyzed as a continuous variable.17
We defined incident dementia for outcome analyses based on relevant International Classification of Diseases, Ninth Revision (ICD-9) codes entered in electronic medical records and/or TICS-m scores of less than 20 (based on published normative data).21,23 We estimated sensitivity and specificity of dementia diagnosis via ICD-9 codes and TICS-m scores in comparison with clinical evaluation by the attending neurologist (when documented in medical records). We performed secondary analyses investigating the rate of cognitive decline, which was quantified by calculating individual-specific slopes for TICS-m scores over time and analyzed as a continuous variable.
We used a time-to-event analysis framework to identify risk factors associated with post-ICH early vs delayed dementia risk. Separate analyses were conducted to determine the risk of EPID and DPID. Risk factors associated with incident dementia were first assessed in univariable analyses using log-rank tests. All variables with P < .20 for association with incident dementia in univariable analyses were included in multivariable analyses, which used Cox proportional hazards regression models. Medication exposures were treated as time-varying variables in all Cox proportional hazards regression analyses. After variable selection, a minimal model was generated by backward elimination of nonsignificant variables (P > .05). Variables associated with either EPID or DPID risk were included in both multivariable analyses for comparison purposes (even if they failed to achieve P < .05 for association in the parallel analysis). We created multivariable linear regression models to analyze predictors of TICS-m slope as an outcome variable. Variable selection procedures for linear regression models were identical to those for Cox proportional hazards regression analyses. Heterogeneity of effects for association of risk factors with early vs delayed dementia after ICH were evaluated for statistical significance using the metareg function, part of the meta package for the R statistical program (The R Foundation for Statistical Computing).
We addressed multiple testing burden by adopting the false discovery rate method as developed by Benjamini and Hochberg.24 All P values reported are adjusted for multiple testing with the false discovery rate methods. All significance tests were 2-tailed, and significance was set at P < .05 (after false discovery rate adjustment). All analyses were performed with R software, version 3.2.0.
A total of 1141 patients 18 years or older presented to our center and were diagnosed with primary ICH without preexisting dementia during the prespecified enrollment time (Figure 1). Of these, 738 met all eligibility criteria and participated in the analyses of EPID (Table 1). Two hundred ninety-one of the 379 excluded patients (76.8%) were ineligible owing to early death (Figure 1). Overall, 279 patients (37.8%) who experienced ICH in our study developed dementia. We compared accuracy of dementia diagnosis against clinical examination by the attending neurologist in 522 patients (70.7%) with documented cognitive evaluations. Sensitivity and specificity for a diagnosis of dementia based on TICS-m scores and ICD-9 codes were 90% and 94%, respectively, vs in-person evaluation. We observed 55 recurrent ICH events (44 recurrent cases of lobar ICH and 11 cases of deep ICH), for an overall recurrence rate of 5.2% per year. (Recurrence rates are calculated on the basis of the hazard function in time-to-event analysis, which dynamically adjusts the denominator over time to account for study exit.) We repeated all multivariable analyses after removal of recurrent cases of ICH, with no significant difference in results (eTable 1 in the Supplement).
One hundred forty participants (19.0%) developed incident dementia within 6 months of ICH. Among the participants included in these analyses, 397 (53.8%) had available APOE and MRI data for additional analyses (Table 2). Among the 598 participants who did not develop dementia within 6 months of ICH, 435 were alive at 6 months and therefore eligible for analyses of incidence of delayed dementia. Of these patients, 257 (59.1%) had available APOE and MRI data for additional analyses (Table 2). Median longitudinal follow-up duration was 47.4 months (interquartile range, 43.4-52.1 months). Mean censoring owing to loss to follow-up (other than death or incident dementia) was 1.2% per year. We estimated a yearly dementia incidence rate of 5.8% per year (95% CI, 5.1%-7.0%), corresponding to 139 of 435 diagnoses (32.0%) during follow-up. Cumulative rates of delayed incident dementia after ICH are shown in Figure 2. Based on findings reported above, EPID (140 of 279 dementia cases) and DPID (139 of 279 dementia cases) accounted for approximately 50% of diagnoses each.
We initially performed univariable analyses to identify associations between characteristics listed in Table 1 and risk of EPID; the variables selected for further multivariable modeling (univariable P < .20) were age at index ICH, African American ethnicity, ICH location, and ICH volume. Results of multivariable analyses are presented in Table 3 (model 1), with additional risk factors associated with DPID included for comparison. Significant associations with EPID risk included age at index ICH, ICH location, and ICH volume. We repeated univariable and multivariable analyses including APOE and MRI data listed in Table 2 in the smaller group of 397 patients with these data points available. In multivariable analyses (Table 3, model 2), an additional significant association with EPID risk was uncovered for the APOE ε2 variant.
Univariable analyses of DPID risk identified significant associations with age at index ICH, educational level, African American ethnicity, diagnosis of mood disorder, and increasing severity of CT-WMD (all P < .05). All these associations were confirmed in multivariable analysis (Table 3, model 1) (as above, additional risk factors associated with EPID risk are included for comparison purposes only). We separately included APOE and MRI data from 257 patients in univariable and multivariable analyses (Table 3, model 2); in these analyses, we uncovered additional significant associations with DPID risk for increasing burden of lobar CMBs and the APOE ε4 variant.
We formally compared risk factor profiles for EPID vs DPID (Table 3). Among all identified risk factors, ICH volume, lobar ICH location, and the APOE ε2 variant were associated with early incident dementia (P < .05). Conversely, educational level, diagnosis of mood disorder, increasing CT-WMD severity, increasing lobar CMB burden, and the APOE ε4 variant were associated with risk of delayed dementia but not with EPID diagnosis. Of all identified risk factors, only advancing age at index ICH represented a shared risk factor for both EPID and DPID. We performed secondary comparative analyses of cognitive decline rates before vs more than 6 months after ICH (eTable 2 in the Supplement). Volume of ICH and lobar ICH location were associated with the cognitive decline rate before 6 months after ICH, while educational level, diagnosis of mood disorder, and increasing CT-WMD severity were associated with the cognitive decline rate more than 6 months after ICH (all P < .05 for heterogeneity).
We conducted the first comprehensive longitudinal study, to our knowledge, of cognitive impairment after primary ICH, leveraging a large cohort of consecutive cases with in-depth characterization and extended follow-up to demonstrate a high incidence of dementia after primary intraparenchymal hemorrhage. We demonstrated that early and delayed dementias were closely matched in incidence, but there was a significant discrepancy in risk factor profiles between risks for EPID and those for DPID: the former was primarily associated with acute hematoma parameters (location and size), whereas the latter was not. These findings support the hypothesis that different mechanisms underlie cognitive impairment after ICH depending on temporal dynamics.
The rates of dementia after ICH derived from our analyses are substantial, particularly as all dementia diagnoses were incident during follow-up. Removal of the small number of patients experiencing recurrent ICH did not lower the rates of cognitive decline substantially. As mentioned above, far from being a limited occurrence, incident dementia more than 6 months after ICH accounts for half of all cases. These findings are of immediate clinical relevance to health care professionals and patients who have experienced ICH. Assuming replication of our findings in future studies, adequate communication of the risk of cognitive decline (especially beyond the immediate period after ICH) will represent a critical issue for physicians, their patients who have experienced ICH, and patients’ family and caregivers.
Previous studies of cognitive impairment after ICH or hemorrhagic stroke have been limited in their ability to separate the effect on cognitive outcomes of the acute bleeding event vs potential underlying disease processes.7-10 As a result, identified predictors of cognitive performance (other than age) were primarily hematoma size and location. We have confirmed that these variables are strongly associated with risk of EPID, likely reflecting cortical areas or networks directly damaged by acute bleeding. By virtue of our study design (and owing to the study’s large sample size and long follow-up), we were able to demonstrate that risk of DPID has little to no association with the acute bleeding event.
We identified several CSVD-related markers and risk factors (APOE ε4, WMD, and CMBs) associated with risk of DPID. The known association between CSVD and ICH may represent the underlying unifying etiologic factor explaining our results, but we are unable to further address this question in our analyses. We identified opposite association patterns for the ε2 and ε4 variants of the APOE gene. Previous studies showed that the APOE ε2 variant is associated with larger hematoma volume and/or hematoma expansion and thus with worse functional outcome at 3 months.25,26 It seems likely that, having adjusted only for initial hematoma volume in our analyses, the known association with hematoma expansion risk accounts for its association with incidence of EPID. In contrast, the APOE ε4 variant is known to increase amyloid burden in both the brain parenchyma and vasculature and is more likely to exert a long-term effect on cognitive outcome after ICH.27,28
Our study has some limitations. First, most of our cognitive outcome information was obtained using the TICS-m tool for telephone-based cognitive evaluations rather than in-person interviews. The TICS-m, however, has been validated multiple times as a reliable, efficient tool for global cognitive assessment.18-22 Scores from the TICS-m have been shown in multiple prior studies to correlate closely with scores from in-person testing (eg, Mini-Mental State Examination or Montreal Cognitive Assessment) and to diagnose dementia with high sensitivity and specificity.19-22 Only a small percentage of patients who experienced ICH were unable to complete 1 or more TICS-m questionnaires and were therefore excluded or censored. We also observed excellent concordance between TICS-m dementia diagnoses and in-person clinical evaluations. Second, although we detected an association between self-reported African American racial background and cognitive decline after ICH, it is possible that other minority groups also may be at higher risk of cognitive impairment after ICH. However, their inadequate representation in this cohort likely limited power to uncover such associations. Third, because of our follow-up frequency, we had limited ability to capture precise timing of dementia onset, particularly for EPID. Finally, we cannot exclude the possibility that pathologic processes of Alzheimer disease play a role in the observed findings. Indeed, all CSVD-related markers associated with risk of DPID in our analyses have previously been observed in patients with late-onset Alzheimer disease.29-31 Additional studies will be required to better clarify the contribution of late-onset Alzheimer disease to cognitive decline after ICH.
We identified a substantial risk of incident cognitive decline among patients who experienced ICH in the first large, comprehensive longitudinal study on the topic. In the short term, within 6 months of ICH, we confirmed that hematoma location and volume are strongly associated with risk of incident dementia. However, we diagnosed at least half of dementia cases beyond the 6-month mark and demonstrated the existence of a significantly different risk factor profile. This latter group of patients will benefit from additional studies investigating the pathophysiological factors of long-term cognitive decline after ICH.
Accepted for Publication: March 10, 2016.
Corresponding Author: Alessandro Biffi, MD, Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge St, Mailbox CPZN-6818, Boston, MA 02114 (email@example.com).
Published Online: June 13, 2016. doi:10.1001/jamaneurol.2016.0955.
Author Contributions: Dr Biffi had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Biffi, Rosand, Viswanathan.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Biffi, Rosand, Viswanathan.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Biffi.
Obtained funding: Anderson, Greenberg, Rosand, Viswanathan.
Administrative, technical, or material support: Biffi, Bailey.
Study supervision: Biffi, Anderson, Ayres, Gurol, Greenberg, Rosand, Viswanathan.
Conflict of Interest Disclosures: None reported.
Funding/Support: The authors’ work on this study was supported by grants R25NS065743, R01NS063925, R01NS059727, K23NS086873, P50NS051343, and R01AG26484 from the National Institutes of Health.
Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
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