Mayo normative studies: regression-based normative data for ages 30-91 years with a focus on the Boston Naming Test, Trail Making Test and Category Fluency.

OBJECTIVE: Normative neuropsychological data are essential for interpretation of test performance in the context of demographic factors. The Mayo Normative Studies (MNS) aim to provide updated normative data for neuropsychological measures administered in the Mayo Clinic Study of Aging (MCSA), a population-based study of aging that randomly samples residents of Olmsted County, Minnesota, from age- and sex-stratified groups. We examined demographic effects on neuropsychological measures and validated the regression-based norms in comparison to existing normative data developed in a similar sample. METHOD: The MNS includes cognitively unimpaired adults ≥30 years of age (n = 4,428) participating in the MCSA. Multivariable linear regressions were used to determine demographic effects on test performance. Regression-based normative formulas were developed by first converting raw scores to normalized scaled scores and then regressing on age, age2, sex, and education. Total and sex-stratified base rates of low scores (T < 40) were examined in an older adult validation sample and compared with Mayo's Older Americans Normative Studies (MOANS) norms. RESULTS: Independent linear regressions revealed variable patterns of linear and/or quadratic effects of age (r2 = 6-27% variance explained), sex (0-13%), and education (2-10%) across measures. MNS norms improved base rates of low performance in the older adult validation sample overall and in sex-specific patterns relative to MOANS. CONCLUSIONS: Our results demonstrate the need for updated norms that consider complex demographic associations on test performance and that specifically exclude participants with mild cognitive impairment from the normative sample.

Stricker Learning Span criterion validity: a remote self-administered multi-device compatible digital word list memory measure shows similar ability to differentiate amyloid and tau PET-defined biomarker groups as in-person Auditory Verbal Learning Test.

OBJECTIVE: The Stricker Learning Span (SLS) is a computer-adaptive digital word list memory test specifically designed for remote assessment and self-administration on a web-based multi-device platform (Mayo Test Drive). We aimed to establish criterion validity of the SLS by comparing its ability to differentiate biomarker-defined groups to the person-administered Rey's Auditory Verbal Learning Test (AVLT). METHOD: Participants (N = 353; mean age = 71, SD = 11; 93% cognitively unimpaired [CU]) completed the AVLT during an in-person visit, the SLS remotely (within 3 months) and had brain amyloid and tau PET scans available (within 3 years). Overlapping groups were formed for 1) those on the Alzheimer's disease (AD) continuum (amyloid PET positive, A+, n = 125) or not (A-, n = 228), and those with biological AD (amyloid and tau PET positive, A+T+, n = 55) vs no evidence of AD pathology (A-T-, n = 195). Analyses were repeated among CU participants only. RESULTS: The SLS and AVLT showed similar ability to differentiate biomarker-defined groups when comparing AUROCs (p's > .05). In logistic regression models, SLS contributed significantly to predicting biomarker group beyond age, education, and sex, including when limited to CU participants. Medium (A- vs A+) to large (A-T- vs A+T+) unadjusted effect sizes were observed for both SLS and AVLT. Learning and delay variables were similar in terms of ability to separate biomarker groups. CONCLUSIONS: Remotely administered SLS performed similarly to in-person-administered AVLT in its ability to separate biomarker-defined groups, providing evidence of criterion validity. Results suggest the SLS may be sensitive to detecting subtle objective cognitive decline in preclinical AD.

A longitudinal investigation of Aß, anxiety, depression, and mild cognitive impairment.

INTRODUCTION: We investigated the longitudinal relationship between cortical amyloid deposition, anxiety, and depression and the risk of incident mild cognitive impairment (MCI). METHODS: We followed 1440 community-dwelling, cognitively unimpaired individuals aged ≥ 50 years for a median of 5.5 years. Clinical anxiety and depression were assessed using Beck Anxiety and Depression Inventories (BAI, BDI-II). Cortical amyloid beta (Aß) was measured by Pittsburgh compound B positron emission tomography (PiB-PET) and elevated deposition (PiB+) was defined as standardized uptake value ratio ≥ 1.48. We calculated Cox proportional hazards models with age as the time scale, adjusted for sex, education, and medical comorbidity. RESULTS: Cortical Aß deposition (PiB+) independent of anxiety (BAI ≥ 10) or depression (BDI-II ≥ 13) increased the risk of MCI. There was a significant additive interaction between PiB+ and anxiety (joint effect hazard ratio 6.77; 95% confidence interval 3.58-12.79; P = .031) that is, being PiB+ and having anxiety further amplified the risk of MCI. DISCUSSION: Anxiety modified the association between PiB+ and incident MCI.

Brain Regional Glucose Metabolism, Neuropsychiatric Symptoms, and the Risk of Incident Mild Cognitive Impairment: The Mayo Clinic Study of Aging.

OBJECTIVE: The authors conducted a prospective cohort study to examine the risk of incident mild cognitive impairment (MCI) as predicted by baseline neuropsychiatric symptoms (NPS) and brain regional glucose metabolic dysfunction. METHODS: About 1,363 cognitively unimpaired individuals (52.8% males) aged ≥50 years were followed for a median of 4.8 years to the outcome of incident MCI. NPS were assessed using Beck Depression and Anxiety Inventories and Neuropsychiatric Inventory Questionnaire. Glucose hypometabolism was measured by fluorodeoxyglucose positron emission tomography and defined as standardized uptake value ratio ≤ 1.47 in regions typically affected in Alzheimer disease. Cox proportional hazards models were adjusted for age, sex, education, and APOE ε4 status. RESULTS: Participants with regional glucose hypometabolism and depression (Beck Depression Inventory-II ≥13) had a more than threefold increased risk of incident MCI (hazard ratio [95% confidence interval], 3.66 [1.75, 7.65], p <0.001, χ2 = 11.83, degree of freedom [df] = 1) as compared to the reference group (normal regional glucose metabolism and no depression), and the risk was also significantly elevated (7.21 [3.54, 14.7], p <0.001, χ2 = 29.68, df = 1) for participants with glucose hypometabolism and anxiety (Beck Anxiety Inventory ≥10). Having glucose hypometabolism and ≥1 NPS (3.74 [2.40, 5.82], p <0.001, χ2 = 34.13, df = 1) or ≥2 NPS (3.89 [2.20, 6.86], p <0.001, χ2 = 21.92, df = 1) increased the risk of incident MCI by more than three times, and having ≥3 NPS increased the risk by more than four times (4.12 [2.03, 8.37], p <0.001, χ2 = 15.39, df = 1). CONCLUSION: Combined presence of NPS with regional glucose hypometabolism is associated with an increased risk of incident MCI, with fluorodeoxyglucose positron emission tomography appearing to be a stronger driving force of cognitive decline than NPS.

Mayo Normative Studies: Regression-Based Normative Data for the Auditory Verbal Learning Test for Ages 30-91 Years and the Importance of Adjusting for Sex.

OBJECTIVE: Rey's Auditory Verbal Learning Test (AVLT) is a widely used word list memory test. We update normative data to include adjustment for verbal memory performance differences between men and women and illustrate the effect of this sex adjustment and the importance of excluding participants with mild cognitive impairment (MCI) from normative samples. METHOD: This study advances the Mayo's Older Americans Normative Studies (MOANS) by using a new population-based sample through the Mayo Clinic Study of Aging, which randomly samples residents of Olmsted County, Minnesota, from age- and sex-stratified groups. Regression-based normative T-score formulas were derived from 4428 cognitively unimpaired adults aged 30-91 years. Fully adjusted T-scores correct for age, sex, and education. We also derived T-scores that correct for (1) age or (2) age and sex. Test-retest reliability data are provided. RESULTS: From raw score analyses, sex explained a significant amount of variance in performance above and beyond age (8-10%). Applying original age-adjusted MOANS norms to the current sample resulted in significantly fewer-than-expected participants with low delayed recall performance, particularly in women. After application of new T-scores adjusted only for age, even in normative data derived from this sample, these age-adjusted T-scores showed scores <40 T occurred more frequently among men and less frequently among women relative to T-scores that also adjusted for sex. CONCLUSIONS: Our findings highlight the importance of using normative data that adjust for sex with measures of verbal memory and provide new normative data that allow for this adjustment for the AVLT.

Neuropsychiatric symptoms and the outcome of cognitive trajectories in older adults free of dementia: The Mayo Clinic Study of Aging.

OBJECTIVE: Neuropsychiatric symptoms (NPS) are associated with the risk of incident mild cognitive impairment (MCI) and dementia. We examined associations between NPS and the outcomes of global and domain-specific cognitive trajectories. METHODS: In this longitudinal study conducted in the setting of the population-based Mayo Clinic Study of Aging, 5081 community-dwelling, nondemented individuals aged ≥50 years (51% males) underwent NPS assessment using Neuropsychiatric Inventory Questionnaire (NPI-Q), and Beck Depression and Anxiety Inventories (BDI-II, BAI). Global and domain-specific (memory, language, attention, and visuospatial skills) cognitive performance was assessed through neuropsychological testing every 15 months. Associations between baseline NPS and trajectories for individual yearly change in cognitive z-scores were calculated using linear mixed-effect models. RESULTS: Cognition declined regardless of NPS status over the median follow-up of 4.5 years. Presence of NPS was associated with increased cognitive decline. Differences in annualized change in global cognition z-scores for participants with NPS compared to without NPS ranged from -0.018 (95% CI -0.032, -0.004; p = 0.011) for irritability to -0.159 (-0.254, -0.065; p = 0.001) for hallucinations. Associations between NPS and annual decline in global cognition were significant for most NPI-Q-assessed NPS and clinical depression (BDI-II≥13). Participants with NPI-Q-assessed depression, apathy, nighttime behavior, and clinical depression had greater decline in all domain-specific z-scores; presence of delusions and anxiety was associated with more pronounced decline in language, attention and visuospatial skills. CONCLUSION: NPS were associated with a more accelerated cognitive decline. Clinical assessment and potential treatment of NPS is warranted even in a community setting as NPS may impact cognitive decline in nondemented individuals.

Primary central nervous system vasculitis mimicking brain tumor: Comprehensive analysis of 13 cases from a single institutional cohort of 191 cases.

OBJECTIVE: To describe the clinical, laboratory, and imaging features and course of patients with primary central nervous system vasculitis (PCNSV) presenting with an intracranial tumor-like mass (TLM). METHODS: We retrospectively studied a cohort of 191 consecutive patients with PCNSV seen at the Mayo Clinic, Rochester, MN over a 35-year period (1982-2017). 13/191 patients presented with a TLM. We compared the findings in these 13 patients with those from the 178 without this presentation. RESULTS: In 13 of 191 (6.8%) patients with TLM the diagnosis of PCNSV was established by cerebral biopsy. Granulomatous vasculitis was found in 11/13 patients, accompanied by vascular deposits of ß-amyloid peptide in 7. Compared to the 178 patients without TLM, the patients with TLM were more likely to be male (p = 0.04), and less likely to have a transient ischemic attack (p = 0.023), bilateral cerebral infarcts (p = 0.018), or vasculitic lesions on angiography (p = 0.045). They were more likely to have seizures (p = 0.022), gadolinium-enhanced lesions (p = 0.007), and amyloid angiopathy (p = 0.046). All 13 patients responded to therapy and 8/13 (61.5%) had a Rankin disability score of 0 at last visit. Overall, high disability scores (Rankin scores 4-6) at last follow-up were associated with increasing age (odds ratio, OR, 1.49) and cerebral infarction (OR, 3.47), but were less likely in patients with gadolinium-enhanced lesions (OR, 0.36) and amyloid angiopathy (OR, 0.21). CONCLUSION: In PCNSV a TLM at presentation represents a definable subgroup of patients with a favourable treatment response.

Neuroimaging biomarkers and impaired olfaction in cognitively normal individuals.

OBJECTIVE: There is a need for inexpensive noninvasive tests to identify older healthy persons at risk for Alzheimer disease (AD) for enrollment in AD prevention trials. Our objective was to examine whether abnormalities in neuroimaging measures of amyloid and neurodegeneration are correlated with odor identification (OI) in the population-based Mayo Clinic Study of Aging. METHODS: Cognitively normal (CN) participants had olfactory function assessed using the Brief Smell Identification Test (B-SIT), underwent magnetic resonance imaging (n = 829) to assess a composite AD signature cortical thickness and hippocampal volume (HVa), and underwent 11 C-Pittsburgh compound B (n = 306) and 18 fluorodeoxyglucose (n = 305) positron emission tomography scanning to assess amyloid accumulation and brain hypometabolism, respectively. The association of neuroimaging biomarkers with OI was examined using multinomial logistic regression and simple linear regression models adjusted for potential confounders. RESULTS: Among 829 CN participants (mean age = 79.2 years; 51.5% men), 248 (29.9%) were normosmic and 78 (9.4%) had anosmia (B-SIT score < 6). Abnormal AD signature cortical thickness and reduced HVa were associated with decreased OI as a continuous measure (slope = -0.43, 95% confidence interval [CI] = -0.76 to -0.09, p = 0.01 and slope = -0.72, 95% CI = -1.15 to -0.28, p < 0.01, respectively). Reduced HVa, decreased AD signature cortical thickness, and increased amyloid accumulation were significantly associated with increased odds of anosmia. INTERPRETATION: Our findings suggest that OI may be a noninvasive, inexpensive marker for risk stratification, for identifying participants at the preclinical stage of AD who may be at risk for cognitive impairment and eligible for inclusion in AD prevention clinical trials. These cross-sectional findings remain to be validated prospectively. Ann Neurol 2017;81:871-882.

Depressive and anxiety symptoms and cortical amyloid deposition among cognitively normal elderly persons: the Mayo Clinic Study of Aging.

BACKGROUND: Little is known about the association of cortical Aß with depression and anxiety among cognitively normal (CN) elderly persons. METHODS: We conducted a cross-sectional study derived from the population-based Mayo Clinic Study of Aging in Olmsted County, Minnesota; involving CN persons aged ≥ 60 years that underwent PiB-PET scans and completed Beck Depression Inventory-II (BDI-II) and Beck Anxiety Inventory (BAI). Cognitive diagnosis was made by an expert consensus panel. Participants were classified as having abnormal (≥1.4; PiB+) or normal PiB-PET (<1.4; PiB-) using a global cortical to cerebellar ratio. Multi-variable logistic regression analyses were performed to calculate odds ratios (OR) and 95% confidence intervals (95% CI) after adjusting for age and sex. RESULTS: Of 1,038 CN participants (53.1% males), 379 were PiB+. Each one point symptom increase in the BDI (OR = 1.03; 1.00-1.06) and BAI (OR = 1.04; 1.01-1.08) was associated with increased odds of PiB-PET+. The number of participants with BDI > 13 (clinical depression) was greater in the PiB-PET+ than PiB-PET- group but the difference was not significant (OR = 1.42; 0.83-2.43). Similarly, the number of participants with BAI > 10 (clinical anxiety) was greater in the PiB-PET+ than PiB-PET- group but the difference was not significant (OR = 1.77; 0.97-3.22). CONCLUSIONS: As expected, depression and anxiety levels were low in this community-dwelling sample, which likely reduced our statistical power. However, we observed an informative albeit weak association between increased BDI and BAI scores and elevated cortical amyloid deposition. This observation needs to be tested in a longitudinal cohort study.

Influence of amyloid and APOE on cognitive performance in a late middle-aged cohort.

INTRODUCTION: Few studies have examined the effects of amyloid and apolipoprotein E (APOE) genotype on cognition among middle-aged individuals. METHODS: We included 464 cognitively normal, test-naïve, participants with Pittsburgh compound B positron emission tomography amyloid imaging, mean age of 62.7 (range, 51-71 years), enrolled in the Mayo Clinic Study of Aging. Participants completed multiple cognitive assessments, including a standard neuropsychological battery and the CogState computerized battery, over 30 months of follow-up. Linear mixed models were used to examine the effects of amyloid and APOE genotype on baseline cognition and cognitive decline. RESULTS: Elevated amyloid was not associated with tests of episodic memory but did predict declines on tests of executive function. APOE genotype was not associated with cognition. Among APOE ɛ4 noncarriers, higher amyloid was predictive of decline on tests of executive function and on one episodic memory test. DISCUSSION: Elevated amyloidosis and APOE genotype do not appear to exert a dramatic influence on cognition in middle age.

Primary central nervous system vasculitis with intracranial aneurysm.

BACKGROUND: Unruptured intracranial aneurysms (UIAs) are rarely reported in primary central nervous system vasculitis (PCNSV). In this study we described the clinical findings, response to therapy, and outcomes of UIA in a large cohort of PCNSV patients. METHODS: We retrospectively studied 216 consecutive patients with PCNSV, selected by predetermined diagnostic criteria, who were seen during a 40-year period. UIAs were identified on cerebral angiography. The clinical, laboratory, radiologic and pathologic findings, management, and outcomes of patients with UIA were described and compared with those without UIA. RESULTS: 12/216 (5.5 %) PCNSV patients had at least one UIA. Two patients underwent biopsies; one yielded negative results, while the other showed necrotizing vasculitis. Eleven patients had evidence of UIA on angiogram at diagnosis. One patient developed an aneurysm during the follow-up associated with a worsening of vasculitic radiological findings. The most common presenting symptom for PCNSV in the setting of UIA was headache (67 %), followed by persistent neurologic deficit or stroke (50 %). Most patients with UIA presented with multiple cerebral infarcts on MRI (67 %), one patient had subarachnoid hemorrhage, and one left parieto-occipital intracerebral hematoma, both unrelated to the aneurysm. Black blood imaging was performed in 4 patients and 2 showed segmental circumferential mural enhancement involving multiple vessels. Two patients had 2 UIAs, while the other 10 had 1. The most frequent UIA location was internal carotid artery (50 %), followed by anterior cerebral artery (21 %). Ten of the UIAs were < 5 mm in diameter, and 3 were 5-7 mm in diameter; the size was not available for one. All UIAs were unchanged in size and configuration during follow-up (median: 18.5 months; range 1-151 months) and no new aneurysms were detected. Compared to the 204 patients with PCNSV without a UIA, no significant clinical differences were observed, except for a reduced disability at last follow-up (p = 0.038). CONCLUSIONS: UIAs uncommonly occur in PCNSV.

Mayo Normative Studies: Amyloid and Neurodegeneration Negative Normative Data for the Auditory Verbal Learning Test and Sex-Specific Sensitivity to Mild Cognitive Impairment/Dementia.

Background: Conventional normative samples include individuals with undetected Alzheimer's disease neuropathology, lowering test sensitivity for cognitive impairment. Objective: We developed Mayo Normative Studies (MNS) norms limited to individuals without elevated amyloid or neurodegeneration (A-N-) for Rey's Auditory Verbal Learning Test (AVLT). We compared these MNS A-N- norms in female, male, and total samples to conventional MNS norms with varying levels of demographic adjustments. Methods: The A-N- sample included 1,059 Mayo Clinic Study of Aging cognitively unimpaired (CU) participants living in Olmsted County, MN, who are predominantly non-Hispanic White. Using a regression-based approach correcting for age, sex, and education, we derived fully-adjusted T-score formulas for AVLT variables. We validated these A-N- norms in two independent samples of CU (n = 261) and mild cognitive impairment (MCI)/dementia participants (n = 392) > 55 years of age. Results: Variability associated with age decreased by almost half in the A-N- norm sample relative to the conventional norm sample. Fully-adjusted MNS A-N- norms showed approximately 7- 9% higher sensitivity to MCI/dementia compared to fully-adjusted MNS conventional norms for trials 1- 5 total and sum of trials. Among women, sensitivity to MCI/dementia increased with each normative data refinement. In contrast, age-adjusted conventional MNS norms showed greatest sensitivity to MCI/dementia in men. Conclusions: A-N- norms show some benefits over conventional normative approaches to MCI/dementia sensitivity, especially for women. We recommend using these MNS A-N- norms alongside MNS conventional norms. Future work is needed to determine if normative samples that are not well characterized clinically show greater benefit from biomarker-refined approaches.

Probable rapid eye movement sleep behavior disorder increases risk for mild cognitive impairment and Parkinson disease: a population-based study.

OBJECTIVE: Rapid eye movement sleep behavior disorder (RBD) is associated with neurodegenerative disease and particularly with the synucleinopathies. Convenience samples involving subjects with idiopathic RBD have suggested an increased risk of incident mild cognitive impairment (MCI), dementia (usually dementia with Lewy bodies), and Parkinson disease (PD). There are no data on such risks in a population-based sample. METHODS: Cognitively normal subjects aged 70 to 89 years in a population-based study of aging who screened positive for probable RBD using the Mayo Sleep Questionnaire were followed at 15-month intervals. In a Cox proportional hazards model, we measured the risk of developing MCI, dementia, and PD among the exposed (probable RBD [pRBD](+)) and unexposed (pRBD(-)) cohorts. RESULTS: Forty-four subjects with pRBD(+) status at enrollment (median duration of pRBD features was 7.5 years) and 607 pRBD(-) subjects were followed prospectively for a median of 3.8 years. Fourteen of the pRBD(+) subjects developed MCI, and 1 developed PD (15/44 = 34% developed MCI/PD); none developed dementia. After adjustment for age, sex, education, and medical comorbidity, pRBD(+) subjects were at increased risk of MCI/PD (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.3-3.9; p = 0.005). Inclusion of subjects who withdrew from the study produced similar results, as did exclusion of subjects with medication-associated RBD. Duration of pRBD symptoms did not predict the development of MCI/PD (HR, 1.05 per 10 years; 95% CI, 0.84-1.3; p = 0.68). INTERPRETATION: In this population-based cohort study, we observed that pRBD confers a 2.2-fold increased risk of developing MCI/PD over 4 years.

Subtle gait changes in patients with REM sleep behavior disorder.

Many people with rapid eye movement (REM) sleep behavior disorder (RBD) have an underlying synucleinopathy, the most common of which is Lewy body disease. Identifying additional abnormal clinical features may help in identifying those at greater risk of evolving to a more severe syndrome. Because gait disorders are common in the synucleinopathies, early abnormalities in gait in those with RBD could help in identifying those at increased risk of developing overt parkinsonism and/or cognitive impairment. We identified 42 probable RBD subjects and 492 controls using the Mayo Sleep Questionnaire and assessed gait velocity, cadence, and stride dynamics with an automated gait analysis system. Cases and controls were similar in age (79.9 ± 4.7 and 80.1 ± 4.7, P = 0.74), Unified Parkinson's Disease Rating Scale Part III (UPDRS) score (3.3 ± 5.5 and 1.9 ± 4.1, P = 0.21) and Mini-Mental State Examination scores (27.2 ± 1.9 and 27.7 ± 1.6, P = 0.10). A diagnosis of probable RBD was associated with decreased velocity (-7.9 cm/s; 95% confidence interval [CI], -13.8 to -2.0; P < 0.01), cadence (-4.4 steps/min; 95% CI, -7.6 to -1.3; P < 0.01), significantly increased double limb support variability (30%; 95% CI, 6-60; P = 0.01), and greater stride time variability (29%; 95% CI, 2-63; P = 0.03) and swing time variability (46%; 95% CI, 15-84; P < 0.01). Probable RBD is associated with subtle gait changes prior to overt clinical parkinsonism. Diagnosis of probable RBD supplemented by gait analysis may help as a screening tool for disorders of α-synuclein.

Bleeding complications associated with warfarin treatment in ischemic stroke patients with atrial fibrillation: a population-based cohort study.

BACKGROUND: Bleeding events are the major obstacle to the widespread use of warfarin for secondary stroke prevention. Previous studies have not examined the use of risk stratification scores to estimate lifetime bleeding risk associated with warfarin treatment in a population-based setting. The purpose of this study is to determine the lifetime risk of bleeding events in ischemic stroke patients with atrial fibrillation (AF) undergoing warfarin treatment in a population-based cohort and to evaluate the use of bleeding risk scores to identify patients at high risk for lifetime bleeding events. METHODS: The resources of the Rochester Epidemiology Project Medical Linkage System were used to identify acute ischemic stroke patients with AF undergoing warfarin treatment for secondary stroke prevention from 1980 to 1994. Medical information for patients seen at Mayo Clinic and at Olmsted Medical Center was used to retrospectively risk-stratify stroke patients according to bleeding risk scores (including the HAS-BLED and HEMORR2HAGES scores) before warfarin initiation. These scores were reassessed 1 and 5 years later and compared with lifetime bleeding events. RESULTS: One hundred patients (mean age, 79.3 years; 68% women) were studied. Ninety-nine patients were observed until death. Major bleeding events occurred in 41 patients at a median of 19 months after warfarin initiation. Patients with a history of hemorrhage before warfarin treatment were more likely to develop major hemorrhage (15% versus 3%, P = .04). Patients with baseline HAS-BLED scores of 2 or more had a higher lifetime risk of major bleeding events compared with those with scores of 1 or less (53% versus 7%, P < .01), whereas those with HEMORR2HAGES scores of 2 or more had a higher lifetime risk of major bleeding events compared with those with scores of 1 or less (52% versus 16%, P = .03). Patients with an increase in the HAS-BLED and HEMORR2HAGES scores during follow-up had a higher remaining lifetime risk of major bleeding events compared with those with no change. CONCLUSIONS: Our findings indicate high lifetime bleeding risk associated with warfarin treatment for patients with ischemic stroke. Risk stratification scores are useful to identify patients at high risk of developing bleeding complications and should be recalculated at regular intervals to evaluate the bleeding risk in anticoagulated patients with ischemic stroke.

Primary central nervous system vasculitis presenting with intracranial hemorrhage.

OBJECTIVE: To describe a subset of cases in a large retrospectively identified cohort of patients with primary central nervous system vasculitis (PCNSV) who present with intracranial hemorrhage. METHODS: The study consisted of a cohort of 131 consecutive patients with PCNSV who were seen at the Mayo Clinic over a 25-year period from 1983 to 2007. The diagnosis of PCNSV was based on findings of brain or spinal cord biopsy, cerebral angiography, or both. Intracranial hemorrhage at presentation was defined as the presence of intracerebral or subarachnoid hemorrhage on computed tomography or magnetic resonance imaging (MRI) of the brain within 3 months of the date of PCNSV diagnosis. The clinical, laboratory, radiologic, and pathologic findings, therapy, and outcomes in patients presenting with intracranial hemorrhage were compared with those without intracranial hemorrhage. RESULTS: Sixteen patients (12.2%) had evidence of intracranial hemorrhage at or near the time of diagnosis. Twelve patients had intracerebral hemorrhage, and 4 had subarachnoid hemorrhage. Twelve patients were diagnosed by findings on angiography and 4 by findings on CNS biopsy. Compared with the 115 patients without intracranial hemorrhage, the 16 patients presenting with intracranial hemorrhage were more frequently women, less frequently had altered cognition, a persistent neurologic deficit, or stroke at presentation, less frequently had MRI evidence of cerebral infarctions, and less frequently needed therapy at last followup. A necrotizing histopathologic pattern of vasculitis was observed in 3 of the 4 patients with positive biopsy findings (75%). CONCLUSION: Our findings suggest that intracranial hemorrhage may not be an infrequent occurrence in early PCNSV. Necrotizing vasculitis may be a predominant histopathologic pattern.

Mayo normative studies: A conditional normative model for longitudinal change on the Auditory Verbal Learning Test and preliminary validation in preclinical Alzheimer's disease.

Introduction: The aim of this study was to develop a conditional normative model for Rey's Auditory Verbal Learning Test (AVLT) that accounts for practice effects. Methods: In our normative sample, robust conditional norms were derived from 1001 cognitively unimpaired (CU) adults ages 50 to 89 who completed the AVLT up to eight times. Linear mixed-effects models adjusted for baseline performance, prior test exposures, time, demographics, and interaction terms. In our preliminary validation, mean performance on conditional and typical normative scores across two to four completed follow-up tests in preclinical Alzheimer's disease participants at baseline with positive amyloid and tau positron emission (n = 27 CU amyloid [A]+tau[T]+) was compared to biomarker negative individuals (n = 269 CU A-T-). Results: AVLT performance using typical norms did not differ across A+T+ and A-T- groups. Conditional norms z-scores were lower in the A+T+ relative to the A-T- group for 30-minute recall (P = .033) and sum of trials (P = .030). Discussion: Conditional normative methods that account for practice effects show promise for identifying longitudinal cognitive decline.

Incidence and predictors of myocardial infarction after transient ischemic attack: a population-based study.

BACKGROUND AND PURPOSE: Coronary artery disease is the leading cause of death after TIA. Reliable estimates of the risk of MI after TIA, however, are lacking. METHODS: Our purpose was to determine the incidence of and risk factors for MI after TIA. We cross-referenced preexisting incidence cohorts from the Rochester Epidemiology Project for TIA (1985-1994) and MI (1979-2006) to identify all community residents with incident MI after incident TIA. Incidence of MI after TIA was determined using Kaplan-Meier life-table methods. This was compared to the age-, sex-, and period-specific MI incidences in the general population. Proportional hazards regression analysis was used to examine associations between clinical variables and the occurrence of MI after TIA. RESULTS: Average annual incidence of MI after TIA was 0.95%. Relative risk for incident MI in the TIA cohort compared to the general population was 2.09 (95% CI, 1.52-2.81). This was highest in patients younger than 60 years old (relative risk, 15.1; 95% CI, 4.11-38.6). Increasing age (hazard ratio, 1.51 per 10 years; 95% CI, 1.14-2.01), male sex (hazard ratio, 2.19; 95% CI, 1.18-4.06), and the use of lipid-lowering therapy at the time of TIA (hazard ratio, 3.10; 95% CI, 1.20-8.00) were independent risk factors for MI after TIA. CONCLUSIONS: Average annual incidence of MI after TIA is ≈1%, approximately double that of the general population. The relative risk increase is especially high in patients younger than 60 years old. These data are useful for identifying subgroups of patients with TIA at highest risk for subsequent MI.

Rapidly progressive primary central nervous system vasculitis.

OBJECTIVE: To describe a subset of cases in a large cohort of patients with primary CNS vasculitis (PCNSV) who appear to have a rapidly progressive clinical course. METHOD: In the present study, we use our updated cohort of 131 consecutive patients with PCNSV seen over the 25-year period of 1983-2007 at Mayo Clinic, Rochester, MN, USA. The diagnosis of PCNSV was based on brain/spinal cord biopsy or cerebral angiography. The modified Rankin scale was used to identify rapidly progressive disease and included patients with Rankin scores indicating severe disability or death at diagnosis or within 6 months after the diagnosis. We compared patients with rapidly progressive disease to those without. RESULTS: Compared with the 120 patients without rapidly progressive vasculitis, the 11 patients with rapidly progressive vasculitis more frequently had paraparesis/quadriparesis at presentation, angiographic presence of bilateral, large-vessel vasculitis and MRI evidence of cerebral infarctions; those infarctions were more frequently multiple and bilateral, and more frequently involved both the cortex and subcortical regions on initial MRI. Granulomatous and/or necrotizing histopathological patterns of vasculitis were observed in patients with positive biopsies. CONCLUSION: Rapidly progressive PCNSV appears to form a subset of PCNSV at the worst end of the clinical spectrum of this vasculitis, characterized by bilateral, multiple, large cerebral vessel lesions and multiple CNS infarctions.