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.

Long-term remission, relapses and maintenance therapy in adult primary central nervous system vasculitis: A single-center 35-year experience.

OBJECTIVES: To evaluate long-term treatment and outcomes of patients with primary central nervous system vasculitis (PCNSV). METHODS: In this cohort of 191 consecutive patients with PCNSV seen at Mayo Clinic, Rochester, MN, over 35 years with long-term follow-up we analyzed response to and duration of therapy, frequency of relapses, long-term remission, efficacy of maintenance therapy and initial intravenous glucocorticoid (GC) pulses, survival and degree of disability. We also compared the efficacy of initial IV and oral cyclophosphamide (CYC). RESULTS: A favorable initial response was observed in 83% of patients treated with prednisone (PDN) alone, 81% of those treated with PDN and CYC and 95% of those initially treated with PDN and an immunosuppressant other than CYC. One or more relapses were observed in 30% of patients, 35% had discontinued therapy by last follow-up, and 21.5% maintained remission for at least 12 months after discontinuing therapy. Maintenance therapy was prescribed in 19% of all patients and 34% of patients initially treated with CYC and PDN. High disability scores (Rankin 4-6) and deaths were less frequently observed in patients receiving maintenance therapy and more frequently in patients with Aß-related angiitis. Large vessel involvement and cerebral infarction at diagnosis were associated with a poor treatment response. Aspirin use was positively associated with long-term remission and having gadolinium-enhanced cerebral lesions or meninges was negatively associated. A high disability score at last follow-up and higher mortality rate were associated with increasing age, cerebral infarction and cognitive dysfunction at diagnosis. Lymphocytic vasculitis on biopsy was associated with a more benign course with reduced disability and mortality. Patients initially treated with mycophenolate mofetil had better outcomes compared to those treated with CYC and PDN. No therapeutic advantages were observed in the patients initially treated with intravenous GC pulses. Intravenous and oral CYC were equally effective in inducing the remission. CONCLUSIONS: The majority of patients with PCNSV responded to treatment. We found patient subsets with different outcomes. Mycophenolate mofetil may be an effective alternative to CYC.

Rituximab therapy for primary central nervous system vasculitis: A 6 patient experience and review of the literature.

OBJECTIVES: To assess the efficacy and safety of Rituximab (RTX) in adult primary central nervous system vasculitis (PCNSV). METHODS: We retrospectively assessed the effect of RTX in 6 patients with PCNSV. Five of the 6 were refractory to high dose glucocorticoids (GCs) and/or conventional immunosuppressants (IS). The sixth was newly diagnosed and received RTX in combination with GCs. Clinical evaluation, laboratory tests, and imaging modalities were performed at initial RTX administration and during the follow-up. Treatment response was assessed using the treating physician's global opinion regarding response and the degree of disability using the modified Rankin scale (mRS). We also performed a literature review for previous use of RTX in PCNSV using PubMed, Ovid Medline, and the Cochrane library. RESULTS: The six patients (3 females) had a median age at diagnosis of 50.5 years (range 17-68 years). All had active disease when RTX was started. In 4 patients, RTX administration was associated with a marked reduction in the number of flares (from 18 before starting RTX to 3 after). One patient, after an initial improvement, had 2 flares when B cells were depleted and he was not able to reduce prednisone below 20 mg/day. A 6th patient had a flare when B cells recovered and retreatment with RTX re-induced and maintained remission. The median mRS score at last visit (median: 2; range 0-4) was lower than that prior to treatment (median 3; range 1-5). The median prednisone daily dose before RTX administration was significantly higher than that at last follow-up (p = .006). In the literature review, we identified 5 papers describing 7 patients treated with RTX. Six patients responded to RTX with clinical and MRI improvement with no reported flares after RTX treatment. CONCLUSIONS: Our data support a potential role for RTX treatment in selected patients with PCNSV.

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.

Primary central nervous system vasculitis associated with lymphoma.

OBJECTIVES: To record the clinical findings, response to therapy, and course of patients with primary CNS vasculitis (PCNSV) associated with lymphoma. PATIENTS AND METHODS: We reviewed the histories of 936 patients with a diagnosis of any type of vasculitis and lymphoma who were seen at the Mayo Clinic over a 32-year period. Ten patients with both PCNSV and lymphoma were identified. We compared the findings in these 10 patients with those from 158 patients with PCNSV without lymphoma seen over 29 years. RESULTS: Ten of a total of 168 (5.9%) patients with PCNSV also had a history of lymphoma: 6 with Hodgkin lymphoma (HL) and 4 with non-HL (NHL). A granulomatous vasculitis was found in all 8 patients with cerebral biopsies, accompanied by vascular deposits of ß-amyloid peptide in 2. In 7 patients, medical diagnostic workup for PCNSV revealed the lymphoma. Compared to the 158 patients with PCNSV without lymphoma, patients with lymphoma were more frequently male (p = 0.04), had increased gadolinium leptomeningeal enhancement (p = 0.03) at presentation, and had more neurologic disability at last follow-up (p = 0.01). No significant differences in treatment response were observed in the 2 groups (p = 0.202). Considering all 168 patients, increased disability at last follow-up was associated with increasing age at diagnosis (odds ratio [OR] 1.4), lymphoma (OR 5.9), and cerebral infarction (OR 3.2), while reduced disability was associated with gadolinium-enhanced lesions (OR 0.43) and amyloid angiopathy (OR O.23). CONCLUSIONS: Lymphoma may be diagnosed simultaneously with PCNSV, suggesting an immunologic paraneoplastic mechanism.

Phenoconversion from probable rapid eye movement sleep behavior disorder to mild cognitive impairment to dementia in a population-based sample.

INTRODUCTION: Rapid eye movement sleep behavior disorder (RBD) is strongly associated with synucleinopathies. In 2012, we reported an increased risk of mild cognitive impairment (MCI) and Parkinson disease (PD) in cognitively normal Olmsted County, Minnesota, residents, aged 70 to 89 years with probable RBD. Here, we examine their progression to dementia and other neurodegenerative phenotypes. METHODS: Fifteen participants with RBD who were diagnosed with either MCI or PD were longitudinally followed, and their subsequent clinical courses were reviewed. RESULTS: Over 6.4 ± 2.9 years, six of the 14 participants with MCI developed additional neurodegenerative signs, five of whom had Lewy body disease features. Four of them progressed to dementia at a mean age 84.8 ± 4.9 years, three of whom met the criteria for probable dementia with Lewy bodies. One subject with PD developed MCI, but not dementia. DISCUSSION: Our findings from the population-based sample of Olmsted County, Minnesota, residents suggest that a substantial number of RBD patients tend to develop overt synucleinopathy features over time, and RBD patients who develop MCI and subsequent dementia have clinical features most consistent with dementia with Lewy bodies.

Association Between Mentally Stimulating Activities in Late Life and the Outcome of Incident Mild Cognitive Impairment, With an Analysis of the APOE ε4 Genotype.

Importance: Cross-sectional associations between engagement in mentally stimulating activities and decreased odds of having mild cognitive impairment (MCI) or Alzheimer disease have been reported. However, little is known about the longitudinal outcome of incident MCI as predicted by late-life (aged ≥70 years) mentally stimulating activities. Objectives: To test the hypothesis of an association between mentally stimulating activities in late life and the risk of incident MCI and to evaluate the influence of the apolipoprotein E (APOE) ε4 genotype. Design, Setting, and Participants: This investigation was a prospective, population-based cohort study of participants in the Mayo Clinic Study of Aging in Olmsted County, Minnesota. Participants 70 years or older who were cognitively normal at baseline were followed up to the outcome of incident MCI. The study dates were April 2006 to June 2016. Main Outcomes and Measures: At baseline, participants provided information about mentally stimulating activities within 1 year before enrollment into the study. Neurocognitive assessment was conducted at baseline, with evaluations at 15-month intervals. Cognitive diagnosis was made by an expert consensus panel based on published criteria. Hazard ratios (HRs) and 95% CIs were calculated using Cox proportional hazards regression models after adjusting for sex, age, and educational level. Results: The final cohort consisted of 1929 cognitively normal persons (median age at baseline, 77 years [interquartile range, 74-82 years]; 50.4% [n = 973] female) who were followed up to the outcome of incident MCI. During a median follow-up period of 4.0 years, it was observed that playing games (HR, 0.78; 95% CI, 0.65-0.95) and engaging in craft activities (HR, 0.72; 95% CI, 0.57-0.90), computer use (HR, 0.70; 95% CI, 0.57-0.85), and social activities (HR, 0.77; 95% CI, 0.63-0.94) were associated with a decreased risk of incident MCI. In a stratified analysis by APOE ε4 carrier status, the data point toward the lowest risk of incident MCI for APOE ɛ4 noncarriers who engage in mentally stimulating activities (eg, computer use: HR, 0.73; 95% CI, 0.58-0.92) and toward the highest risk of incident MCI for APOE ɛ4 carriers who do not engage in mentally stimulating activities (eg, no computer use: HR, 1.74; 95% CI, 1.33-2.27). Conclusions and Relevance: Cognitively normal elderly individuals who engage in specific mentally stimulating activities even in late life have a decreased risk of incident MCI. The associations may vary by APOE ε4 carrier status.

Timing of Physical Activity, Apolipoprotein E ε4 Genotype, and Risk of Incident Mild Cognitive Impairment.

OBJECTIVES: To investigate the timing (mid- vs late life) of physical activity, apolipoprotein (APO)E ε4, and risk of incident mild cognitive impairment (MCI). DESIGN: Prospective cohort study. SETTING: Mayo Clinic Study of Aging (Olmsted County, MN). PARTICIPANTS: Cognitively normal elderly adults (N = 1,830, median age 78, 50.2% female). MEASUREMENTS: Light, moderate, and vigorous physical activities in mid- and late life were assessed using a validated questionnaire. An expert consensus panel measured MCI based on published criteria. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) with age as a time scale after adjusting for sex, education, medical comorbidity, and depression. RESULTS: Light (HR = 0.58, 95% CI = 0.43-0.79) and vigorous (HR = 0.78, 95% CI = 0.63-0.97) physical activity in midlife were associated with lower risk of incident MCI. The association between moderate activity and incident MCI was not significant (HR = 0.85, 95% CI = 0.67-1.09). In late life, light (HR = 0.75, 95% CI = 0.58-0.97) and moderate (HR = 0.81, 95% CI = 0.66-0.99) but not vigorous physical activity were associated with lower risk of incident MCI. A synergistic interaction was also observed between mid- and late-life activity in reducing risk of incident MCI. Furthermore, APOE ε4 carriers who did not exercise had a higher risk of incident MCI than noncarriers who reported physical activity. CONCLUSION: Physical activity reduced the risk of incident MCI. Exercising in mid- and late life had an additive synergistic interaction in reducing the risk of MCI.

Frailty and Mortality Outcomes in Cognitively Normal Older People: Sex Differences in a Population-Based Study.

OBJECTIVES: To characterize frailty in cognitively normal older adults at baseline and to investigate the relationship between frailty and mortality. DESIGN: Population-based prospective cohort study: Mayo Clinic Study of Aging. SETTING: Olmsted County, Minnesota. PARTICIPANTS: Cognitively normal older persons aged 70 and older (mean age 78.8±5.2, 50.2% male; N=2,356). MEASUREMENTS: Frailty was assessed at baseline using a 36-item Frailty Index. Four frailty subgroups were identified based on the Frailty Index (≤0.10 (fit), 0.11-0.20 (at risk), 0.21-0.30 (frail), >0.30 (frailest)). All participants underwent comprehensive clinical and cognitive assessments. The association between frailty and mortality was assessed using Cox proportional hazards models. RESULTS: The median Frailty Index was 0.17 (interquartile range 0.11-0.22). Frailty increased with age and was more common in older men than in older women. Over a median follow-up of 6.5 years (range 7 days to 8.9 years), 500 of the 2,356 participants died, including 292 men. The frailest participants had the greatest risk of death (hazard ratio (HR)=3.91, 95% confidence interval (CI)=2.69-5.68). The association was stronger in women (HR=5.26, 95% CI=2.88-9.61) than men (HR=3.15, 95% CI=1.98-5.02). CONCLUSION: Baseline frailty was common, especially in older men, and increased with age. Frailty was associated with significantly greater risk of death, particularly in women. These sex differences should be considered when designing a geriatric care plan.

Association Between Olfactory Dysfunction and Amnestic Mild Cognitive Impairment and Alzheimer Disease Dementia.

IMPORTANCE: To increase the opportunity to delay or prevent mild cognitive impairment (MCI) or Alzheimer disease (AD) dementia, markers of early detection are essential. Olfactory impairment may be an important clinical marker and predictor of these conditions and may help identify persons at increased risk. OBJECTIVE: To examine associations of impaired olfaction with incident MCI subtypes and progression from MCI subtypes to AD dementia. DESIGN, SETTING, AND PARTICIPANTS: Participants enrolled in the population-based, prospective Mayo Clinic Study of Aging between 2004 and 2010 were clinically evaluated at baseline and every 15 months through 2014. Participants (N = 1630) were classified as having normal cognition, MCI (amnestic MCI [aMCI] and nonamnestic MCI [naMCI]), and dementia. We administered the Brief Smell Identification Test (B-SIT) to assess olfactory function. MAIN OUTCOMES AND MEASURES: Mild cognitive impairment, AD dementia, and longitudinal change in cognitive performance measures. RESULTS: Of the 1630 participants who were cognitively normal at the time of the smell test, 33 died before follow-up and 167 were lost to follow-up. Among the 1430 cognitively normal participants included, the mean (SD) age was 79.5 (5.3) years, 49.4% were men, the mean duration of education was 14.3 years, and 25.4% were APOE ε4 carriers. Over a mean 3.5 years of follow-up, there were 250 incident cases of MCI among 1430 cognitively normal participants. We observed an association between decreasing olfactory identification, as measured by a decrease in the number of correct responses in B-SIT score, and an increased risk of aMCI. Compared with the upper B-SIT quartile (quartile [Q] 4, best scores), hazard ratios (HRs) (95% CI) were 1.12 (0.65-1.92) for Q3 (P = .68); 1.95 (1.25-3.03) for Q2 (P = .003); and 2.18 (1.36-3.51) for Q1 (P = .001) (worst scores; P for trend <.001) after adjustment for sex and education, with age as the time scale. There was no association with naMCI. There were 64 incident dementia cases among 221 prevalent MCI cases. The B-SIT score also predicted progression from aMCI to AD dementia, with a significant dose-response with worsening B-SIT quartiles. Compared with Q4, HR (95% CI) estimates were 3.02 (1.06-8.57) for Q3 (P = .04); 3.63 (1.19-11.10) for Q2 (P = .02); and 5.20 (1.90-14.20) for Q1 (P = .001). After adjusting for key predictors of MCI risk, B-SIT (as a continuous measure) remained a significant predictor of MCI (HR, 1.10 [95% CI, 1.04-1.16]; P < .001) and improved the model concordance. CONCLUSIONS AND RELEVANCE: Olfactory impairment is associated with incident aMCI and progression from aMCI to AD dementia. These findings are consistent with previous studies that have reported associations of olfactory impairment with cognitive impairment in late life and suggest that olfactory tests have potential utility for screening for MCI and MCI that is likely to progress.

Diabetes is Associated with Worse Executive Function in Both Eastern and Western Populations: Shanghai Aging Study and Mayo Clinic Study of Aging.

BACKGROUND AND OBJECTIVES: It remains unknown whether the association between diabetes mellitus (DM) and cognitive function differs in Eastern and Western populations. This study aimed to elucidate whether DM is associated with worse cognitive performance in both populations. METHODS: The Shanghai Aging Study (SAS) and the Mayo Clinic Study of Aging (MCSA) are two population-based studies with similar design and methodology in Shanghai, China and Rochester, MN, USA. Non-demented participants underwent cognitive testing, and DM was assessed from the medical record. Separate analyses were performed in SAS and MCSA regarding the association between DM and cognitive performance. RESULTS: A total of 3,348 Chinese participants in the SAS and 3,734 American subjects in the MCSA were included. Compared with MCSA subjects, SAS participants were younger, less educated, and had lower frequency of vascular disease, APOE ɛ4 carriers and obesity. Participants with DM (compared to non-DM participants) performed significantly worse on all the cognitive domains in both the SAS and MCSA. After adjustment for age, gender, education, and vascular covariates, DM was associated with worse performance in executive function (ß=-0.15, p = 0.001 for SAS, and ß=-0.10, p = 0.008 for MCSA) in the total sample and in the cognitively normal sub-sample. Furthermore, DM was associated with poor performance in visuospatial skills, language, and memory in the SAS, but not in the MCSA. CONCLUSIONS: Diabetes is associated with cognitive dysfunction and, in particular, exerts a negative impact on executive function regardless of race, age, and prevalence of vascular risk factors.

Mycophenolate mofetil in primary central nervous system vasculitis.

OBJECTIVE: To evaluate the efficacy and safety of mycophenolate mofetil (MMF) in adult primary central nervous system vasculitis (PCNSV). METHODS: We studied a cohort of 163 patients with PCNSV who were seen at the Mayo Clinic from 1983 to 2011. We compared patients treated with MMF and those receiving other therapies. RESULTS: We identified 16 patients treated with MMF. MMF in combination with GCs achieved a favorable response in most patients. A significant proportion of patients treated with MMF had a less severe disability at last follow-up compared to those receiving other therapies (p = 0.023) and cyclophosphamide and prednisone (p = 0.017). No statistically significant differences were observed regarding relapses and ability to discontinue therapy at last follow-up. A trend to a more favorable treatment response was observed in patients treated with MMF compared to those treated with other therapies (p = 0.075). Only 1 patient suspended MMF for severe leukopenia. CONCLUSION: MMF seems to be an effective and safe therapy for adult PCNSV.

Adult primary central nervous system vasculitis treatment and course: analysis of one hundred sixty-three patients.

OBJECTIVE: To describe the treatment and outcomes of patients with primary central nervous system (CNS) vasculitis. METHODS: We retrospectively studied a cohort of 163 consecutive patients with primary CNS vasculitis who were seen at the Mayo Clinic over a 29-year period. We analyzed treatments, treatment responses, and factors predictive of outcomes. RESULTS: A favorable response was observed in 85% of patients treated with prednisone alone and in 80% of patients treated with prednisone and cyclophosphamide. Relapses were observed in 27% of patients, and 25% of patients had discontinued therapy by the time of the last followup visit. Treatment with prednisone alone was associated with more frequent relapses (odds ratio [OR] 2.90), while large vessel involvement (OR 6.14) and cerebral infarcts at the time of diagnosis (OR 3.32) were associated with a poor response to treatment. Prominent gadolinium-enhanced cerebral lesions or meninges were linked with continued treatment at the last followup encounter (OR 2.28). Higher disability scores at the last followup visit were associated with increasing age at the time of diagnosis (OR 1.44) and cerebral infarctions (OR 3.74), while lower disability scores were associated with gadolinium-enhanced cerebral lesions or meninges (OR 0.35) and cerebral amyloid angiopathy (OR 0.24). Increased mortality was associated with increasing age at diagnosis (hazard ratio [HR] 1.39), diagnosis by angiography (HR 3.28), cerebral infarction (HR 4.44), and large vessel involvement (HR 4.98), while reduced mortality was associated with gadolinium-enhanced cerebral lesions or meninges (HR 0.20). CONCLUSION: The majority of patients with primary CNS vasculitis responded to treatment. Recognition of findings at diagnosis that predict the course or outcome may aid in decision-making regarding therapy.

Short and long telomeres increase risk of amnestic mild cognitive impairment.

Peripheral blood telomere length has been associated with age-related conditions including Alzheimer's disease (AD). This suggests that telomere length may identify subjects at increased risk of AD. Thus, we investigated the associations of peripheral blood telomere length with amnestic mild cognitive impairment (aMCI), a putative precursor of AD, among Mayo Clinic Study of Aging participants who were prospectively followed for incident aMCI. We matched 137 incident aMCI cases (mean age 81.1 years, [range 70.9-90.8]; 49.6% men) by age and sex to 137 cognitively normal controls. We measured telomere length (T/S ratio) at baseline using quantitative PCR. Compared to the middle T/S quintile (Q3), the risk of aMCI was elevated for subjects with the shortest (Q1: HR, 2.85, 95% Confidence interval [CI] 0.98, 8.25; p=0.05) and the longest telomere lengths (Q5: HR, 5.58, 95%CI, 2.21, 14.11; p=0.0003). In this elderly cohort, short and long telomeres were associated with increased risk of aMCI. Our findings suggest that both long and short telomere lengths may play a role in the pathogenesis of aMCI, and may be markers of increased risk of aMCI.

Baseline neuropsychiatric symptoms and the risk of incident mild cognitive impairment: a population-based study.

OBJECTIVE: The authors conducted a prospective cohort study to estimate the risk of incident mild cognitive impairment in cognitively normal elderly (aged ≥70 years) individuals with or without neuropsychiatric symptoms at baseline. The research was conducted in the setting of the population-based Mayo Clinic Study of Aging. METHOD: A classification of normal cognitive aging, mild cognitive impairment, and dementia was adjudicated by an expert consensus panel based on published criteria. Hazard ratios and 95% confidence intervals were computed using Cox proportional hazards model, with age as a time scale. Baseline Neuropsychiatric Inventory Questionnaire data were available for 1,587 cognitively normal persons who underwent at least one follow-up visit. RESULTS: The cohort was followed to incident mild cognitive impairment (N=365) or censoring variables (N=179) for a median of 5 years. Agitation (hazard ratio=3.06, 95% CI=1.89-4.93), apathy (hazard ratio=2.26, 95% CI=1.49-3.41), anxiety (hazard ratio=1.87, 95% CI=1.28-2.73), irritability (hazard ratio=1.84, 95% CI=1.31-2.58), and depression (hazard ratio=1.63, 95% CI=1.23-2.16), observed initially, increased risk for later mild cognitive impairment. Delusion and hallucination did not. A secondary analysis, limited in significance by the small number of study participants, showed that euphoria, disinhibition, and nighttime behaviors were significant predictors of nonamnestic mild cognitive impairment but not amnestic mild cognitive impairment. By contrast, depression predicted amnestic mild cognitive impairment (hazard ratio=1.74, 95% CI=1.22-2.47) but not nonamnestic mild cognitive impairment. CONCLUSIONS: An increased incidence of mild cognitive impairment was observed in community-dwelling elderly adults who had nonpsychotic psychiatric symptoms at baseline. These baseline psychiatric symptoms were of similar or greater magnitude as biomarkers (genetic and structural MRI) in increasing the risk of incident mild cognitive impairment.

Long-term natural history of incidentally discovered cavernous malformations in a single-center cohort.

OBJECT: The aim of this study was to determine the prospective hemorrhage rate in a group of retrospectively identified patients in whom symptoms had an unclear relationship to an intracerebral cavernous malformation (ICM) or the malformation itself was an incidental finding. METHODS: Patients with incidentally discovered ICMs diagnosed between 1989 and 1999 were identified from a previously published cohort. Those with ICMs having an unclear relationship with existing symptoms were also eligible for analysis. Updated clinical and radiographic data pertaining to symptomatic intracerebral hemorrhage related to the ICM or new seizures were obtained through medical chart review and mail survey. In select patients, phone calls were made and death certificates were obtained when possible. The prospective hemorrhage rate was calculated as the number of prospective hemorrhages divided by the number of patient-years of follow-up. RESULTS: There were 1311 patient-years of follow-up among the 107 patients (49.5% male; mean age at diagnosis 52 years) eligible for this study. Forty-four patients died in the follow-up period, and the cause of death could be determined in 34 (77%). Two patients had a prospective hemorrhage, which was definitively related to the ICM in only one. Thus, the definitive prospective bleed rate was 0.08% per patient-year. No new seizures developed in any of the patients during the follow-up period. CONCLUSIONS: The risk of prospective hemorrhage in patients presenting asymptomatically with ICM is very low. This information can be useful in managing such patients and may be most applicable to those with a single ICM.

Higher risk of progression to dementia in mild cognitive impairment cases who revert to normal.

OBJECTIVE: To estimate rates of progression from mild cognitive impairment (MCI) to dementia and of reversion from MCI to being cognitively normal (CN) in a population-based cohort. METHODS: Participants (n = 534, aged 70 years and older) enrolled in the prospective Mayo Clinic Study of Aging were evaluated at baseline and every 15 months to identify incident MCI or dementia. RESULTS: Over a median follow-up of 5.1 years, 153 of 534 participants (28.7%) with prevalent or incident MCI progressed to dementia (71.3 per 1,000 person-years). The cumulative incidence of dementia was 5.4% at 1 year, 16.1% at 2, 23.4% at 3, 31.1% at 4, and 42.5% at 5 years. The risk of dementia was elevated in MCI cases (hazard ratio [HR] 23.2, p < 0.001) compared with CN subjects. Thirty-eight percent (n = 201) of MCI participants reverted to CN (175.0/1,000 person-years), but 65% subsequently developed MCI or dementia; the HR was 6.6 (p < 0.001) compared with CN subjects. The risk of reversion was reduced in subjects with an APOE ε4 allele (HR 0.53, p < 0.001), higher Clinical Dementia Rating Scale-Sum of Boxes (HR 0.56, p < 0.001), and poorer cognitive function (HR 0.56, p < 0.001). The risk was also reduced in subjects with amnestic MCI (HR 0.70, p = 0.02) and multidomain MCI (HR 0.61, p = 0.003). CONCLUSIONS: MCI cases, including those who revert to CN, have a high risk of progressing to dementia. This suggests that diagnosis of MCI at any time has prognostic value.

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.

Caloric intake, aging, and mild cognitive impairment: a population-based study.

In a population-based case-control study, we examined whether moderate and high caloric intakes are differentially associated with the odds of having mild cognitive impairment (MCI). The sample was derived from the Mayo Clinic Study of Aging in Olmsted County, Minnesota. Non-demented study participants aged 70-92 years (1,072 cognitively normal persons and 161 subjects with MCI) reported their caloric consumption within 1 year of the date of interview by completing a Food Frequency Questionnaire. An expert consensus panel classified each subject as either cognitively normal or having MCI based on published criteria. We conducted multivariable logistic regression analyses to compute odds ratios (OR) and 95% confidence intervals (95% CI) after adjusting for age, gender, education, depression, medical comorbidity, and body mass index. We also conducted stratified analyses by apolipoprotein E ε4 genotype status. Analyses were conducted in tertiles of caloric intake: 600 to <1,526 kcals per day (reference group); 1,526 to 2,143 kcals per day (moderate caloric intake group); and >2,143 kcals per day (high caloric intake group). In the primary analysis, there was no significant difference between the moderate caloric intake group and the reference group (OR 0.87, 95% CI 0.53-1.42, p = 0.57). However, high caloric intake was associated with a nearly two-fold increased odds of having MCI (OR 1.96, 95% CI 1.26-3.06, p = 0.003) as compared to the reference group. Therefore, high caloric intake was associated with MCI but not moderate caloric intake. This association is not necessarily a cause-effect relationship.