Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease.

RIPK1 is a key regulator of innate immune signalling pathways. To ensure an optimal inflammatory response, RIPK1 is regulated post-translationally by well-characterized ubiquitylation and phosphorylation events, as well as by caspase-8-mediated cleavage1-7. The physiological relevance of this cleavage event remains unclear, although it is thought to inhibit activation of RIPK3 and necroptosis8. Here we show that the heterozygous missense mutations D324N, D324H and D324Y prevent caspase cleavage of RIPK1 in humans and result in an early-onset periodic fever syndrome and severe intermittent lymphadenopathy-a condition we term 'cleavage-resistant RIPK1-induced autoinflammatory syndrome'. To define the mechanism for this disease, we generated a cleavage-resistant Ripk1D325A mutant mouse strain. Whereas Ripk1-/- mice died postnatally from systemic inflammation, Ripk1D325A/D325A mice died during embryogenesis. Embryonic lethality was completely prevented by the combined loss of Casp8 and Ripk3, but not by loss of Ripk3 or Mlkl alone. Loss of RIPK1 kinase activity also prevented Ripk1D325A/D325A embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner. Consistently, Ripk1D325A/D325A and Ripk1D325A/+ cells were hypersensitive to RIPK3-dependent TNF-induced apoptosis and necroptosis. Heterozygous Ripk1D325A/+ mice were viable and grossly normal, but were hyper-responsive to inflammatory stimuli in vivo. Our results demonstrate the importance of caspase-mediated RIPK1 cleavage during embryonic development and show that caspase cleavage of RIPK1 not only inhibits necroptosis but also maintains inflammatory homeostasis throughout life.

Medical and environmental risk factors associated with frontotemporal dementia: a case-control study in a veteran population.

BACKGROUND: Compared with other major dementias, very little is known about the medical and environmental risk factors associated with frontotemporal dementia (FTD). In this study, we evaluated medical and environmental disorders associated with FTD in a veteran population. METHODS: The medical records of 845 consecutive veterans who were evaluated for cognitive and/or behavioral complaints at a cognitive disorders clinic in an academic medical center between March 1, 2003, and June 30, 2008, were reviewed and 554 patients received a diagnosis of dementia. Medical disorders and environmental risk factors in 63 patients with behavioral variant of FTD were compared with 491 patients with non-FTD dementias. RESULTS: The prevalence of traumatic brain injury (TBI) was significantly greater in patients with FTD versus those with non-FTD dementias (12.7% vs 3.5%; P < .05). The FTD group also had a lower prevalence of heart disease (19.0% vs 36.7%; P < .05) and cerebrovascular diseases (12.7% vs 26.1%; P < .05), although the prevalence of vascular risk factors was comparable between FTD and non-FTD dementia groups: hypertension (65.1% vs 68.2%), diabetes (31.7% vs 26.9%), hyperlipidemia (42.9% vs 48.9%), and tobacco use (7.9% vs 8.8%; P > .05 for all). In multivariate analysis, the risk for FTD was increased in patients with TBI (OR, 4.4; 95% CI, 1.6-11.8). The risk for FTD was marginally decreased in patients with heart disease (OR, 0.4; 95% CI, 0.3-0.96). CONCLUSIONS: In a clinical sample of veterans, risk of FTD was increased in patients with TBI and marginally decreased in patients with heart disease. Prospective studies are needed to confirm these associations temporally and to identify their underlying mechanisms.

Differences between clinical subspecialties in the outpatient evaluation and treatment of dementia in an academic medical center.

BACKGROUND: Professional organizations have recommended guidelines for the optimal investigation and management of dementia. It is unknown whether physicians from different subspecialties investigate and treat dementia in the same manner or according to these guidelines. METHODS: We screened 1,401 charts of patients who were seen in neurology, mental health, geropsychiatry and geriatrics clinics. The charts of 410 patients who were diagnosed with dementia were reviewed in detail to determine how they were evaluated and managed. RESULTS: Overall, 40% of patients received a complete laboratory workup to rule out comorbidities, 70% of patients received neuroimaging with either computerized tomography or magnetic resonance imaging of the brain, 63% had a depression screen and 38% of patients underwent neuropsychological testing. However, the frequency with which they were obtained differed significantly across clinics (p < 0.05). The frequency with which acetylcholinesterase inhibitors (CHEIs) were used did not differ significantly (p = 0.07) for patients with Alzheimer's disease (AD), but differed significantly (p < 0.05) for dementia categories where CHEIs are thought to be useful (AD, vascular dementia and dementia with Lewy bodies). CONCLUSIONS: There were significant differences between subspecialties in the evaluation and treatment of dementia. It will be important to investigate whether these differences alter patient outcomes.

Ethnic disparities in the treatment of dementia in veterans.

OBJECTIVES: To test for ethnic disparities in the evaluation and treatment of dementia. METHODS: We reviewed 1,401 charts of patients from 4 veteran clinics that routinely evaluate dementia patients. A total of 410 patients met criteria for dementia or mild cognitive impairment (MCI) and their charts were reviewed in detail. RESULTS: Regarding their evaluation, laboratory and imaging testing did not differ between ethnic groups (p > 0.05). Depression screening was more common in African-American (AA) patients (p = 0.03). Significantly more Caucasian patients underwent neuropsychologic testing (p = 0.001). Regarding management, in a multivariate analysis, AA patients with Alzheimer's disease (AD) (odds ratio (OR) 0.09, 95% confidence interval (CI) 0.02-0.5) or 'all dementia types' (OR 0.6, 0.3-0.9) were significantly less likely to receive acetylcholinesterase inhibitors (CHEIs). Other independent predictors of CHEI use were age >or=71 years (OR 5.2, 2.8-9.6), a diagnosis of AD (OR 3.1, 1.6-6.3) or MCI (OR 0.3, 0.1-0.7), and if their evaluation included imaging (head CT or MRI; OR 1.9, 1.05-3.3). CONCLUSIONS: AA patients underwent comparable evaluations for dementia and the percentage of CHEI-responsive diagnoses rendered was similar across ethnic groups. However, dementia management differed significantly: AAs were prescribed CHEIs at considerably reduced rates. The reasons for this great disparity warrant further investigation because it may produce significantly greater cognitive impairment and hence suffering amongst AA patients.