Neuroleptics are associated with more severe tangle pathology in dementia with Lewy bodies

BACKGROUND: Neuroleptics are only modestly effective in dementia and associated with a range of adverse effects including cognitive decline. Effects of the drugs on molecular pathology in brain tissue from people with dementia have not been investigated. OBJECTIVES: To compare the severity of Alzheimer type pathology in matched groups of people with dementia with Lewy bodies (DLB), treated and not treated with neuroleptics. METHODS: The relationship between neuroleptics and Alzheimer-type pathology was determined in 40 (17 neuroleptic treated, 23 neuroleptic free, matched for age, disease duration and psychosis) clinically prospectively studied, autopsy diagnosed DLB patients. RESULTS: In regression analyses, taking neuroleptics was significantly associated with increased neurofibrillary tangles but not amyloid plaques in cortical areas examined. The patient characteristics and the frequencies of key psychiatric symptoms were similar in the patients taking and not taking neuroleptics. CONCLUSION: Although patients were not randomized and the results which are observed need to be interpreted cautiously, if substantiated, this is an important finding with major implications for the pharmacological management of DLB patients and highlights the need to determine the impact of neuroleptics upon tangle pathology in AD.     

The pattern of cognitive performance in CADASIL: a monogenic condition leading to subcortical ischemic vascular dementia

OBJECTIVE: Subcortical ischemic vascular lesions, which are closely related to small vessel disease, are a common substrate of cognitive impairment and dementia. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic variant of small vessel disease resulting from mutations in NOTCH3. Mutation carriers almost invariably develop cognitive deficits and eventually dementia. The current study describes the profile of cognitive abnormalities in CADASIL subjects. METHOD: A cross-sectional study of 65 mutation carriers (mean age=47.3 years, SD=10.5) and 30 matched comparison subjects (mean age=47.2 years, SD=14.0) was conducted. Participants underwent a series of assessments that included ratings of global cognition, the cognitive portion of the Vascular Dementia Assessment Scale, and specific tests of executive function and attention with measures of processing speed and error monitoring. RESULTS: CADASIL subjects had pronounced impairments of the timed measures (Stroop II and III, Trail Making Test, symbol digit, digit cancellation). Measures of error monitoring (Stroop III, Trail Making Test, symbol digit, maze task) were also significantly affected but to a lesser extent. Prominent deficits further included verbal fluency and ideational praxis. Recall, orientation, and receptive language skills were largely preserved. Subgroup analyses indicated a similar profile in subjects with early and advanced impairment of global cognitive performance. CONCLUSIONS: The findings highlight processing speed as the most substantial area of cognitive impairment in CADASIL subjects, with less pronounced yet significant deficits in other aspects of executive performance and attention. This profile of cognitive impairment is present at an early stage and enables the construction of targeted test batteries for clinical trials. It is hypothesized that the profile of dysfunction described here represents the core of the cognitive syndrome associated with small vessel disease and subcortical ischemic vascular lesions.     

Absence of cholinergic deficits in "pure" vascular dementia

Choline acetyltransferase in temporal cortex was evaluated as a marker of cholinergic function in autopsied dementia cases (9 vascular dementia [VaD] cases, 12 "mixed" VaD and Alzheimer disease [AD] cases, 10 AD cases, 12 control subjects). Patients with AD (t = 2.5, p = 0.02) and "mixed" VaD and AD (t = 3.8, p = 0.001) had greater cholinergic deficits than age-matched control subjects and patients with "pure" VaD. The absence of cholinergic deficits in "pure" VaD may be relevant to the pharmacologic treatment of these patients.     

Neuroleptic sensitivity in Parkinson's disease and parkinsonian dementias

BACKGROUND: Severe sensitivity to neuroleptic agents is a major clinical problem in dementia with Lewy bodies (DLB), but has not been determined in Parkinson's disease (PD) and PD with dementia (PDD). METHOD: Severe neuroleptic sensitivity reactions (NSRs) were evaluated according to an operationalized definition blind to clinical and neuropathologic diagnoses in prospectively studied patients exposed to neuroleptics from 2 centers. The study was conducted from June 1995 to May 2003. RESULTS: Ninety-four patients were included (15 with DLB, 36 with PDD, 26 with PD, 17 with Alzheimer's disease, all diagnosed with various operational criteria). Severe NSR only occurred in patients with Lewy body disease: DLB (8 [53%]), PDD (14 [39%]), and PD (7 [27%]), but did not occur in Alzheimer's disease (p = .006). Severe NSR was not associated with other clinical or demographic features. In DLB, severe NSR was not associated with neuropathologic indices (Consortium to Establish a Registry for Alzheimer's Disease staging, Braak staging, or cortical distribution of Lewy bodies). CONCLUSIONS: An operationalized evaluation of severe NSR blind to diagnosis confirmed the high prevalence in DLB and identified high frequencies in Parkinson's disease and PDD with important implications for clinical practice.     

Ischemic Colitis following Translumbar Thrombin Injection for Treatment of Endoleak

Endoleaks remain a significant challenge after endovascular abdominal aortic aneurysm repair (EVAR). Translumbar thrombin injection of the aneurysm sac has been used to treat endoleaks, with low reported morbidity. We present an unusual case of ischemic colitis following translumbar thrombin injection of an endoleak. A 67-year-old male with a 5.8-cm abdominal aortic aneurysm (AAA) was evaluated for endograft repair. The patient underwent preoperative embolization of the right hypogastric artery. The AAA was repaired using a unibody bifurcated graft (Ancure). Completion aortogram revealed no endoleak and a widely patent left hypogastric artery. Computed tomography (CT) at 2 months showed an endoleak appearing to originate from a lumbar artery near the proximal attachment site with outflow via the inferior mesenteric artery (IMA). The endoleak was successfully treated with CT-guided translumbar injection of 8000 units of thrombin into the aneurysm sac. The patient subsequently developed chronic abdominal pain, diarrhea, and a weight loss of 20 lbs. Colonoscopy revealed ischemic colitis of the rectosigmoid colon. Duplex evaluation indicated a patent superior mesenteric artery and IMA distal to its origin. Medical treatment failed and the patient underwent a low anterior resection 2 months later (4 months post-EVAR). Subsequently, the aneurysm has decreased to 5.4 cm, with no evidence of endoleak at 1 year. We conclude that ischemic colitis may occur following translumbar thrombin injection. Thrombin embolization into the rectosigmoid arcade via the IMA was most likely the cause in this case. This problem can potentially be avoided by treating the IMA endoleak outflow prior to translumbar thrombin injection of the aneurysm sac. Thorough arteriographic evaluation of endoleaks should be performed prior to any interventions. Presented at the Annual Meeting of the Southern California Vascular Surgical Society, Carlsbad, CA, April 11-13, 2003.     

Critical care clinical experience for novice students: reinforcing basic nursing skills

To better match students' learning priorities with their practicum experiences and to facilitate skills learning, undergraduate faculty devised the innovative strategy of incorporating a critical care rotation into the first semester of students' clinical experience. The authors describe the basics of this previously untested critical care clinical experience and the essential planning steps prior to implementation, including faculty approval, hospital administrative and nurse manager approval, preceptor identification and education, means of evaluating and grading the students, and evaluation of the overall experience.     

LY317615 decreases plasma VEGF levels in human tumor xenograft-bearing mice

Angiogenesis plays an important role in tumor growth. Angiogenic growth factors may be useful as biomarkers of antiangiogenic activity since their plasma concentrations correlate with the efficacy of treatments directed toward angiogenic targets. SW2 small-cell lung carcinoma (SCLC), Caki-1 renal cell carcinoma and HCT-116 colon carcinoma tumors produce measurable plasma VEGF, bFGF and TGF in nude mice. Mice bearing these human tumor xenografts were treated orally twice daily with the PKC inhibitor, LY317615 (days 14–30 for SW2 and HCT116, and days 21–39 for Caki-1). Plasma was collected every 3 days from control and treated mice. LY317615 significantly decreased plasma VEGF levels in mice bearing SW2 SCLC and Caki-1 renal cell carcinoma compared to control plasma concentrations beginning 5–7 days after initiating therapy. VEGF plasma levels remained suppressed after termination of LY317615 treatment and for the duration of the study (an additional 2 to 3 weeks). Plasma VEGF levels in mice bearing HCT116 xenografts were not altered by LY317615 treatment and plasma bFGF and TGF- were not altered by LY317615 in any of the animals. As shown by CD31 immunohistochemical staining, LY317615 decreased intratumoral vessel density by nearly 40% in all three tumors. Only the Caki-1 tumor responded to single-agent LY317615 therapy with a measurable tumor growth delay. Thus, unexpectedly inhibition of PKC in vivo led to decreased VEGF production that persisted after therapy as well as to decreased intratumoral vessels. Plasma VEGF was a weak marker of response to LY317615, and plasma bFGF and TGF were not markers of LY317615 activity.Abbreviations bFGF Basic fibroblast growth factor - PKC- Protein kinase C-beta - SCLC Small-cell lung cancer - TGD Tumor growth delay - TGF- Transforming growth factor-beta - VEGF Vascular endothelial growth factor