Early age-related progression of AD-like neuropathology in Down's syndrome.

We have previously reported that increased numbers of Alz-50-reactive (apoptotic) neurons occurred in young DS subjects compared to controls, but increased in density with increasing age, and in advance of identifiable senile plaques (SP) in DS. The purpose of the study was to determine if there are further differences in Alzheimer's disease (AD)-like neuropathology with increasing age among individuals with Down's syndrome (DS) compared to cognitively normal age-matched controls. The two populations compared were age-matched normal controls (N = 14) between 11 months and 61 years of age and individuals with DS (N = 8) between 1 and 54 years of age. There were 7 cognitively intact DS and 10 control subjects under 35 years of age. The single demented 54 year old DS subject was compared to 4 non-demented controls between 48 and 61 years of age. 50 µm Vibratome sections of formalin fixed hippocampal formations were immunohistochemically stained for amyloid-ß (6E10), APP (22C11) and phosphorylated tau (AT8) using standard methods. AT8 immunoreactive features were found only in the oldest DS subject. In contrast, the number and intensity of amyloid-ß-immunoreactive neurons were maximal in the youngest DS subjects (1-24 years), reduced in the young adults (25-35 years) synchronous with the appearance of only diffuse-form SP, and were further reduced in the 54 year-old DS subject exhibiting abundant multiform SP. Distribution of APP immunoreactivity (22C11) was distinct from amyloid-ß (6E10) in appearance and by location and age in both DS and normal controls. The data indicates that the earliest observable neuropathologic feature in DS may be neuronal accumulation of amyloid-ß. Such accumulation of amyloid-ß occurs decades in advance of deposition as SP, which in turn occurs decades before cognitive decline.

The Atorvastatin/Donepezil in Alzheimer's Disease Study (LEADe): design and baseline characteristics.

BACKGROUND: Growing evidence suggests that elevated cholesterol levels in mid-life are associated with increased risk of developing Alzheimer's disease (AD), and that statins might have a protective effect against AD and dementia. The Lipitor's Effect in Alzheimer's Dementia (LEADe) study tests the hypothesis that a statin (atorvastatin 80 mg daily) will provide a benefit on the course of mild to moderate AD in patients receiving background therapy of a cholinesterase inhibitor (donepezil 10 mg daily). METHODS: This is an international, multicenter, double-blind, randomized, parallel-group study with a double-blind randomized withdrawal phase of patients with mild to moderate AD (Mini-Mental State Examination [MMSE] score, 13 to 25). Inclusion criteria included age 50 to 90 years, receiving donepezil 10 mg for at least 3 months before randomization, and low-density lipoprotein cholesterol levels (LDL-C) 2.5 to 3.5 mmol/L (95 to 195 mg/dL). Co-primary end points are changes in AD Assessment Scale-cognitive subscale (ADAS-cog) and AD Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) scale scores. A confirmatory end point is rate of change in whole brain and hippocampal volumes in patients who enrolled in the magnetic resonance imaging substudy. RESULTS: Enrollment of 641 subjects is complete. The baseline mean data are age 74 +/- 8 years, 53% women, MMSE 22 +/- 3, ADAS-cog 23 +/- 10, AD Functional Assessment and Change Scale (ADFACS) 13 +/- 9, Neuropsychiatric Inventory (NPI) 10 +/- 11, and Clinical Dementia Rating-Sum of Boxes (CDR-SB) 6 +/- 3. Mean prior donepezil treatment was 409 +/- 407 days. Mean baseline lipid levels are total cholesterol 5.8 +/- 0.8 mmol/L (224 +/- 33 mg/dL), LDL-C 3.7 +/- 0.7 mmol/L (143 +/- 26 mg/dL), triglycerides 1.5 +/- 0.7 mmol/L (132 +/- 64 mg/dL), and high-density lipoprotein cholesterol 1.6 +/- 0.5 mmol/L (64 +/- 18 mg/dL). CONCLUSIONS: LEADe will report in 2008 and is expected to provide a more definitive evaluation of the potential for statins in the treatment of people with AD.

An assessment of statin safety by neurologists.

The National Lipid Association's (NLA) Statin Safety Task Force charged the Neurology Expert Panel with the task of reviewing the scientific evidence related to adverse effects with statins and providing assessments and advice regarding the safety of statins. The evidence included key adverse reaction statin literature identified via a Medline search by the Task Force and Panel members and the commissioned reviews and research presented in this supplement. Panel members were asked to use this evidence to independently form explicit answers to a series of questions posed by the Task Force. Panelists were asked to grade the type of literature and the confidence they had in it in forming their answers using prescribed scales. Panelists were encouraged to seek the highest level of evidence available to answer their questions and to concentrate on literature involving humans. In addition, the Neurology Expert Panel was asked to propose recommendations to regulatory authorities, health professionals, patients, researchers, and the pharmaceutical industry to address statin safety issues.

Low Temperature Thermocouples: KP, "normal" silver, and copper versus Au-0.02 at% Fe and Au-0.07 at% Fe.

The Seebeck thermoelectric voltages of two dilute alloys of iron in gold, Au 0.02 at% Fe and Au-0.07 at% Fe, have been determined with respect to KP (a particular Ni-Cr alloy), "normal" silver, and copper in the temperature range from 4 to 280 K. The power series representation of these data, along with the calculated Seebeck coefficients and derivatives of the Seebeck coefficients, have been extrapolated to 0 K and are presented as a function of temperature. In addition to these reference data, seven different Au-0.07 at% Fe alloys were thermoelectrically intercompared in order to determine the variability in wires from different melts and from different manufacturers. The largest deviation found amounted to about 9 percent of the output of a KP versus Au-0.07 at% Fe thermocouple pair between 4 and 20 K. A more typical variation for this temperature range was 2 to 4 percent. Initial indications are that the reference data can be adjusted satisfactorily with data from spot calibrations on particular wires. The effect of heat treatment is illustrated by comparing our results to Rosenbaum's data for annealed and unannealed specimens of both Au-Fe alloys.