Oxidative lipidomics of programmed cell death.

Oxidized phospholipids play an important role in execution of the mitochondrial stage of apoptosis and clearance of apoptotic cells by macrophages. Therefore, the identification and quantification of oxidized phospholipids generated during apoptosis are very important. These can be achieved successfully by a newly developed approach--oxidative lipidomics, including a combination of electrospray ionization/mass spectrometry (ESI-MS) and fluorescence high-performance liquid chromatography techniques.

Characterizing regional correlation, laterality and symmetry of amyloid deposition in mild cognitive impairment and Alzheimer's disease with Pittsburgh Compound B.

We evaluated the region-to-region correlation, laterality and asymmetry of amyloid deposition in subjects with mild cognitive impairment (MCI) or Alzheimer's disease (AD) using the amyloid tracer, Pittsburgh Compound B (PiB). Seventeen subjects, including 7 with MCI (MMSE 26.7+/-2.

Imaging Alzheimer pathology in late-life depression with PET and Pittsburgh Compound-B.

There is increasing evidence for an empiric link between late-life depression and Alzheimer disease (AD). The neuropathology of AD, previously only confirmed at autopsy, may now be detectable in vivo using selective imaging ligands for beta-amyloid. Positron emission tomography (PET) with [11C] 6-OH-BTA-1 [Pittsburgh Compound-B (PiB)] has shown high tracer retention in cortical areas in patients with clinical diagnoses of probable AD and low retention in age-matched controls.

No association of SORL1 SNPs with Alzheimer's disease.

SORL1 is an element of the amyloid precursor protein processing pathway and is therefore a good candidate for affecting Alzheimer's disease (AD) risk. Indeed, there have been reports of associations between variation in SORL1 and AD risk. We examined six statistically significant single-nucleotide polymorphisms from the initial observation in a large Caucasian American case-controls cohort (1000 late-onset AD [LOAD] cases and 1000 older controls).

Plasma amyloid levels and the risk of AD in normal subjects in the Cardiovascular Health Study.

Objectives: To examine the association between incident Alzheimer disease (AD), and plasma A beta 1-40 and A beta 1-42 levels in normal and mild cognitive impairment (MCI) subjects in a subgroup of participants of the Cardiovascular Health Study Cognition Study.

Methods: We determined the plasma A beta 1-40 and A beta 1-42 levels of 274 nondemented subjects (232 normals and 42 with MCI) in 1998-1999 and repeated the measurements in 2002-2003. The mean age of the subjects at baseline was 79.

Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease.

The positron emission tomography (PET) radiotracer Pittsburgh Compound-B (PiB) binds with high affinity to beta-pleated sheet aggregates of the amyloid-beta (Abeta) peptide in vitro. The in vivo retention of PiB in brains of people with Alzheimer's disease shows a regional distribution that is very similar to distribution of Abeta deposits observed post-mortem. However, the basis for regional variations in PiB binding in vivo, and the extent to which it binds to different types of Abeta-containing plaques and tau-containing neurofibrillary tangles (NFT), has not been thoroughly investigated.

No association of DAPK1 and ABCA2 SNPs on chromosome 9 with Alzheimer's disease.

Recently genetic variation in the DAPK1 and ABCA2 genes has been reported to be associated with late- and early-onset Alzheimer's disease (AD), respectively. We examined the most significant two single-nucleotide polymorphisms (SNPs) in DAPK1 in a large case-control cohort of late-onset subjects and matched controls and one of the most significant SNPs in ABCA2 in a small set of early-onset subjects as well. We did not detect associations with AD for any variation.

Recollection and familiarity in amnestic mild cognitive impairment: a global decline in recognition memory.

Despite memory failures being a central feature of amnestic mild cognitive impairment (a-MCI), there is limited research into the nature of the memory impairment associated with this condition. A further understanding could lead to refinement of criteria needed to qualify for this designation and aid in prediction of who will progress to development of clinical Alzheimer's disease. Dual process models posit that recognition memory is supported by the dissociable processes of recollection and familiarity.

Comparison of the design differences between the Ginkgo Evaluation of Memory study and the GuidAge study.

The epidemic of late life dementia, prominence of use of alternative medications and supplements, and initiation of efforts to determine how to prevent dementia have led to efforts to conduct studies aimed at prevention of dementia. The GEM (Ginkgo Evaluation of Memory) and GuidAge studies are ongoing randomized double-blind, placebo-controlled trials of Ginkgo biloba, administered in a dose of 120 mg twice per day as EGb761, to test whether Ginkgo biloba is effective in the prevention of dementia (and especially Alzheimer's disease) in normal elderly or those early cognitive impairment. Both GEM and GuidAge will also add substantial knowledge to the growing need for expertise in designing and implementing clinical trials to test the efficacy of putative disease-modifying agents for the dementias.

Alpha7 nicotinic receptor up-regulation in cholinergic basal forebrain neurons in Alzheimer disease.

Background: Dysfunction of basocortical cholinergic projection neurons of the nucleus basalis (NB) correlates with cognitive deficits in Alzheimer disease (AD). Nucleus basalis neurons receive cholinergic inputs and express nicotinic acetylcholine receptors (nAChRs) and muscarinic AChRs (mAChRs), which may regulate NB neuron activity in AD. Although alterations in these AChRs occur in the AD cortex, there is little information detailing whether defects in nAChR and mAChR gene expression occur in cholinergic NB neurons during disease progression.

Associations of gait speed and other measures of physical function with cognition in a healthy cohort of elderly persons.

Background: Recent evidence suggests that physical decline and slower gait may be associated with early signs of dementia, but more information on healthy older adults is needed.

Methods: We determined associations between cognitive function, gait speed, and self-reported measures of physical function in 3035 healthy mobile participants of the Ginkgo Evaluation of Memory Study evaluated in 2000-2001. Gait speed was measured over a 15-foot course with participants walking at both their usual and rapid pace.

Marital quality in the context of mild cognitive impairment.

Profound behavioral changes in persons with dementia often negatively affect the quality of marital relationships. Yet, little is known about the extent to which the marital relationship may be affected when the care recipient has milder degrees of cognitive impairment. This study characterizes marital quality among 27 adults who live with a spouse with mild cognitive impairment (MCI).

Imaging of amyloid plaques and cerebral glucose metabolism in semantic dementia and Alzheimer's disease.

Semantic dementia (SD) is a rare clinical syndrome, assigned to the group of frontotemporal lobar degenerations (FTLD). Histopathological analysis has not revealed the deposition of amyloid plaques in the majority of SD cases, in contrast to dementia of the Alzheimer type (AD). However, based on clinical examination alone a reliable differentiation of the underlying pathology cannot be guaranteed, i.

Superior frontal cortex cholinergic axon density in mild cognitive impairment and early Alzheimer disease.

Background: Loss of cortical choline acetyltransferase (ChAT) activity contributes to end-stage Alzheimer disease (AD) dementia. In general, ChAT activity levels are stable in the neocortex in mild to moderate AD (mAD) and there is a selective up-regulation in the superior frontal cortex (SFC) in mild cognitive impairment (MCI), indicating a transient, region-specific cholinergic neuroplastic response.

Objective: To assess whether a proliferation of cholinergic axons underlies increased ChAT activity levels in the SFC in subjects with MCI.

Redox-reactive autoantibodies in cerebrospinal fluids.

The oxidative stress associated with increased transitional metal concentrations in neurodegenerative diseases served as the impetus for our testing the status of redox-reactive autoantibodies in the cerebrospinal fluids from autopsy-confirmed Alzheimer's patients. Here we describe a novel family of autoantibodies capable of recognizing autoantigens subsequent to in vitro oxidation-reduction (redox) reactions in the blood and spinal fluids of all normal individuals tested. Redox autoantibodies are not detected in conventional immunoassays, thereby differentiating them from natural and hidden autoantibodies described by others.

Imaging of amyloid burden and distribution in cerebral amyloid angiopathy.

Objective: Cerebrovascular deposition of beta-amyloid (cerebral amyloid angiopathy [CAA]) is a major cause of hemorrhagic stroke and a likely contributor to vascular cognitive impairment. We evaluated positron emission tomographic imaging with the beta-amyloid-binding compound Pittsburgh Compound B (PiB) as a potential noninvasive method for detection of CAA. We hypothesized that amyloid deposition would be observed with PiB in CAA, and based on the occipital predilection of CAA pathology and associated hemorrhages, that specific PiB retention would be disproportionately greater in occipital lobes.

Cholinergic forebrain degeneration in the APPswe/PS1DeltaE9 transgenic mouse.

The impact of Abeta deposition upon cholinergic intrinsic cortical and striatal, as well as basal forebrain long projection neuronal systems was qualitatively and quantitatively evaluated in young (2-6 months) and middle-aged (10-16 months) APPswe/PS1DeltaE9 transgenic (tg) mice. Cholinergic neuritic swellings occurred as early as 2-3 months of age in the cortex and hippocampus and 5-6 months in the striatum of tg mice. However, cholinergic neuron number or choline acetyltransferase (ChAT) optical density measurements remained unchanged in the forebrain structures with age in APPswe/PS1DeltaE9 tg mice.

Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria.

The NINCDS-ADRDA and the DSM-IV-TR criteria for Alzheimer's disease (AD) are the prevailing diagnostic standards in research; however, they have now fallen behind the unprecedented growth of scientific knowledge. Distinctive and reliable biomarkers of AD are now available through structural MRI, molecular neuroimaging with PET, and cerebrospinal fluid analyses. This progress provides the impetus for our proposal of revised diagnostic criteria for AD.

Redox-reactive autoantibodies in Alzheimer's patients' cerebrospinal fluids: preliminary studies.

Oxidation of cerebrospinal fluid (CSF) causes differential unmasking of autoantibodies in control CSF vs. that obtained from postmortem CSF samples from autopsy confirmed Alzheimer's disease (AD) cases. This study demonstrates that normal CSF from both living patients and from non-demented autopsy cases contains redox-reactive autoantibodies with specificities that include antiphospholipid antibodies (aPL).

Evidence for the association of the S100beta gene with low cognitive performance and dementia in the elderly.

Variations in the S100beta gene may be instrumental in producing a continuum from mild cognitive decline to overt dementia. After screening 25 single nucleotide polymorphisms (SNPs) in S100beta, we observed association of the rs2300403 intron 2 SNP with poorer cognitive function in three independent populations. Moreover, we detected a significant association of this SNP with increased risk of developing dementia or Alzheimer's disease (AD) in six independent populations, especially in women and in the oldest.

Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees.

The amyloid cascade hypothesis suggests that the aggregation and deposition of amyloid-beta protein is an initiating event in Alzheimer's disease (AD). Using amyloid imaging technology, such as the positron emission tomography (PET) agent Pittsburgh compound-B (PiB), it is possible to explore the natural history of preclinical amyloid deposition in people at high risk for AD. With this goal in mind, asymptomatic (n = 5) and symptomatic (n = 5) carriers of presenilin-1 (PS1) mutations (C410Y or A426P) that lead to early-onset AD and noncarrier controls from both kindreds (n = 2) were studied with PiB-PET imaging and compared with sporadic AD subjects (n = 12) and controls from the general population (n = 18).