Emotional reactions to pain predict psychological distress in adult patients with Sickle Cell Disease (SCD).

Differentiating somatic from emotional influences on the experience of chronic pain has been of interest to clinicians and researchers for many years. Although prior research has not well specified these pathways at the anatomical level, some evidence, both theoretical and empirical, suggest that emotional reactions influence the experience of disease and non-disease-related pains. Other studies suggest that treatments directed at negative emotional responses reduce suffering associated with pain. The current study was conducted to explore the influence of emotional reactions to pain as a predictor of psychological distress in a sample of adult Blacks with Sickle Cell Disease (SCD). Using cross-sectional survey data, we evaluated whether negative emotional reactions to the experience of pain were predictive of psychological distress after controlling for the somatic dimension of pain and age in n = 67 Black patients with Sickle Cell Disease (SCD). Results showed that greater negative emotion associated with pain predicted Somatization (p < .01), Anxiety (p < .05), Phobic Anxiety (p < .05), and Psychoticism (p < .05). Increased negative emotion associated with pain was also predictive of the General Symptoms Index (p < .05) and the Positive Symptoms Total from the SCL-90-R (p < .01). We believe the current study demonstrates that negative emotional reactions to the experience of pain in adults with SCD are predictive of psychological distress above and beyond the influences of age and the direct nociceptive experience. We also believe these data to be valuable in conceptualizing the allocation of treatment resources toward a proactive approach with early identification of patients who are responding poorly for the purpose of potentially reducing later psychopathology. A deeper understanding of the ways that subpopulations cope with chronic disease-related pain may produce models that can be ultimately generalized to the consumers of the majority of healthcare resources.

Deficiency of α-1-antitrypsin influences systemic iron homeostasis.

There is evidence that proteases and antiproteases participate in the iron homeostasis of cells and living systems. We tested the postulate that α-1 antitrypsin (A1AT) polymorphism and the consequent deficiency of this antiprotease in humans are associated with a systemic disruption in iron homeostasis. Archived plasma samples from Alpha-1 Foundation (30 MM, 30 MZ, and 30 ZZ individuals) were analyzed for A1AT, ferritin, transferrin, and C-reactive protein (CRP). Plasma samples were also assayed for metals using inductively coupled plasma atomic emission spectroscopy (ICPAES). Plasma levels of A1AT in MZ and ZZ individuals were approximately 60% and 20% of those for MM individuals respectively. Plasma ferritin concentrations in those with the ZZ genotype were greater relative to those individuals with either MM or MZ genotype. Plasma transferrin for MM, MZ, and ZZ genotypes showed no significant differences. Linear regression analysis revealed a significant (negative) relationship between plasma concentrations of A1AT and ferritin while that between A1AT and transferrin levels was not significant. Plasma CRP concentrations were not significantly different between MM, MZ, and ZZ individuals. ICPAES measurement of metals confirmed elevated plasma concentrations of nonheme iron among ZZ individuals. Nonheme iron concentrations correlated (negatively) with levels of A1AT. A1AT deficiency is associated with evidence of a disruption in iron homeostasis with plasma ferritin and nonheme iron concentrations being elevated among those with the ZZ genotype.

Fibromyalgia, mood disorders, and intense creative energy: A1AT polymorphisms are not always silent.

Persons with single copies of common alpha-1-antitrypsin polymorphisms such as S and Z are often considered "silent carriers". Published evidence however supports a complex behavioral phenotype or trait - intense creative energy ("ICE")-associated with A1AT polymorphisms. We now confirm that phenotype and present an association of fibromyalgia syndrome (FMS) and A1AT in a consecutive series of neurological patients. This is a retrospective case control series of 3176 consecutive patients presenting to Duke University Memory Clinic (747 patients) and to regional community-based Caldwell Hospital Neurology and Memory center (2429 patients). Work-up included medical history and examination, psychological evaluation, and genetic analysis. Chronic widespread pain (CWP) or FMS were diagnosed according to clinical guidelines, mostly as secondary diagnoses. Neurological patients carrying A1AT polymorphisms were common (ca 16% prevalence) and carriers had significantly higher use of inhaler and anxiolytic medications. Patients with ICE phenotype had a significantly higher proportion of A1AT polymorphisms (42%) compared to non-ICE patients (13%). Presence of CWP or FMS was common (14-22%) with average age at presentation of 56 years old and mostly female gender (82%). Patients with CWP/FMS had again significantly higher proportion of A1AT polymorphisms (38%) compared to other neurological patients (13%). Patients with anxiety disorders, bipolar I or bipolar II disorders or PTSD also had increased proportion of A1AT polymorphisms and significant overlap with ICE and FMS phenotype. Significant reductions in CWP/FMS prevalence are seen in apolipoprotein E4 carriers and methylene tetrahydrofolate reductase (MTHFR) mutation homozygotes. Since ICE phenotype is reported as a lifelong behavioral attribute, the presumption is that A1AT carriers have fundamental differences in brain development and inflammatory response. In support of this concept is finding those persons reporting a diagnosis of juvenile rheumatoid or idiopathic arthritis (JRA, JIA) had a significantly high proportion of A1AT polymorphisms (63%), suggesting a spectrum for JRA to later FMS presentations. Likewise, persons reporting a history of attention deficit disorder (ADD) had an increased proportion of A1AT polymorphisms (26%) compared to non-ADD persons (13%). Toxic environmental exposures are common (23%) and associated with diagnoses of PSP, PPA, FTD, FTD-PD, PD and ADVD. A1AT carriers were increased in cases of toxic exposure and PSP, PPA and FTD-PD. Our findings support the ICE behavioral phenotype for A1AT polymorphism carriers and the reported association with anxiety and bipolar spectrum disorders. We now extend that phenotype to apparent vulnerability to inflammatory muscle disease in a spectrum from JRA to fibromyalgia (FMS) and specific behavioral subsets of ADD, PTSD, and specific late onset neurological syndromes (FTD-PD and PPA). High and low risk FMS subsets can be defined using A1AT, MTHFR and APOE genotyping. Clinical diagnoses associated with A1AT polymorphisms included fibromyalgia, JRA/JIA, bipolar disorder, PTSD, primary progressive aphasia and FTDPD, but not most Alzheimer Disease subtypes. These results support an extended phenotype for A1AT mutation carriers beyond liver and lung vulnerability to selective advantages: ICE phenotype and disadvantages: fibromyalgia, affective disorders, and selected late onset neurological syndromes.

Human apolipoprotein E4 targeted replacement mice show increased prevalence of intracerebral hemorrhage associated with vascular amyloid deposition.

Previous studies show that APOE *4 carriers are at increased risk for ischemic stroke and intracerebral hemorrhage (ICH). The APOE *4 gene is also linked to increased incidence of cerebral amyloid angiopathy. It has been suggested that apolipoprotein E4 expression leads to increased vascular amyloid deposition, which may explain the increased incidence of ICH in APOE *4 carriers. Here we show a significant increase in ICH in apoE4 targeted replacement mice compared with apoE3 mice. In all, 89% of the vessels in the apoE4 mice that showed evidence for hemorrhage contained fibrillar amyloid beta based on thioflavine-S staining. Aged apoE4 mice contained predominantly vascular amyloid deposits in the frontal cortex and hippocampus, but also showed evidence for parenchymal amyloid deposits. Most of the parenchymal amyloid appeared diffuse in nature; however, a small fraction was thioflavine-S positive, indicating presence of fibrillar amyloid. Electron microscopy further revealed evidence for fibrillar deposits in the vessel walls of apoE4 mice, but not apoE3 mice. The apoE4 targeted replacement mice do not harbor any mutation in the amyloid precursor protein gene and, therefore, are similar to the majority of humans susceptible to cerebral amyloid angiopathy and ICH, where the APOE genetic polymorphism is the only known genetic risk factor.

Neuroanatomical correlates of malingered memory impairment: event-related fMRI of deception on a recognition memory task.

PRIMARY OBJECTIVE: Event-related, functional magnetic resonance imaging (fMRI) data were acquired in healthy participants during purposefully malingered and normal recognition memory performances to evaluate the neural substrates of feigned memory impairment. METHODS AND PROCEDURES: Pairwise, between-condition contrasts of neural activity associated with discrete recognition memory responses were conducted to isolate dissociable neural activity between normal and malingered responding while simultaneously controlling for shared stimulus familiarity and novelty effects. Response timing characteristics were also examined for any association with observed between-condition activity differences. OUTCOMES AND RESULTS: Malingered recognition memory errors, regardless of type, were associated with inferior parietal and superior temporal activity relative to normal performance, while feigned recognition target misses produced additional dorsomedial frontal activation and feigned foil false alarms activated bilateral ventrolateral frontal regions. Malingered response times were associated with activity in the dorsomedial frontal, temporal and inferior parietal regions. Normal memory responses were associated with greater inferior occipitotemporal and dorsomedial parietal activity, suggesting greater reliance upon visual/attentional networks for proper task performance. CONCLUSIONS: The neural substrates subserving feigned recognition memory deficits are influenced by response demand and error type, producing differential activation of cortical regions important to complex visual processing, executive control, response planning and working memory processes.

A SAGE study of apolipoprotein E3/3, E3/4 and E4/4 allele-specific gene expression in hippocampus in Alzheimer disease.

APOE4 allele is a major risk factor for late-onset Alzheimer disease (AD). The mechanism of action of APOE in AD remains unclear. To study the effects of APOE alleles on gene expression in AD, we have analyzed the gene transcription patterns of human hippocampus from APOE3/3, APOE3/4, APOE4/4 AD patients and normal control using Serial Analysis of Gene Expression (SAGE). Using SAGE, we found gene expression patterns in hippocampus of APOE3/4 and APOE4/4 AD patients differ substantially from those of APOE3/3 AD patients. APOE3/4 and APOE4/4 allele expression may activate similar genes or gene pools with associated functions. APOE4 AD alleles activate multiple tumor suppressors, tumor inducers and negative regulator of cell growth or repressors that may lead to increased cell arrest, senescence and apoptosis. In contrast, there is decreased expression of large clusters of genes associated with synaptic plasticity, synaptic vesicle docking and fusing and axonal/neuronal outgrowth. In addition, reduction of neurotransmitter receptors and Ca2+ homeostasis, disruption of multiple signal transduction pathways, loss of cell protection, and perhaps most notably, mitochondrial oxidative phosphorylation/energy metabolism are associated with APOE3/4 and APOE4/4 AD alleles. These findings may help define the mechanisms that APOE4 contribute that increase risk for AD and identify new candidate genes conferring susceptibility to AD.

A comparative analysis of the information content in long and short SAGE libraries.

BACKGROUND: Serial Analysis of Gene Expression (SAGE) is a powerful tool to determine gene expression profiles. Two types of SAGE libraries, ShortSAGE and LongSAGE, are classified based on the length of the SAGE tag (10 vs. 17 basepairs). LongSAGE libraries are thought to be more useful than ShortSAGE libraries, but their information content has not been widely compared. To dissect the differences between these two types of libraries, we utilized four libraries (two LongSAGE and two ShortSAGE libraries) generated from the hippocampus of Alzheimer and control samples. In addition, we generated two additional short SAGE libraries, the truncated long SAGE libraries (tSAGE), from LongSAGE libraries by deleting seven 5' basepairs from each LongSAGE tag. RESULTS: One problem that occurred in the SAGE study is that individual tags may have matched to multiple different genes - due to the short length of a tag. We found that the LongSAGE tag maps up to 15 UniGene clusters, while the ShortSAGE and tSAGE tags map up to 279 UniGene clusters. Both long and short SAGE libraries exhibit a large number of orphan tags (no gene information in UniGene), implying the limitation of the UniGene database. Among 100 orphan LongSAGE tags, the complete sequences (17 basepairs) of nine orphan tags match to 17 genomic sequences; four of the orphan tags match to a single genomic sequence. Our data show the potential to resolve 4-9% of orphan LongSAGE tags. Finally, among 400 tSAGE tags showing significant differential expression between AD and control, 79 tags (19.8%) were derived from multiple non-significant LongSAGE tags, implying the false positive results. CONCLUSION: Our data show that LongSAGE tags have high specificity in gene mapping compared to ShortSAGE tags. LongSAGE tags show an advantage over ShortSAGE in identifying novel genes by BLAST analysis. Most importantly, the chances of obtaining false positive results are higher for ShortSAGE than LongSAGE libraries due to their specificity in gene mapping. Therefore, it is recommended that the number of corresponding UniGene clusters (gene or ESTs) of a tag for prioritizing the significant results be considered.

Strategies for dissecting genetic-environmental interactions in neurodegenerative disorders.

Complex genetic and environmental interactions contribute to abnormal aging and neurodegenerative disorders. We present information from a series of 1136 consecutive patients presenting with cognitive disorders and show possible significant contribution of toxic environmental and occupational exposures to pathological aging (21% of patients) and interactions of these exposures with common polymorphisms that affect cell injury and inflammation. Such exposures may lower age of onset to same degree as APOE4/4. Common polymorphisms in apolipoprotein E (APOE), hemochromatosis gene (Hfe) and alpha-1-antitrypsin (AAT) are present in up to 40+% of patients and may partially account for differences in clinical syndrome, age of onset and rate of progression. Strategies for the study of these disorders must also consider the role and treatment of common co-morbid illnesses such as alcohol use, nutritional deficiencies, sleep disorders, and pre-existing affective disorder. APOE, Hfe, and AAT genes are expressed in liver tissue and in macrophages and are involved in the host innate immune response to stress, inflammation and infections. Hfe and AAT are involved in iron metabolism and their polymorphisms may contribute to hepatosteatosis and altered homeostasis of lipids (role of APOE), iron, and trace minerals. Some of these responses may be adaptive. Hfe and AAT modulate the apparent effects of toxic exposures on age of onset and progression rate. C282Y polymorphism paradoxically reverses APOE4/4 effect on age of onset. S and Z AAT polymorphisms may attenuate earlier age of onset in persons with toxic or environmental exposure. AAT S or Z polymorphisms are present in 25% of persons with anxiety disorder and 42% of persons with bipolar disorder compared to 10% of control group without pre-existing affective disorder. Common genetic polymorphisms that affect the response to inflammation and cell injury provide a beginning strategy for dissecting neurodegenerative disorders. The effects of APOE, Hfe, and AAT on glucose, lipid, iron and trace mineral homeostasis may affect normal development and aging of the nervous system in addition to their effects on outcome of toxic environmental and occupational exposures and susceptibility and outcome of neurodegenerative illnesses.

Parsing the genetic heterogeneity of chromosome 12q susceptibility genes for Alzheimer disease by family-based association analysis.

Previous linkage studies have suggested that chromosome 12 may harbor susceptibility genes for late-onset Alzheimer disease (LOAD). No risk genes on chromosome 12 have been conclusively identified yet. We have reported that the linkage evidence for LOAD in a 12q region was significantly increased in autopsy-confirmed families particularly for those showing no linkage to alpha-T catenin gene, a LOAD candidate gene on chromosome 10 [LOD score increased from 0.1 in the autopsy-confirmed subset to 4.19 in the unlinked subset (optimal subset); p<0.0001 for the increase in LOD score], indicating a one-LOD support interval spanning 6 Mb. To further investigate this finding and to identify potential candidate LOAD risk genes for follow-up analysis, we analyzed 99 single nucleotide polymorphisms in this region, for the overall sample, the autopsy-confirmed subset, and the optimal subset, respectively, for comparison. We saw no significant association (p<0.01) in the overall sample. In the autopsy-confirmed subset, the best finding was obtained in the activation transcription factor 7 (ATF7) gene (single-locus association, p=0.002; haplotype association global, p=0.007). In the optimal subset, the best finding was obtained in the hypothetical protein FLJ20436 (FLJ20436) gene (single-locus association, p=0.0026). These results suggest that subset and covariate analyses may be one approach to help identify novel susceptibility genes on chromosome 12q for LOAD.

Differences in apolipoprotein E3/3 and E4/4 allele-specific gene expression in hippocampus in Alzheimer disease.

Apolipoprotein E4 (APOE4) allele is a major risk factor for late-onset familial and sporadic Alzheimer disease (AD). The mechanism of action of APOE in the etiology of AD remains unclear. Using gene expression (microarray) analysis of human hippocampus from APOE3/3 AD and APOE4/4 AD cases, we found different gene transcription patterns between APOE4/4 and APOE3/3 AD cases. The expression of APOE4/4 alleles, in comparison to APOE3/3, is associated with upregulation of multiple gene transcripts encoding cell growth suppresser or arrest, signal transduction, myelinogenesis, cell adhesion and migration, heavy metal metabolism and detoxification. Whereas the APOE4 gene expression is associated with downregulation of gene transcripts involved in mitochondrial oxidative phosphorylation and energy metabolism, synaptic vesicle docking and fusing, and synaptic plasticity compared to APOE3. These mechanisms may contribute increased risk for AD and for cognitive dysfunction in AD patients who carry the APOE4 allele(s).

Cardiovascular damage in Alzheimer disease: autopsy findings from the Bryan ADRC.

Autopsy information on cardiovascular damage was investigated for pathologically confirmed Alzheimer disease (AD) patients (n=84) and non-AD control patients (n=60). The 51 relevant items were entered into a grade-of-membership model to describe vascular damage in AD. Five latent groups were identified "I: early-onset AD," "II: controls, cancer," "III: controls, extensive atherosclerosis," "IV: late-onset AD, male," and "V: late-onset AD, female." Expectedly, Groups IV and V had elevated APOE epsilon 4 frequency. Unexpectedly, there was limited atherosclerosis and frequent myocardial valve and ventricular damage. The findings do not indicate a strong relationship between atherosclerosis and AD, although both are associated with the APOE epsilon 4. Instead, autopsy findings of extensive atherosclerosis were associated with possible, not probable or definite AD, and premature death. They are consistent with the hypothesis that brain hypoperfusion contributes to dementia, possibly to AD pathogenesis, and raise the possibility that the APOE allele epsilon 4 contributes directly to heart valve and myocardial damage.

Expression profiling of substantia nigra in Parkinson disease, progressive supranuclear palsy, and frontotemporal dementia with parkinsonism.

BACKGROUND: Parkinson disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra. Genes contributing to rare mendelian forms of PD have been identified, but the genes involved in the more common idiopathic PD are not well understood. OBJECTIVES: To identify genes important to PD pathogenesis using microarrays and to investigate their potential to aid in diagnosing parkinsonism. DESIGN: Microarray expression analysis of postmortem substantia nigra tissue. PATIENTS: Substantia nigra samples from 14 unrelated individuals were analyzed, including 6 with PD, 2 with progressive supranuclear palsy, 1 with frontotemporal dementia with parkinsonism, and 5 control subjects. MAIN OUTCOME MEASURES: Identification of genes significantly differentially expressed (P<.05) using Affymetrix U133A microarrays. RESULTS: There were 142 genes that were significantly differentially expressed between PD cases and controls and 96 genes that were significantly differentially expressed between the combined progressive supranuclear palsy and frontotemporal dementia with parkinsonism cases and controls. The 12 genes common to all 3 disorders may be related to secondary effects. Hierarchical cluster analysis after exclusion of these 12 genes differentiated 4 of the 6 PD cases from progressive supranuclear palsy and frontotemporal dementia with parkinsonism. CONCLUSIONS: Four main molecular pathways are altered in PD substantia nigra: chaperones, ubiquitination, vesicle trafficking, and nuclear-encoded mitochondrial genes. These results correlate well with expression analyses performed in several PD animal models. Expression analyses have promising potential to aid in postmortem diagnostic evaluation of parkinsonism.

Neuropathologic, biochemical, and molecular characterization of the frontotemporal dementias.

The frontotemporal dementias (FTDs) are a heterogeneous group of neurodegenerative disorders that are characterized clinically by dementia, personality changes, language impairment, and occasionally extrapyramidal movement disorders. Historically, the diagnosis and classification of FTDs has been fraught with difficulties, especially with regard to establishing a consensus on the neuropathologic diagnosis. Recently, an international group of scientists participated in a consensus conference to develop such neuropathologic criteria. They recommended a diagnostic classification scheme that incorporated a biochemical analysis of the insoluble tau isoform composition, as well as ubiquitin immunohistochemistry. The use and reliability of this classification system has yet to be examined. In this study, we evaluated 21 cases of FTD. Using traditional histochemical stains and tau protein and ubiquitin immunohistochemistry, we separated each case into one of the following categories: classic Pick disease (PiD; n = 7), corticobasal degeneration (CBD; n = 5), dementia lacking distinctive histopathologic features (DLDH; n = 4), progressive supranuclear palsy (PSP; n = 2), frontotemporal lobar degeneration with motor neuron disease or motor neuron disease-type inclusions (FTLD-MND/MNI; n = 2), and neurofibrillary tangle dementia (NFTD; n = 1). Additionally, we independently categorized each case by the insoluble tau isoform pattern, including 3R (n = 5), 4R (n = 7), 3R/4R (n = 3), and no insoluble tau (n = 6). As suggested by the proposed diagnostic scheme, we found that the insoluble tau isoform patterns correlated strongly with the independently derived histopathologic diagnoses (p < 0.001). The data show that cases containing predominantly 3R tau were classic PiD (100%). Cases with predominantly 4R tau were either CBD (71%) or PSP (29%). Cases with both 3R and 4R tau were either a combination of PiD and Alzheimer disease (67%) or NFTD (33%). Finally, cases with no insoluble tau were either DLDH (67%) or FTLD-MND/MNI (33%). To further characterize these cases, we also performed quantitative Western blots for soluble tau, APOE genotyping, and, in selected cases, tau gene sequencing. We show that soluble tau is reduced in DLDH and FTLD-MND/MNI and that APOE4 is overrepresented in PiD and DLDH. We also identified a new family with the R406W mutation and pathology consistent with NFTD. This study validates the recently proposed diagnostic criteria and forms a framework for further refinement of this classification scheme.

Human apoE4-targeted replacement mice display synaptic deficits in the absence of neuropathology.

The human APOE*4 allele is associated with an early age of onset and increased risk of Alzheimer's disease (AD). Long before the onset of AD, cognitive deficits can be identified in APOE*4 carriers. We examined neurons in the lateral amygdala of young apolipoprotein (apo) E3 and apoE4 targeted replacement (TR) mice for changes in synaptic integrity. ApoE4 mice displayed significantly reduced excitatory synaptic transmission and dendritic arborization. Despite these changes there were no signs of gliosis, amyloid deposition or neurofibrillary tangles in these mice. To our knowledge, this is the first study to suggest that cognitive deficits in APOE*4 carriers are due to inherent defects in synaptic function that appear prior to any age-dependent markers of neuropathology.

Comprehensive association analysis of APOE regulatory region polymorphisms in Alzheimer disease.

Several recent case-control studies have examined the association between single nucleotide polymorphisms (SNPs) in the promoter region of the apolipoprotein E gene (APOE) and risk of Alzheimer disease (AD), with conflicting results. We assessed the relation between five APOE region SNPs and risk of AD in both case-control and family-based analyses. We observed a statistically significant association with the +5361T allele in the overall case-control analysis (P value=0.04) after adjusting for the known effect of the APOE-4 allele. Further analysis revealed this association to be limited to carriers of the APOE-4 allele. Age-stratified analyses in the patients with age at onset of 80 years or greater and age-matched controls showed that the -219T allele (P value=0.009) and the +113C allele (P value=0.03) are associated with increased risk of AD. Despite these findings, haplotype and family-based association analyses were unable to provide evidence that the APOE region SNPs influenced risk of AD independent of the APOE-4 allele. In addition to risk, we tested for association between the SNPs and age at onset of AD, but found no association in the case-control or family based analyses. In conclusion, SNPs +5361, or a SNP in strong linkage disequilibrium, may confer some additional risk for developing AD beyond the risk due to APOE-4; however, the effect independent of APOE-4 is likely to be small.

Vascular smooth muscle actin is reduced in Alzheimer disease brain: a quantitative analysis.

We analyzed smooth muscle actin (SMA) immunoreactivity in brain blood vessels of 10 ApoE 4,4 Alzheimer disease (AD) patients and 10 ApoE 3,3 AD patients matched for age, sex, and duration of dementia. We also examined 10 cognitively and neuropathologically normal controls matched for age and sex. Vascular SMA immunoreactivity in the arachnoid, grey matter, and white matter was quantified by image analysis. There was less SMA immunoreactivity in blood vessels of all AD patients when compared to cognitively and neuropathologically normal controls (p < 0.001). In addition, arachnoidal vessels of ApoE 4,4 AD patients had less SMA immunoreactivity than ApoE 3,3 AD patients (p < 0.05). There is decreased vascular SMA density in arachnoid, grey matter, and white matter blood vessels in patients with AD when compared to age matched, cognitively and neuropathologically normal controls. The severity of the loss of SMA within the AD group may depend on ApoE type.

Analysis of European mitochondrial haplogroups with Alzheimer disease risk.

We examined the association of mtDNA variation with Alzheimer disease (AD) risk in Caucasians (989 cases and 328 controls) testing the effect of individual haplogroups and single nucleotide polymorphisms (SNPs). Logistic regression analyses were used to assess risk of haplogroups and SNPs with AD in both main effects and interaction models. Males classified as haplogroup U showed an increase in risk (OR = 2.30; 95% CI, 1.03-5.11; P = 0.04) of AD relative to the most common haplogroup H, while females demonstrated a significant decrease in risk with haplogroup U (OR = 0.44 ; 95% CI, 0.24-0.80; P = 0.007). Our results were independent of APOE genotype, demonstrating that the effect of mt variation is not confounded by APOE4 carrier status. We suggest that variations within haplogroup U may be involved in AD expression in combination with environmental exposures or nuclear proteins other than APOE.

APOE genotype-specific differences in human and mouse macrophage nitric oxide production.

Individuals expressing an APOE4 genotype demonstrate increased Alzheimer's disease (AD) neuropathology and a decreased onset age. The APOE4 gene may act by modulating the CNS immune response. Using human monocyte-derived macrophages (MDM), we show a significantly greater increase in NO production during immune activation in MDM from APOE4 AD patients compared to normal, age-matched individuals or to AD patients with an APOE 3/3 genotype. Microglia and peritoneal macrophages from APOE4 targeted replacement mice demonstrate a similar increase in NO compared to the APOE3 targeted replacement mice. The enhanced macrophage responsiveness and the increased production of NO in APOE4 AD patients may predispose the CNS to an increased potential for nitration and nitrosation, consistent with the redox imbalance and neuroinflammatory state seen in AD.

When should functional neuroimaging techniques be used in the diagnosis and management of Alzheimer's dementia? A decision analysis.

BACKGROUND: Functional neuroimaging, including positron emission tomography (PET), has been proposed for use in diagnosing Alzheimer's disease-related dementia (AD). OBJECTIVE: The objective of this study was identify the circumstances under which PET scanning for the diagnosis of AD maximizes health outcomes. METHODS: A Markov-model-based decision analysis was conducted using estimates derived from the literature on AD epidemiology, the accuracy of PET, and donepezil treatment efficacy. The target population for the analysis was assumed to be US men and women who either have mild AD or are asymptomatic but at an elevated risk of developing AD owing to disease in a first-degree relative (parent or sibling). The time horizon was the patient lifetime. We compared treatment 1) based on an American Academy of Neurology (AAN) clinical evaluation either alone; 2) in combination with PET scanning; or 3) empirically based on a family history. Outcomes measures were life expectancy, quality-adjusted life-years (QALYs), and (severe) dementia-free life expectancy (SDFLE). RESULTS: For both patient populations, treating all patients based on an AAN evaluation without further testing using PET resulted in the greatest gains in life expectancy, QALYs, and SDFLEs. PET-based testing was the second preferred strategy compared to no intervention. The rankings of the strategies were sensitive to severity of treatment complications: analyses of hypothetical treatments with the potential for severe complications indicated that testing was preferred if the treatment was effective but had moderate complications. CONCLUSIONS: These results suggest that current treatments, which are relatively benign and may slow progression of disease, should be offered to patients who are identified as having AD based solely on an AAN clinical evaluation. A clinical evaluation that includes functional neuroimaging based testing will be warranted, however, when new treatments that are effective at slowing disease progression but have the potential for moderate to severe complications become available.