Alzheimer Disease

Alzheimer's disease (AD) pathology is estimated to develop many years before detectable cognitive decline. Fluid and imaging biomarkers may identify people in early symptomatic and even preclinical stages, possibly when potential treatments can best preserve cognitive function. We previously reported that cerebrospinal fluid (CSF) levels of amyloid-b 42 (Ab 42 ) serve as an excellent marker for brain amyloid as detected by the amyloid tracer, Pittsburgh compound B (PIB). Using data from 189 cognitively normal participants, we now report a positive linear relationship between CSF tau/ptau 181 (primary constituents of neurofibrillary tangles) with the amount of cortical amyloid. We observe a strong inverse relationship of cortical PIB binding with CSF Ab 42 but not for plasma Ab species. Some individuals have low CSF Ab 42 but no cortical PIB binding. Together, these data suggest that changes in brain Ab 42 metabolism and amyloid formation are early pathogenic events in AD, and that significant disruptions in CSF tau metabolism likely occur after Ab 42 initially aggregates and increases as amyloid accumulates. These findings have important implications for preclinical AD diagnosis and treatment.

Autosomal-dominant Alzheimer disease (ADAD) is a genetic disorder caused by mutations in Amyloid Precursor Protein (APP) or Presenilin (PSEN) genes. Studies from families with ADAD have been critical to support the amyloid cascade hypothesis of Alzheimer disease (AD), the basis for the current development of amyloid-based disease-modifying therapies in sporadic AD (SAD). However, whether the pathological changes in APP processing in the CNS in ADAD are similar to those observed in SAD remains unclear. In this study, we measured b-site APP-cleaving enzyme (BACE) protein levels and activity, APP and APP C-terminal fragments in brain samples from subjects with ADAD carrying APP or PSEN1 mutations (n = 18), patients with SAD (n = 27) and agematched controls (n = 22). We also measured sAPPb and BACE protein levels, as well as BACE activity, in CSF from individuals carrying PSEN1 mutations (10 mutation carriers and 7 non-carrier controls), patients with SAD (n = 32) and age-matched controls (n = 11). We found that in the brain, the pattern in ADAD was characterized by an increase in APP b-C-terminal fragment (b-CTF) levels despite no changes in BACE protein levels or activity. In contrast, the pattern in SAD in the brain was mainly characterized by an increase in BACE levels and activity, with less APP b-CTF accumulation than ADAD. In the CSF, no differences were found between groups in BACE activity or expression or sAPPb levels. Taken together, these data suggest that the physiopathological events underlying the chronic Ab production/clearance imbalance in SAD and ADAD are different. These differences should be considered in the design of intervention trials in AD.

Caring for Caregivers The Need: With the growth of the aged population, more adults with chronic illnesses and conditions require assistance in going about their daily living. More than 80 percent of this assistance is provided by informal caregivers, primarily family members. Surveys by the North Carolina Division of Aging and Adult Services indicate that roughly a quarter of North Carolinians reported they had cared for a family member or friend age 60 or older during the past month. Caregiving often takes a physical, emotional and financial toll on caregivers. Studies have shown that caregivers can be helped by a variety of interventions, including information and case assistance, education for self-care, skills training and access to other community services such as respite care, support groups and flexible workplace options.

Bé né fice d'un programme cognitivo-comportemental et pluridisciplinaire de prise en charge de la maladie d'Alzheimer sur l'anxié té du conjoint : é tude française ELMMA Beneficial effect of a cognitive behavioral and multidisciplinary program in Alzheimer Disease on spouse caregiver anxiety: French study ELMMA

The global prevalence of dementia has been estimated to be as high as 24 million, and is predicted to double every 20 years until at least 2040. As the population worldwide continues to age, the number of individuals at risk will also increase, particularly among the very old. Alzheimer disease is the leading cause of dementia beginning with impaired memory. The neuropathological hallmarks of Alzheimer disease include diffuse and neuritic extracellular amyloid plaques in brain that are frequently surrounded by dystrophic neurites and intraneuronal neurofibrillary tangles. The etiology of Alzheimer disease remains unclear, but it is likely to be the result of both genetic and environmental factors. In this review we discuss the prevalence and incidence rates, the established environmental risk factors, and the protective factors, and briefly review genetic variants predisposing to disease.

To investigate whether variations within normal ranges of thyroid functioning are related to cognitive and neuropsychiatric functioning in Alzheimer disease (AD). Mild alterations of thyroid hormone levels, even in the normal range, are associated with changes in mood and cognitive functioning in older, nondemented adults, and lower concentrations of thyroid hormones have been shown to be associated with an increased risk for cognitive decline. Less is known about the relationship between thyroid hormone levels and cognitive and neuropsychiatric dysfunction in AD. Twenty-eight euthyroid patients with AD on donepezil underwent evaluation of thyroid status, including measures of thyroid-stimulating hormone (TSH) and free thyroxine (FT4), and cognitive and neuropsychiatric assessment with the Alzheimer's Disease Assessment Scale, Neuropsychiatric Inventory, and Visual Analog Mood Scales. Correlational analyses indicated statistically significant associations between FT4 concentrati...

The endoplasmic reticulum (ER) is involved in several crucial cellular functions, e.g. protein folding and quality control, maintenance of Ca 2+ balance, and cholesterol synthesis. Many genetic and environmental insults can disturb the function of ER and induce ER stress. ER contains three branches of stress sensors, i.e. IRE1, PERK and ATF6 transducers, which recognize the misfolding of proteins in ER and activate a complex signaling network to generate the unfolded protein response (UPR). Alzheimer's disease (AD) is a progressive neurodegenerative disorder involving misfolding and aggregation of proteins in conjunction with prolonged cellular stress, e.g. in redox regulation and Ca 2+ homeostasis. Emerging evidence indicates that the UPR is activated in neurons but not in glial cells in AD brains. Neurons display pPERK, peIF2α and pIRE1α immunostaining along with abundant diffuse staining of phosphorylated tau protein. Recent studies have demonstrated that ER stress can also induce an inflammatory response via different UPR transducers. The most potent pathways are IRE1-TRAF2, PERK-eIF2α, PERK-GSK-3, ATF6-CREBH, as well as inflammatory caspase-induced signaling pathways. We will describe the mechanisms which could link the ER stress of neurons to the activation of the inflammatory response and the evolution of pathological changes in AD.

This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn.

The study evaluates the efficacy of a procedural memory stimulation programme in mild and mild-moderate Alzheimer's disease (AD). Twenty basic and instrumental activities of daily living have been selected, and divided into two groups, comparable for difficulty. Ten normal elderly subjects (age 68.0L4.8 years; MMSE score: 28.7+ 0.9; education: 7.6k3.5 years) were asked to perform the two groups of daily activities and the time required to perform the tasks of each group was recorded and used as a reference. Ten mild and mild-moderate AD patients (age 77.2k5.3 years; MMSE score: 19.823.5; education: 7.3k4.7 years) without major behavioural disturbances constituted the experimental group. Patients were evaluated in all 20 daily activities and the time employed was recorded at baseline and after a 3-week training (1 h/d, 5 d/week) period. Five patients were trained during the 3 weeks on half of the 20 daily activities and the other five patients were trained on the remainder. This procedure was adopted in order to detect separately the improvement in "trained" and "not trained" activities, allowing to control better the effects of the intervention. The assessment of the functional impact of the training was directly measured, through the variation of time employed to perform tasks before and after training. After 3 weeks of training a significant improvement was observed for the trained activities, from 3.6 to 1.9 standard deviations below the performance of the normal elderly controls (P<O.O5). A D patients improved also in not-trained activities from 3.5 to 2.7 standard deviations below the controls' performance (P<O.O5). The rehabilitation of activities of daily living through developing procedural memory strategies may be effective in mild and mild-moderate problem is the

In this review we summarize the epidemiological, cross-sectional, and interventional studies examining the association between physical activity and brain volume, function, and risk for Alzheimer's disease. The epidemiological literature provides compelling evidence that greater amounts of physical activity are associated with a reduced risk of dementia in late life. In addition, randomized interventions using neuroimaging tools have reported that participation in physical activity increases the size of prefrontal and hippocampal brain areas, which may lead to a reduction in memory impairments. Consistent with these findings, longitudinal studies using neuroimaging tools also find that the volume of prefrontal and hippocampal brain areas are larger in individuals who engaged in more physical activity earlier in life. We conclude from this review that there is convincing evidence that physical activity has a consistent and robust association with brain regions implicated in age-related cognitive decline and Alzheimer's disease. In addition to summarizing this literature we provide recommendations for future research on physical activity and brain health.

The apolipoprotein E ε4 (APOE ε4) allele is a genetic risk factor for Alzheimer disease. Recently, depression has also become recognized as a risk factor for dementia. However, the possible effect of the APOE genotype on the association between depression and dementia is unexamined.

Objectives-It has been shown that atrophy of medial temporal lobe structures such as the hippocampus and entorhinal cortex shown on MRI may distinguish patients with Alzheimer's disease from healthy controls. However, the diagnostic value of visual inspection and volumetry of medial temporal lobe atrophy (MTA) on MRI in a clinical setting is insuYciently known. Methods-Medial temporal lobe atrophy in 143 patients was visually rated from hard copies, using a 0-4 rating scale and a comparison was made with the volumes (cm 3 ) of the medial temporal lobe as estimated with volumetry, using a stereological method. All patients were recruited in an unselected way in a clinical setting in the centre for memory impairments at the Huddinge University Hospital. Patients with Alzheimer's disease (n=41), patients with other dementias (vascular dementia, frontotemporal dementia, and unspecified dementia; n=36) as well as non-demented subjects (n=66) were included. Medial temporal atrophy and volumetry were evaluated as a diagnostic tool by performing logistic regression analysis including age, sex, and mini mental state examination (MMSE) score and calculating the sensitivity and specificity and percentage correct classification.

A large number of micropropagated Euphorbia millii shoots from temporary immersion bioreactor showed thick broad leaves that were translucent, wrinkled and/or curled and brittle, symptoms of hyperhydricity. The environment inside bioreactor normally used in plant micropropagation is characterised by high relative humidity, poor gaseous exchange between the internal atmosphere of the bioreactor and its surrounding environment, and the accumulation of ethylene, conditions that may induce physiological disorders. A comparison of hyperhydric shoots (HS) with normal plants shows marked increase in malondialdehyde (MDA) content in HS plants. MDA, a decomposition product of polyunsaturated fatty acids hydroperoxides, has been utilized very often as a suitable biomarker for lipid peroxidation, which is an effect of oxidative damage. This hypothesis is also confirmed by the higher lipoxygenase (LOX) activity in HS plants. The potential role of antioxidant enzymes in protecting hyperhydric shoots from oxidative injury was examined by analyzing enzyme activities and isozyme profiles of hyperhydric and non-hyperhydric leaves of E. millii. Superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) activity were significantly higher in hyperhydric tissue as compared to non-hyperhydric normal leaf tissue. After native polyacrylamide gel electrophoresis (PAGE) analysis, seven SOD isoenzymes were detected and the increase in SOD activity observed in hyperhydric tissue seemed to be mainly due to Mn-SOD and Cu/Zn-SOD. The activity of ascorbate peroxidase (APX), glutathione reductase (GR), monodehydroascorbate reductase (MDHAR) and dehydroascorbate reductase (DHAR) was proportionally increased in HS tissue compared to normal leaves indicating a crucial role in eliminating toxic H 2 O 2 from plant cells. The depletion of GSH and total glutathione in spite of higher GR activities observed in HS tissue indicates that mechanism of antioxidant defense was by enhanced oxidation of GSH to GSSG by DHAR yielding ascorbate (AA). The antioxidant metabolism has been shown to be important in determining the ability of plants to survive in hyperhydric stress and the up regulation of these enzymes would help to reduce the build up of ROS.

Mutations in the beta-amyloid precursor protein gene (APP) have been found in familial early-onset Alzheímer’s disease (AD). DNA variants at several genes have been linked to the risk of developing the most common late-onset form of AD (LOAD). A few studies analyzed the contribution of APP variants to LOAD, with negative or conflicting results. We determined the variation in the 18 APP exons and flanking intronic sequences in a total of 350 LOAD patients from Spain. A total of 13 nucleotide changes were found and 6 were new and not found among 340 healthy controls, including the only missense change (D243N). The in silico analysis suggested that none of them would have an effect on pre-mRNA splicing or protein folding (D243N). Patients and controls were also genotyped for three APP promoter polymorphisms, and none of them was significantly associated with LOAD. We concluded that APP variants would not contribute to the risk of developing LOAD in our population.

Alzheimer’s disease (AD) is the major cause of dementia in the elderly. The biochemical changes that precede AD may be present up to 20 years before the clinical manifestation of the disease. The translational development of AD biomarkers may be theoretically achieved via two different strategies: the first strategy can be defined as ‘knowledge-based’ (deductive method), while the second one

Despite being considered the archetypal non-genetic neurological disorder, genetic analysis of Parkinson's disease has shown that there are at least three genetic loci. Furthermore, these analyses have suggested that the phenotype of the pathogenic loci is wider than simple Parkinson's disease and may include Lewy body dementia and some forms of essential tremor. Identification of α α α α-synuclein as the first of the loci involved in Parkinson's disease and the identification of this protein in pathological deposits in other disorders has led to the suggestion that it may share pathogenic mechanisms with multiple system atrophy, Alzheimer's disease and prion disease and that these mechanisms are related to a synuclein pathway to cell death. Finally, genetic analysis of the synuclein diseases and the tau diseases may indicate that this synuclein pathway is an alternative to the tau pathway to cell death.

and preparation in relation to patients with deseases affecting the central nervous system. Those patients may undergo various forms of surgery unrelated to the central nervous system disease. We discuss the effect of physiologic and pharmacological factors on cerebral autoregulation and control of intracranial pressure alongside its clinical relevance with the help of new evidence. Recent findings: Regardless of the reason for surgery, coexisting diseases of brain often have important implications when selecting anesthetic drugs, procedures and monitoring techniques. Suppression of cerebral metabolic rate is not the sole mechanism for the neuroprotective effect of anaesthetic agents. There are certain general principles, but also some specific circumstances, when we are talking about optimal anesthetic procedure for a patient with coexisting brain disease. . Summary: Intraoperative cerebral autoregulation monitoring is an important consideration for the patients with coexisting neurological disease. Transcranial Doppler based static autoregulation measurements appears to be the most robust bedside method for this purpose.

with enhanced A␤ immunoreactivity and birefringent Congo Red staining. Synthetic A␤ bound ␣B-crystallin, an abundant cytosolic lens protein. A␤ promoted lens protein aggregation that showed protofibrils, birefringent Congo Red staining, and A␤/␣B-crystallin coimmunoreactivity.

Neuropsychological, neuropathological and neurochemical findings show different types of dementias. Few of them have been able to confirm a division into "subcortical" and "cortical" dementia, so this concept has to be questioned. The present clinical study compared type and severity of dementia in 12 Parkinson-patients (PD) and 12 Alzheimer-patients (AD). The age-adjusted normal value differed a significantly from both patient groups. No significant difference in pattern of neuropsychological deficits between PD-and AD-patients was apparent. However, after similar duration of illness, dementia was more severe in AD-than in PD-patients.

Latrepirdine (Dimebon) is a pro-neurogenic, antihistaminic compound that has yielded mixed results in clinical trials of mild to moderate Alzheimer's disease, with a dramatically positive outcome in a Russian clinical trial that was unconfirmed in a replication trial in the United States. We sought to determine whether latrepirdine (LAT)-stimulated amyloid precursor protein (APP) catabolism is at least partially attributable to regulation of macroautophagy, a highly conserved protein catabolism pathway that is known to be impaired in brains of patients with Alzheimer's disease (AD). We utilized several mammalian cellular models to determine whether LAT regulates mammalian target of rapamycin (mTOR) and Atg5-dependent autophagy. Male TgCRND8 mice were chronically administered LAT prior to behavior analysis in the cued and contextual fear conditioning paradigm, as well as immunohistological and biochemical analysis of AD-related neuropathology. Treatment of cultured mammalian cells with LAT led to enhanced mTOR-and Atg5-dependent autophagy. Latrepirdine treatment of TgCRND8 transgenic mice was associated with improved learning behavior and with a reduction in accumulation of Ab42 and a-synuclein. We conclude that LAT possesses pro-autophagic properties in addition to the previously reported pro-neurogenic properties, both of which are potentially relevant to the treatment and/or prevention of neurodegenerative diseases. We suggest that elucidation of the molecular mechanism(s) underlying LAT effects on neurogenesis, autophagy and behavior might warranty the further study of LAT as a potentially viable lead compound that might yield more consistent clinical benefit following the optimization of its pro-neurogenic, pro-autophagic and/or pro-cognitive activities.

We have extensively analyzed the biochemical and histochemical profiles of the tau protein from the rTg4510 transgenic mouse model in which the animals uniquely develop forebrain tau pathologies similar to those found in human tauopathies. Levels of several soluble phosphorylated tau species were highest at 1 month relative to later time points , suggesting that certain tau hyperphosphorylation events were insufficient to drive tangle formation in young mice. Despite a robust , pre-tangle-like accumulation of phospho-tau in 1-month-old mice , this material was cleared by 3 months , indicating that the young mouse brain either fails to facilitate tau insolubility or possesses an enhanced ability to clear tau relative to the adult. We also found that while heat shock protein expression increased with normal aging , this process was accelerated in rTg4510 mice. Moreover , by exploiting an exon 10 (؊) specific antibody , we demonstrated that endogenous mouse tau turnover was slowed in response to human tau over-expression, and that this endogenous tau adopted disease-related properties. These data suggest that a younger brain fails to develop lasting tau pathology despite elevated levels of phosphorylated tau , perhaps because of reduced expression of stress-related proteins. Moreover , we show that the active production of small amounts of abnormal tau protein facilitates dysfunction and accumulation of otherwise normal tau , a significant implication for the pathogenesis of patients with Alzheimer's disease.

Background: Alzhcimcr's disease (AD) is the most common cause of cognitive impairment in older patients and is expected to increase greatly in prevalence. Interventions that could delay disease onset would have a major public health impact. Objective: The objective of this article is to review evidence from epidemiologic studies and controlled trials addressing whether AD can be prevented. Methods: Data were gathered through a comprehensive, systematic search of MEDLINE using focused search criteria and spanning a 6-year period from January 1998 through January 2004; a hand search of reference lists from these studies and reviews; a review of the Cochrane Database of Systematic Reviews; and a hand search of relevant journals. Selection of articles was based on the clinical focus. Additional inclusion criteria were used to select key articles that contained higher-level evidence in accordance with explicit, validated criteria. Results: Preventive interventions for AD include vitamins, nonsteroidal anti-inflammatory drugs, and agents that protect the endothelium (eg, statins). Good control of hypertension with angiotensinconverting enzyme inhibitors and long-acting dihydropyridines also confers neuroprotective benefits. Conclusions: The paradigm that AD is pharmacologically unresponsive is shifting as more effective pharmacotherapies for prevention and treatment rapidly emerge. Our understanding of the molecular mechanisms of neurodegeneration will soon allow us to more specifically target and interrupt the processes that contribute to this progressive dementia.

Growing evidence suggests that decreased brainderived neurotrophic factor (BDNF) levels are associated with Alzheimer's disease (AD) pathogenesis. Therefore, BDNF gene therapy is considered to be a promising therapeutic strategy for treating AD. Sendai virus (SeV) is a type I parainfluenza virus that does not interact with host chromosomes because of its strict cytoplasmic life cycle. Although SeV is nonpathogenic in primates, including humans, its infectivity for neurons is strong. Here we demonstrate that SeV vectors effectively infected neurons, even though they were injected into subcortical white matter. Moreover, SeV vectors significantly induced BDNF expression, ameliorating synaptic degeneration and memory deficits in a transgenic mouse model of AD (Tg2576). This is the first study to demonstrate that viral vector administration in white matter is sufficient to restore cognitive function in vivo. These results also support the feasibility of using SeV vectors for gene therapy targeting the brain. V

We compared CSF and serum selenium levels, measured by atomic absorption spectrophotometry, in 27 patients with Alzheimer's disease (AD) (13 females, 14 males, mean Ϯ SD age 73.6 Ϯ 7.4 years) without major clinical signs of undernutrition, and 34 matched controls (18 females, 16 males, mean Ϯ SD age 70.7 Ϯ 7.8 years). CSF and serum selenium levels did not differ significantly between AD-patient (11.4 Ϯ 7.8 ng/ml and 28.5 Ϯ 13.0 ng/ml, respectively) and control groups (13.3 Ϯ 7.0 ng/ml and 22.5 Ϯ 17.5 ng/ml). These values were not correlated with age, age at onset, duration of the disease, and scores of the MiniMental State Examination in the AD group. Weight and body mass index were significantly lower in AD patients than in controls. These results suggest that CSF selenium concentrations are apparently unrelated with the reported oxidative stress processes in patients with AD.

In order to assess peripheral levels and activities of a broad spectrum of non-enzymatic and enzymatic antioxidants in elderly subjects with mild cognitive impairment (MCI) and Alzheimer's disease (AD), plasma levels of water-soluble (Vitamin C and uric acid) and of lipophilic (Vitamin A, Vitamin E and carotenoids including lutein, zeaxanthin, ␤-cryptoxanthin, lycopene, ␣and ␤-carotene) antioxidant micronutrients as well as activities of plasma and red blood cell (RBC) superoxide dismutase (SOD) and of plasma glutathione peroxidase (GPx) were measured in 25 patients with MCI, 63 AD patients and 53 controls. Peripheral levels and activities of antioxidants were similarly lower in MCI and AD patients as compared to controls. As MCI may represent a prodromal stage of AD, and oxidative damage appears to occur as one of the earliest pathophysiological events in AD, an increased intake of antioxidants in patients with MCI could be helpful in lowering the risk of conversion to dementia.

Previous studies have shown that in platelets of mild Alzheimer Disease (AD) patients there are alterations of specific APP forms, paralleled by alteration in expression level of both ADAM 10 and BACE when compared to control subjects. Due to the poor linear relation among each key-element of beta-amyloid cascade and the target diagnosis, the use of systems able to afford non linear tasks, like artificial neural networks (ANNs), should allow a better discriminating capacity in comparison with classical statistics.

This team takes the position that what is commonly referred to as nonfamilial Alzheimer's disease (AD) is predominantly due to genetic factors. There are many genetic factors that already have been clearly associated with AD. In particular, there are genes with high penetrance that cause AD in individuals with onsets below 60 years of age, although these autosomal dominant genes account for less than 3% of the cases. The genes that cause AD in subjects over 60 years of age have penetrance that does not produce as clear of a line of heritability. However, population-based studies suggest that genetic factors may cause the majority of cases that begin after age 60 as well. There are several lines of evidence supporting this position:

Keywords: hAChE hBuChE Dual AChE inhibitors 6-Chloro-pyridonepezils In vitro blood brain barrier Molecular modeling ADME Alzheimer's disease a b s t r a c t 6-Chloro-pyridonepezils are chloropyridineedonepezil hybrids designed by combining the N-benzylpiperidine moiety present in donepezil with the 2-chloropyridine-3,5-dicarbonitrile heterocyclic ring system, both connected by an appropriate polymethylene linker. 6-Chloro-pyridonepezils 1e8 were prepared by reaction of 2,6-dichloro-4-phenylpyridine-3,5-dicarbonitrile (13) [or 2,6-dichloropyridine-3,5-dicarbonitrile ] with suitable 2-(1-benzylpiperidin-4-yl)alkylamines (9e12). The biological evaluation showed that these new compounds are cholinesterase inhibitors, in the submicromolar range, one of them (6) being a potent hBuChE inhibitor (IC 50 ¼ 0.47 AE 0.08 mM). 6-Chloro-pyridonepezils 4, 7 and 8 are potent hAChE inhibitors showing IC 50 in the 0.013e0.054 mM range. Particularly, 6-chloro-pyridonepezil 8 is 625-fold more selective for hAChE than for hBuChE and compared to donepezil is equipotent for the inhibition of hAChE. Molecular modeling investigation on 6-chloro-pyridonepezils 4, 6e8 supports its dual AChE inhibitory profile, by binding simultaneously at the catalytic active and at peripheral anionic sites of the enzyme. The in vitro Blood Brain Barrier (BBB) and theoretical ADME analysis of 6-chloro-pyridonepezils 1e8 have been carried out. Overall, compound 8, is a permeable potent and selective dual AChEI that can be considered as a good candidate with potential impact for further pharmacological development in Alzheimer's therapy.

Three groups of healthy younger adults, healthy older adults, and probable AD patients, performed an addition/number comparison task. They compared 128 couples of additions and numbers (e.g., 4 + 9 15) and had to identify the largest item for each problem by pressing one of two buttons located under each item. Manipulations of problem characteristics (i.e., Problem difficulty and splits between correct sums and proposed numbers) enabled us to examine strategy selection and specific arithmetic fact retrieval processes. Results showed that arithmetic facts retrieval processes, which were spared with aging, were impaired in AD patients. However, AD patients were able to switch between strategies across trials according to problem characteristics as well as healthy older adults, and less systematically than healthy younger adults. We discuss implications of these findings for further understanding AD-related differences in arithmetic in particular, and problem solving in general.

A case-control study of Alzheimer's disease (AD) was conducted to evaluate the roles of family history of dementing disease and AD, and medical conditions, particularly those related to the viral and immune hypotheses in AD, One hundred and eighty-three clinically diagnosed patients were identified between 1980 and 1985 through the Geriatric and Family Services clinic at the University of Washington hospital, and 18 patients were identified during the same time period through the Veteran's Administration Medical Center in Seattle, Washington. Telephone interviews were conducted with spouses (87.7%) and children (12.3%) of the patients. Each patient was matched to a friend or nonblood relative of the patient by age, sex, and the relationship between the patient and his or her respondent, for a total of 130 matched pairs. The odds ratio for AD was elevated if a first-degree relative was reported to have a history of dementia (odds ratio, 2.21; 95% confidence interval, 1.17 to 4.18). This risk was especially elevated if a sibling was affected (odds ratio, 4.04; 95% confidence interval, 1.37 to 11.90); the highest risk to the proband was observed if a sibling had presumed AD (odds ratio, 5.92; 95% confidence interval, 1.59 to 21.96). The risk increased with increasing numbers of first-degree family members affected for both a history of dementia and presumed AD. We found little difference between patients and control subjects with respect to the age of the mother or father at the time of the subject's birth. No statistically significant differences were observed between the two groups with regard to conditions that might support the immune and viral hypothesis in AD, smoking, or alcohol problems.

The detrimental effect of activation of the chemokine CCL4/MIP-1A on neuronal integrity in patients with HIV-associated dementia has directed attention to the potential role of CCL4 expression and regulation in Alzheimer disease. Here, we show that CCL4 mRNA and protein are overexpressed in the brains of APP swe /PS1 $E9 (APP/PS1) doubletransgenic mice, a model of cerebral amyloid deposition; expression was minimal in brains from nontransgenic littermates or single-mutant controls. Increased levels of CCL4 mRNA and protein directly correlated with the age-related progression of cerebral amyloid-A (AA) levels in APP/PS1 mice. We also found significantly increased expression of activating transcription factor 3 (ATF3), which was positively correlated with age-related AA deposition and CCL4 in the brains of APP/PS1 mice. Results from chromatin immunoprecipitationYquantitative polymerase chain reaction confirmed that ATF3 binds to the promoter region of the CCL4 gene, consistent with a potential role in regulating CCL4 transcription. Finally, elevated ATF3 mRNA expression in APP/PS1 brains was associated with hypomethylation of the ATF3 gene promoter region. These observations prompt the testable hypothesis for future study that CCL4 overexpression, regulated in part by hypomethylation of the ATF3 gene, may contribute to neuropathologic progression associated with amyloid deposition in Alzheimer disease.

Family, twin, and adoption studies have indicated that human intelligence quotient (IQ) has significant genetic components. We performed a low-density genome-wide association analysis with a family-based association test to identify genetic variants influencing IQ, as measured by Wechsler Adult Intelligence Scale full-score IQ (FSIQ). We examined 11,120 single-nucleotide polymorphisms (SNPs) from the Affymetrix GeneChips 10K mapping array genotyped in 292 nuclear families from Genetic Analysis Workshop 14, a subset from the Collaborative Study on the Genetics of Alcoholism (COGA). A replication analysis was performed using part of International Multi-Center ADHD Genetics Project (IMAGE) dataset. Twenty-two SNPs were identified as having suggestive associations with IQ (p&lt;10(-3)) in the COGA sample and eleven of the SNPs were located within known genes. In particular, NTM at 11q25 (rs411280, p = 0.000764) and NR3C2 at 4q31.1 (rs3846329, p = 0.000675) were two novel genes which hav...

Individuals with Alzheimer's disease (AD) retain certain cognitive abilities over the course of the disease. In this article, we describe retained cognitive-linguistic abilities and the status of activities of daily living (ADLs) of individuals in the early, middle, and late stages of AD. Knowledge of preserved abilities in AD is necessary for clinicians to structure communication-stimulation programs and to train caregivers in the most effective ways to facilitate communication. Using the Global Deterioration Scale (GDS) for staging severity of AD, an outline of preserved abilities by disease stage is provided. Attention, memory, and communication abilities are discussed, and samples of discourse from patients at different stages are included.

This pilot study of ethyl-eicosapentaenoate (ethyl-EPA) in the treatment of Alzheimer's disease aimed to estimate the magnitude of any change in measures of cognition during a 12-week treatment period. A simple linear design was used in which each patient had a baseline period of 12 weeks without treatment, followed by 12 weeks' treatment with ethyl-EPA. Blood samples were taken both before and after the treatment period to measure erythrocyte membrane fatty acids. Assessments comprised cognitive measures and visual analogue ratings of overall assessment of functioning.

As Alzheimer's disease (AD) is a complex disease, we decided to estimate how previously reported genetic polymorphisms interact to increase the risk for the disease. Five candidate genes were chosen: apolipoprotein E (APOE), a2-macroglobulin, cathepsin D, myeloperoxidase and nitric oxide synthase. Genotyping was performed in 100 cases of late-onset AD and 100 healthy controls. We found a highly significant difference in APOE 14 distribution between groups (P , 0:005). However, no evidence of association for other studied loci was found. Cumulative analysis of five genetic polymorphisms was performed, but it also failed to reveal any synergistic effect of candidate genes greater than that caused by APOE itself. Our results suggest that the APOE 14 allele is the only known genetic risk factor for late-onset, sporadic AD. q