High dietary advanced glycation end products are associated with poorer spatial learning and accelerated Aß deposition in an Alzheimer mouse model.

There is growing evidence of the involvement of advanced glycation end products (AGEs) in the pathogenesis of neurodegenerative processes including Alzheimer's disease (AD) and their function as a seed for the aggregation of Aß, a hallmark feature of AD. AGEs are formed endogenously and exogenously during heating and irradiation of foods. We here examined the effect of a diet high in AGEs in the context of an irradiated diet on memory, insoluble Aß42 , AGEs levels in hippocampus, on expression of the receptor for AGEs (RAGE), and on oxidative stress in the vasculature. We found that AD-like model mice on high-AGE diet due to irradiation had significantly poorer memory, higher hippocampal levels of insoluble Aß42 and AGEs as well as higher levels of oxidative stress on vascular walls, compared to littermates fed an isocaloric diet. These differences were not due to weight gain. The data were further supported by the overexpression of RAGE, which binds to Aß42 and regulates its transport across the blood-brain barrier, suggesting a mediating pathway. Because exposure to AGEs can be diminished, these insights provide an important simple noninvasive potential therapeutic strategy for alleviating a major lifestyle-linked disease epidemic.

The Israel Diabetes and Cognitive Decline (IDCD) study: Design and baseline characteristics.

BACKGROUND: Type 2 diabetes (T2D) is associated with increased risk of dementia. The prospective longitudinal Israel Diabetes and Cognitive Decline study aims at identifying T2D-related characteristics associated with cognitive decline. METHODS: Subjects are population-based T2D 65+, initially cognitively intact. Medical conditions, blood examinations, and medication use data are since 1998; cognitive, functional, demographic, psychiatric, DNA, and inflammatory marker study assessments were conducted every 18 months. Because the duration of T2D reflects its chronicity and implications, we compared short (0-4.99 years), moderate (5-9.99), and long (10+) duration for the first 897 subjects. RESULTS: The long duration group used more T2D medications, had higher glucose, lower glomerular filtration rate, slower walking speed, and poorer cognitive functioning. Duration was not associated with most medical, blood, urine, and vital characteristics. CONCLUSIONS: Tracking cognition, with face-to-face evaluations, exploiting 15 years of historical detailed computerized, easily accessible, and validated T2D-related characteristics may provide novel insights into T2D-related dementia.

The TOMM40 poly-T rs10524523 variant is associated with cognitive performance among non-demented elderly with type 2 diabetes.

The variable length poly-T, rs10524523 ('523') located within the TOMM40 gene, was recently associated with several phenotypes of cognitive function. The short (S) allele is associated with later AD onset age and better cognitive performance, compared to the longer alleles (long and very-long (VL)). There is strong linkage disequilibrium between variants in the TOMM40 and APOE genes. In this study, we investigated the effect of '523' on cognitive performance in a sample of cognitively normal Jewish elderly with type 2 diabetes, a group at particularly high risk for cognitive impairment. Using a MANCOVA procedure, we compared homozygous carriers of the S/S allele (N=179) to carriers of the VL/VL allele (N=152), controlling for demographic and cardiovascular covariates. The S/S group performed better than the VL/VL group (p=0.048), specifically in the executive function (p=0.04) and episodic memory (p=0.050) domains. These results suggest that previous findings of an association of the TOMM40 short allele with better cognitive performance, independently from the APOE variant status, are pertinent to elderly with diabetes.

Hippocampus-specific deficiency in RNA editing of GluA2 in Alzheimer's disease.

Adenosine to inosine (A-to-I) RNA editing is a base recoding process within precursor messenger RNA, catalyzed by members of the adenosine deaminase acting on RNA (ADAR) family. A notable example occurs at the Q/R site of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptor subunit GluA2. Abnormally, low editing at this site leads to excessive calcium influx and cell death. We studied hippocampus and caudate samples from Alzheimer's disease (AD) patients and age-matched healthy controls, using direct sequencing and a high accuracy primer-extension technique to assess RNA editing at the Q/R GluA2 site. Both techniques revealed lower, more variable RNA editing in AD, specific to the hippocampus and the GluA2 site. Deficient editing also characterized the hippocampus of apolipoprotein ε4 allele carriers, regardless of clinical diagnosis. In AD, messenger RNA expression of neuronal markers was decreased in the hippocampus, and expression of the Q/R-site editing enzyme ADAR2 was decreased in caudate. These findings provide a link between neurodegenerative processes and deficient RNA editing of the GluA2 Q/R site, and may contribute to both diagnosis and treatment of AD.

Hippocampal glutamate NMDA receptor loss tracks progression in Alzheimer's disease: quantitative autoradiography in postmortem human brain.

Early Alzheimer's disease (AD) is characterized by memory loss and hippocampal atrophy with relative sparing of basal ganglia. Activation of glutamate NMDA receptors in the hippocampus is an important step in memory formation. We measured the density of NMDA receptors in samples of hippocampus, entorhinal cortex and basal ganglia obtained from subjects who died with pathologically confirmed AD and age- and sex- matched non-demented controls. We found significant decreases in NMDA receptor density in the hippocampus and entorhinal cortex but not in the basal ganglia. Loss of NMDA receptors was significantly correlated with neuropathological progression as assessed by Braak staging postmortem. The same samples were probed for neuroinflammation by measuring the density and gene expression of translocator protein 18 kDA (TSPO), an established marker of microglial activation. Unlike NMDA receptor loss, increased densities of TSPO were found in all of the brain regions sampled. However hippocampal, but not striatal TSPO density and gene expression were inversely correlated with NMDA receptor density and positively correlated with Braak stage, suggesting NMDA receptors exacerbate neuroniflammatory damage. The high correlation between hippocampal NMDA receptor loss and disease progression supports the use of non invasive imaging with NMDA receptor tracers and positron emission tomography as a superior method for diagnosis, staging and treatment monitoring of AD in vivo.

Type 2 diabetes and cognitive compromise: potential roles of diabetes-related therapies.

Type 2 diabetes, like dementia, disproportionately affects the elderly. Diabetes has consistently been associated with risk of dementia, mild cognitive impairment, and cognitive decline suggesting that cognitive compromise is a deleterious manifestation of diabetes. This review summarizes observational studies and clinical trials of diabetes medications and their respective associations and effects on cognitive outcomes. Despite biological plausibility, results from most human clinical trials have failed to show any efficacy in treating Alzheimer disease symptomatology and pathology. Clinical trials targeting vascular-related outcomes, diabetic patients, or cognitively normal elderly at risk for dementia, may provide greater cognitive benefits.

Parkinson's disease genes do not segregate with breast cancer genes' loci.

BACKGROUND: Breast cancer and skin cancer rates among patients with Parkinson's disease are higher than in non-Parkinson's disease cases, and Jewish-Ashkenazi LRRK2*G2019S mutation carriers have higher breast cancer rates than noncarriers. Because additional Parkinson's disease predisposition genes are implicated in the malignant transformation process, we hypothesized that the association between breast cancer and Parkinson's disease may be related to segregation of breast cancer loci with known Parkinson's disease predisposition loci. METHODS: Data mining for single-nucleotide polymorphisms (SNP), reportedly associated with breast cancer in genome-wide association study (GWAS) that localize to chromosomes bearing known Parkinson's disease predisposition loci: PARK7, PINK1 (chromosome 1); SNCA (chromosome 4); PARK2 (chromosome 6); and LRRK2 (chromosome 12), was carried out. RESULTS: A total of 188 breast cancer-associated SNPs were identified in 29 eligible manuscripts: 43 SNPs on chromosome 1 (PINK1), 46 SNPs on chromosome 4 (SNCA), 72 SNPs on chromosome 6 (PARK2), and 27 SNPs on chromosome 12 (LRRK2). No breast cancer-associated SNP was located at distance less than 500,000 bp from any of the analyzed Parkinson's disease predisposition genes. CONCLUSIONS: The association between breast cancer and the most common genetic-inherited forms of Parkinson's disease cannot be accounted for by allele cosegregation at the genomic level. IMPACT: To elucidate the association between Parkinson's disease and breast cancer, a comprehensive approach that spans beyond a simple genetic association is required.

Prayer at midlife is associated with reduced risk of cognitive decline in Arabic women.

Midlife habits may be important for the later development of Alzheimer's disease (AD). We estimated the contribution of midlife prayer to the development of cognitive decline. In a door-to-door survey, residents aged ≥65 years were systematically evaluated in Arabic including medical history, neurological, cognitive examination, and a midlife leisure-activities questionnaire. Praying was assessed by the number of monthly praying hours at midlife. Stepwise logistic regression models were used to evaluate the effect of prayer on the odds of mild cognitive impairment (MCI) and AD versus cognitively normal individuals. Of 935 individuals that were approached, 778 [normal controls (n=448), AD (n=92) and MCI (n=238)] were evaluated. A higher proportion of cognitively normal individuals engaged in prayer at midlife [(87%) versus MCI (71%) or AD (69%) (p<0.0001)]. Since 94% of males engaged in prayer, the effect on cognitive decline could not be assessed in men. Among women, stepwise logistic regression adjusted for age and education, showed that prayer was significantly associated with reduced risk of MCI (p=0.027, OR=0.55, 95% CI 0.33-0.94), but not AD. Among individuals endorsing prayer activity, the amount of prayer was not associated with MCI or AD in either gender. Praying at midlife is associated with lower risk of mild cognitive impairment in women.

Cognitive decline and dementia in the oldest-old.

The oldest-old are the fastest growing segment of the Western population. Over half of the oldest-old will have dementia, but the etiology is yet unknown. Age is the only risk factor consistently associated with dementia in the oldest-old. Many of the risk and protective factors for dementia in the young elderly, such as ApoE genotype, physical activity, and healthy lifestyle, are not relevant for the oldest-old. Neuropathology is abundant in the oldest-old brains, but specific pathologies of Alzheimer's disease (AD) or vascular dementia are not necessarily correlated with cognition, as in younger persons. It has been suggested that accumulation of both AD-like and vascular pathologies, loss of synaptic proteins, and neuronal loss contribute to the cognitive decline observed in the oldest-old. Several characteristics of the oldest-old may confound the diagnosis of dementia in this age group. A gradual age-related cognitive decline, particularly in executive function and mental speed, is evident even in non-demented oldest-old. Hearing and vision losses, which are also prevalent in the oldest-old and found in some cases to precede/predict cognitive decline, may mechanically interfere in neuropsychological evaluations. Difficulties in carrying out everyday activities, observed in the majority of the oldest-old, may be the result of motor or physical dysfunction and of neurodegenerative processes. The oldest-old appear to be a select population, who escapes major illnesses or delays their onset and duration toward the end of life. Dementia in the oldest-old may be manifested when a substantial amount of pathology is accumulated, or with a composition of a variety of pathologies. Investigating the clinical and pathological features of dementia in the oldest-old is of great importance in order to develop therapeutic strategies and to provide the most elderly of our population with good quality of life.

Cognitive test scores in male adolescent cigarette smokers compared to non-smokers: a population-based study.

BACKGROUND: Although previous studies indicate that people with lower intelligence quotient (IQ) scores are more likely to become cigarette smokers, IQ scores of siblings discordant for smoking and of adolescents who began smoking between ages 18-21 years have not been studied systematically. METHODS: Each year a random sample of Israeli military recruits complete a smoking questionnaire. Cognitive functioning is assessed by the military using standardized tests equivalent to IQ. RESULTS: Of 20 221 18-year-old males, 28.5% reported smoking at least one cigarette a day (smokers). An unadjusted comparison found that smokers scored 0.41 effect sizes (ES, P < 0.001) lower than non-smokers; adjusted analyses remained significant (adjusted ES = 0.27, P < 0.001). Adolescents smoking one to five, six to 10, 11-20 and 21+ cigarettes/day had cognitive test scores 0.14, 0.22, 0.33 and 0.5 adjusted ES poorer than those of non-smokers (P < 0.001). Adolescents who did not smoke by age 18, and then began to smoke between ages 18-21 had lower cognitive test scores compared to never-smokers (adjusted ES = 0.14, P < 0.001). An analysis of brothers discordant for smoking found that smoking brothers had lower cognitive scores than non-smoking brothers (adjusted ES = 0.27; P = 0.014). CONCLUSION: Controlled analyses from this large population-based cohort of male adolescents indicate that IQ scores are lower in male adolescents who smoke compared to non-smokers and in brothers who smoke compared to their non-smoking brothers. The IQs of adolescents who began smoking between ages 18-21 are lower than those of non-smokers. Adolescents with poorer IQ scores might be targeted for programmes designed to prevent smoking.

Effects of testosterone replacement in middle-aged men with dysthymia: a randomized, placebo-controlled clinical trial.

Mid-life onset male dysthymic disorder (DD) seems to be a distinct clinical condition with limited therapeutic options. Testosterone replacement is mood-enhancing and has been proposed as an antidepressant therapy, though this strategy has received limited systematic study. We therefore conducted a six-week double-blind placebo-controlled clinical trial in 23 men with DD and with low or low-normal testosterone (T) level (i.e, screening total serum testosterone <350 ng/dL). Enrolled men were randomized to receive intramuscular injections of 200 mg of testosterone cypionate or placebo every 10 days. The primary outcome measures were the Clinical Global Impression (CGI) improvement score and the 21-item Hamilton Depression Rating Scale (HDRS) score.Twenty-three patients were randomized. The mean (SD) age of the enrolled patients was 50.6 (7.0) years and that of total testosterone level was 339 (93) ng/dL. The median duration of the current dysthymic episode was 3.6 (2.3) years, and the mean (SD) HDRS was 14.0 (2.9). After the intervention, the mean HDRS score decreased significantly more in the testosterone group (7.46 [4.56]) than in the placebo group (1.8 [4.13], t21 = -3.07, P = 0.006). Remission, defined as a CGI improvement score of 1 or 2 and a final HDRS score lower than 8, was achieved by 7 (53.8%) of 13 in the testosterone group and 1 (10%) of 10 in the placebo group (P = 0.03). Testosterone replacement may be an effective antidepressant strategy for late-onset male dysthymia.

Subtle cognitive dysfunction in nonaffected siblings of individuals affected by nonpsychotic disorders.

BACKGROUND: Previous studies have reported that as a group, individuals affected by psychotic and nonpsychotic disorders perform below norms on cognitive tests. Other studies have indicated that unaffected siblings of individuals affected by psychotic disorders also perform below norms on the same tests. We investigated cognitive performance on a large, population-based sample of individuals, affected at the time of testing by nonpsychotic disorders, and their unaffected siblings. METHODS: Subjects were taken from a population-based cohort of 523,375, 16- to 17-year-old male adolescents who had been assessed by the Israeli Draft Board. Cognitive test scores were examined in sib-pairs discordant for nonpsychotic (n = 19,489) and psychotic (n = 888) disorders and compared with 224,082 individuals from sibships with no evidence of mental illness. RESULTS: There appears to be a gradient in cognitive performance (worst to best) from individuals currently affected by psychotic illnesses (Cohen's d = -.82), followed by individuals currently affected by nonpsychotic illness (Cohen's d = -.58), unaffected siblings of individuals affected by psychotic illness (Cohen's d = -.37), unaffected siblings of individuals affected by nonpsychotic illness (Cohen's d = -.27), and members of sibships with no evidence of mental illness. Unaffected siblings of both psychotic and nonpsychotic individuals from multiple affected sibships (more then one affected sibling) had worse cognitive test scores compared with unaffected siblings from simplex sibships (only one affected sibling). CONCLUSIONS: The results support, but do not prove, the notion that cognitive impairment in psychiatric disorders is familial and cuts across diagnostic entities.

Impaired reading comprehension and mathematical abilities in male adolescents with average or above general intellectual abilities are associated with comorbid and future psychopathology.

Research indicates that persons with learning disorders often suffer from psychopathology. We assessed current and future psychopathology in male adolescents with discrete impairments in reading comprehension (IRC) or arithmetic abilities (IAA) but with average or above-average general intellectual abilities. Subjects were a population-based cohort of 174,994 male adolescents screened by the Israeli Draft Board with average or above-average intellectual abilities but with low scores (8.6th and 10th lowest percentile respectively) on reading or arithmetic tests. They were compared with adolescents who scored in the 10th percentile and above on these tests (comparison group). Relative to the comparison group, male adolescents with IRC, IAA, or IRC and IAA (0.69%), had poorer scores on most behavioral assessments and higher prevalence of current psychopathology: 4.2% (comparison group), 8.0% (IRC), 7.0% (IAA), and 9.8% (IRC and IAA). Adolescents with IRC were also at increased risk for later hospitalization for schizophrenia (hazard ratios = 1.8, 95% confidence interval: 1.3-2.6). Male adolescents with average and above-average general intellectual abilities but with IRC or IAA are more likely to have current and future psychopathology. Impairments in intellectual functioning and abnormal behaviors leading to mental illnesses may share common neurobiological substrates. The results support screening male adolescents with learning disorders for psychopathology.

Social and cognitive functioning, urbanicity and risk for schizophrenia.

BACKGROUND: Previous work suggests that the association between urbanicity and schizophrenia may be greatest in those with pre-existing vulnerability. AIMS: To test for synergism in risk of schizophrenia between population density and a combined exposure of poor premorbid social and cognitive functioning. METHOD: For 371 603 adolescent males examined by the Israeli Draft Board on social and cognitive functioning, data on population density of place of residence and later hospitalisation for schizophrenia were obtained from population-based registries. RESULTS: There was an interaction between population density (five levels) and poor premorbid social and cognitive functioning (interaction chi(2)=4.6, P=0.032). The adjusted increase in cumulative incidence associated with one unit change in population density was 0.10% in the vulnerable group (95% CI 0.019-0.18, P=0.015), nine times larger than that in the non-vulnerable group (0.011%, 95% CI 0.0017-0.020, P=0.021). CONCLUSIONS: Risk of schizophrenia may increase when people with a genetic liability to the disorder, expressed as poor social and cognitive functioning, need to cope with city life.

Body mass index and future schizophrenia in Israeli male adolescents.

BACKGROUND: Compared with the general population, individuals suffering from schizophrenia are more likely to be overweight, a finding attributed to the effect of antipsychotic medications, poor nutrition, and sedentary lifestyle. As evidence accumulates indicating that some aspects of the illness manifest before the onset of psychosis and establishment of the diagnosis, it has been suggested that increased weight, like other metabolic dysfunctions, might precede active illness. METHOD: Data on height and weight of 203,257 male adolescents assessed by the Israeli Draft Board, and followed for 2-6 years for later hospitalization for schizophrenia using the Israeli National Psychiatric Hospitalization Case Registry, were analyzed. RESULTS: From the entire cohort, 309 (0.15%) were later hospitalized for schizophrenia (ICD-10). After removing adolescents with evidence of illness before or within 1 year of the Draft Board assessment, 204 future schizophrenia patients were available for analysis. Compared with the rest of the cohort, future schizophrenia patients had lower body mass indexes (21.24 +/- 3.3 kg/m2 vs. 21.77 +/- 3.5 kg/m2; F = 4.682, df = 1, p = .03) and weighed slightly but significantly less (64.2 +/- 11.6 kg vs. 66.3 +/- 12.0 kg; F = 6.615, df = 1, p = .01). The mean height of the future patients did not differ significantly from the mean height of the remaining cohort (173.63 +/- 6.7 cm vs. 174.40 +/- 6.9 cm; F = 2.520, df = 1, p = .112). When reanalyzing the data, controlling for physical activity and socioeconomic status, the differences between the groups remained significant. CONCLUSION: Before the onset of illness, future schizophrenia patients are not heavier compared with their peers. This implies that the increased weight of patients with schizophrenia is related to illness effects, including the effects of antipsychotic medication.