Local translation of proteins in distal dendrites is thought to support synaptic structural plasticity. We have previously shown that metabotropic glutamate receptor (mGluR1) stimulation initiates a phosphorylation cascade, triggering rapid association of some mRNAs with translation machinery near synapses, and leading to protein synthesis. To determine the identity of these mRNAs, a cDNA library produced from distal nerve processes was used to screen synaptic polyribosome-associated mRNA. We identified mRNA for the fragile X mental retardation protein (FMRP) in these processes by use of synaptic subcellular fractions, termed synaptoneurosomes. We found that this mRNA associates with translational complexes in synaptoneurosomes within 1-2 min after mGluR1 stimulation of this preparation, and we observed increased expression of FMRP after mGluR1 stimulation. In addition, we found that FMRP is associated with polyribosomal complexes in these fractions. In vivo, we observed FMRP immunoreactivity in spines, dendrites, and somata of the developing rat brain, but not in nuclei or axons. We suggest that rapid production of FMRP near synapses in response to activation may be important for normal maturation of synaptic connections.Changes in synaptic connectivity are likely to be a key mechanism by which nervous system organization is permanently changed by experience. Local translation of some proteins in dendrites is increasingly considered to be important for changes in synaptic structure and receptor composition. Certain mRNAs are known to be targeted to dendrites (1, 2), and polyribosomal aggregates are observed in or near dendritic spines, more frequently at newly forming synapses (3-5). Dendrites have been shown to be equipped with components necessary for protein synthesis (6), and synthesis of proteins has been demonstrated directly in synaptoneurosomes (7,8) and in preparations of dendrites isolated from hippocampal neurons in culture (9). Local translation of transfected reporter-tagged mRNA has been demonstrated in transected dendrites (10).Protein translation induced by metabotropic receptor stimulation has previously been proposed to play a role in longterm potentiation (LTP), a model for synaptic plasticity (1,11,12). LTP induction also alters levels of specific mRNAs in tissue slices (13), and isotope-tagged leucine is taken up in dendritic regions of hippocampal slices in response to stimulation (14). We have demonstrated that phosphoinositidelinked metabotropic glutamate receptors (mGluR1), known to trigger a phosphorylation cascade, cause certain mRNAs to associate rapidly with protein translation complexes in synaptoneurosomes (15); this process is modulated by ionotropic receptors (16). Furthermore, we have shown that depolarization by 40 mM K ϩ or stimulation by phosphoinositide receptorspecific mGluR agonists increases [ 35 S]methionine incorporation into trichloroacetic acid-precipitable polypeptides (15, 17), indicating that de novo protein synthesis at the synapse occurs as a result of t...

Background: Type 2 diabetes mellitus is an important risk factor for Alzheimer disease and is more prevalent in elderly minority persons compared with non-Hispanic white persons. Objective: To determine whether diabetes is related to a higher risk of mild cognitive impairment (MCI), a transitional stage between normal cognition and Alzheimer disease, in a multiethnic cohort with a high prevalence of diabetes.

Background: Studies relating adiposity to dementia are conflicting. We explored the associations of body mass index (BMI), (calculated as weight in kilograms divided by the square of height in meters) waist circumference, and weight change to dementia, probable Alzheimer disease, and dementia associated with stroke (DAS). Design: Persons without dementia were followed up for 5 years; 893 persons had BMI data, 907 had waist circumference data, and 709 had a second weight measurement. Dementia was ascertained using standard methods. Cox proportional hazards regression was used for analyses using follow-up as time to event, adjusting for demographics and apolipoprotein E-ε4 status. Results: Compared with persons in the first quartile of BMI, persons in the third quartile had a lower dementia

C ardiovascular diseases (CVDs) are the greatest contributors to the global burden of disease, and finding ways to reduce this burden are a major challenge faced by health systems worldwide.1 Most guidelines recommend that the decision to use vascular disease preventive drug therapy should be on the basis of a patient's overall or absolute cardiovascular risk. 2 The broader application of risk-based care with safe, effective treatments has the potential to reduce disease burden substantially Background-Despite effective treatments to reduce cardiovascular disease risk, their translation into practice is limited. Methods and Results-Using a parallel arm cluster-randomized controlled trial in 60 Australian primary healthcare centers, we tested whether a multifaceted quality improvement intervention comprising computerized decision support, audit/ feedback tools, and staff training improved (1) guideline-indicated risk factor measurements and (2)

No abstract

Background: Deposition of the ␤-amyloid peptide A␤ 42 is thought to be an important initial step in the pathogenesis of Alzheimer disease (AD). Individuals with Down syndrome have increased levels of ␤-amyloid peptides and an increased risk for AD. Objective: To examine the relation of plasma levels of A␤ 42 and A␤ 40 to the risk of dementia in nondemented participants and all-cause mortality in adults with Down syndrome.

Multisecond oscillations in firing rate in the basal ganglia: robust modulation by dopamine receptor activation and anesthesia. Studies of CNS electrophysiology have suggested an important role for oscillatory neuronal activity in sensory perception, sensorimotor integration, and movement timing. In extracellular single-unit recording studies in awake, immobilized rats, we have found that many tonically active neurons in the entopeduncular nucleus ( n = 15), globus pallidus ( n = 31), and substantia nigra pars reticulata ( n = 31) have slow oscillations in firing rate in the seconds-to-minutes range. Basal oscillation amplitude ranged up to ±50% of the mean firing rate. Spectral analysis was performed on spike trains to determine whether these multisecond oscillations were significantly periodic. Significant activity in power spectra (in the 2- to 60-s range of periods) from basal spike trains was found for 56% of neurons in these three nuclei. Spectral peaks corresponded to oscillations with mean periods of ∼30 s in each nucleus. Multisecond baseline oscillations were also found in 21% of substantia nigra dopaminergic neurons. The dopamine agonist apomorphine (0.32 mg/kg iv, n = 10–15) profoundly affected multisecond oscillations, increasing oscillatory frequency (means of spectral peak periods were reduced to ∼15 s) and increasing the regularity of the oscillations. Apomorphine effects on oscillations in firing rate were more consistent from unit to unit than were its effects on mean firing rates in the entopeduncular nucleus and substantia nigra. Apomorphine modulation of multisecond periodic oscillations was reversed by either D1 or D2antagonists and was mimicked by the combination of selective D1 (SKF 81297) and D2 (quinpirole) agonists. Seventeen percent of neurons had additional baseline periodic activity in a faster range (0.4–2.0 s) related to ventilation. Multisecond periodicities were rarely found in neurons in anesthetized rats ( n = 29), suggesting that this phenomenon is sensitive to overall reductions in central activity. The data demonstrate significant structure in basal ganglia neuron spiking activity at unexpectedly long time scales, as well as a novel effect of dopamine on firing pattern in this slow temporal domain. The modulation of multisecond periodicities in firing rate by dopaminergic agonists suggests the involvement of these patterns in behaviors and cognitive processes that are affected by dopamine. Periodic firing rate oscillations in basal ganglia output nuclei should strongly affect the firing patterns of target neurons and are likely involved in coordinating neural activity responsible for motor sequences. Modulation of slow, periodic oscillations in firing rate may be an important mechanism by which dopamine influences motor and cognitive processes in normal and dysfunctional states.

Women with Down's syndrome experience early onset of both menopause and Alzheimer's disease. This timing provides an opportunity to examine the influence of endogenous estrogen deficiency, indicated by age at menopause, on risk of Alzheimer's disease. A community-based sample of 163 postmenopausal women with Down's syndrome, 40 to 60 years of age, was ascertained through the New York State Developmental Disability service system. Information from cognitive assessments, medical record review, neurological evaluation, and caregiver interviews was used to establish ages for onset of menopause and dementia. We used survival and multivariate regression analyses to determine the relation of age at menopause to age at onset of Alzheimer's disease, adjusting for age, level of mental retardation, body mass index, and history of hypothyroidism or depression. Women with early onset of menopause (46 years or younger) had earlier onset and increased risk of Alzheimer's disease (AD) compared with women with onset of menopause after 46 years (rate ratio, 2.7; 95% confidence interval [CI], 1.2-5.9). Demented women had higher mean serum sex hormone binding globulin levels than nondemented women (86.4 vs 56.6 nmol/L, p = 0.02), but similar levels of total estradiol, suggesting that bioavailable estradiol, rather than total estradiol, is associated with dementia. Our findings support the hypothesis that reductions in estrogens after menopause contribute to the cascade of pathological processes leading to AD.