Associations of the plasma interleukin 6 (IL-6) levels with disability and mortality in the elderly in the Treviso Longeva (Trelong) study.

IL-6 expression is regulated by the interplay of several transcriptional and hormonal factors, including sex steroids and glucocorticoids. In late life IL-6 expression increases as a result from loss of the normally inhibiting sex steroids. IL-6 is one of several proinflammatory cytokines. It has been proposed that many chronic inflammatory diseases are the result of a dysregulation of IL-6 expression. In this work we demonstrate that increased IL-6 levels in elderly are associated with higher disability and mortality, also independently of age and comorbidity.

The Treviso Longeva (Trelong) study: a biomedical, demographic, economic and social investigation on people 70 years and over in a typical town of North-East of Italy.

Longevity is a complex process resulting from genetic and environmental factors, as well as their interaction. These factors are poorly understood, and the comparison among health status, socio-economics, demographic and other characteristics of the elderly people can help in understanding these complex interactions. Such an interdisciplinary approach is necessary to allow an appropriate evaluation of longevity. Here we report the methodology and the first results of a representative study performed in 2003-2004 on people of 70 years and over, living in a typical town of North-East of Italy. In the research we collected biomedical, demographic, socio-economic and quality of life (QoL) data.

Interferon-gamma potentiates interleukin (IL)-6 and tumor necrosis factor-alpha but not IL-1beta induced by endotoxin in the brain.

Because interferon-gamma (IFN gamma) is present in the central nervous system during neurologic diseases associated with inflammation, its effect on endotoxin-induced cytokines was studied. Cerebrospinal fluid (CSF) and serum levels of interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha (TNF alpha), their messenger RNA expression in brain areas (hypothalamus, hippocampus, and striatum) and in spleen were evaluated 2 and 8 h after endotoxin [lipopolysaccharide (LPS), 25 microg/rat i.c.v.], IFN gamma (2.5 microg/rat i.c.v.) or after their coadministration in rats. CSF and serum IL-1beta levels were increased by LPS alone and IFN gamma coadministration did not furtherly increase them. IFN gamma potentiated LPS effect on IL-6 and TNF alpha levels in both CSF and serum. LPS and IFN-gamma coadministration did not alter IL-1beta messenger RNA expression induced by LPS in brain areas and in spleen, but it potentiated that of IL-6 and TNF alpha. The present in vivo data show that i.c.v. coadministration of LPS and IFN gamma results in a potentiation of cytokine production (IL-6 and TNF alpha) which may trigger a cascade of events relevant to neurodegenerative processes. This action is independent of IL-1beta because the production of this cytokine is not altered by IFN gamma treatment.

Deprivation of growth hormone-releasing hormone early in the rat's neonatal life permanently affects somatotropic function.

This work investigated in rats whether passive immunization against the endogenous GHRF in the early postnatal period led to permanent alterations of somatotropic function, similar to those observed in several human growth disorders, e.g. constitutional growth delay (CGD). On postnatal days 1, 2, 4, 6, 8, and 10, rats were given an anti-GHRF-serum (GHRH-Ab, 100 microliters/rat, sc) and were tested 1, 30, and 60 days after this treatment for basal and GHRH-stimulated GH secretion both in vivo and in vitro. GHRH-Ab reduced both basal and GHRF-stimulated GH secretion at all intervals and induced marked and chronic impairment of growth rate. The following differences were observed in the GHRH-Ab treated rats compared to normal rabbit serum-treated controls: 1) GH biosynthesis (incorporation of L-[3H]leucine into the electrophoretic band of GH): reduction of about 70%, 1 day but not 30 days after treatment; 2) Pituitary weight: significant reduction in absolute weight (30-40%) at all posttreatment intervals, and relative weight, 1 and 30 days after treatment. 3) Pituitary GH concentration: significant reduction in GH content (about 40%) but not concentration, at all posttreatment intervals; 4) Percentage of somatotrophs (immunocytochemistry): about 40% reduction 1 day, but not 30 and 60 days after treatment; 5) Hypothalamic somatostatin messenger RNA (mRNA) levels in situ hybridization): selective reduction (40%) in the periventricular nucleus 1 day but not 30 days after treatment; 6) Hypothalamic somatostatin cell number (immunocytochemistry): no significant changes in any hypothalamic area at any interval; 7) Pituitary somatostatin binding (in situ autoradiography): significant reduction, 1 day and 30 days after treatment; 8) Somatostatin inhibition of GH release "in vitro": somatostatin effect on GH release was reduced 30 days after treatment. These and previous data indicate that: 1) Transient deprivation of GHRF in the immediate postnatal period of the rat leads to permanent impairment of growth rate and somatotropic function; 2) GHRF deficiency itself or through reduction of GH secretion impairs somatostatin functions temporarily in the hypothalamus and permanently in the pituitary; 3) This rat model may mimic some forms of growth disorders in humans and holds promise as useful tools for investigating the underlying pathophysiological mechanisms.

Neurodegenerative Effects Induced by Chronic Infusion of Quinolinic Acid in Rat Striatum and Hippocampus.

In this study we examined whether the potency of quinolinic acid (Quin) in inducing neurodegeneration in vivo was dependent on the exposure time of the tissue to the excitotoxin. The effect of chronic infusion of Quin into rat striatum and hippocampus was examined at the light microscopic level and by cell count on 40 microm Cresyl violet stained brain sections. Continuous infusion was at a constant speed (0.5 microl/h) for various times (15 h - 2 weeks) by osmotic minipumps (Alzet 2002). No build up of [3H]Quin occurred in the tissue during infusion; this was assessed by measuring the radioactivity 3 - 14 days after minipump placement. Intrastriatal infusion of 6 and 10 nmol/h Quin, but not of nicotinic acid, for 1 week induced a dose-dependent neurodegeneration (70 and 90% loss of neurons, respectively, compared to the contralateral striatum) extending 1.2 - 2 mm from the centre of the injection. The onset of the neurotoxicity caused by 10 nmol/h Quin was >24 h. One week's infusion of 4 nmol/h Quin did not induce neurotoxicity, but a 40% drop of neurons, compared to the contralateral side, occurred after 2 weeks. One week's intrahippocampal infusion of 2.4 and 6 nmol/h Quin, but not of nicotinic acid, caused a dose-dependent neurodegeneration with a radius of approximately 1 - 1.5 mm around the injection track. The onset of the neurotoxicity induced by 2.4 nmol/h Quin was < 15 h. The pattern of nerve cell loss induced by 1.2 nmol/h Quin after 1 week (CA4 cells lost in 50% of the rats) did not differ from that observed after 2 weeks of infusion. Nerve cell loss caused by Quin in the striatum and in the hippocampus was restricted to the injected area and antagonized by coinfusion with d(-)-2-amino-7-phosphonoheptanoic and kynurenic acids in molar ratios of 1:0.1 and 1:3, respectively. These data show that Quin's potency in inducing neurodegeneration in the striatum, but not in the hippocampus, depends on the exposure time of the tissue to the excitotoxin. In addition, neurodegeneration is induced faster by Quin in the hippocampus than in the striatum. The usefulness of this model to study the sequelae of the neurotoxic process in vivo will be discussed.

Cholinergic neurons of the pontomesencephalic tegmentum release acetylcholine in the basal nuclear complex of freely moving rats.

Two major systems of cholinergic projection neurons are found within the centrum of the mammalian brain: the basal nuclear complex, projecting predominantly to the cerebral cortex, amygdala, and hippocampus, and the pontomesencephalotegmental network, innervating primarily the thalamus. Neurons comprising the latter network also project to the basal forebrain, but the functional properties of that fiber connection, if any, are unknown. In an attempt to address this issue, the extracellular concentration of acetylcholine was measured in the basal nuclear complex of freely moving rats, both singularly and in combination with lesions and pharmacologic manipulations. Acetylcholine release monitored in the presence of physostigmine sulfate in the basal forebrain was (a) calcium-dependent, (b) increased by systemic scopolamine injection, the rise persisting in the presence of quisqualate lesions of the basal nuclear complex, (c) blocked by tetrodotoxin, and (d) abolished by ablation of cell bodies in the pontomesencephalic tegmentum, which also produced a decrease of choline acetyltransferase activity in the nucleus basalis/substantia innominata region, but not by quisqualate lesions of the basal forebrain. It is concluded from these data that the calcium-dependent release of acetylcholine in the basal nuclear complex (a) is largely axonal in nature, (b) derives substantially from axons of the cholinergic pontomesencephalic tegmentum, and (c) appears to be controlled by presynaptic muscarinic receptors on axon terminals of the latter system. The pontomesencephalotegmental cholinergic complex might thus influence cortical acetylcholine release, in part at least, by means of serial-order cholinergic-cholinergic interactions in the basal nuclear complex.

Functional and histological consequences of quinolinic and kainic acid-induced seizures on hippocampal somatostatin neurons.

Changes in endogenous somatostatin after quinolinic and kainic acids were investigated by measuring somatostatin-like peaks by in vivo voltammetry and by assessing the distribution of somatostatin-positive neurons by immunocytochemistry. Kainic acid (0.19 nmol/0.5 microliter) or quinolinic acid (120 nmol/0.5 microliter) in doses inducing comparable electroencephalographic seizure patterns, were injected into the hippocampus of freely moving rats. Somatostatin-like peaks were measured every 6 min for 3 h by a carbon fiber electrode implanted in the proximity of the injection needle. Kainic acid kept somatostatin-like peaks significantly higher than saline from 48 min after the injection till the end of the recording. Somatostatin-like peaks were dramatically elevated by quinolinic acid, reaching a maximum of 482% 60 min after the injection. Three days later, administration of kainic acid resulted in selective degeneration of CA3 pyramidal neurons but did not affect the number of somatostatin-positive cells, while quinolinic acid induced cell loss in all pyramidal layers and complete degeneration of somatostatin-positive cells in the whole hippocampus. Thus, the quantitative difference in somatostatin release in response to doses of kainic and quinolinic acids inducing comparable electroencephalographic seizure patterns was reflected in a substantial difference in the neurodegenerative consequences. In both models, the release of somatostatin in response to seizures may be interpreted as a "defense" mechanism aimed at reducing the spread of excitation in the tissue.

Neurochemical effects of minaprine, a novel psychotropic drug, on the central cholinergic system of the rat.

Minaprine, a novel psychotropic drug with antidepressant, anticataleptic and antiaggressive properties, produced an increase in rat brain regional acetylcholine content at a subconvulsant dose of 30 mg/kg IP. The greatest increase (60%) was produced in the striatum, whereas an increase of about 35% was obtained in the hippocampus and the rest of the cortex. A small but significant increase of 14% was also found in the midbrain-hindbrain region. Minaprine decreased choline content only in the striatum. No tolerance to acute challenge was observed after 10-day chronic treatment. In vitro, the drug had no effect on striatal choline acetyltransferase activity up to a concentration of 160 microM and only weakly displaced (3H) dexetimide from its specific muscarinic receptor binding sites in striatum (IC50, 2 X 10(-4) M). After in vivo administration the drug did not affect sodium-dependent high affinity choline uptake by a hippocampal homogenate. On the other hand, the drug inhibited both striatal and hippocampal acetylcholinesterase activity at high (40-160 microM) concentrations in vitro. In vivo the drug produced a brief (5 min), small (18%) decrease in the enzymic activity which corresponded in time to the peak drug level attained in the brain, but was not concomitant with a change in striatal acetylcholine content. By contrast, the increase in striatal acetylcholine appeared after 30 min when there was no longer inhibition of acetylcholinesterase activity and when the level of minaprine in brain was reduced by 78%. Blockade of dopamine receptors by pimozide pretreatment partially prevented the increase in striatal acetylcholine produced by minaprine, whereas interference with cholinergic or serontonergic neurotransmission was without effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanical deafferentation of basal forebrain-cortical pathways and neurotoxic lesions of the nucleus basalis magnocellularis: comparative effect on spatial learning and cortical acetylcholine release in vivo.

Rats were assigned to one of the following treatments: bilateral cut of basal forebrain-cortical fibers (DEAFF), ibotenic (IBO) or quisqualic (QUIS) acid lesions of the NBM and sham operations (SHAM). They were trained to perform a radial eight-arm maze task with all the paths or only four paths baited. Cortical cholinergic release measured by microdialysis in vivo and choline acetyltransferase activity were also assessed in the four lesion conditions. The results show that, in the full baited maze task, only the DEAFF group showed a severe spatial learning impairment. In the four-baited path task, the DEAFF group was still more impaired than the other groups but a performance deficit also emerged in rats with IBO lesions. Neurochemical data indicated that cortical choline acetyltransferase activity was reduced by 25% after IBO lesions, by 52% after DEAFF and by 46% after Quis lesions. However, cortical cholinergic release, which dropped in the same fashion after DEAFF or QUIS lesions, was unaffected by IBO lesions. Thus, in spite of the distinctive patterns of behaviour exhibited by the three lesioned groups, no correlation between cortical cholinergic deficiencies and spatial learning impairment was found. The similar behavioural effects produced by DEAFF and fornix sections suggests that, among the basal forebrain-cortical pathways, descending fibers projecting onto the septo-hippocampal system could exert a strong control on spatial learning performance.

Modifications in recognition sites for neurotransmitters in rat hippocampus by kainic acid lesion.

The specific binding of the tritiated radioligands of dexetimide, serotonin, clonidine, prazosin, WB-4101 and dihydroalprenolol to hippocampal membranes was determined two weeks after producing a virtual complete degeneration of perikarya by the local application of 0.5 micrograms of kainic acid in the dorsal and ventral parts of the hippocampus. Afferent terminals were unaffected by the neurotoxin since the contents of noradrenaline, serotonin and acetylcholine, as well as the activity of choline acetyltransferase, were not modified. Scatchard analysis revealed that the kainic acid lesion produced a 60% decrease in the density of both cholinergic muscarinic binding sites and serotonin binding sites. A significant portion of alpha 1- and alpha 2-adrenoceptor binding sites are also associated with intrinsic neurons of the hippocampus, as shown by the approximately 30% reduction in the densities of tritiated WB-4101, prazosin and clonidine produced by the action of kainic acid. By contrast, the affinity and density of beta-adrenoceptor binding sites were unaffected by the lesion. It is suggested that the recognition sites of the different receptor populations surviving the lesion most likely reside on homologous and/or heterologous nerve terminals.

Quantitation of N-acetyl-aspartyl-glutamate in microdissected rat brain nuclei and peripheral tissues: findings with a novel liquid phase radioimmunoassay.

Antibodies were raised in rabbits against the neuropeptide N-acetyl-L-aspartyl-L-glutamate (NAAG) coupled to bovine serum albumin via a carbodiimide linkage. One of these rabbit antisera, which preferentially recognizes coupled NAAG-like immunoreactivity (LIR), has been previously used to immunocytochemically localize NAAG-LIR. We have now employed a second of these antisera, which preferentially recognizes free NAAG, to develop a competitive liquid phase radioimmunoassay (RIA). Using this assay, we were able to detect picomole amounts of NAAG in rat tissue extracts. The specificity of the assay revealed a 60-fold greater affinity of the antibody for NAAG over N-acetyl-aspartate (NAA) and greater than one million-fold specificity for NAAG over both aspartate and glutamate. High-pressure liquid chromatographic (HPLC) separation of tissue extracts yielded only two detectable peaks of NAAG-LIR in collected fractions and these co-chromatographed with NAAG and NAA. NAAG levels determined by this liquid phase RIA and by HPLC were essentially identical after correction for the presence of NAA crossreactivity. The antibody that preferentially recognizes coupled NAAG was used to immunocytochemically localize NAAG-LIR to the red nucleus, the facial nucleus, the dorsal raphe, and the locus coeruleus. To further confirm this localization of NAAG, these and other nuclei were microdissected and levels of NAAG were determined by liquid phase RIA. Nuclei which stained intensely were found to contain high levels of NAAG by RIA and between 60 and 100% of this NAAG-LIR co-chromatographed with NAAG. These results support our previous conclusion that NAAG is co-localized in noradrenergic, serotonergic and cholinergic neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Culture of dorsal root ganglion neurons from aged rats: effects of acetyl-L-carnitine and NGF.

In vitro neuronal preparations are used to study the action mechanism of substances which are active in normal and pathological brain aging. One major concern with in vitro assays is that the use of embryonic or adult neurons may hamper an appreciation of the relevance of these substances on aged nervous tissue. In the present study for the first time cultures of aged dorsal root ganglia from 24-months-old rats were maintained in vitro up to 2 weeks. This model was used to investigate the neurotrophic/neuroprotective action of nerve growth factor and acetyl-L-carnitine. A large population of aged dorsal root ganglia neurons was responsive to nerve growth factor (100 ng/ml). Nerve growth factor induced an increase of initial rate of axonal regeneration and influenced the survival time of these neurons. Acetyl-L-carnitine (250 microM) did not affect the axonal regeneration but substantially attenuated the rate of neuronal mortality. A significant difference was evident between the acetyl-L-carnitine-treated and the untreated neurons from the first cell counting (day 3 in culture). After 2 weeks the number of aged neurons treated with acetyl-L-carnitine was almost double that of the controls. The effects of acetyl-L-carnitine on aged DRG neurons potentially explain the positive effects in clinical and in vivo experimental studies.

Chronic infusion of quinolinic acid in rat striatum: effects on discrete neuronal populations.

The intrastriatal infusion of relatively low doses of quinolinic acid (Quin, 4-10 nmol/h) for 1 or 2 weeks induced time-dependent degeneration of neuronal cells. We examined the effects of these infusions on discrete cellular populations. The distribution of somatostatin (SOM)-positive neurons labelled by immunocytochemistry or by NADPH-diaphorase histochemistry and of cholinergic cells stained by acetylcholinesterase was quantified in the peripheral portion of the lesioned area. SOM-positive cells did not appear selectively spared by Quin infusion. The proportion of SOM- and NADPH-diaphorase-positive neurons killed by exposure to Quin was similar to or higher than the percentage of total neurons degenerated (from 30 to 85%). A selective sparing of cholinergic cells was observed in all conditions examined; perfusion of 6 nmol/h for a week induced 65% of cell death while not more than 30% of cholinergic neurons were killed. Thus, the neurochemical similarity between the degenerative effects of intrastriatal Quin and Huntington's disease (HD) did not appear confirmed by the chronic perfusion of low doses of Quin for SOM-positive neurons, whereas an analogy between Quin's effects and HD was suggested by the pattern of AChE staining.

Qualitative differences in the effects of adenosine analogs on the cholinergic systems of rat striatum and hippocampus.

The effect of the purinergic agonist, 2-chloroadenosine (2-CADO), on central cholinergic parameters was studied in the rat. The drug (20 micrograms, i.c.v.) increased acetylcholine (ACh) content (approximately 30%) and inhibited sodium dependent high affinity choline uptake (30%) in the hippocampus. In striatum, the increase of ACh content was less marked (approximately 15%) and was not associated with inhibition of choline uptake. In both areas, ACh accumulation was prevented by theophylline but not by atropine or oxotremorine pretreatments. Differences were noted in the purinergic control of cholinergic function in the hippocampus and striatum. In hippocampus, the selective degeneration of noradrenergic, serotonergic and glutamatergic afferent pathways or the destructions of intrinsic neurons did not prevent the rise in ACh content induced by 2-CADO. Differently, in striatum, the action of 2-CADO was potentiated both by raphe deafferentation and by inhibition of serotonin synthesis and was completely prevented by chronic unilateral decortication. The cholinergic effect of 2-CADO was unchanged after impairment of the noradrenergic or dopaminergic systems. In addition, the D- and L-isomers of phenylisopropyladenosine, which have different affinities for A1 purinergic receptors but equal affinity for the A2 purinergic subtype, differed in their ability to affect acetylcholine content in these two brain regions, suggesting that A1 purinergic receptor activation mediates the effect of 2-CADO in the hippocampus and A2 receptor activation mediates the drug's action in the striatum.

Modulation of the hippocampal alpha-adrenoceptor population by lesion of the serotonergic raphe-hippocampal pathway in rats.

Electrolytic lesion of the ascending serotonergic fibers in the median raphe nucleus or in both the median raphe nucleus and dorsal raphe nucleus caused after 18 days more than 80% depletion of serotonin in the hippocampus and frontal cortex, respectively, without affecting norepinephrine and acetylcholine contents. alpha 1-Adrenoceptor binding of (3H) WB-4104 was increased in the hippocampus but not in the frontal cortex. Scatchard analysis revealed that the increase in (3H) WB-4101 binding in the lesioned hippocampus was the result of an elevated density of alpha 1-adrenergic receptors of about 65%. This phenomenon began 8 days postlesion and persisted for at least 90 days postlesion. Similar qualitative and quantitative results were obtained following chemical lesion of the serotonergic cells of origin in the median raphe nucleus with 5,7-dihydroxytryptamine. Selectivity of the phenomenon was further demonstrated as or beta-adrenoceptor binding with (3H) dihydroalprenolol and cholinergic muscarinic receptor binding with (3H) dexetimide were not significantly affected in the hippocampus. By comparison, when norepinephrine in the hippocampus was depleted by more than 90% by bilateral lesion of the ascending noradrenergic fibers with 6-hydroxydopamine (18 days), the alpha 1-adrenoceptor number was significantly increased by only about 20% while the beta-adrenoceptor number was enhance by 40%. The area-selective increase in alpha 1-adrenoceptor number in the hippocampus in the presence of unchanged norepinephrine content and in the absence of serotonin probably signifies that serotonin actively participates in the modulation of the noradrenergic receptor population.

Characterization of the alpha adrenergic receptor population in hippocampus up regulated by serotonergic raphe deafferentiation.

Serotonergic raphe deafferentiation elicits an up regulation of a nM (3H)WB-4101 binding site in rat hippocampus for which norepinephrine displays high affinity and prazosin displays low affinity. Guanine nucleotide affects the nM binding to hippocampal alpha-1 adrenergic receptors. Firstly, Gpp(NH)p, a nonhydrolyzable analog of GTP, inhibits (3H)WB-4101 binding at 3 nM concentration of the radioligand, the ligand concentration labelling the lower affinity, nM, binding site. Secondly, the addition of Gpp(NH)p causes recovery of the heterogeneity of binding sites lost upon preincubation of the membranes with 100 microM epinephrine, apparently by decreasing the affinity of the nM (3H)WB-4101 binding site for the adrenergic receptors. The phenomenon was still observed in the presence of saturating concentrations of the alpha-2 antagonist, yohimbine, and the beta antagonist, propranolol. The results imply that Gpp(NH)p regulates ligand binding to hippocampal alpha-1 agonist sites. It is likely that agonist and antagonist binding sites for the alpha-1 receptor exist in hippocampus with the agonist site being modulated by serotonin.

Studies on the up regulation of alpha-adrenoceptors on rat hippocampal perikarya by chemical lesion of the median raphe nucleus.

Neurotoxin-induced lesion of the serotonergic raphe-hippocampal pathway produced about a 50% increase in the density of a nM affinity alpha-adrenergic binding site for (3H)WB-4101 in rat hippocampus 18 days postlesion without altering the specific binding of (3H)5-HT to serotonergic receptors. The chronic i.c.v. infusion of serotonin by minipump started at the appropriate time averted or reverted the effect. The dynamics of noradrenergic neurotransmission in the hippocampus was not impaired by lesion of the median raphe nucleus as determined by the uptake and turnover of noradrenaline as well as its release - as reflected by the normetanephrine concentration. In addition, neurotoxin-induced lesion of the dorsal noradrenergic bundle failed to alter either the Bmax or the Kd of (3H)WB-4101 binding to the nM site. Kainic acid-induced destruction of perikarya depressed the nM (3H)WB-4101 binding sites by 60% and completely prevented the up regulation caused by lesion of the median raphe nucleus. Thus, the supersensitivity-like response of the adrenoceptors to the lack of serotonin appears to be localized on kainate-sensitive cells within the hippocampus.

Comparison of the effects of the stereoisomers of fenfluramine on the acetylcholine content of rat striatum, hippocampus and nucleus accumbens.

The (+)- and (-)- isomeric forms of fenfluramine were compared for their effects on rat brain area acetylcholine (ACh) content. The drugs showed similar patterns in increasing ACh content in the accumbens and hippocampus and in being ineffective in the brainstem. The actions differed in the striatum where the (+)-form markedly increased ACh content while the (-)-form produced no change. Both isomer-induced increases in ACh in the accumbens were prevented when 5-HT synthesis was blocked by p-chlorophenylalanine, thus denoting 5-hydroxytryptaminergic mediation of these effects. In striatum, the increase in ACh induced by (+)-fenfluramine was summated with the increase in ACh induced by dopamine receptor stimulation with apomorphine and was not prevented by dopamine receptor blockade with pimozide. On the other hand, apomorphine's effect was blocked by (-)-fenfluramine while pimozide pretreatment unmasked an increase in ACh induced by (-)-fenfluramine. The results favour the notion that there is a population of cholinergic neurons intrinsic to the striatum which is under inhibitory 5-HT regulation and independent of inhibitory dopamine regulation.

Body mass index, lifestyles, physical performance and cognitive decline: the "Treviso Longeva (TRELONG)" study.

OBJECTIVES: The relative contributions of risk factors, as body mass index (BMI), depression, chronic diseases, smoking, and lifestyles (as physical and performance activity, social contacts and reading habit) to cognitive decline in the elderly are unclear. We explored these variables in relation to 7-year cognitive decline in long-lived Italian elderly. DESIGN: Secondary data analysis of a longitudinal study of a representative, age-stratified, population sample. SETTING: The TREVISO LONGEVA (TRELONG) Study, in Treviso, Italy. PARTICIPANTS: 120 men and 189 women, age 77 years and older (mean age 80.2 ± 6.9 years) survivors after seven years of follow up. MEASUREMENTS: Cognitive decline measured as difference between Mini-Mental State Examination (MMSE) score in 2003 and in 2010; Body mass index (BMI), handgrip, Short Physical Performance Battery (SPPB) score, social contacts, reading habit, sight, hearing, schooling, mediterranean diet and multiple clinical and survey data recorded at baseline in 2003. RESULTS: In separate univariate analyses, age, SPPB score < 5, depressive symptoms (GDS) and more comorbidities (CCI) were associated with greater cognitive decline. Otherwise higher BMI, higher handgrip, reading habit, non-deteriorated sight and hearing, and schooling were protective. In a final multivariate model, age and higher BMI were associated with greater cognitive decline while reading habits was protective. SPPB score < 5 tends, though weakly, to be associated with greater cognitive decline. These associations remained with multivariate adjustment for gender, schooling, Charlson co-morbidity index (CCI) and baseline MMSE. CONCLUSION: Age and higher baseline BMI, independent of gender, and other confounding factors, are risk factors for cognitive decline. Reading habit plays a protective role seven years later among northern Italian adults aged 70 years or older. Low physical performance tends, though weakly, to be associated with greater cognitive decline.

The Treviso Dementia (TREDEM) Study: A Biomedical, Neuroradiological, Neuropsychological and Social Investigation of Dementia in North-Eastern Italy.

BACKGROUND: The incidence of dementia increases exponentially with age but knowledge of real disease-modifying interventions is still limited. OBJECTIVES: To describe the study design and methods of a large prospective cohort study aimed at exploring the complex underlying relationships existing among cognition, frailty, and health-related events in older persons with cognitive impairment. DESIGN: Prospective cohort study of a representative population of outpatients attending the Treviso Cognitive Impairment Center between 2000 and 2010. SETTING: The TREVISO DEMENTIA (TREDEM) Study conducted in Treviso, Italy. PARTICIPANTS: 490 men and 874 women, mean age 79.1 ± 7.8 years (range 40.2-100 years). MEASUREMENTS: Physiological data, biochemical parameters, clinical conditions, neuroradiological parameters (e.g., brain atrophy and cerebral vascular lesions identified by computerized tomography scans), neuropsychological assessment, and physical function markers were measured at baseline. Patients were followed-up to 10 years. RESULTS: The final sample included in the study was predominantly composed of women and characterized by an initial physical function impairment and increased vascular risk profile. Cognitive function of the sample population showed moderate cognitive impairment (Mini Mental State Examination 20.2 ± 6.3; Clinical Dementia Rating 1.2 ± 0.7), and a prevalence of vascular dementia of 26.9%. Cortical, subcortical and hippocampus atrophy were all significantly correlated with age and cognitive function. CONCLUSION: Results obtained from the preliminary analyses conducted in the TREDEM study suggest that the database will support the accomplishment of important goals in understanding the nature of cognitive frailty and neurodegenerative diseases.