The added value of MRI measures of atrophy in the diagnosis of AD.
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Biomedical subjects
Publications and source records attributed to M Trabucchi.
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Neuropeptides play a crucial role in cell communication as neurotransmitters, neuromodulators or neurohormones, and are involved in a number of biological activities including neuroendocrine regulations, control of neurovegetative functions, trophic effects and modulation of the immune response. The number of neuropeptides that have been fully characterized so far is rather limited, as compared to the number of precursor proteins that are actually expressed in nerve cells. Owing to the development of powerful analytical and structural identification methods, and the rapid advance in molecular biology techniques, a number of novel neuropeptides have been characterized during the last decade, in both vertebrates and invertebrates. The aim of the present review is to provide a comprehensive coverage of the different approaches which are currently used to identify novel neuropeptides.
The anatomical distribution of somatostatin-immunoreactive structures and the autoradiographic localization of somatostatin binding sites were investigated in the brain of the African lungfish, Protopterus annectens. In general, there was a good correlation between the distribution of somatostatin-immunoreactive elements and the location of somatostatin binding sites in several areas of the brain, particularly in the anterior olfactory nucleus, the rostral part of the dorsal pallium, the medial subpallium, the anterior preoptic area, the tectum, and the tegmentum of the mesencephalon. However, mismatching was found in the mid-caudal dorsal pallium, the reticular formation, and the cerebellum, which contained moderate to high concentrations of binding sites and very low densities of immunoreactive fibers. In contrast, the caudal hypothalamus and the neural lobe of the pituitary exhibited low concentrations of binding sites and a high to moderate density of somatostatin-immunoreactive fibers. The present results provide the first localization of somatostatin in the brain of a dipnoan and the first anatomical distribution of somatostatin binding sites in the brain of a fish. The location of somatostatin-immunoreactive elements in the brain of P. annectens is consistent with that reported in anuran amphibians, suggesting that the general organization of the somatostatin peptidergic systems occurred in a common ancestor of dipnoans and tetrapods. The anatomical distribution of somatostatin-immunoreactive elements and somatostatin binding sites suggests that somatostatin acts as a hypophysiotropic neurohormone as well as a neurotransmitter and/or neuromodulator in the lungfish brain.
Fibroblasts from Alzheimer's disease (AD) patients displayed decreased cytochrome c oxidase (complex IV) activity (P < 0.05). The basal oxygen consumption rate (QO2) and the response to an uncoupler of oxidative phosphorylation did not differ between AD and control fibroblasts. The QO2 of AD fibroblasts was more susceptible (P < 0.05) to inhibition by azide in the range 0.5-5 mM. The basal intracellular pH (pHi) in AD fibroblasts was significantly more acidic than in control ones. The results support the hypothesis that subtle dysfunctions of oxidative energy-producing processes are present in fibroblasts from sporadic AD patients. The alterations observed scantly influence the fibroblasts functioning even in stressful conditions; however in tissues, such as the brain, that rely heavily on oxidative metabolism for their function, similar alterations may trigger molecular mechanisms leading to cell damage.
The present study investigates the influence of energy related metabolic stress on amyloid precursor protein (APP) non-amyloidogenic secretory processing in COS cells. The effect of glucose deprivation on soluble APP (sAPP) secretion has been evaluated: incubation of COS cells with 50 mM 2-deoxy-D-glucose (2-DG) in glucose free medium was able to reduce sAPP secretion (-26%). Sodium azide (NaN3), an inhibitor of cytochrome c oxidase (complex IV of the mitochondrial electron transfer chain) decreased sAPP release in a concentration dependent way (maximum -75%). Treatment of COS cells with the antioxidant glutathione (GSH) fully antagonized the inhibitory effect of azide (1 mM) and elicited sAPP release over basal level. These results suggest that the inhibition of energy metabolism can influence APP processing leading to a decreased secretion of non-amyloidogenic fragments of APP.
Plasma-membrane composition plays a crucial role in most of the cellular functions that depend on membrane processes. In virtually all cell types the proteolytic processing of Alzheimer amyloid precursor protein (APP) to generate soluble APP (sAPP) is believed to occur at the plasma membrane or in its immediate proximity. Alteration of this metabolic pathway has been linked to the pathogenesis of Alzheimer's disease. We analysed the effect of membrane cholesterol enrichment on APP metabolism. Incubation of COS cells with increasing concentrations of non-esterified cholesterol carried by rabbit beta-very low-density lipoprotein caused a dose-dependent inhibition of sAPP release: 70% inhibition with 10 microg/ml non-esterified cholesterol. A less pronounced inhibitory effect was observed on treatment with human low-density lipoprotein. Inhibition of sAPP release was independent of receptor-mediated lipoprotein metabolism since simultaneous treatment with chloroquine did not modify the effect of lipoprotein treatment. In addition, treatment with cholesterol dissolved in either ethanol or methyl-beta-cyclodextrin elicited the same effect. Excess non-esterified cholesterol did not cause cell toxicity. Cell cholesterol mass inversely correlated with sAPP release. Progesterone, which inhibits shuttling of non-esterified cholesterol between the plasma membrane and intracellular pools, had no effect on the inhibition of sAPP release from cholesterol-loaded cells, providing indirect evidence that cholesterol may act at the plasma membrane.
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The aim of this survey study is to describe the association of symptomatic depression with the co-occurrence of psycho-social, functional, and somatic disadvantage conditions in 390 over 70 subjects living at home. The most disadvantaged tertile of various conditions (age, social support, cognition, social interactions, self evaluation of health, disability, number of diseases, and somatic symptoms) was associated with greater risk of symptomatic depression. A subset of conditions that might be causally related to depression (age, social support, financial welfare, diseases, and disability) was used to divide subjects into five levels of increasing multiple disadvantage conditions (MDC). Increasing severity of MDC level was associated with greater risk of symptomatic depression even after adjustment for gender and all five conditions used to define MDC levels (odds ratios ranging from 2.7 to 11.3).
Gonadotrophin-releasing hormone (GnRH) immunoreactivity is detectable in the brain, ovary, and testis of the newt, Triturus carnifex, collected during February (reproductive phase), May, and July (nonreproductive phase). In the brain of May animals, chicken GnRH-II positive cell bodies are located within the terminal nerve, the anterior preoptic area, and the preoptic nucleus, which appears to be devoid of immunoreactive mammalian GnRH cell bodies. During February and July, both chicken GnRH-II and mammalian GnRH are detected only within the terminal nerve and anterior preoptic area. Generally, in the reproductive as well as the nonreproductive periods, chicken GnRH-II fibers are widely distributed in the brain; however, the distribution of fibers of both molecular forms suggests that they exert hypophysiotropic activity. High-pressure liquid chromatography (HPLC) coupled with radioimmunoassay indicates the presence of an early-eluting GnRH peak in brains and gonads but not in plasma. Using chicken GnRH-II antiserum, immunoreactivity is observed in spermatocytes, spermatozoa, and the external theca layer. Seasonal changes of the GnRH-like material are observed in both sexes, and its high concentration detectable during February is in good correlation with the timing of reproduction.
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1. This study was undertaken to investigate the relationship between a reduction in brain GABAA receptor function and the cerebro-cortical content of 3 alpha-hydroxy-5 alpha-pregnan-20 one (allopregnanolone, AP), a potent endogenous positive modulator of 7-aminobutyric acid (GABA) action at GABAA receptors, with anticonflict and anticonvulsant effects in rodents. 2. An acute depletion of the cerebral content of GABA or an attenuation of GABAA receptor-mediated transmission by systemic injections of isoniazid (375 mg kg-1, s.c.) or FG 7142 (15 mg kg-1, i.p.) induced a transient increase in the cerebro-cortical and plasma concentrations of AP in handling-habituated (not stressed) rats. 3. Two stress paradigms, handling in naive rats and mild foot shock in handling-habituated rats, that reduce central GABAergic tone mimicked the effects of isoniazid and FG 7142 on cortical AP content; foot shock in handling-habituated rats, but not handling in naive animals, also increased plasma AP. Isoniazid, FG 7142, and foot shock also each increased the concentrations of the AP precursors, pregnenolone and progesterone, in both brain and plasma of handling-habituated rats, whereas handling in naive rats increased the concentrations of these steroids only in brain. 4. Pretreatment of handling-habituated rats with the anxiolytic beta-carboline derivative abecarnil, a positive allosteric modulator of GABAA receptors, which per se failed to affect the AP concentration in brain or plasma, prevented the increase in brain and plasma AP induced by foot shock or isoniazid. 5. In adrenalectomized and castrated rats foot shock or isoniazid failed to increase AP both in brain cortex and plasma. 6. These observations indicate that inhibition of GABAergic transmission, induced by foot shock or pharmacological manipulations, results in an increase in the concentrations of AP in brain and plasma, possibly via a modulation of hypothalamic-pituitary-adrenal (HPA) axis. 7. Given that AP enhances GABAA receptor function with high efficacy and potency, an increase in brain AP concentration may be important in the fine tuning of the GABA-mediated inhibitory transmission in the central nervous system.
AIM: to verify the capacity of basic and instrumental activities of daily living (BADL and IADL) disability scales and of a performance-based test (Physical Performance Test; PPT) to detect the effect on the functional capacity of several common chronic conditions in elderly people. METHOD: a cross-sectional survey of the entire population aged 70 and over, living in Ospitaletto (Brescia, northern Italy)-549 subjects; 89.6% of the eligible population; 179 males and 370 females-was carried out in 1992. A multi-dimensional questionnaire administered at the subject's home was used to collect information on demographics, presence of several common chronic diseases and BADL and IADL. Objective physical capacity was assessed using the PPT. RESULTS: only cognitive deterioration and depression were independently associated with disability, as detected by BADL or IADL scales. Cognitive deterioration, stroke, parkinsonism, heart disease and hearing and visual loss were independently associated with PPT. The performance at PPT remained statistically associated with most of the same diseases when the analysis was restricted to subjects with no BADL or IADL disability. CONCLUSION: a performance-based measure, such as PPT, may detect a functional limitation before it becomes measurable by traditional self-reported BADL and IADL scales.
OBJECTIVE: to evaluate the relationships between a functional measure of dental status (FDS), the nutrients intake profile (NIP) and mortality in a community elderly population. DESIGN: cross-sectional analysis for FDS and NIP and a prospective study for mortality. SETTING: the central district of Brescia, northern Italy. PARTICIPANTS: of the entire cohort of 70-75-year-old elderly subjects living in the district (n = 1303), 1189 subjects were interviewed and examined at baseline. Fifty-two of these were lost to follow-up; data are presented for the remaining 1137 subjects. MEASUREMENTS: baseline data were collected by a door-to-door interview using a standardized questionnaire which included a section about the dietary intake in the 24 h preceding the interview. The 24-h NIP was calculated and compared with the US Food and Drug Administration's 1980 Recommended Dietary Allowances to obtain a percentage value of each nutrient for each respondent. The dental examination considered the direct assessment of the number and position of residual teeth as well as the use of dentures; subjects were classified into three groups: naturally adequate or naturally inadequate dentition and denture wearers. Association of NIP with FDS was computed using ANCOVA and multiple logistic regression models. Mortality data were collected over a 78-month follow-up period. Association of survival with FDS was estimated by Kaplan-Meier analysis and multivariate Cox proportional hazard models. RESULTS: multiple logistic regression showed a significant and independent association between the dental status and the intake of micronutrients, but not of macronutrients. Moreover, denture wearers had a dietary intake very similar to adequate dentition and substantially better than inadequate dentition. Inadequate dentition in women was associated with higher mortality than adequate dentition. In elderly women, both inadequate dental status and folate intake were significant and independent predictors of mortality in a multivariate analysis based on nutritional parameters. However, inadequate dentition did not remain an independent predictor of mortality in a general multivariate model. CONCLUSION: in this cohort of urban elderly people, FDS is significantly associated with the NIP and indirectly with mortality.
A small feasibility study was performed in Italy to evaluate whether the special care unit (SCU) model could minimize behavioral disturbances in demented patients. In a nursing home an area was selected to provide an appropriate environment for individuals with dementia. The physical environment was adapted, and the staff was trained to meet the needs of demented patients. Sixteen residents were transferred from traditional wards to the SCU. Functional status, cognitive performance, behavioral symptoms, and use of psychotropic drugs or physical restraints were assessed before and 6 months after admission to the SCU. Our findings show that transferring demented persons from traditional nursing home wards to an SCU significantly lessens behavioral problems but does not improve functional abilities or cognitive status after a short period of follow-up. Changes in caring strategies (in particular the use of physical restraints) seem to be important in reducing behavioral problems. The regional government of Lombardia (8.5 million inhabitants) decided to open small (20-bed) SCUs in 60 nursing homes (corresponding to 3.5% of the total nursing home beds in our region) and to reserve these units for demented patients with a high level of behavioral disturbances.
We evaluated the floor effect and convergent, discriminant, and known-group validity of the Bedford Alzheimer Nursing Severity scale (BANS-s), a rating scale comprising cognitive and functional items recently developed for grading severe dementia. Ninety-nine demented patients (81 females and 18 males aged 55-100 years) in two nursing homes were assessed with the BANS-s, established cognitive and functional scales [Mini Mental State Examination, the extended version of the Clinical Dementia Rating (CDR), Katz's basic activities of daily living, Tinetti balance and gait, and Crichton scales], a behavioral scale (UCLA Neuropsychiatric Inventory), and indicators of malnutrition (Prognostic Nutritional Index). A relevant proportion (40%) of patients scored close to the floor of all scales except BANS-s and CDR, which showed a more uniform distribution of scores throughout the possible range. Convergent validity of BANS-s with the other cognitive and functional scales was good, with Pearson's r ranging from 0.62 to 0.79. Discriminant validity analysis of BANS-s versus the UCLA Neuropsychiatric Inventory showed that the two scales measure different domains (Pearson's r = 0.36). To test known-group validity, all patients were divided into two groups of different severity as defined by the Prognostic Nutritional Index. BANS-s and CDR were the scales with the best ability to discriminate malnourished from nonmalnourished patients. As a further validity test, the 37 patients reaching the floor on other cognitive and functional scales were divided into two subgroups of different dementia severity as defined by the Tinetti scale. BANS-s but not CDR was able to differentiate the two groups.
OBJECTIVE: To evaluate the relationships between a functional measure of dental status (FDS), several variables belonging to a quality of life (QOL) profile, and mortality in an older community population. DESIGN: Cross-sectional analysis for FDS and QOL; 10-year prospective study for mortality. SETTING: The historical and central district of the city of Brescia, northern Italy. PARTICIPANTS: The entire cohort of 70 to 75-year-old people living in the above-mentioned district (n = 1303): 1201 subjects were eligible for interview at baseline; 11 refused the physical examination; 52 were lost to follow-up; data are presented for the remaining sample of 1137 subjects. MEASUREMENTS: FDS examination was used to classify the subjects into three groups: naturally adequate (ADS) (25.2%), naturally inadequate (IDS) (14.3%) dental status, and denture wearers (DW) (60.4%). Various QOL domains were assessed: mood level, cognitive status, instrumental activities of daily living (IADL), social relationships, indexes of somatic health, and health behaviors. The demographic and socioeconomic parameters were used as covariates. RESULTS: Univariate analysis showed that both the ADS and the DW groups had a better QOL profile than the IDS group. Multiple logistic regression indicated that ADS and DW conditions were predicted independently by better educational and financial conditions, higher social relationships and a better IADL level in comparison with IDS. Moreover, compared with IDS, DS was a significant predictor of a better level at the SELF, IADL, and HCU scales whereas DW predicted only a better IADL level. Crude survival analysis showed that ADS was associated with a lower mortality risk compared with both DW and IDS, which did not differ from each other. FDS also remained a significant and independent predictor of mortality in a more general Cox's regression model. CONCLUSIONS: Within this cohort of 70 to 75-year-old urban residents, FDS is associated with several QOL domains and with long-term survival. A hierarchy of reciprocal relationships exists among these parameters. The present study provides a basis for encouraging more extensive use of dentures. Longitudinal studies using oral health outcomes are warranted before clinical recommendations can be made.
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