Gustavo Vedana

Reversal of age-associated memory impairment by rosuvastatin in rats

Increased levels of iron in brain regions have been reported in neurodegenerative disorders as well as in normal brain aging. We have previously demonstrated that neonatal iron loading induces cognitive impairment in adult rats. Here, we evaluate the effects of neonatal iron treatment on cognition in aged rats. We also investigated the effects of a late subchronic rosuvastatin treatment on iron- and age-induced cognitive deficits. Rats received vehicle or 10.0mg/kg Fe(2+) orally at postnatal days 12-14. When animals reached the age of 23 months, they received daily intraperitoneal injections of saline or rosuvastatin (0.2 or 2.0mg/kg) for 21 days. Twenty-four hours after the last injection, they were submitted to novel object recognition training. Retention test sessions were performed 1.5 and 24h after training, in order to assess short-term and long-term memory, respectively. Results indicated that aged animals that received iron in the neonatal period showed more severe memory deficits than vehicle-treated ones, suggesting that iron potentiates age-associated memory impairments. Rosuvastatin improved recognition memory deficits associated with iron loading and aging, providing evidence that statins may be considered for the treatment of age-associated cognitive decline.

Iron Leads to Memory Impairment that is Associated with a Decrease in Acetylcholinesterase Pathways

Increasing evidence indicates that excessive iron in selective regions of the brain may be involved in the etiology of neurodegenerative disorders. Accordingly, increased levels of iron have been described in brain regions of patients in Parkinsons and Alzheimers diseases. We have characterized neonatal iron loading in rodents as a novel experimental model that mimics the brain iron accumulation observed in patients with neurodegenerative diseases and produces severe cognitive impairment in the adulthood. In the present study we have investigated the involvement of the cholinergic system on iron-induced memory impairment. The effects of a single administration of the acetylcholinesterase (AChE) inhibitor galantamine or the muscarinic receptor agonist oxotremorine on iron-induced memory deficits in rats were examined. Male Wistar rats received vehicle or iron (10.0 mg/kg) orally at postnatal days 12 to 14. At the age of 2-3 months, animals were trained in a novel object recognition task. Iron-treated rats showed long-term impairments in recognition memory. The impairing effect was reversed by systemic administration of galantamine (1 mg/kg) immediately after training. In addition, iron-treated rats that received oxotremorine (0.5 mg/kg) showed enhanced memory retention. Rats given iron showed a decreased AChE activity in the striatum when compared to controls. The results suggest that, at least in part, iron-induced cognitive deficits are related to a dysfunction of cholinergic neural transmission in the brain. These findings might have implications for the development of novel therapeutic strategies aimed at ameliorating cognitive decline associated with neurodegenerative disorders.

Subjective Mild Depressive Symptoms are Associated With Abnormal Diurnal Cycle of Salivary Cortisol in Older Adults

Background: Alterations in cortisol secretion pattern seem to be involved in the associations between aging, depression, and cognitive decline. Objective: The aim of this study was to mainly assess cortisol circadian profile in older adults with subjective depressive symptoms. Methods: Salivary cortisol samples from healthy young (n = 22) and old adults (n = 22), and from older adults who self-reported depressive symptoms in Geriatric Depression Scale (n = 22) were collected at 7 AM, 4 PM, and 10 PM and were analyzed by radioimmunoassay. Results: Older adults with depressive symptoms presented the characteristic cortisol circadian pattern, but they showed higher cortisol levels at 10 PM than healthy young and elderly controls. Conclusions: Our data suggest that mild depressive symptoms could be associated with a cortisol secretion pattern previously described as being predictive of cognitive decline.

Contextual memory and encoding strategies in young and older adults with and without depressive symptoms

Objectives: This study examines the role of depressive symptoms associated with age on contextual memory and how this association could impair the use of strategic instructions during encoding. Method: Young and older controls and older adults with depressive symptoms performed memory recognition tests for item and context. Results: Memory results indicated that mild depressive symptoms did not aggravate the age-related contextual memory pattern, but interfered with the magnitude of the memory enhancement provided by specific encoding instructions when compared with young adults. These between-group differences in the use of memory strategies were eliminated with the inclusion of the performance on Wisconsin Card Sorting Test as a covariate. Conclusion: Mild depressive symptoms were associated with an impaired ability to use incidental memory strategies at encoding, suggesting the need for further investigation on the effects of non-clinical depressive symptomatology on cognitive decline in aging.

Rescue of social behavior impairment by clozapine and alterations in the expression of neuronal receptors in a rat model of neurodevelopmental impairment induced by GRPR blockade

We have previously shown that pharmacological blockade of the gastrin-releasing peptide receptor (GRPR) during the neonatal period in rats produces behavioral features of developmental neuropsychiatric disorders. Here, we show that social interaction deficits in this model are reversed by the atypical antipsychotic clozapine given in the adulthood. In addition, we analyzed the mRNA expression of three neuronal receptors potentially involved in the etiology of disorders of the autism spectrum. Rats were injected with the GRPR antagonist RC-3095 or saline (SAL) from postnatal days 1–10, and tested for social behavior and recognition memory in the adulthood. One hour prior to the behavioral testing, rats were given a systemic injection of clozapine or saline. The mRNA expression of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor, the epidermal growth factor receptor (EGFR), and GRPR was measured in the hippocampus and cortex of a separate set of rats given RC-3095 or SAL neonatally. Rats given neonatal RC-3095 showed decreased social interaction and impaired object recognition memory. Clozapine rescued the social interaction impairment. Neonatal treatment with RC-3095 also resulted in dose-dependent decreases in the expression of GRPR, NR1, and EGFR in the cortex, whereas all three receptor mRNAs were increased in the hippocampus in rats treated with the lower dose of RC-3095. The results contribute to further validate the novel rat model of neurodevelopmental disorders induced by GRPR blockade, and shows alterations in the expression of neuronal receptors in this model.

Neuropathological Changes in Adult and Old Rats Following Early Post-Natal Iron Administration

acetylcholine esterase (AChE) activity. Evidence for cholinergic dysfunction in early stages of Alzheimer’s disease (AD) or mild cognitive impairment (MCI) is inconclusive, and human studies of the relationship of cholinergic function with neuropsychological performance in vivo are rare. Methods: We included 21 healthy controls, 20 MCI and 15 mild AD patients. A comprehensive neuropsychological battery was administered to indicate the general cognitive function and to define performance of verbal and non-verbal memory, language, executive function and visuoconstructive abilities. [11C]-MP4A PET was applied in all subjects, parametric images of tracer hydrolysis rate constant k3 were generated and analysed using standard atlas regions. After principal component analysis (PCA) of k3 values correlational analysis with neuropsychological test results was performed. Results: The mean global k3 values of MCI (0.076 6 0.011 min-1) and AD patients (0.066 6 0.009 min-1) were significantly lower than that of controls (0.084 6 0.006 min-1) (p < 0.05 and p < 0.001, respectively) with the temporal regions showing the strongest decline in both patient groups. PCA revealed three main components representing frontal and parietal regions (PC1), temporal regions (PC2) and hippocampus and amygdala (PC3). PC 2 could separate all three diagnostic groups. Significant correlations in the whole group between PC2 and neuropsychological performances were found, most strongly with impaired verbal and visual memory function as well as impaired working memory, but also with deficient visuo-spatial and executive functions. The association of verbal and non-verbal memory with the ‘‘temporal’’ PC 2 was confirmed in MCI patients. This is in line with neuropathological studies showing the greatest and most consistent loss of cholinergic neurons in AD in the posterior part of the nucleus basalis Meynert (nbM-Ch4p), which primarily sends cholinergic projections to the temporal cortex (Geula and Mesulam, 1999). Conclusions: Cholinergic dysfunction in the temporal lobe is an early hallmark in MCI and mild AD and it is associated with impaired neuropsychological function.