Filipa F. Ribeiro

Mild cognitive impairment: deficits in cognitive domains other than memory.

Patients with mild cognitive impairment (MCI) typically present with memory complaints, but may have mild deficits in other cognitive domains. We compared the neuropsychological profiles of a series of consecutive MCI patients (n = 116) with a control group of healthy elderly subjects (n = 63). The presence of a memory deficit on delayed recall was consistent in the MCI sample, as it was an inclusion criterion in the study. Impairment on immediate recall was present in 62.6% of the patients on paragraph recall of the logical memory test and in 63.1% of the patients on the word paired-associate learning test. Remarkably, patients with MCI frequently had deficits in cognitive domains beyond memory. As much as 68.7% of the patients had deficits in temporal orientation, 30.2% had deficits in semantic fluency, 33.7% in the Token test, 23.4% in calculation, and 23.9% in motor initiative. If detailed neuropsychological testing is performed, the majority of MCI patients will have deficits in cognitive domains other than memory.

Verbal learning and memory deficits in Mild Cognitive Impairment

Criteria for amnestic MCI rely on the use of delayed recall tasks to establish the presence of memory impairment. This study applied the California Verbal Learning Test to detail memory performance in MCI patients (n = 70), as compared to control subjects (n = 92) and AD patients (n = 21). Learning across the 5 trials was different among the 3 groups. Learning strategy was also different, the MCI group showing less semantic clustering than the control group. However, both MCI patients and controls could benefit from semantic cueing. This study showed that beyond consolidation deficits, MCI patients have marked difficulties in acquisition and recall strategies.

Memory complaints in healthy young and elderly adults: reliability of memory reporting.

The relationship between memory complaints and objective memory performance remains poorly understood, particularly in young and middle aged people. We studied the relationship between reports of memory complaints and objective memory performance, and the possibility of differentiating good and poor reporters across the lifespan based on concordance between reported abilities and objectively assessed performance. This cross-sectional study enrolled 292 healthy individuals, aged 18 to 87 years, able to perform common activities of daily living and without neurological or psychiatric conditions or systemic diseases likely to interfere with cognition. No correlation between memory complaints, as assessed by the Subjective Memory Complaints scale (SMC) score and the objective memory performance, evaluated by the long-delay free recall (LDFR) score of the California Verbal Learning Test (CVLT), was found, even when grouping the participants by decade. The SMC score was influenced by the presence of depressive symptoms. Participants who were more educated, female and younger tended to have a higher CVLT-LDFR score. Younger subjects were more likely to have good memory performance and report few memory complaints than older subjects. In conclusion, there are differences in the reliability of memory reporting across the lifespan, younger subjects being more likely to correctly report good memory than older subjects.

Memory complaints are frequent but qualitatively different in young and elderly healthy people.

Background: Subjective memory complaints are frequently reported by the elderly. There is less information about the characterization of subjective memory complaints in young people. Objective: To determine different memory complaints between young and elderly people with the use of the Subjective Memory Complaints (SMC) scale. Methods: Participants were volunteers attending a health itinerant unit, a blood donor centre, a leisure centre for retired people, a senior citizens college or university. All participants were questioned about their own memory abilities using the SMC scale and assessed for the presence of depressive symptoms. Results: Nine-hundred and forty-six subjects aged 18–92 years were included in the study. The mean total score on the SMC scale was 4.89 ± 3.03, and 75.9% of the participants had at least minor complaints about their memory. Older people had more general memory complaints and reported they were more likely to become transiently confused, whereas younger people reported they were more frequently told by others that they were forgetful and would more often take notes. Conclusions: Memory complaints were frequent both in young and elderly subjects, but the detailed assessment revealed age-related differences in the type of complaints.

Clinical significance of subcortical vascular disease in patients with mild cognitive impairment

Patients with mild cognitive impairment (MCI) typically present with memory complaints. Some of these patients have subcortical vascular disease on computed tomography (CT) scan, namely white matter changes and lacunar infarcts, however it is not known whether these findings are associated with more pronounced cognitive deficits. In the present study we compare demographic, clinical and neuropsychological characteristics of MCI patients according to the presence or the absence of subcortical vascular disease. Forty consecutive patients with memory complaints, at least one neuropsychological memory test below 1 SD the normal for age and education, and maintained activities of daily living, were included. Patients with dementia, history of stroke or transient ischemic attack, or other brain disorders, were excluded. Twenty‐five (62.5%) patients with MCI had no ischemic lesions on CT scan, and 15 (37.5%) were found to have subcortical vascular changes. MCI patients with subcortical vascular changes were older (77.1 ± 6.8 vs. 70.8 ± 7.5 years old), and more often males. The number of vascular risk factors, the frequency of neurological signs, the Hachinski score and the neuropsychological tests scores were not significantly different. The presence of subcortical vascular disease on CT scan is frequent in older patients with MCI, but does not appear to be associated with the severity of cognitive deficits.

Frontotemporal mild cognitive impairment

Mild Cognitive Impairment appears to be a heterogeneous clinical entity comprising patients in the initial phases of distinct neurological disorders. Since frontotemporal dementia (FTD) is a relatively common neurodegenerative disease with an insidious onset, it might be possible to detect the patients in the initial phases of the disorder, before being demented. In the present work we proposed a set of criteria to identify patients with mild cognitive impairment of the frontotemporal type (FT-MCI), applied these criteria retrospectively to a large patient database, and evaluated the progression of the patients. Seven subjects fulfilling the proposed criteria for frontotemporal MCI were identified. They had symptoms of apathy, disinhibition, irritability and aggressiveness, untidiness, difficulties in decision making, obsessions and lack of concern for the others, for 1.5 +/- 0.8 years before the diagnosis of FT-MCI. Brain CT or MRI scan displayed fronto-temporal atrophy in five. Neuropsychological examination revealed deficits in tests dependent upon the frontal lobe, namely attention, verbal, motor and graphomotor initiatives and conceptual thinking. The patients kept their professional and daily activities, and were not demented. It was possible to have the follow-up of all patients. All but one patient diagnosed FT-MCI developed dementia of the frontotemporal type within 1.8 +/- 1.0 years. Application of the proposed criteria for FT-MCI, at least in this clinical neurological setting, can identify a group of patients with a high probability of further cognitive decline to dementia of the frontotemporal type.

Activation of type 1 cannabinoid receptor (CB1R) promotes neurogenesis in murine subventricular zone cell cultures.

The endocannabinoid system has been implicated in the modulation of adult neurogenesis. Here, we describe the effect of type 1 cannabinoid receptor (CB1R) activation on self-renewal, proliferation and neuronal differentiation in mouse neonatal subventricular zone (SVZ) stem/progenitor cell cultures. Expression of CB1R was detected in SVZ-derived immature cells (Nestin-positive), neurons and astrocytes. Stimulation of the CB1R by (R)-(+)-Methanandamide (R-m-AEA) increased self-renewal of SVZ cells, as assessed by counting the number of secondary neurospheres and the number of Sox2+/+ cell pairs, an effect blocked by Notch pathway inhibition. Moreover, R-m-AEA treatment for 48 h, increased proliferation as assessed by BrdU incorporation assay, an effect mediated by activation of MAPK-ERK and AKT pathways. Surprisingly, stimulation of CB1R by R-m-AEA also promoted neuronal differentiation (without affecting glial differentiation), at 7 days, as shown by counting the number of NeuN-positive neurons in the cultures. Moreover, by monitoring intracellular calcium concentrations ([Ca2+]i) in single cells following KCl and histamine stimuli, a method that allows the functional evaluation of neuronal differentiation, we observed an increase in neuronal-like cells. This proneurogenic effect was blocked when SVZ cells were co-incubated with R-m-AEA and the CB1R antagonist AM 251, for 7 days, thus indicating that this effect involves CB1R activation. In accordance with an effect on neuronal differentiation and maturation, R-m-AEA also increased neurite growth, as evaluated by quantifying and measuring the number of MAP2-positive processes. Taken together, these results demonstrate that CB1R activation induces proliferation, self-renewal and neuronal differentiation from mouse neonatal SVZ cell cultures.

Mild cognitive impairment: focus on diagnosis.

Great interest is now devoted to elderly people with memory or other cognitive complaints who are not demented. The determination of this impairment from normality is difficult, because memory performance may decline slowly along the lifetime of the individual. On the other hand, the identification of dementia depends on the criteria used for dementia (DSM-IV or ICD-10). Furthermore, cognitive deterioration of the elderly appears to be heterogenous and may forerun not only Alzheimer’s disease but also other forms of dementia. By applying a set of criteria for frontotemporal mild cognitive impairment, it was possible to identify, retrospectively, a series of patients with behavioral, affective, or speech symptoms suggestive of frontotemporal dysfunction and deficits in frontal lobe-dependent neuropsychological tests, but who have maintained activities of daily living and are not demented. These patients appear to have a high probability of progressing subsequently to dementia of the frontotemporal type. Several potential neuroprotective compounds are now being subjected to clinical trials. Should they be effective in delaying the progression to dementia, the need to detect and treat elderly people with cognitive impairment will become very important.

Axonal elongation and dendritic branching is enhanced by adenosine A2A receptors activation in cerebral cortical neurons

Axon growth and dendrite development are key processes for the establishment of a functional neuronal network. Adenosine, which is released by neurons and glia, is a known modulator of synaptic transmission but its influence over neuronal growth has been much less investigated. We now explored the action of adenosine A2A receptors (A2AR) upon neurite outgrowth, discriminating actions over the axon or dendrites, and the mechanisms involved. Morphometric analysis of primary cultures of cortical neurons from E18 Sprague–Dawley rats demonstrated that an A2AR agonist, CGS 21680, enhances axonal elongation and dendritic branching, being the former prevented by inhibitors of phosphoinositide 3-kinase, mitogen-activated protein kinase and phospholipase C, but not of protein kinase A. By testing the influence of a scavenger of BDNF (brain-derived neurotrophic factor) over the action of the A2AR agonist and the action of a selective A2AR antagonist over the action of BDNF, we could conclude that while the action of A2ARs upon dendritic branching is dependent on the presence of endogenous BDNF, the influence of A2ARs upon axonal elongation is independent of endogenous BDNF. In consonance with the action over axonal elongation, A2AR activation promoted a decrease in microtubule stability and an increase in microtubule growth speed in axonal growth cones. In conclusion, we disclose a facilitatory action of A2ARs upon axonal elongation and microtubule dynamics, providing new insights for A2ARs regulation of neuronal differentiation and axonal regeneration.

Modulation of subventricular zone oligodendrogenesis: a role for hemopressin?

Neural stem cells (NSCs) from the subventricular zone (SVZ) have been indicated as a source of new oligodendrocytes to use in regenerative medicine for myelin pathologies. Indeed, NSCs are multipotent cells that can self-renew and differentiate into all neural cell types of the central nervous system. In normal conditions, SVZ cells are poorly oligodendrogenic, nevertheless their oligodendrogenic potential is boosted following demyelination. Importantly, progressive restriction into the oligodendrocyte fate is specified by extrinsic and intrinsic factors, endocannabinoids being one of these factors. Although a role for endocannabinoids in oligodendrogenesis has already been foreseen, selective agonists and antagonists of cannabinoids receptors produce severe adverse side effects. Herein, we show that hemopressin (Hp), a modulator of CB1 receptors, increased oligodendroglial differentiation in SVZ neural stem/progenitor cell cultures derived from neonatal mice. The original results presented in this work suggest that Hp and derivates may be of potential interest for the development of future strategies to treat demyelinating diseases.