Non-pharmacological interventions on cognitive functions in older people with mild cognitive impairment (MCI)

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Mild cognitive impairment (part 1): Clinical characteristics and predictors of dementia

Objective: To critically review and evaluate existing knowledge on the conceptual limits and clinical usefulness of the diagnosis of mild cognitive impairment (MCI) and the neuropsychological assessment and short- and long-term prognosis thereof. Methods: We conducted a systematic search of the PubMed and Web of Science electronic databases, limited to articles published in English between 1999 and 2012. Based on the search terms mild cognitive impairment or MCI and epidemiology or diagnosis, we retrieved 1,698 articles, of which 248 were critically eligible (cross-sectional and longitudinal studies); the abstracts of the remaining 1,450 articles were also reviewed. Results: A critical review on the MCI construct is provided, including conceptual and diagnostic aspects; epidemiological relevance; clinical assessment; prognosis; and outcome. The distinct definitions of cognitive impairment, MCI included, yield clinically heterogeneous groups of individuals. Those who will eventually progress to dementia may present with symptoms consistent with the definition of MCI; conversely, individuals with MCI may remain stable or return to normal cognitive function. Conclusion: On clinical grounds, the cross-sectional diagnosis of MCI has limited prognostic relevance. The characterization of persistent and/or progressive cognitive deficits over time is a better approach for identification of cases at the pre-dementia stages, particularly if these cognitive abnormalities are consistent with the natural history of incipient Alzheimer's disease. © 2013 Associação Brasileira de Psiquiatria.

White matter abnormalities associated with Alzheimer's disease and mild cognitive impairment: A critical review of MRI studies

In this article, the authors aim to present a critical review of recent MRI studies addressing white matter (WM) abnormalities in Alzheimer's disease (AD) and mild cognitive impairment (MCI), by searching PubMed and reviewing MRI studies evaluating subjects with AD or MCI using WM volumetric methods, diffusion tensor imaging and assessment of WM hyperintensities. Studies have found that, compared with healthy controls, AD and MCI samples display WM volumetric reductions and diffusion tensor imaging findings suggestive of reduced WM integrity. These changes affect complex networks relevant to episodic memory and other cognitive processes, including fiber connections that directly link medial temporal structures and the corpus callosum. Abnormalities in cortico-cortical and cortico-subcortical WM interconnections are associated with an increased risk of progression from MCI to dementia. It can be concluded that WM abnormalities are detectable in early stages of AD and MCI. Degeneration of WM networks causes disconnection among neural cells and the degree of such changes is related to cognitive decline. © 2013 2013 Expert Reviews Ltd.

Mild cognitive impairment (part 2): Biological markers for diagnosis and prediction of dementia in Alzheimer's disease

To present a critical review of publications reporting on the rationale and clinical implications of the use of biomarkers for the early diagnosis of Alzheimer's disease (AD). Methods: We conducted a systematic search of the PubMed and Web of Science electronic databases, limited to articles published in English between 1999 and 2012, and based on the following terms: mild cognitive impairment, Alzheimer's disease OR dementia, biomarkers. We retrieved 1,130 articles, of which 175 were reviews. Overall, 955 original articles were eligible. Results: The following points were considered relevant for the present review: a) rationale for biomarkers research in AD and mild cognitive impairment (MCI); b) usefulness of distinct biomarkers for the diagnosis and prediction of AD; c) the role of multimodality biomarkers for the diagnosis and prediction of AD; d) the role of biomarkers in clinical trials of patients with AD and MCI; and e) current limitations to the widespread use of biomarkers in research and clinical settings. Conclusion: Different biomarkers are useful for the early diagnosis and prediction of AD in at-risk subjects. Nonetheless, important methodological limitations need to be overcome for widespread use of biomarkers in research and clinical settings. © 2013 Associação Brasileira de Psiquiatria.

Neurobiological Correlates of Apathy in Alzheimer's Disease and Mild Cognitive Impairment: A Critical Review

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Physical Exercise Improves Peripheral BDNF Levels and Cognitive Functions in Mild Cognitive Impairment Elderly with Different BDNF Val66Met Genotypes

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Cognitive impairment in chronic kidney disease

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Reduced platelet amyloid precursor protein ratio (APP ratio) predicts conversion from mild cognitive impairment to Alzheimer's disease

Studies have shown that platelet APP ratio (representing the percentage of 120-130 kDa to 110 kDa isoforms of the amyloid precursor protein) is reduced in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). In the present study, we sought to determine if baseline APP ratio predicts the conversion from MCI to AD dementia after 4 years of longitudinal assessment. Fifty-five older adults with varying degrees of cognitive impairment (34 with MCI and 21 with AD) were assessed at baseline and after 4 years. MCI patients were re-classified according to the conversion status upon follow-up: 25 individuals retained the diagnostic status of MCI and were considered as stable cases (MCI-MCI); conversely, in nine cases the diagnosis of dementia due to AD was ascertained. The APP ratio (APPr) was determined by the Western blot method in samples of platelets collected at baseline. We found a significant reduction of APPr in MCI patients who converted to dementia upon follow-up. These individuals had baseline APPr values similar to those of demented AD patients. The overall accuracy of APPr to identify subjects with MCI who will progress to AD was 0.74 +/- A 0.10, p = 0.05. The cut-off of 1.12 yielded a sensitivity of 75 % and a specificity of 75 %. Platelet APPr may be a surrogate marker of the disease process in AD, with potential implications for the assessment of abnormalities in the APP metabolism in patients with and at risk for dementia. However, diagnostic accuracy was relatively low. Therefore, studies in larger samples are needed to determine whether APPr may warrant its use as a biomarker to support the early diagnosis of AD.

Memory-rescuing effects of cannabidiol in an animal model of cognitive impairment relevant to neurodegenerative disorders

Rationale Cannabidiol, the main nonpsychotropic constituent of Cannabis sativa, possesses a large number of pharmacological effects including anticonvulsive, sedative, hypnotic, anxiolytic, antipsychotic, anti-inflammatory, and neuroprotective, as demonstrated in clinical and preclinical studies. Many neurodegenerative disorders involve cognitive deficits, and this has led to interest in whether cannabidiol could be useful in the treatment of memory impairment associated to these diseases. Objectives We used an animal model of cognitive impairment induced by iron overload in order to test the effects of cannabidiol in memory-impaired rats. Methods Rats received vehicle or iron at postnatal days 12-14. At the age of 2 months, they received an acute intraperitoneal injection of vehicle or cannabidiol (5.0 or 10.0 mg/kg) immediately after the training session of the novel object recognition task. In order to investigate the effects of chronic cannabidiol, iron-treated rats received daily intraperitoneal injections of cannabidiol for 14 days. Twenty-four hours after the last injection, they were submitted to object recognition training. Retention tests were performed 24 h after training. Results A single acute injection of cannabidiol at the highest dose was able to recover memory in iron-treated rats. Chronic cannabidiol improved recognition memory in iron-treated rats. Acute or chronic cannabidiol does not affect memory in control rats. Conclusions The present findings provide evidence suggesting the potential use of cannabidiol for the treatment of cognitive decline associated with neurodegenerative disorders. Further studies, including clinical trials, are warranted to determine the usefulness of cannabidiol in humans suffering from neurodegenerative disorders.

Spectrum of cognitive impairment in neurocysticercosis Differences according to disease phase

Objectives: Cognitive decline related to neurocysticercosis (NC) remains poorly characterized and underdiagnosed. In a cross-sectional study with a prospective phase, we evaluated cognitive decline in patients with strictly calcified form (C-NC), the epidemiologically largest subgroup of NC, and investigated whether there is a spectrum of cognitive abnormalities in the disease. Methods: Forty treatment-naive patients with C-NC aged 37.6 +/- 11.3 years and fulfilling criteria for definitive C-NC were submitted to a comprehensive cognitive and functional evaluation and were compared with 40 patients with active NC (A-NC) and 40 healthy controls (HC) matched for age and education. Patients with dementia were reassessed after 24 months. Results: Patients with C-NC presented 9.4 +/- 3.1 altered test scores out of the 30 from the cognitive battery when compared to HC. No patient with C-NC had dementia and 10 patients (25%) presented cognitive impairment-no dementia (CIND). The A-NC group had 5 patients (12.5%) with dementia and 11 patients (27.5%) with CIND. On follow-up, 3 out of 5 patients with A-NC with dementia previously still presented cystic lesions with scolex on MRI and still had dementia. One patient died and the remaining patient no longer fulfilled criteria for either dementia or CIND, presenting exclusively calcified lesions on neuroimaging. Conclusions: Independently of its phase, NC leads to a spectrum of cognitive abnormalities, ranging from impairment in a single domain, to CIND and, occasionally, to dementia. These findings are more conspicuous during active vesicular phase and less prominent in calcified stages. Neurology (R) 2012; 78: 861-866

Curcumin requires tumor necrosis Factor α signaling to alleviate cognitive impairment elicited by Lipopolysaccharide

A decline in cognitive ability is a typical feature of the normal aging process, and of neurodegenerative disorders such as Alzheimer’s, Parkinson’s and Huntington’s diseases. Although their etiologies differ, all of these disorders involve local activation of innate immune pathways and associated inflammatory cytokines. However, clinical trials of anti-inflammatory agents in neurodegenerative disorders have been disappointing, and it is therefore necessary to better understand the complex roles of the inflammatory process in neurological dysfunction. The dietary phytochemical curcumin can exert anti-inflammatory, antioxidant and neuroprotective actions. Here we provide evidence that curcumin ameliorates cognitive deficits associated with activation of the innate immune response by mechanisms requiring functional tumor necrosis factor α receptor 2 (TNFR2) signaling. In vivo, the ability of curcumin to counteract hippocampusdependent spatial memory deficits, to stimulate neuroprotective mechanisms such as upregulation of BDNF, to decrease glutaminase levels, and to modulate N-methyl- D –aspartate receptor levels was absent in mice lacking functional TNFRs. Curcumin treatment protected cultured neurons against glutamate-induced excitotoxicity by a mechanism requiring TNFR2 activation. Our results suggest the possibility that therapeutic approaches against cognitive decline designed to selectively enhance TNFR2 signaling are likely to be more beneficial than the use of anti-inflammatory drugs per se.

The role of Nox2-derived ROS in the development of cognitive impairment after sepsis

BACKGROUND: Sepsis- associated encephalopathy (SAE) is an early and common feature of severe infections. Oxidative stress is one of the mechanisms associated with the pathophysiology of SAE. The goal of this study was to investigate the involvement of NADPH oxidase in neuroinflammation and in the long-term cognitive impairment of sepsis survivors. METHODS: Sepsis was induced in WT and gp91phox knockout mice (gp91phox-/-) by cecal ligation and puncture (CLP) to induce fecal peritonitis. We measured oxidative stress, Nox2 and Nox4 gene expression and neuroinflammation in the hippocampus at six hours, twenty-four hours and five days post-sepsis. Mice were also treated with apocynin, a NADPH oxidase inhibitor. Behavioral outcomes were evaluated 15 days after sepsis with the inhibitory avoidance test and the Morris water maze in control and apocynin-treated WT mice. RESULTS: Acute oxidative damage to the hippocampus was identified by increased 4-HNE expression in parallel with an increase in Nox2 gene expression after sepsis. Pharmacological inhibition of Nox2 with apocynin completely inhibited hippocampal oxidative stress in septic animals. Pharmacologic inhibition or the absence of Nox2 in gp91phox-/- mice prevented glial cell activation, one of the central mechanisms associated with SAE. Finally, treatment with apocynin and inhibition of hippocampal oxidative stress in the acute phase of sepsis prevented the development of long-term cognitive impairment. CONCLUSIONS: Our results demonstrate that Nox2 is the main source of reactive oxygen species (ROS) involved in the oxidative damage to the hippocampus in SAE and that Nox2-derived ROS are determining factors for cognitive impairments after sepsis. These findings highlight the importance of Nox2-derived ROS as a central mechanism in the development of neuroinflammation associated with SAE.

Mild cognitive impairment in medical inpatients: the mini-mental state examination is a promising screening tool

AIM: To assess the prevalence of mild cognitive impairment (MCI) in medical inpatients aged 55-85 years without known cognitive deficits, and how often ward physicians mentioned MCI in their discharge notes. Moreover, we aimed to identify variables associated with MCI and to assess the sensitivity and specificity of the Mini-Mental State Examination (MMSE) for MCI. METHODS: Two neuropsychologists administered a 60-min battery of validated tests to evaluate different cognitive domains. The diagnosis of MCI was based on a prespecified algorithm. The sensitivity and specificity of the MMSE for MCI were calculated. RESULTS: Fifteen patients showed a normal cognitive profile (21.4%), while 55 patients (78.6%) showed MCI. Ward physicians, blinded to the results of the neuropsychological evaluation, did not mention MCI in their discharge notes of any of the evaluated patients. The only variable independently associated with MCI was the MMSE. A MMSE score of < or =28 showed a sensitivity of 85.5% and a specificity of 66.7% for MCI. CONCLUSION: MCI is frequent albeit overlooked in elderly medical inpatients without previously known cognitive deficits. In view of therapies preventing the progression of MCI to dementia, MCI screening will be crucial. The MMSE represents a promising screening tool for MCI in medical inpatients.

Cataract and cognitive impairment: a review of the literature

Acquired cataract and cognitive impairment are both common age-related problems, and ophthalmologists are increasingly likely to encounter patients who have both. Patients with dementia types who display early visuoperceptual impairment may present first to ophthalmology services. When these patients have coexisting cataract, it may be difficult to distinguish visual complaints due to cataract from those due to dementia. The interaction between visual impairment due to cataract and neurodegenerative disorders affecting the central visual pathways, is not fully understood. Visual impairment due to cataract may stress impaired attentional mechanisms and cataract extraction may improve cognitive performance in some patients with early cognitive impairment; however, the benefits of cataract surgery in established dementia are less clear. In this study, the literature on this subject was reviewed and the implications for practice were considered.