João Carlos Barbosa Machado

The Pietà study: epidemiological investigation on successful brain aging in Caeté (MG), Brazil. Methods and baseline cohort characteristics

OBJECTIVES To present the methods and baseline characteristics of the Pietà study, a population-based survey investigating successful brain aging in the oldest-old. METHOD The study was conducted in Caeté (MG), Brazil. In 2007, 1,251 individuals aged 75+ years were living in the city and were invited to participate. Participants responded to a general health questionnaire and were submitted to clinical, neurological, cognitive, psychiatric and functional evaluations. A subgroup was submitted to neuropsychological testing, blood tests and magnetic resonance of the skull. Individuals were classified as having cognitive impairment-no dementia, dementia, parkinsonism, psychiatric disorders or successful brain aging. RESULTS We evaluated 639 individuals (51.1% of the target population; 64% women), aged 81.4±5.2 years and with 2.7±2.6 years of schooling. Almost 30% of the elderly were illiterates and 82.1% belonged to middle/middle-low socioeconomic levels. Almost 50% were widows, but only 14.3% were living alone. CONCLUSION The Pietà cohort is representative of the oldest-old Brazilian population. We believe the results of the study may contribute to increase our knowledge about healthy and pathological brain aging in the oldest-old.

Effects of galantamine on attention and memory in Alzheimer's disease measured by computerized neuropsychological tests: results of the Brazilian Multi-Center Galantamine Study (GAL-BRA-01)

OBJECTIVE To investigate the effects of galantamine on the performance of patients with mild to moderate Alzheimers disease (AD) in a computerized neuropsychological test battery (CNTB). METHOD Thirty-three patients with probable AD were treated with galantamine for three months and evaluated in a prospective, open-label, multi-center study. The CNTB and the ADAS-Cog were administered at baseline and after 12 weeks. The CNTB includes reaction time tests to evaluate attention, implicit and episodic memory for faces and words. Statistical comparisons were performed between the results in week 12 versus baseline. Patients who did not reach the therapeutic doses were excluded from the efficacy analysis. RESULTS Four patients (12.1%) were excluded from the analysis either because of treatment discontinuation (n=3) or because a therapeutic dose was not reached (n=1). The remaining 29 patients were treated with doses of 24 mg/day (n=22) and 16 mg/day (n=7). After 12 weeks, significant reductions in reaction time were seen in the test of episodic memory for faces (p=0.023) and in the test of two-choice reaction time (p=0.039) of the CNTB. CONCLUSION Treatment with galantamine produced improvement in computerized tests of attention and episodic memory after 12 weeks, leading to statistically significant reduction in the reaction times.

Treatment of dementia: anything new?

Purpose of review The aim of this article is to discuss new data on presently approved drugs for dementia, such as cholinesterase inhibitors and memantine, and concerns regarding the use of antipsychotics for treating neuropsychiatric symptoms, as well as to summarize some relevant studies recently published on emerging therapies with potential disease-modifying effects. Recent findings The main focuses of recent studies of cholinesterase inhibitors and memantine have been on efficacy and safety aspects in extended clinical trials, combined treatments or comparative analysis between agents, and also on potential neuroprotective effects and new indications. Other publications have assessed the evidence of efficacy and the increased risk of cerebrovascular events, rapid cognitive decline, and mortality with the use of antipsychotics in dementia, providing important information in relation to the controversy surrounding its use. Although more studies are warranted, a sizable literature on novel treatment options under investigation is currently available as a result of a better understanding of pathogenesis of dementia. Summary So far, there is no established method to predict better responders or long-term benefits with currently approved drugs for treatment of dementia. Recent systematic reviews and new research on current treatment, however, provide valuable information for clinicians, and novel drugs under investigation reveal promising new therapeutic strategies.

Somatic Mutation Analysis of the APP and Presenilin 1 and 2 Genes in Alzheimer's Disease Brains

The molecular basis for sporadic Alzheimer disease (AD) remains largely unknown. We hypothesized that in some cases of sporadic AD, a somatic mutation in an embryonic cell committed to neuronal development within the amyloid precursor protein (APP), the presenilin 1 (PS-1) or the presenilin 2 (PS-2) genes (genes known to be involved in familial AD) may result in AD phenotype. Using PCR, denaturing gradient gel electrophoresis (DGGE), restriction enzyme digest and direct DNA sequencing, we analyzed these genes in 99 brain tissues from patients with histopathologically proven AD. One brain sample showed a mutation within the PS-1 gene, His163 Arg, later shown to be a germline mutation. No other migration abnormalities were demonstrated in any sample in exon 16 or 17 of the APP gene or the coding exons of the PS-1 gene. Restriction digest pattern was normal with regard to the predominant PS-2 gene mutation (N141I). A known mutation in the APP gene, as well as novel mutations within the PS-1 gene were easily detected by DGGE (Reznick Wolf et al. manuscript submitted). We conclude that the genes that are involved in familial AD do not display somatic mutations in the brains of sporadic AD patients, and that other molecular mechanisms are probably involved in the pathogenesis of sporadic AD.

Effects of galantamine and galantamine combined with nimodipine on cognitive speed and quality of life in mixed dementia: a 24-week, randomized, placebo-controlled exploratory trial (the REMIX study)

UNLABELLED The effects of galantamine (GAL) on quality of life (QoL) and cognitive speed, as well its effects combined with nimodipine (NIM) in Alzheimer disease (AD) with cerebrovascular disease (mixed dementia), have not been explored. METHOD Double-blind, placebo-controlled, multicenter Brazilian trial, studying the effects of GAL/NIM vs. GAL/placebo (PLA) in mild to moderate mixed dementia. Patients were randomized to receive GAL/NIM or GAL/PLA for 24 weeks. Primary efficacy measures were changes on a computerized neuropsychological battery (CNTB) and QoL Scale in Alzheimers Disease (QoL-AD) from baseline to week 24. RESULTS Twenty-one patients received at least one drug dose (9 GAL/NIM and 12 GAL/PLA). Groups were matched for age, sex, education, cognitive and QoL scores at baseline. No significant differences were observed between groups on primary or secondary measures. QoL and cognitive performance showed significant improvement (p<0.05) from baseline when all GAL-treated patients were analyzed. Adverse events were predominantly mild to moderate. CONCLUSION GAL treatment improved QoL in mixed dementia, in addition to its previously known cognitive benefits. The combination GAL/NIM was not advantageous. However, the small sample size precludes any definitive conclusions. Trial registered at ClinicalTrials.gov: NCT00814658.

Treatment of Alzheimer’s disease in Brazil. I. Cognitive disorders

This article reports the recommendations of the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology for the treatment of Alzheimer’s disease (AD) in Brazil, with special focus on cognitive disorders. It constitutes a revision and broadening of the 2005 guidelines based on a consensus involving researchers (physicians and non-physicians) in the field. The authors carried out a search of articles published since 2005 on the MEDLINE, LILACS and Cochrane Library databases. The search criteria were pharmacological and non-pharmacological treatment of cognitive disorders in AD. Studies retrieved were categorized into four classes, and evidence into four levels, based on the 2008 recommendations of the American Academy of Neurology. The recommendations on therapy are pertinent to the dementia phase of AD. Recommendations are proposed for the treatment of cognitive disorders encompassing both pharmacological (including acetyl-cholinesterase inhibitors, memantine and other drugs and substances) and non-pharmacological (including cognitive rehabilitation, physical activity, occupational therapy, and music therapy) approaches. Recommendations for the treatment of behavioral and psychological symptoms of dementia due to Alzheimer’s disease are included in a separate article of this edition.

Ischemic cerebrovascular burden evaluated by magnetic resonance imaging in an elderly Brazilian community: The Pietà study

In developing countries, cardiovascular risk factors are poorly controlled, leading to high prevalence of cerebrovascular diseases. The aim of the study was to evaluate the burden of white matter lesions in magnetic resonance through the Fazekas scale in a population aged 75 + years living in the community, and to investigate possible associations between vascular lesions, cardiovascular risk factors and cognitive status. Subjects were selected from a community-based study on brain aging conducted in Caeté (Minas Gerais state), Brazil. Overall, 177 participants (112 cognitively healthy, 36 with cognitive impairment-no dementia and 29 with dementia), being 108 women, aged 79.3 ± 3.8 years, with 3.1 ± 2.9 years of educational level, underwent a 3 Tesla magnetic resonance scanner with fluid attenuated image recovery acquisition. Severity of white matter lesions was assessed through the Fazekas scale. Severe white matter lesions were present in 31.1% of the whole sample and in 25.0% of the cognitively healthy individuals. A significant association was found between severe white matter lesions and cognitive impairment (OR = 2.20, 95% CI 1.17–6.53; p = 0.021), as well as with hypertension (OR = 1.92, 95% CI 1.03–7.39; p = 0.043). In conclusion, a high prevalence of severe white matter lesions was observed in this elderly Brazilian population sample, and white matter lesions were associated with hypertension and cognitive status. Importantly, the prevalence of white matter lesions was also high in cognitively healthy subjects.

GRN and MAPT Mutations in 2 Frontotemporal Dementia Research Centers in Brazil.

Background:Mutations in GRN (progranulin) and MAPT (microtubule-associated protein tau) are among the most frequent causes of monogenic frontotemporal dementia (FTD), but data on the frequency of these mutations in regions such as Latin America are still lacking. Objective:We aimed to investigate the frequencies of GRN and MAPT mutations in FTD cohorts from 2 Brazilian dementia research centers, the University of Sao Paulo and the Federal University of Minas Gerais medical schools. Methods:We included 76 probands diagnosed with behavioral-variant FTD (n=55), semantic-variant Primary Progressive Aphasia (PPA) (n=11), or nonfluent-variant PPA (n=10). Twenty-five percent of the cohort had at least 1 relative affected with FTD. Results:Mutations in GRN were identified in 7 probands, and in MAPT, in 2 probands. We identified 3 novel GRN mutations (p.Q130X, p.317Afs*12, and p.K259Afs*23) in patients diagnosed with nonfluent-variant PPA or behavioral-variant FTD. Plasma progranulin levels were measured and a cutoff value of 70 ng/mL was found, with 100% sensitivity and specificity to detect null GRN mutations. Conclusions:The frequency of GRN mutations was 9.6% and that of MAPT mutations was 7.1%. Among familial cases of FTD, the frequency of GRN mutations was 31.5% and that of MAPT mutations was 10.5%.

Prevalence of late-life depression and its correlates in a community-dwelling low-educated population aged 75+ years: The Pietà study

BACKGROUND The number of individuals with advanced age is growing worldwide, especially in developing countries. Depression is the most common mental disorder in the elderly. The aim of this study was to evaluate the prevalence rates and the correlates of late-life depression (LLD) and clinically significant depressive symptoms (CSDS) in a population aged 75+ years. METHODS We evaluated 639 community-dwelling individuals aged 75+ years in Caeté (MG), Brazil, and used the MINI to diagnose LLD according to DSM-IV criteria and the GDS-15 to identify CSDS. Quality of life was assessed by the WHOQOL-OLD scale. RESULTS Overall, 639 individuals (64% female, with a mean age of 81.1 ± 5.2 and 2.6 ± 2.8 years of schooling) were evaluated; 70 (11.1%) were diagnosed with LLD and 146 (25.6%) with CSDS. Depressed subjects (both with LLD and CSDS) had poorer measures of quality of life. Logistic regression analyses showed that LLD was independently associated to a history of falls/fracture, a diagnosis of cognitive impairment-no dementia, the number of regular drugs used, lack of reading habit and, inversely, to systolic blood pressure. LIMITATIONS The use of MINI which has not been validated in the elderly. No information was available on the number of previous depressive episodes or on the age of first episode. CONCLUSION Both dimensional and categorical diagnoses of depression were prevalent among community-dwelling oldest-old individuals. Different clinical and personal variables were associated with depression, which negatively influenced the quality of life of the affected individuals.

Variables associated with cognitive impairment-no dementia in a low-educated cohort aged 75+ years: The Pietà study

Background: Older adults with memory-centered and informant-validated cognitive complaints (CC) in the absence of neuropsychological deficits or depression represent a potential at-risk group for progression to amnestic MCI and Alzheimer’s disease (AD). The goals of the present study were to evaluate 1) the rate of conversion of CC participants to MCI over two years and 2) potential antecedent markers associated with future progression to MCI, including baseline cognition, self and informant ratings, genetics, and atrophy on MRI. Amyloid and TSPO/microglial PET and fluid biomarkers were available for a subgroup. Methods: 42 CC participants with baseline and 2-year follow-up data were analyzed from an ongoing 2-site study of memory and aging (Dartmouth and Indiana University). The CognitiveComplaint Index [1]was used to quantitate self and informant ratings. CC participants were categorized as converters to MCI (CC-C) or stable (CC-S) based on clinical consensus. 44 cognitively normal controls (HC) were included for comparison. Baseline structural MRI scans were processed using voxel-based morphometry (VBM) and Freesurfer to extract grey matter density (GMD)andvolumetricmeasures from targeted regions of interest (ROIs). Demographics and medical history, APOE ε4 status, baseline cognitive performance, selfand informant-ratings of cognition, and neuroimaging ROI measures were compared between groupswith age, gender, education and intracranial volume (ICV) included as covariates where appropriate. Results: 10 of 42CC participants (23.8%) converted to early (5) or late (5)MCIwithin 2 years (annualized rate, 12%).At baseline, CC-Cdidnot show consistent differences in cognition from CC-S, except for lower Mattis Dementia Rating Scale total score. Higher self and especially informant-based cognitive complaints at baseline were associated with conversion. Converters compared to CC-S trended toward decreasedMRI volumes andGMDbut this did not reach significance due to insufficient power. Additional imaging and genetic pathway data are being evaluated. Conclusions: Euthymic older adults with elevated levels of cognitive complaints, particularly based on informant ratings, appear to be at-risk for conversion toMCI even in the context of generally normal neuropsychological performance. Additional studies in larger samples are warranted as this this may represent the earliest symptomatic stage of preclinical AD. [1] Saykin Neurology; 2006;67:834-842.