Breno Satler Diniz

Late-life depression and risk of vascular dementia and Alzheimer’s disease: systematic review and meta-analysis of community-based cohort studies

BACKGROUND Late-life depression may increase the risk of incident dementia, in particular of Alzheimers disease and vascular dementia. AIMS To conduct a systematic review and meta-analysis to evaluate the risk of incident all-cause dementia, Alzheimers disease and vascular dementia in individuals with late-life depression in population-based prospective studies. METHOD A total of 23 studies were included in the meta-analysis. We used the generic inverse variance method with a random-effects model to calculate the pooled risk of dementia, Alzheimers disease and vascular dementia in older adults with late-life depression. RESULTS Late-life depression was associated with a significant risk of all-cause dementia (1.85, 95% CI 1.67-2.04, P<0.001), Alzheimers disease (1.65, 95% CI 1.42-1.92, P<0.001) and vascular dementia (2.52, 95% CI 1.77-3.59, P<0.001). Subgroup analysis, based on five studies, showed that the risk of vascular dementia was significantly higher than for Alzheimers disease (P = 0.03). CONCLUSIONS Late-life depression is associated with an increased risk for all-cause dementia, vascular dementia and Alzheimers disease. The present results suggest that it will be valuable to design clinical trials to investigate the effect of late-life depression prevention on risk of dementia, in particular vascular dementia and Alzheimers disease.

Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial {

BACKGROUND Two recent clinical studies support the feasibility of trials to evaluate the disease-modifying properties of lithium in Alzheimers disease, although no benefits were obtained from short-term treatment. AIMS To evaluate the effect of long-term lithium treatment on cognitive and biological outcomes in people with amnestic mild cognitive impairment (aMCI). METHOD Forty-five participants with aMCI were randomised to receive lithium (0.25-0.5 mmol/l) (n = 24) or placebo (n = 21) in a 12-month, double-blind trial. Primary outcome measures were the modification of cognitive and functional test scores, and concentrations of cerebrospinal fluid (CSF) biomarkers (amyloid-beta peptide (Aβ(42)), total tau (T-tau), phosphorylated-tau) (P-tau). TRIAL REGISTRATION NCT01055392. RESULTS Lithium treatment was associated with a significant decrease in CSF concentrations of P-tau (P = 0.03) and better perform-ance on the cognitive subscale of the Alzheimers Disease Assessment Scale and in attention tasks. Overall tolerability of lithium was good and the adherence rate was 91%. CONCLUSIONS The present data support the notion that lithium has disease-modifying properties with potential clinical implications in the prevention of Alzheimers disease.

Do CSF total tau, phosphorylated tau, and β-amyloid 42 help to predict progression of mild cognitive impairment to Alzheimer's disease? A systematic review and meta-analysis of the literature

The search for biomarkers as a diagnostic aid to the identification of patients in pre-dementia stages is a fast growing research area. In view of the low specificity attained with the clinically based diagnostic criteria, including those for mild cognitive impairment (MCI), biomarker information will add precision to the incipient dementia diagnostic work-up, particularly Alzheimers disease (AD). We present a systematic review of the literature and meta-analysis of the most relevant publications about the role of CSF biomarkers in the identification of patients with probable Alzheimers disease at pre-dementia stages. A total of 16 studies were included in the systematic review, five of which were suitable for meta-analysis. We compared the standard mean differences (SMD) of β-amyloid 42 (Aβ42), total tau (T-tau) and phosphorylated tau (P-tau) for 130, 169 and 123 patients with MCI who converted to AD (MCI-AD) and 142, 157 and 130 controls, respectively. We conclude that when a clinical diagnosis of MCI is made at baseline assessment, low CSF levels of Aβ42 (SMD: −1.57, CI95% [−2.30 to −0.84], P<0.001), along with high T-tau (SMD: 1.52, CI95% [1.25 to 1.79], P<0.001), and high P-tau (SMD: 1.75, CI95% [0.99 to 2.51], P<0.001), help to predict the conversion to Alzheimers disease as compared to controls subjects.

Brain-Derived Neurotrophic Factor and Alzheimer’s Disease: Physiopathology and Beyond

Brain-derived neurotrophic factor (BDNF) is the most widely distributed neurotrophin in the central nervous system where it plays several pivotal roles in synaptic plasticity and neuronal survival. As a consequence, BDNF became a key target in the physiopathology of several neurological and psychiatric diseases. Recent studies have reported altered levels of BDNF in the circulation, i.e. serum or plasma, of patients with Alzheimer’s disease (AD), and low BDNF levels in the CSF as predictor of future cognitive decline in healthy older subjects. Altered BDNF circulating levels have also been reported in other neurodegenerative and psychiatric disorders, hampering its use as a specific biomarker for AD. Therefore, BDNF seems to be an unspecific biomarker of neuropsychiatric disorders marked by neurodegenerative changes.

Diagnosis and biomarkers of predementia in Alzheimer's disease

In view of the growing prevalence of Alzheimers disease (AD) worldwide, there is an urgent need for the development of better diagnostic tools and more effective therapeutic interventions. At the earliest stages of AD, no significant cognitive or functional impairment is detected by conventional clinical methods. However, new technologies based on structural and functional neuroimaging, and on the biochemical analysis of cerebrospinal fluid (CSF) may reveal correlates of intracerebral pathology in individuals with mild, predementia symptoms. These putative correlates are commonly referred to as AD-related biomarkers. The relevance of the early diagnosis of AD relies on the hypothesis that pharmacological interventions with disease-modifying compounds are likely to produce clinically relevant benefits if started early enough in the continuum towards dementia. Here we review the clinical characteristics of the prodromal and transitional states from normal cognitive ageing to dementia in AD. We further address recent developments in biomarker research to support the early diagnosis and prediction of dementia, and point out the challenges and perspectives for the translation of research data into clinical practice.

Increased Serum IL-1β Level in Alzheimer’s Disease and Mild Cognitive Impairment

Background/Aims: Abnormal inflammatory response has been associated to the pathogenesis of Alzheimer’s disease (AD) and may be a marker of an ongoing neurodegenerative process. The aim of this study was to evaluate the serum levels of interleukin-1β (IL-1β) in patients with mild cognitive impairment (MCI) and AD. Methods: One hundred and sixty-three older adults (58 with mild to moderate AD, 74 with MCI and 31 healthy controls) were recruited for this study. Serum IL-1β levels were measured by ELISA. Patients with MCI were subcategorized in single-domain amnestic (aMCI), nonamnestic (naMCI), and multiple-domain (mdMCI) subtypes. Results: Patients with AD and MCI (all subtypes) had a significant increase in serum IL-1β levels as compared to controls (p = 0.03). Patients with mdMCI had serum IL-1β levels comparable to those with AD, and significantly higher than those observed in aMCI and naMCI (p = 0.02). Discussion: The present study provides evidence that inflammatory mechanisms, represented by elevated IL-1β, are observed in patients with MCI, specifically in those with impairment in multiple cognitive domains. As these patients are at higher risk of conversion to dementia, we propose that an increased serum IL-1β level is a stage marker of the ongoing brain neurodegeneration in the continuum between normal ageing and AD.

Effect of brain-derived neurotrophic factor Val66Met polymorphism and serum levels on the progression of mild cognitive impairment

Abstract Objectives. Abnormalities in neurotrophic systems have been reported in Alzheimers disease (AD), as shown by decreased serum brain-derived neurotrophic factor (BDNF) levels and association with BDNF genetic polymorphisms. In this study, we investigate whether these findings can be detected in patients with mild cognitive impairment (MCI), which is recognized as a high risk condition for AD. We also address the impact of these variables on the progression of cognitive deficits within the MCI-AD continuum. Methods. One hundred and sixty older adults with varying degrees of cognitive impairment (30 patients with AD, 71 with MCI, and 59 healthy controls) were longitudinally assessed for up to 60 months. Baseline serum BDNF levels were determined by sandwich ELISA, and the presence of polymorphisms of BDNF and apolipoprotein E (Val66Met and APOE*E4, respectively) was determined by allelic discrimination analysis on real time PCR. Modifications of cognitive state were ascertained for non-demented subjects. Results. Mean serum BDNF levels were reduced in patients with MCI and AD, as compared to controls (509.2±210.5; 581.9±379.4; and 777.5±467.8 pg/l respectively; P<0.001). Baseline serum BDNF levels were not associated with the progression of cognitive impairment upon follow-up in patients with MCI (progressive MCI, 750.8±463.0; stable MCI, 724.0±343.4; P=0.8), nor with the conversion to AD. Although Val66Met polymorphisms were not associated with the cross-sectional diagnoses of MCI or AD, the presence of Met-BDNF allele was associated with a higher risk of disease-progression in patients with MCI (OR=3.0 CI95% [1.2–7.8], P=0.02). We also found a significant interaction between the APOE*E4 and Met-BDNF allele increasing the risk of progression of cognitive impairment in MCI patients (OR=4.4 CI95% [1.6–12.1], P=0.004). Conclusion. Decreased neurotrophic support, as indicated by a reduced systemic availability of BDNF, may play role in the neurodegenerative processes that underlie the continuum from MCI to AD. The presence of Met-BDNF allele, particularly in association with APOE*E4, may predict a worse cognitive outcome in patients with MCI.

Voxel-based morphometry in Alzheimer’s disease

Recent morphometric MRI studies have investigated brain volume abnormalities associated with the diagnosis of Alzheimer’s disease (AD) using voxel-based morphometry (VBM). This technique allows the assessment of gray matter volumes in subjects with AD or related conditions compared with healthy controls in an automated fashion, across the whole brain. This article reviews VBM findings related to different AD stages and its prodrome, mild cognitive impairment. These findings include not only gray matter deficits in medial temporal structures as seen in former MRI studies of AD conducted using manual region-of-interest measurements, but also volume changes in several other brain regions not assessed in previous MRI studies. We also discuss potential applications of VBM to improve AD diagnostic accuracy in routine clinical practice. Finally, we highlight future research directions in this field, including: investigations on the relationship between VBM findings of multifocal gray matter deficits and changes in white matter tracts that interconnect such regions; the need for population-based VBM studies using large AD samples; and the potential of studies combining VBM measurements with other potential biological markers (such as brain imaging indices of amyloid-β deposition and cerebrospinal fluid AD markers) to further advance our knowledge about the physiopathology of AD.

CAMcog as a screening tool for diagnosis of mild cognitive impairment and dementia in a Brazilian clinical sample of moderate to high education

The CAMCOG is a brief neuropsychological battery designed to assess global cognitive function and ascertain the impairments that are required for the diagnosis of dementia. To date, the cut‐off scores for mild cognitive impairment (MCI) have not been determined. Given the need for an earlier diagnosis of mild dementia, new cut‐off values are also necessary, taking into account cultural and educational effects.

Lithium increases plasma brain-derived neurotrophic factor in acute bipolar mania: a preliminary 4-week study.

Several studies have suggested an important role for brain-derived neurotrophic factor (BDNF) in the pathophysiology and therapeutics of bipolar disorder (BPD). The mechanisms underlying the therapeutic effects of lithium in BPD seem to involve a direct regulation of neurotrophic cascades. However, no clinical study evaluated the specific effects of lithium on BDNF levels in subjects with BPD. This study aims to investigate the effects of lithium monotherapy on BDNF levels in acute mania. Ten subjects with bipolar I disorder in a manic episode were evaluated at baseline and after 28 days of lithium therapy. Changes in plasma BDNF levels and Young Mania Rating Scale (YMRS) scores were analyzed. A significant increase in plasma BDNF levels was observed after 28 days of therapy with lithium monotherapy (510.9±127.1pg/mL) compared to pre-treatment (406.3±69.5pg/mL) (p=0.03). Although it was not found a significant association between BDNF levels and clinical improvement (YMRS), 87% of responders presented an increase in BDNF levels after treatment with lithium. These preliminary data showed lithiums direct effects on BDNF levels in bipolar mania, suggesting that short-term lithium treatment may activate neurotrophic cascades. Further studies with larger samples and longer period may confirm whether this biological effect is involved in the therapeutic efficacy of lithium in BPD.