Orestes Vicente Forlenza

Cellular prion protein binds laminin and mediates neuritogenesis

Laminin (LN) plays a major role in neuronal differentiation, migration and survival. Here, we show that the cellular prion protein (PrPc) is a saturable, specific, high-affinity receptor for LN. The PrPc-LN interaction is involved in the neuritogenesis induced by NGF plus LN in the PC-12 cell line and the binding site resides in a carboxy-terminal decapeptide from the gamma-1 LN chain. Neuritogenesis induced by LN or its gamma-1-derived peptide in primary cultures from rat or either wild type or PrP null mice hippocampal neurons, indicated that PrPc is the main cellular receptor for that particular LN domain. These results point out to the importance of the PrPc-LN interaction for the neuronal plasticity mechanism.

The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers.

The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)‐42, total‐tau (T‐tau), and phosphorylated‐tau (P‐tau) demonstrate good diagnostic accuracy for Alzheimers disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimers Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch‐to‐batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program.

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.

Executive dysfunction correlates with impaired functional status in older adults with varying degrees of cognitive impairment.

BACKGROUND Previous studies have reported an association between executive dysfunction and the ability to perform activities of daily living (ADL)s among older adults. This study aims to examine the association between executive functions and functional status in a cross-section of older adults with varying degrees of cognitive impairment. METHODS 89 individuals (mean age 73.8 years) were recruited at a memory clinic in São Paulo, Brazil. Subjects underwent evaluation, and were allocated into three diagnostic groups according to cognitive status: normal controls (NC, n = 32), mild cognitive impairment (MCI, n = 31) and mild Alzheimers disease (AD, n = 26). Executive functions were assessed with the 25-item Executive Interview (EXIT25), and functional status was measured with the Direct Assessment of Functional Status test (DAFS-R). RESULTS Significantly different total DAFS-R scores were observed across the three diagnostic groups. Patients with AD performed significantly worse in EXIT25 compared with subjects without dementia, and no significant differences were detected between NC and MCI patients. We found a robust negative correlation between the DAFS-R and the EXIT25 scores (r =-0.872, p < 0.001). Linear regression analyses suggested a significant influence of the EXIT-25 and the CAMCOG on the DAFS-R scores. CONCLUSION Executive dysfunction and decline in general measures of cognitive functioning are associated with a lower ability to undertake instrumental ADLs. MCI patients showed worse functional status than NC subjects. MCI patients may show subtle changes in functional status that may only be captured by objective measures of ADLs.

Psychiatric manifestations of neurocysticercosis: a study of 38 patients from a neurology clinic in Brazil.

OBJECTIVE: To determine the frequency and features of psychiatric morbidity in a cross section of 38 outpatients with neurocysticercosis. METHODS: Diagnosis of neurocysticercosis was established by CT, MRI, and CSF analysis. Psychiatric diagnoses were made by using the present state examination and the schedule for affective disorders and schizophrenia-lifetime version; cognitive state was assessed by mini mental state examination and Strub and Blacks mental status examination. RESULTS: Signs of psychiatric disease and cognitive decline were found in 65.8 and 87.5% of the cases respectively. Depression was the most frequent psychiatric diagnosis (52.6%) and 14.2% of the patients were psychotic. Active disease and intracranial hypertension were associated with higher psychiatric morbidity, and previous history of mood disorders was strongly related to current depression. Other variables, such as number and type of brain lesions, severity of neuropsychological deficits, epilepsy, and use of steroids did not correlate with mental disturbances in this sample. CONCLUSIONS: Psychiatric abnormalities, particularly depression syndromes, are frequent in patients with neurocysticercosis. Although regarded as a rare cause of dementia, mild cognitive impairment may be a much more prevalent neuropsychological feature of patients with neurocysticercosis. The extent to which organic mechanisms related to brain lesions may underlie the mental changes is yet unclear, although the similar sex distribution of patients with and without depression, as well as the above mentioned correlations, provide further evidence of the part played by organic factors in the cause of these syndromes.

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.

Diagnóstico diferencial das demências

Dementia is a syndrome characterized by progressive impairment of cognitive functions, particularly in memory, which affects social and occupational activities. The differential diagnosis must, firstly, identify potentially treatable causes of cognitive impairment, addressing the different etiologies of reversible dementia such as metabolic alterations, intoxications, CNS infections, and nutritional deficiencies. The correct and early diagnosis of primary degenerative dementia carries therapeutic and prognostic implications, which may attenuate the inevitable cognitive and behavioral deficits.

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.