Manuel Lavados

Anomalously phosphorylated tau and Aβ fragments in the CSF correlates with cognitive impairment in MCI subjects

Alzheimers disease (AD) is a neurodegenerative disorder characterized by the presence of extracellular amyloid deposits, consisting largely of Abeta peptide and the presence of intraneuronal aggregates of neurofibillary tangles formed by tau. Development of cerebrospinal fluid (CSF) biomarkers has become a rapidly growing research field, considering the need for diagnostic tools for AD, thus allowing therapeutic compounds to have the greatest potential for being effective. We have focused on the relationships between critical biomarkers such as tau and Abeta in the CSF and the cognitive impairment of patients, as assessed by a battery of neuropsychological tests derived from CDR and CERAD, of value in the evaluation of AD patients. As part of a longitudinal study, we analyzed by ELISA and Western blots the levels and molecular patterns of hyperphosphorylated tau in the CSF of three different groups of patients: AD patients between 69- and 73-years-old, a group characterized with mild cognitive impairment (MCI) between 65- and 70-years-old, and a non-demented neurological control group of comparable ages. The levels of AT8-reactive phosphorylated tau were significantly higher (P<0.05) in AD patients (0.604+/-0.078, n=23) as compared with the control group (0.457+/-0.086, n=25). No differences between the levels of AT8-reactive tau of MCI patients (0.510+/-0.090, n=45) and controls were observed. However, when the MCI group was divided on the basis of the total box score (TBS) from CDR, those subjects with a TBS<1.5 presented tau levels (0.456+/-0.032, n=31) similar to controls, whereas those patients with TBS>or=1.5 displayed tau levels (0.590+/-0.086, n=14) comparable with those of AD. Western blot analyses revealed a higher AT8 reactivity in CSF samples of AD patients as compared with MCI and control samples, indicating higher levels of AD tau phosphoepitopes in the CSF. Tau heterogeneity was observed in samples of AD and MCI with higher impairment as compared with controls. As expected from previous reports, levels of Abeta (1-42) were lower (0.052+/-0.005) than controls (0.070+/-0.010), whereas the levels of MCI group were 0.060+/-0.007. The MCI group with a TBS>or=1.5 presented Abeta levels of 0.053+/-0.005 similar to those of AD patients, whereas the MCI group with TBS<1.5 exhibited Abeta levels (0.066+/-0.007) similar to controls. Studies highlight the relationships between anomalously phosphorylated tau markers in CSF with the information from TBS analysis of the different groups of patients.

The alien hand syndrome: classification of forms reported and discussion of a new condition

Abstract.The term “alien hand” refers to a variety of clinical conditions whose common characteristic is the uncontrolled behavior or the feeling of strangeness of one extremity, most commonly the left hand. Acommon classification distinguishes between the posterior or sensory form of the alien hand, and the anterior or motor form of this condition. However, there are inconsistencies, such as the phenomenon of diagonistic dyspraxia, which is largely a motor syndrome despite being more frequently associated with posterior callosal lesions. We discuss critically the existing nomenclature and we also describe a case recently reported by us which does not fit any previously reported condition, termed agonistic dyspraxia. We propose that the cases of alien hand described in the literature can be classified into at least five broad categories: (i) diagonistic dyspraxia and related syndromes, (ii) alien hand, (iii) way-ward hand and related syndromes, (iv) supernumerary hands and (v) agonistic dyspraxia.

Mild Cognitive Impairment and Alzheimer Patients Display Different Levels of Redox-Active CSF Iron

Oxidative stress constitutes a hallmark of Alzheimers disease (AD). Recent studies also point to redox active metals such as iron, copper and zinc in mediating oxidative stress in AD pathogenesis. However, the reactivity of cerebrospinal fluid (CSF) iron and its possible correlation with the severity of cognitive decline in both Alzheimers patients and subjects with mild cognitive impairment (MCI) is still unknown. Here we show that different stages of cognitive and functional impairment are associated with changes in CSF reactive iron. In this work, we compared CSF samples from 56 elders, classified into 4 groups according to their scores on the Clinical Dementia Rating scale (CDR). Total CSF iron was analyzed by atomic absorption spectrometry. Redox-active iron was analyzed by a novel fluorimetric assay. One-way ANOVA was used to test differences in mean values, and Newman-Keuls Multiple Comparison Test was used for multi group comparisons. No difference in total CSF iron was found between different groups. Significant amounts of redox-active iron were found in CSF and their levels correlated with the extent of cognitive impairment. Redox-active CSF iron levels increased with the degree of cognitive impairment from normal to MCI subjects, while AD patients showed an abrupt decrease to levels close to zero. Given the relevance of oxidative damage in neurodegeneration, it might be possible to associate the development of cognitive and functional decline with the presence of redox-active iron in the CSF. The decrease in redox-active iron found in AD patients may represent a terminal situation, whereby the central nervous system attempts to minimize iron-associated toxicity.

Biological Markers of Alzheimers Disease and Mild Cognitive Impairment

The diagnosis of Alzheimers disease (AD) is mainly performed by excluding other disorders with similar clinical features. In addition, an analysis of symptoms and signs, blood studies and brain imaging are major ingredients of the clinical diagnostic work-up. However, the diagnosis based on these instruments is unsatisfactory, indicating the need of a highly sensitive and reliable approaches, selective for AD and based on biological markers. Ideally, such markers should reflect the pathophysiological mechanisms of AD, which according to the current hypotheses, derive from the actions of two major protein aggregates, the extracellular beta-amyloid (Abeta) plaques and the neurofibrillary tangles. Since AD is a multifactorial disease, other factors that cause neuronal insult and that contribute to neuronal degeneration in AD include free radical and oxidative stress promoting molecules, proinflammatory cytokines and neurotoxic agents. In this context, the search for anomalous levels or changes in the molecular patterns of Abeta(1-42) or Abeta(1-40), hyperphosphorylated tau isoforms, oxidation products in the cell or cytokines such as interleukin-1 or 6 facilitates the selection of biomarkers in AD. There is clear evidence that the cerebrospinal fluid (CSF) levels of beta(1-42) are significantly reduced in AD patients as compared with senile controls, while increased levels of tau have been revealed. The CSF levels of these proteins reflect their metabolism in the central nervous system. Approaches using ELISA and immunochemical methods for the quantification of these markers in CSF have been preferentially used. Diagnosis criteria and number of patients exhibits variations in the different reports, while clinico-pathological studies are scarce. An increasing number of studies suggest that supplementary use of these CSF markers preferably in combination, adds to the accuracy of an AD diagnosis.

Déficit de vitamina B-12 en adultos mayores: ¿Un problema de salud pública en Chile?

BACKGROUND There is a correlation between aging and the decrease of plasma levels of vitamin B-12. AIM To determine the prevalence of vitamin B-12 and folate deficiency and its hematological impact among older adults (AM). MATERIAL AND METHODS Cross-sectional study, in 1028 subjects aged 65 to 87years, living in community and evaluated between 2005 and 2008. Percentile distribution of vitamin B-12, folate, hemoglobin, packed red cell volume and mean cell volume by gender and age were analyzed. Deficiency was defined as vitamin B-12 levels < 148 pmol/L, marginal deficiency as vitamin B-12 levels < 221 pmol/L, anemia was defined as a hemoglobin < 13 and 12 g/dL among men and women, respectively. RESULTS The prevalence of vitamin B-12 deficiency was 12% and the figure for marginal deficiency was 25.4%. Males were more affected than females (p < 0.001). The frequency of anemia was 8.6%o, and was higher among women (p = 0.004). CONCLUSIONS There is a high prevalence of full blown and marginal deficit of vitamin B-12 among the elderly. This deficiency should be considered for correction through public nutrition policies.

A New Sign of Callosal Disconnection Syndrome: Agonistic Dyspraxia. A Case Study

We report a patient with callosal haemorrhage and no extracallosal involvement who developed a unique form of intermanual conflict. In the acute phase the patient showed a mild speech disturbance and right hemiparesis, and in her right hand, a grasp reflex and compulsive manipulation of tools, all attributable to transient frontal involvement. In the chronic phase there was intermanual conflict occasionally associated with the sensation of a second left hand. The patient also presented a sign consisting of compulsive, automatic execution of orders by one hand (the left or the right) when the patient was specifically asked to perform the movement with the other hand (the right or the left, respectively). There was no left-right confusion in this patient. We call this condition agonistic dyspraxia. In contrast with diagonistic dyspraxia, this consists of the agonistic behaviour of the other hand under conditions in which the hand that has been instructed to respond cannot execute the request.

Comparison of two modes of vitamin B(12) supplementation on neuroconduction and cognitive function among older people living in Santiago, Chile: a cluster randomized controlled trial. a study protocol ISRCTN 02694183

BackgroundOlder people have a high risk of vitamin B12 deficiency; this can lead to varying degrees of cognitive and neurological impairment. CBL deficiency may present as macrocytic anemia, subacute combined degeneration of the spinal cord, or as neuropathy, but is often asymptomatic in older people. Less is known about subclinical vitamin B12 deficiency and concurrent neuroconduction and cognitive impairment. A Programme of Complementary Feeding for the Older Population (PACAM) in Chile delivers 2 complementary fortified foods that provide approximately 1.4 μg/day of vitamin B12 (2.4 μg/day elderly RDA). The aim of the present study is to assess whether supplementation with vitamin B12 will improve neuroconduction and cognitive function in older people who have biochemical evidence of vitamin B12 insufficiency in the absence of clinical deficiency.MethodsWe designed a cluster double-blind placebo-controlled trial involving community dwelling people aged 70-79 living in Santiago, Chile. We randomized 15 clusters (health centers) involving 300 people (20 per cluster). Each cluster will be randomly assigned to one of three arms: a) a 1 mg vitamin B12 pill taken daily and a routine PACAM food; b) a placebo pill and the milk-PACAM food fortified to provide 1 mg of vitamin B12; c) the routine PACAM food and a placebo pill.The study has been designed as an 18 month follow up period. The primary outcomes assessed at baseline, 4, 9 and 18 months will be: serum levels of vitamin B12, neuroconduction and cognitive function.ConclusionsIn view of the high prevalence of vitamin B12 deficiency in later life, the present study has potential public health interest because since it will measure the impact of the existing program of complementary feeding as compared to two options that provide higher vitamin B12 intakes that might potentially may contribute in preserving neurophysiologic and cognitive function and thus improve quality of life for older people in Chile.Trial registrationISRCTN: ISRCTN02694183

Evaluación del minimental abreviado de la evaluación funcional del adulto mayor (EFAM) como screening para la detección de demencia en la atención primaria.

BACKGROUND The usefulness of the abbreviated Mini-Mental State Examination included in the Chilean Functional assessment of elderly people (MM-SE-EFAM) to detect Dementia has not been determined. AIM To assess the performance of the MMSE-EFAM to detect dementia. MATERIAL AND METHODS We studied a non-probabilistic sample of subjects older than 65 years who had been assessed by the MMSE-EFAM in a Chilean primary care center during a period of 6 months. Patients underwent clinical evaluation by a neurologist blinded to MMSE-EFAM score, to establish the diagnosis of dementia using DSM-IV-TR criteria. Besides, the full Mini-Mental State Examination (MMSE) was applied. RESULTS The clinical diagnosis of Dementia was established in 13 of the 54 peoples evaluated. MMSE-EFAM had a sensitivity of 30.8% (95% confidence intervals (CI); 9-61.4) and a specificity of 90.2% (95% CI; 76.9%-97.3%), while MMSE had a sensitivity of 84.6% (95% CI; 54.6-98.1) and a specificity of 58.5% (95% CI; 42.1-73.7). In a receiver operating characteristic (ROC) curve analysis, the areas under the curve (AUC) were 0.77 (95% CI; 0.61-0.93) and 0.82 (95% CI; 0.70-0.95) for MMSE-EFAM and MMSE, respectively. Socio-demographic variables did not influence test performance in both cases. CONCLUSIONS MMSE-EFAM has a low sensitivity to detect patients with Dementia and it is not an effective screening tool. These results are in agreement with the evidence and international guidelines that do not support the use of cognitive screening tools to detect dementia in the older general population.