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The search for molecular biomarkers for diagnosing and classifying dementias is becoming a high priority need. Neurosin (Kallikrein 6, hk6) is one molecule with promising preliminary results since its levels in brain tissue, cerebrospinal fluid and blood have been found to be abnormal in Alzheimer's disease (AD). In this study, we measured plasmatic levels of neurosin in healthy individuals and patients with cognitive symptoms independently of what the final diagnosis was. We collected plasma samples from 228 controls and 447 patients finally diagnosed with either AD, Mild Cognitive Impairment, Dementia with Lewy Bodies or Parkinson-Dementia, Frontotemporal Dementia, Huntington's disease, Primary Progressive Aphasia, Corticobasal degeneration, Creutzfeldt-Jakob's disease or Pseudodementia. We found that plasmatic levels of neurosin increase with age in healthy individuals and decrease in patients with AD. Plasmatic levels of neurosin differ significantly between AD and Vascular Dementia, Pseudodementia and the control group. Analyses comparing any other form of neurodegenerative dementia to the AD group did not show significant differences. In conclusion, measurement of plasmatic levels of neurosin is useful to distinguish AD patients from subjects without neurodegenerative dementia (either Pseudodementia, Vascular Dementia or controls) although it is not useful to distinguish among neurodegenerative dementias. [ABSTRACT FROM AUTHOR]

Mutations in the beta-amyloid precursor protein gene (APP) have been found in familial early-onset Alzheímer's disease (AD). DNA variants at several genes have been linked to the risk of developing the most common late-onset form of AD (LOAD). A few studies analyzed the contribution of APP variants to LOAD, with negative or conflicting results. We determined the variation in the 18 APP exons and flanking intronic sequences in a total of 350 LOAD patients from Spain. A total of 13 nucleotide changes were found and 6 were new and not found among 340 healthy controls, including the only missense change (D243N). The in silico analysis suggested that none of them would have an effect on pre-mRNA splicing or protein folding (D243N). Patients and controls were also genotyped for three APP promoter polymorphisms, and none of them was significantly associated with LOAD. We concluded that APP variants would not contribute to the risk of developing LOAD in our population.

Background: Mild Cognitive Impairment (MCI) is a disorder considered to be a transitional stage from health to dementia. Diagnosis of dementias at these early stages is always troublesome because the pathophysiologic events leading to dementia precede clinical symptoms. Thus, the development of biomarkers that can be used to support the diagnosis of dementias at early stages is rapidly becoming a high priority. We have recently reported the value of measuring plasmatic levels of neurosin in the diagnosis of Alzheimer's disease (AD). The aim of this study is to determine whether measuring plasmatic concentration of neurosin is a valuable test to predict progression of MCI., Methods: Plasmatic neurosin concentrations were measured in 68 MCI patients and 70 controls subjects. Blood samples were obtained at the beginning of the study. Sixty six patients diagnosed with MCI were observed for 18 months. In 36 patients a second blood sample was obtained at the endpoint., Results: The mean value of plasmatic neurosin concentration differs significantly between MCI patients who converted to Dementia with vascular component, those who converted to AD, or those who remained at MCI stage. The relative risk of developing Dementia with vascular component when neurosin levels are higher than 5.25 ng/ml is 13 while the relative risk of developing mild AD when neurosin levels are lower than 5.25 ng/ml is 2. Increases in the levels of neurosin indicate progression to Dementia with vascular component., Conclusion: The measurement of plasmatic neurosin level in patients diagnosed with MCI may predict conversion from MCI to Dementia with vascular component. A single measurement is also valuable to estimate the risk of developing AD and Dementia with vascular component. Finally, repeated measurement of plasmatic neurosin might be a useful test to predict outcome in patients with MCI.

Polymorphisms at different genes have been proposed as determinants of the risk for developing late-onset Alzheimer's disease (LOAD). Among the several candidate genes are those that encode proteins involved in neuronal degeneration/survival. Studies of primary neuronal cultures supported that members of the myocyte enhancing factor-2 (MEF2) family of transcription factors have an anti-apoptotic effect, regulating the expression of proteins involved in neuronal survival and differentiation. We analysed the MEF2A gene in a total of 357 patients (mean age 72 years, range 60-97 years). Among others, a Pro279Leu in exon 8 and a polyglutamine (CAG) repeat polymorphisms in exon 12 were found. These variants were also genotyped in 495 healthy controls (>50 years old), and the frequencies were statistically compared. Eight patients were 279L (six P/L and two L/L), compared to only one control (2% vs. 0.2%; p=0.004, OR=11.32). There was a significantly higher frequency of 279L-carriers among APOE epsilon4+ (7/154=4.5%), compared to epsilon4- (1/203) (p=0.02). In conclusion, our work suggests that the variation at the MEF2A gene could be involved in the risk of developing LOAD. Because MEF2 has been related with neuronal survival, and the 279L allele has been related with a reduction in the transcriptional activation activity of MEF2A, the effect of this allele could be mediated through a down-regulation of antiapoptotic genes.

Introduction: Lewy body dementia (DLB) is common but frequently misdiagnosed as Alzheimer's disease plus delirium or parkinsonism. DRUGS USED IN THIS DISORDER CAN CAUSE EXACERBATIONS: neuroleptic medication is relatively contraindicated because some patients show severe neuroleptic sensitivity, antiparkinsonian medication has the potential to exacerbate psychotic symptoms, and even cholinesterase inhibitors, while relatively safe, have provoked adverse responses in some DLB patients. There are few data available about the use of memantine in DLB., Case Presentation: A 74-year-old man was diagnosed with Alzheimer disease and parkinsonism. After memantine was started he developed severe fluctuations in awareness, visual hallucinations, agitation, and worsened parkinsonism. When he was evaluated thoroughly, the diagnosis was revised to Lewy body dementia, leading to changes in treatment that were associated with dramatic improvement in the patient's mental status., Conclusions: In our patient, motor and cognitive symptoms worsened with memantine treatment; these resolved after memantine was discontinued.

Introduction: Memory loss is an increasingly frequent reason for consultation in neurology. The aim of this work is to know the current frequency as well as the characteristics and disorders of the patients who come for this reason., Methods: We studied 200 patients who came to general neurology consultation due to loss of memory., Results: 18.47% of the patients who came for the first time to a general neurology consultation did so due to memory loss, this being subjective loss of memory (SLM) in 39% of the cases and referred loss of memory (RLM) in 61% of the cases. The diagnostic groups to which the patients belonged are, in diminishing order, the following: degenerative primary dementia type Alzheimer's disease, mild cognitive impairment, mixed dementia, pure vascular dementia, depressive pseudodementia, attributable to drugs, secondary to systemic disease, non-Alzheimer's type disease primary degenerative dementia, structural reasons, transitory global amnesia and epilepsy. No disease was found in 13% of them, and the generally came due to SLM., Conclusions: Frequency of memory loss as a reason for consultation continues to growing. Patients studied due to memory loss, in whom no disease is found, are generally those having SLM. In spite of this, SLM is a good predictor of cognitive deterioration. It is important to systematically study of every patient and consults for loss of memory and to investigate the possible use of drugs or toxics that could alter the memory.

Alternative APP mRNA splicing can generate isoforms of APP containing a Kunitz protease inhibitor (KPI) domain. KPI is one of the main serine protease inhibitors. Protein and mRNA KPI(+)APP levels are elevated in Alzheimer's disease (AD) brain and are associated with increased amyloid beta deposition. In the last years increasing evidence on multiple points in the amyloid cascade where KPI(+)APP is involved has been accumulated, admitting an outstanding position in the pathogenesis of AD to the KPI domain. This review focuses on the APP processing, the molecular activity of KPI and its physiological and pathological roles and the KPI involvement in the amyloid cascade through the nerve growth factor, the lipoprotein receptor-related protein, the tumor necrosis factor-alpha converting enzyme and the Notch1 protein.

Objective: To describe the clinical and electroencephalographic findings from a confused elderly woman with Creutzfeldt-Jakob disease (CJD) that initially were compatible with the diagnosis of non-convulsive status epilepticus (NCSE)., Methods and Results: A 75-year-old right-handed woman was admitted to our hospital because of confusion and alteration of mental status. The two first electroencephalograms (EEGs) showed continuous diffuse spikes, rhythmic sharp waves and sharp-and-slow wave complexes which were completely abolished after the administration of 10 mg of intravenous diazepam. Over the following days, the clinical state of the patient was unmodified despite aggressive antiepileptic therapy. A third EEG revealed pseudo-periodic negative or positive-negative slow waves localised in the right frontal region. Subsequently, two consecutive EEGs showed continuous periodic generalised bi-triphasic complexes at a rate of 1 Hz, compatible with the diagnosis of CJD. Finally, the patient died, and postmortem examination was diagnostic of the sporadic form of CJD., Conclusions: Clinical and electroencephalographic features in the early stages of CJD may resemble NCSE. The administration of intravenous benzodiazepines and its clinical and electroencephalographic correlation, response to the antiepileptic therapy, and monitoring with serial EEG recordings may be helpful considerations in the differential diagnosis.

The objective of this study was to ascertain the prevalence and incidence of Multiple Sclerosis (MS) in a population of 33,775 in two primary health care centres in the sanitary district of Gijon, Asturias, northern Spain. Many information sources were used but the unique advantage of Gijon was that the city has a centralized computerized register of all diagnoses made for all consultations in the clinics and hospitals in the area. The HLA distribution in the population was already known and the Poser classification of MS was used. The crude MS prevalence was 65/100,000, a similar prevalence to that found in southern and eastern Spain, Sicily and Greek-speaking Cyprus. The mean incidence was 3.7/100,000 per year. The study demonstrated the advantage of a centralized and computerized medical recording system and demonstrates that northern Spain is a moderately high or medium MS risk zone.

We sought clinical, paraclinical and genetic (HLA) factors that might have prognostic value in predicting disability produced by multiple sclerosis. An epidemiologically based sample including 146 cases (86% remittent and 14% mainly progressive) was studied. The progression of disability was measured on an index after systematic follow-up of at least 3 years. Our results show that the prognosis is significantly worse for those with a high frequency of attacks (p < 0.001), multiple clinical signs at presentation (p < 0.05) or motor weakness. The best prognosis was associated with those whose symptoms began with sensory alterations (p < 0.05). Late onset correlated significantly with a short interval between the first and second attack (r = 0.24), and this short interval was in turn significantly correlated with higher frequency of attacks in later stages (r = 0.44). We conclude that cases with a short interval between the first two attacks and those with late onset have a poorer prognosis. The following variables also tended to be associated with a more unfavorable prognosis, although the relationship was not statistically significant: female, progressive form, an increase in gammaglobulins in spinal fluid, infratentorial lesions as evidenced by magnetic resonance, and the alleles HLA-DR4, DR7 and DQw8. The allele DQw5 tended to be associated with a better prognosis.

In 1985 Ogasahara observed that treatment with ubiquinone produced improvement in the cardiac conduction and the metabolism of the lactic and pyruvic acids in the Kearns-Sayre syndrome. The results of the administration of 150 mg/day of ubiquinone for 3 years in a patient diagnosed with the Kearns-Sayre syndrome is described. The patient improved notably in strength, ocular movement, visual evoked potentials and in the metabolism of lactic and pyruvic acids. Other beneficial effects reported in the literature have been improvement of ataxia and the somato-sensitive evoked potentials. No side effects have been described.