Manuel Menéndez-González

Dopaminergic reward system: a short integrative review.

Memory is an essential element to adaptive behavior since it allows consolidation of past experience guiding the subject to consider them in future experiences. Among the endogenous molecules that participate in the consolidation of memory, including the drug-seeking reward, considered as a form of learning, is dopamine. This neurotransmitter modulates the activity of specific brain nucleus such as nuclei accumbens, putamen, ventral tegmental area (VTA), among others and synchronizes the activity of these nuclei to establish the neurobiological mechanism to set the hedonic element of learning. We review the experimental evidence that highlights the activity of different brain nuclei modulating the mechanisms whereby dopamine biases memory towards events that are of motivational significance.

Immunotherapy for Alzheimer's disease: rational basis in ongoing clinical trials.

Amyloid-β (Aβ) immunotherapy has recently begun to gain considerable attention as a potentially promising therapeutic approach to reducing the levels of Aβ in the Central Nervous System (CNS) of patients with Alzheimers Disease (AD). Despite extensive preclinical evidence showing that immunization with Aβ(1-42) peptide can prevent or reverse the development of the neuropathological hallmarks of AD, in 2002, the clinical trial of AN-1792, the first trial involving an AD vaccine, was discontinued at Phase II when a subset of patients immunized with Aβ(1-42) developed meningoencephalitis, thereby making it necessary to take a more refined and strategic approach towards developing novel Aβ immunotherapy strategies by first constructing a safe and effective vaccine. This review describes the rational basis in modern clinical trials that have been designed to overcome the many challenges and known hurdles inherent to the search for effective AD immunotherapies. The precise delimitation of the most appropriate targets for AD vaccination remains a major point of discussion and emphasizes the need to target antigens in proteins involved in the early steps of the amyloid cascade. Other obstacles that have been clearly defined include the need to avoid unwanted anti-Aβ/APP Th1 immune responses, the need to achieve adequate responses to vaccination in the elderly and the need for precise monitoring. Novel strategies have been implemented to overcome these problems including the use of N-terminal peptides as antigens, the development of DNA based epitope vaccines and vaccines based on passive immunotherapy, recruitment of patients at earlier stages with support of novel biomarkers, the use of new adjuvants, the use of foreign T cell epitopes and viral-like particles and adopting new efficacy endpoints. These strategies are currently being tested in over 10,000 patients enrolled in one of the more than 40 ongoing clinical trials, most of which are expected to report final results within two years.

Diagnoses behind patients with hard-to-classify tremor and normal DaT-SPECT: a clinical follow up study

The [123I]ioflupane—a dopamine transporter radioligand—SPECT (DaT-SPECT) has proven to be useful in the differential diagnosis of tremor. Here, we investigate the diagnoses behind patients with hard-to-classify tremor and normal DaT-SPECT. Therefore, 30 patients with tremor and normal DaT-SPECT were followed up for 2 years. In 18 cases we were able to make a diagnosis. The residual 12 patients underwent a second DaT-SPECT, were then followed for additional 12 months and thereafter the diagnosis was reconsidered again. The final diagnoses included cases of essential tremor, dystonic tremor, multisystem atrophy, vascular parkinsonism, progressive supranuclear palsy, corticobasal degeneration, fragile X–associated tremor ataxia syndrome, psychogenic parkinsonism, iatrogenic parkinsonism and Parkinsons disease. However, for 6 patients the diagnosis remained uncertain. Larger series are needed to better establish the relative frequency of the different conditions behind these cases.

Exacerbation of Lewy bodies dementia due to memantine.

INTRODUCTION Lewy body dementia (DLB) is common but frequently misdiagnosed as Alzheimers 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 patients mental status. CONCLUSIONS In our patient, motor and cognitive symptoms worsened with memantine treatment; these resolved after memantine was discontinued.

The mirror neuron system in post-stroke rehabilitation.

Different treatments for stroke patients have been proposed; among them the mirror therapy and motion imagery lead to functional recovery by providing a cortical reorganization. Up today the basic concepts of the current literature on mirror neurons and the major findings regarding the use of mirror therapy and motor imagery as potential tools to promote reorganization and functional recovery in post-stroke patients. Bibliographic research was conducted based on publications over the past thirteen years written in English in the databases Scielo, Pubmed/MEDLINE, ISI Web of Knowledge. The studies showed how the interaction among vision, proprioception and motor commands promotes the recruitment of mirror neurons, thus providing cortical reorganization and functional recovery of post-stroke patients. We conclude that the experimental advances on Mirror Neurons will bring new rational therapeutic approaches to post-stroke rehabilitation.

Value of Measuring Plasmatic Levels of Neurosin in the Diagnosis of Alzheimer's Disease

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 Alzheimers 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, Huntingtons disease, Primary Progressive Aphasia, Corticobasal degeneration, Creutzfeldt-Jakobs 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.

Defining the profile of International Archives of Medicine.

This editorial accompanies the launch of International Archives of Medicine, a novel scientific journal born in response to the new needs that have emerged as a result of globalization.

Routine lumbar puncture for the early diagnosis of Alzheimer's disease. Is it safe?

Diagnosing Alzheimers disease (AD) early is itself a controversial topic—not to be addressed here—, as many believe that adequate therapeutics are not available for modifying the course of the disease. Although this may be the case today, it is perhaps due to the fact that existing therapies do not have positive results as the disease process is too far advanced. Distinguishing the cases who will progress to AD among individuals with mild cognitive impairment (MCI), would allow early administration of these currently and future available treatments. Together, this can prolong a meaningful life and also reduce the burden on caregivers as well as the cost of care, now that both the prevalence and cost of AD are rising at a rapid rate. However, diagnosing AD at its early stage still remains a challenge, even in specialized AD centers. Numerous studies suggest that CSF biomarkers have a high potential as diagnostic tools: the measurement of the 2 key AD proteins, Amyloid-beta and Tau, is very helpful for detecting neuropathologic changes related to AD early. CSF levels of Amyloid-beta, but not of Tau, are fully changed already 5–10 years before the onset of clinical AD (Buchhave et al., 2012). CSF TAU changes some time later, when the brain atrophy starts, being a good marker of injury. Thus, in subjects with MCI and evidence of amyloid pathology, CSF Tau can predict further cognitive decline (van Rossum et al., 2012). According to sensitivity, specificity, and predictive values of CSF biomarkers, one may think neurologists should be sharpening their lumbar puncture needles in order to improve their diagnostic accuracy in cases of MCI. Nevertheless, there is a wide range of attitudes and beliefs about the convenience and feasibility of lumbar punctures (LP; commonly referred to as spinal taps), and its practical value in the management of patients today. LP may be regarded as invasive or complicated and time consuming. In addition patients may have fear to undergo LP. One of the most controversial issues when discussing CSF biomarkers for early AD diagnosis has to do with the collection procedure itself. A debate exists on whether or not this technique can and should be used regularly, or if it is still too risky for routine practice. Clinically, LP are performed routinely in clinics for various laboratory analyses to diagnose diseases such as meningitis, encephalitis or inflammatory diseases like Multiple Sclerosis as well as to inject spinal anaesthetics or chemotherapy drugs. However, many still feel that the benefits of its use for testing AD biomarkers do not outweigh the risks. As a result, the use of LP for testing CSF biomarkers in the diagnosis of AD is surprisingly culturally dependent and subject to changes in fashion today. From clinicians who support its use in daily clinical practice (Ariza-Zafra and Torrente-Orihuela, 2005; Lanari and Parnetti, 2009; Galluzzi et al., 2013) and countries where lumbar punture is almost a routine (Scandinavian countries, The Netherlands.) to other territories (Northamerica) where it is regarded as a very serious issue and used for research purposes under strict protocols only (Wilner, 2010; Cummings, 2011). Some studies have already assessed the risks of LP; and the procedure seems to be both “safe and acceptable” to do. In a multi-site US study, 342 people underwent 428 LP. Side effects such as pain, anxiety and the well-known post-lumbar puncture headaches (PLPHAS) were quantified and compared to controls. Overall, pain and anxiety levels were low as rated on a visual analog scale but generally were rated higher in the younger normal subjects as compared to the older participants. This theme remains true amongst studies looking at PLPHA frequency and severity, where those who are younger are at higher risk, especially females (Evans et al., 2000). In terms of PLPHAs, they were unrelated to factors such as the position during the procedure (seated vs. lying) and the frequency of these headaches was lowest in the MCI/AD (over age 60) group than any other subject group. This is a promising conclusion as far as AD is concerned, as all of the participants are older and many have MCI or AD. Other study designed to assess LP procedures specifically in patients with AD also demonstrated that LP performed with a 24 g Sprotte atraumatic needle (blunt, “bullet” tip) is a well-tolerated procedure, with good acceptability (Peskind et al., 2009). As many other medical techniques, the more often a procedure is done, the safer it becomes. In order to obtain more in depth knowledge on the factors affecting the complications of LP for testing biomarkers in patients with cognitive impairment, the Alzheimers Association is supporting a multi-center feasibility study. This study will allow to establish the incidence of post-LP headache and other complications in cases with cognitive disturbances and to know the factors related to the occurrence of post-LP headache, including type of center/experience of physician, patient characteristics (e.g., diagnosis, cognitive function), patient attitude/knowledge on LP and the LP procedure itself. Once it seems that complications related to LP for testing biomarkers in patients with cognitive decline are limited and controllable, next step should be to achieve consensus in order to state which patients should be offered a CSF analysis and how to interprect results in terms of clinical management. There is also a need to homogenize the different analysis techniques, protocols, and establishing universal cut-off levels for the biomarkers. Fortunately several international projects are ongoing in these regards. Hopefully we are envisioning the possibility of using LP for an earlier diagnosis in most AD patients.

Vasomotor Reactivity Is Similarly Impaired in Patients with Alzheimer's Disease and Patients with Amyloid Hemorrhage

Cerebral amyloid angiopathy (CAA) might alter cerebral hemodynamics. Impairment of vasomotor reactivity may constitute a biomarker of amyloid angiopathy and therefore it may be useful to distinguish disorders with CAA from other conditions. The aim of this study was to assess the vasomotor reactivity in two conditions characterized by CAA: Alzheimers disease and amyloid hemorrhage.

MTA index: a simple 2D-method for assessing atrophy of the medial temporal lobe using clinically available neuroimaging

Background and purpose: Despite a strong correlation to severity of AD pathology, the measurement of medial temporal lobe atrophy (MTA) is not being widely used in daily clinical practice as a criterion in the diagnosis of prodromal and probable AD. This is mainly because the methods available to date are sophisticated and difficult to implement for routine use in most hospitals—volumetric methods—or lack objectivity—visual rating scales. In this pilot study we aim to describe a new, simple and objective method for measuring the rate of MTA in relation to the global atrophy using clinically available neuroimaging and describe the rationale behind this method. Description: This method consists of calculating a ratio with the area of 3 regions traced manually on one single coronal MRI slide at the level of the interpeduncular fossa: (1) the medial temporal lobe (MTL) region (A); (2) the parenchima within the medial temporal region, that includes the hippocampus and the parahippocampal gyrus—the fimbria taenia and plexus choroideus are excluded—(B); and (3) the body of the ipsilateral lateral ventricle (C). Therefrom we can compute the ratio “Medial Temporal Atrophy index” at both sides as follows: MTAi = (A − B)× 10/C. Conclusions: The MTAi is a simple 2D-method for measuring the relative extent of atrophy in the MTL in relation to the global brain atrophy. This method can be useful for a more accurate diagnosis of AD in routine clinical practice. Further studies are needed to assess the usefulness of MTAi in the diagnosis of early AD, in tracking the progression of AD and in the differential diagnosis of AD with other dementias.