Analysis of endothelial gene polymorphisms in Spanish patients with vascular dementia and Alzheimer´s disease.

There is increasing evidence for the involvement of blood-brain barrier (BBB) in vascular dementia (VaD) and Alzheimer´s disease (AD) pathogenesis. However, the role of endothelial function-related genes in these disorders remains unclear. We evaluated the association of four single-nucleotide polymorphisms (VEGF, VEGFR2 and NOS3) with diagnosis and rate of cognitive decline in AD and VaD in a Spanish case-control cohort (150 VaD, 147 AD and 150 controls). Participants carrying -604AA genotype in VEGFR2 (rs2071559) were less susceptible to VaD after multiple testing. Further analysis for VaD subtype revealed a significant difference between small-vessel VaD patients and controls, but not for large-vessel VaD patients. In addition, -2578A and -460C alleles in VEGF (rs699947 and rs833061) showed to decrease the risk of AD, whereas NOS3 (rs1799983) influenced disease progression. Our study supports previous findings of a deleterious effect of VEGFR2 reduced expression on small-vessel disease, but not on large-vessel disease; as well as a detrimental effect of down-regulating VEGF and eNOS in AD, affecting vascular permeability and neuronal survival. These data highlight the relevance of endothelial function and, therefore, BBB in both VaD and AD.

The assessment of cognitive and behavioural disturbances in vascular cognitive impairment (VCI) - recommendations of an expert working group.

With newer research-based classification systems, the term Vascular Cognitive Impairment (VCI) is now preferred to vascular dementia. VCI is an umbrella term that includes all forms of cognitive deficits ranging from mild cognitive impairment of vascular origin (VaMCI) to vascular dementia (VaD). The new VCI construct takes into account the fact that in addition to single strategic infarcts, multiple infarcts, and leukoaraiosis, there are other mechanisms of cerebrovascular disease such as chronic hypoperfusion that might account for the pattern of cognitive deficits associated with vascular dementia. The key to defining the spectrum of VCI is neuropsychological testing, bedside or office-based clinical examination, and neuroimaging. The lack of specific cognitive tools that are sufficiently sensitive to detect subtle deficits makes the assessment of cognitive impairment difficult. Prospective cross-sectional and longitudinal studies of VCI from different settings are therefore required. Although there have been few published reports, behavioural and psychological symptoms (BPS) are inherently present in VCI from the onset and during the course of the disease. Besides the type of population (i.e. clinical, community or nursing-home settings), the definition of VCI/VaD and the instruments used, and differences in the prevalence and pattern of BPS between various studies, could be due to other, often unconsidered, factors such as gender, age, education, use of medication and VCI/VaD severity.

The impact of vascular burden on behavioural and psychological symptoms in older adults with dementia: the BEVASDE study.

OBJECTIVES: Behavioural and psychological symptoms (BPS) worsen quality of life and increase institutionalization in dementia, but the relationship between BPS and vascular burden on neuroimaging is unclear. Our aim is to explore whether the profile of BPS differs between patients with large-vessel or cortical vascular dementia (cVaD), small-vessel or subcortical vascular dementia (sVaD) and Alzheimer's disease (AD). METHODS: The BEVASDE study comprised 806 demented patients (cVaD-136, sVaD-184, AD-486) recruited from outpatient consultations in Salamanca and Avila, Spain. The Clinical Dementia Rating Scale (CDR) and the 12-item Neuropsychiatric Inventory (NPI) were used to evaluate dementia severity and BPS. RESULTS: BPS were reported in 98.5%, 97.3% and 96.9% of the cVaD, sVaD and AD cases, respectively. The median NPI score was 36 in both cVaD and sVaD and 34 in AD, with a median number of four symptoms per patient. The most frequent disorders were depression (64.4%), apathy (61.8%) and sleep disturbance (60.5%). Multivariate regression analyses after controlling for possible confounders showed a higher risk of euphoria (p = 0.011), apathy (p = 0.007), irritability (p = 0.002) and sleep disturbance (p = 0.020) in cVaD than in AD and more apathy (p = 0.0001) and irritability (p = 0.0001) in sVaD than in AD. In contrast, AD subjects had a higher risk of delusions (p = 0.007) and hallucinations (p = 0.023) than patients with cVaD as well as more aberrant motor behaviour than both cVaD (p = 0.0001) and sVaD (p = 0.003). CONCLUSION: BPS are common in dementia and may help in differential diagnosis of the various subtypes. We should inquire about them and treat as necessary.

Clinical Features and Treatment in the Spectrum of Paroxysmal Dyskinesias: An Observational Study in South-West Castilla y Leon, Spain.

BACKGROUND: Paroxysmal dyskinesias (PxD) are a group of heterogeneous disorders characterized by intermittent episodes of involuntary movements. PxD include paroxysmal kinesigenic (PKD), nonkinesigenic (PNK), and exercise-induced (PED) varieties. OBJECTIVES: To define the phenotype of primary and secondary PxD forms. METHODS: Twenty-two patients with PxD (9 men/13 women) were evaluated in two hospitals in south-west Castilla y Leon, Spain. Clinical features of the episodes, causes, family history, and response to treatment were collected. RESULTS: Thirteen participants with primary PxD (6 men/7 women) and 9 with secondary PxD (3 men/6 women) were recruited. Nine patients belong to three nonrelated families (2 had PKD and 1 had PED). Mean age at onset in primary PKD cases was 10 years (range 5-23 years), earlier than in PNKD (24 years) and PED (20 years). Most primary PKD cases experienced daily episodes of duration <1 minute, which are more frequent and shorter attacks than in PNKD (1-2 per month, 5 minutes) and PED (1 per day, 15 minutes). The location of the involuntary movements varied widely; isolated dystonia was more common than mixed chorea and dystonia. All PKD patients who received antiepileptic treatment significantly improved. Levodopa and ketogenic diet proved to be effective in two patients with PED. Secondary forms presented a later mean age of onset (51 years). Six cases had PNKD, 1 had PKD, 1 both PNKD and PKD, and 1 had PED. Causes comprised vascular lesions, encephalitis, multiple sclerosis, peripheral trauma, endocrinopathies, and drugs such as selective serotonin reuptake inhibitors (SSRIs). CONCLUSION: The knowledge of the clinical features and spectrum of causes related to PxD is crucial to avoid delays in diagnosis and treatment, or even a nonorganic disorder diagnosis.

Genetics of vascular dementia - review from the ICVD working group.

BACKGROUND: Vascular dementia is a common disorder resulting in considerable morbidity and mortality. Determining the extent to which genes play a role in disease susceptibility and their pathophysiological mechanisms could improve our understanding of vascular dementia, leading to a potential translation of this knowledge to clinical practice. DISCUSSION: In this review, we discuss what is currently known about the genetics of vascular dementia. The identification of causal genes remains limited to monogenic forms of the disease, with findings for sporadic vascular dementia being less robust. However, progress in genetic research on associated phenotypes, such as cerebral small vessel disease, Alzheimer's disease, and stroke, have the potential to inform on the genetics of vascular dementia. We conclude by providing an overview of future developments in the field and how such work could impact patients and clinicians. CONCLUSION: The genetic background of vascular dementia is well established for monogenic disorders, but remains relatively obscure for the sporadic form. More work is needed for providing robust findings that might eventually lead to clinical translation.

Lacosamide for epileptic seizures in patients with co-morbidities and unusual presentations of epilepsy.

Numerous patients who are prescribed antiepileptic drugs (AEDs) for epileptic seizures are already receiving other agents for the treatment of co-morbid conditions, which frequently occur alongside epilepsy. This raises additional clinical considerations and makes the use of AEDs with good safety profiles and fewer drug-drug interactions attractive. Second and third-generation anticonvulsant drugs are associated with fewer pharmacological interactions and improved tolerability compared with first-generation drugs. Furthermore, second and third-generation anticonvulsant drugs are associated with linear pharmacokinetic profiles and differing mechanisms of action, making them ideal for pluripathological and polymedicated patients. In this report, we highlight the efficacy of one such agent, lacosamide, in five patients with co-morbidities and unusual presentations of epilepsy, including a patient with paraneoplastic encephalitis caused by microcytic lung carcinoma, one with a brain tumour and one with Alzheimer's disease, as well as a case of catamenial epilepsy and one of refractory convulsive status epilepticus. In all patients, lacosamide was associated with a substantial reduction in seizure frequency and effective control of seizure episodes. Treatment was generally well tolerated in all patients, indicating that lacosamide is an effective treatment option for a variety of patients with epileptic seizures.

Síntomas no motores en la enfermedad de Parkinson y estimulación cerebral profunda / Nonmotor symptoms in Parkinson’s disease and deep brain stimulation

Introducción. La cirugía funcional ha adquirido gran relevancia en el tratamiento de las complicaciones motoras de la enfermedad de Parkinson (EP) avanzada, y menos conocida es la influencia de la estimulación cerebral profunda (ECP) en los síntomas no motores (SNM). Objetivo. Revisar la bibliografía sobre ECP y SNM en la EP. Desarrollo. Los resultados de la cirugía funcional sobre los SNM de la EP son variables en los distintos estudios. Algunos síntomas mejoran –trastornos del sueño, dolor o disconfort, trastornos obsesivo-compulsivos– y empeoran o aparecen otros –fluencia verbal, apatía, aumento de peso–. En estudios aislados se encuentra mejoría en memoria de trabajo, secuenciación visuomotora y razonamiento, algunos trastornos digestivos, genitourinarios, de termorregulación y olfativos, y empeoran la memoria verbal (recuerdo diferido) y visuoespacial, la velocidad psicomotora y la función ejecutiva, mientras que otros síntomas –hipotensión ortostática– no muestran cambios. Existen otros factores, además de la estimulación, que pueden modificar los SNM, como la vulnerabilidad preoperatoria individual, la disminución de medicación dopaminérgica tras la cirugía, la propia EP y los cambios psicosociales. En pacientes con perfiles determinados pueden existir riesgos específicos –mayor riesgo de alteración cognitiva en pacientes de más de 69 años o con alteración cognitiva precirugía; mayor riesgo de depresión, manía o suicidio en pacientes con patología psiquiátrica previa–. Conclusiones. Es necesario valorar el riesgo-beneficio individualmente para obtener resultados óptimos con este tratamiento. Se requieren estudios multicéntricos que permitan esclarecer el papel de la ECP sobre los SNM (AU)

Introduction. The efficacy of deep brain stimulation (DBS) for the motor symptoms of advanced Parkinson’s disease (PD) is well established. However, the effects of DBS on nonmotor symptoms (NMS) are less clear. Aim. To review the published literature on nonmotor aspects of DBS for PD. Development. The outcome of NMS after DBS in PD varies across studies. Some symptoms improve –sleep disorders, pain or sensory complaints, obsessive-compulsive disorder– and other aspects decline or appear –word fluency, apathy, body weight gain–. Isolated studies note mild improvements in working memory, visuomotor sequencing and conceptual reasoning, some gastrointestinal, urogenital, sweating and olfactory disturbances; whereas other studies have reported declines in verbal memory (long delay recall), visuospatial memory, processing speed and executive function; orthostatic hypotension remains without changes. The reasons for such a range of symptoms observed is due to the multifactorialetiology of the NMS, including preoperative vulnerability, changes in dopaminergic medications, surgical and stimulation effects, underlying PD-related factors and psychosocial effects. Specific patient subgroups may be at greater risk of cognitive deficits –e.g., those older than 69 years or with cognitive impairment prior to surgery– or depression, mania and suicide –e.g., those ones with preoperative psychiatric symptoms–.Conclusions. Patients who undergo DBS must be well-selected, weighing the risks and benefits, in order to obtain the best results with this treatment. Further multicentre studies are necessary to understand the role of DBS on NMS (AU)