A European Academy of Neurology guideline on medical management issues in dementia.

BACKGROUND AND PURPOSE: Dementia is one of the most common disorders and is associated with increased morbidity, mortality and decreased quality of life. The present guideline addresses important medical management issues including systematic medical follow-up, vascular risk factors in dementia, pain in dementia, use of antipsychotics in dementia and epilepsy in dementia. METHODS: A systematic review of the literature was carried out. Based on the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework, we developed a guideline. Where recommendations based on GRADE were not possible, a good practice statement was formulated. RESULTS: Systematic management of vascular risk factors should be performed in patients with mild to moderate dementia as prevention of cerebrovascular pathology may impact on the progression of dementia (Good Practice statement). Individuals with dementia (without previous stroke) and atrial fibrillation should be treated with anticoagulants (weak recommendation). Discontinuation of opioids should be considered in certain individuals with dementia (e.g. for whom there are no signs or symptoms of pain or no clear indication, or suspicion of side effects; Good Practice statement). Behavioral symptoms in persons with dementia should not be treated with mild analgesics (weak recommendation). In all patients with dementia treated with opioids, assessment of the individual risk-benefit ratio should be performed at regular intervals. Regular, preplanned medical follow-up should be offered to all patients with dementia. The setting will depend on the organization of local health services and should, as a minimum, include general practitioners with easy access to dementia specialists (Good Practice statement). Individuals with dementia and agitation and/or aggression should be treated with atypical antipsychotics only after all non-pharmacological measures have been proven to be without benefit or in the case of severe self-harm or harm to others (weak recommendation). Antipsychotics should be discontinued after cessation of behavioral disturbances and in patients in whom there are side effects (Good Practice statement). For treatment of epilepsy in individuals with dementia, newer anticonvulsants should be considered as first-line therapy (Good Practice statement). CONCLUSION: This GRADE-based guideline offers recommendations on several important medical issues in patients with dementia, and thus adds important guidance for clinicians. For some issues, very little or no evidence was identified, highlighting the importance of further studies within these areas.

MMSE and MoCA in Parkinson's disease and dementia with Lewy bodies: a multicenter 1-year follow-up study.

The Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) are the most commonly used scales to test cognitive impairment in Lewy body disease (LBD), but there is no consensus on which is best suited to assess cognition in clinical practice and most sensitive to cognitive decline. Retrospective cohort study of 265 LBD patients [Parkinson's disease (PD) without dementia (PDnD, N = 197), PD with dementia (PDD, N = 40), and dementia with Lewy bodies (DLB, N = 28)] from an international consortium who completed both the MMSE and MoCA at baseline and 1-year follow-up (N = 153). Percentage of relative standard deviation (RSD%) at baseline was the measure of inter-individual variance, and estimation of change (Cohen's d) over time was calculated. RSD% for the MoCA (21 %) was greater than for the MMSE (13 %) (p = 0.03) in the whole group. This difference was significant only in PDnD (11 vs. 5 %, p < 0.01), but not in PDD (30 vs. 19 %, p = 0.37) or DLB (15 vs. 14 %, p = 0.78). In contrast, the 1-year estimation of change did not differ between the two tests in any of the groups (Cohen's effect <0.20 in each group). MMSE and MoCA are equal in measuring the rate of cognitive changes over time in LBD. However, in PDnD, the MoCA is a better measure of cognitive status as it lacks both ceiling and floor effects.

A genome-wide survey and functional brain imaging study identify CTNNBL1 as a memory-related gene.

Unbiased genome-wide screens combined with imaging data on brain function may identify novel molecular pathways related to human cognition. Here we performed a dense genome-wide screen to identify episodic memory-related gene variants. A genomic locus encoding the brain-expressed beta-catenin-like protein 1 (CTNNBL1) was significantly (P=7 × 10(-8)) associated with verbal memory performance in a cognitively healthy cohort from Switzerland (n=1073) and was replicated in a second cohort from Serbia (n=524; P=0.003). Gene expression studies showed CTNNBL1 genotype-dependent differences in beta-catenin-like protein 1 mRNA levels in the human cortex. Functional magnetic resonance imaging in 322 subjects detected CTNNBL1 genotype-dependent differences in memory-related brain activations. Converging evidence from independent experiments and different methodological approaches suggests a role for CTNNBL1 in human memory.

Cerebrospinal fluid biomarkers of neurodegeneration in patients with juvenile and classic myotonic dystrophy type 1.

BACKGROUND AND PURPOSE: The aim of the present study was to analyze cerebrospinal fluid (CSF) levels of total tau (T-tau), phosphorylated tau (P-tau) and the 42-amino-acid form of ß-amyloid (Aß42 ) in patients with myotonic dystrophy type 1 (DM1), and their possible correlations with cognitive and behavioral manifestations in these patients. METHODS: Lumbar puncture was performed in 74 patients with DM1 [27 with the childhood/juvenile form (jDM1) and 47 with the adult form (aDM1) of the disease] and 26 control subjects who were subjected to orthopedic surgery. Sandwich ELISA was used for measuring the levels of T-tau, P-tau and Aß42. RESULTS: The CSF level of Aß42 was at its lowest in patients with jDM1 and at its highest in controls (P < 0.05). A tendency of T-tau and P-tau to increase was greater in aDM1 patients than in jDM1 patients and controls (P > 0.05). In both jDM1 and aDM1 patients, significant correlations were found between Aß42 and T-tau (rho = 0.81 and rho = 0.67, respectively, P < 0.01), as well as between Aß42 and P-tau (rho = 0.87 and rho = 0.67, respectively, P < 0.01). The Aß42/P-tau ratio decreased with age in aDM1 patients (rho = -0.30, P < 0.05). Only the level of Aß42 in the CSF of jDM1 patients was correlated with the size of the CTG expansion (rho = -0.53, P < 0.05). Only a few correlations were observed between levels of biomarkers and neuropsychological testing. CONCLUSION: The CSF level of Aß42 was decreased in patients with jDM1, whilst the Aß42/P-tau ratio was decreased in aDM1 patients. Positive correlations between Aß42 , T-tau and P-tau were observed in both forms of disease. Further studies with larger cohorts of DM1 patients are necessary.

A genome-wide survey of human short-term memory.

Recent advances in the development of high-throughput genotyping platforms allow for the unbiased identification of genes and genomic sequences related to heritable traits. In this study, we analyzed human short-term memory, which refers to the ability to remember information over a brief period of time and which has been found disturbed in many neuropsychiatric conditions, including schizophrenia and depression. We performed a genome-wide survey at 909 622 polymorphic loci and report six genetic variations significantly associated with human short-term memory performance after genome-wide correction for multiple comparisons. A polymorphism within SCN1A (encoding the α subunit of the type I voltage-gated sodium channel) was replicated in three independent populations of 1699 individuals. Functional magnetic resonance imaging during an n-back working memory task detected SCN1A allele-dependent activation differences in brain regions typically involved in working memory processes. These results suggest an important role for SCN1A in human short-term memory.

EFNS-ENS Guidelines on the diagnosis and management of disorders associated with dementia.

BACKGROUND AND OBJECTIVES: The last version of the EFNS dementia guidelines is from 2007. In 2010, the revised guidelines for Alzheimer's disease (AD) were published. The current guidelines involve the revision of the dementia syndromes outside of AD, notably vascular cognitive impairment, frontotemporal lobar degeneration, dementia with Lewy bodies, corticobasal syndrome, progressive supranuclear palsy, Parkinson's disease dementia, Huntington's disease, prion diseases, normal-pressure hydrocephalus, limbic encephalitis and other toxic and metabolic disorders. The aim is to present a peer-reviewed evidence-based statement for the guidance of practice for clinical neurologists, geriatricians, psychiatrists and other specialist physicians responsible for the care of patients with dementing disorders. It represents a statement of minimum desirable standards for practice guidance. METHODS: The task force working group reviewed evidence from original research articles, meta-analyses and systematic reviews, published by June 2011. The evidence was classified (I, II, III, IV) and consensus recommendations graded (A, B, or C) according to the EFNS guidance. Where there was a lack of evidence, but clear consensus, good practice points were provided. RESULTS AND CONCLUSIONS: New recommendations and good practice points are made for clinical diagnosis, blood tests, neuropsychology, neuroimaging, electroencephalography, cerebrospinal fluid (CSF) analysis, genetic testing, disclosure of diagnosis, treatment of behavioural and psychological symptoms in dementia, legal issues, counselling and support for caregivers. All recommendations were revised as compared with the previous EFNS guidelines. The specialist neurologist together with primary care physicians play an important role in the assessment, interpretation and treatment of symptoms, disability and needs of dementia patients.

Effect of invasive ctenophores Mnemiopsis leidyi and Beroe ovata on low trophic webs of the Black Sea ecosystem.

The study focuses on the impact of life excretion and mucus released by the "biological pollutants" invasive ctenophore Mnemiopsis leidyi and its predator Beroe ovata on the marine environment and lower trophic levels of the Black Sea ecosystem (bacteria, pico-phytoplankton, nano-autotrophic/heterotrophic flagellates, micro-phytoplankton, chlorophyll a, primary production (PP), micro-zooplankton). The chemical and biological variables were analysed in two sets of lab experiments with natural communities from mesotrophic (Gelendzhik) and eutrophic (Varna) coastal waters. While both species altered the chemical properties of experimental media, exerting structural and functional changes in the low food-web biological compartments, the results showed a stronger effect of B. ovata, most likely related to the measured higher rate of excretion and amount of released mucus. In addition the alterations in the Gelendzhik experiment were more pronounced, indicating that environmental implications on lower food-web are more conspicuous in mesotrophic than in eutrophic coastal waters.

Cerebral glucose metabolism, cerebrospinal fluid-beta-amyloid1-42 (CSF-Abeta42), tau and apolipoprotein E genotype in long-term rivastigmine and tacrine treated Alzheimer disease (AD) patients.

We evaluated cerebral glucose metabolism (CMRglc) and cerebrospinal fluid (CSF) levels of tau and beta-amyloid(1-42) (Abeta42), in relation to apolipoprotein E (ApoE) genotype, in patients with mild Alzheimer disease (AD) treated with rivastigmine (n=11) and tacrine (n=16) for 1 year; and two untreated AD groups. The rivastigmine-treated AD patients showed a significant increase in CMRglc as compared to both tacrine-treated and untreated AD subjects. The rivastigmine-treated AD group showed no change in CSF-tau levels after 1 year, while in contrast a significant increase as seen in tacrine-treated and untreated AD patients. The CSF-tau changes were mainly seen in ApoE epsilon4 carriers. There was no significant change in Abeta42 after 1-year treatment with either rivastigmine or tacrine. This study shows that the two long-term cholinesterase inhibitor treatments exert different effects on biological markers for AD.

[Behavior of pericentromere heterochromatin regions under different conditions of chromosome decondensation in isolated nuclei]. / Povedenie raionov pritsentromernogo geterokhromatina v razlichnykh usloviiakh dekondensatsii khromatina vydelennykh iader.

In isolated mouse nuclei the chromocenters were shown to be the pericentromeric heterochromatin regions (PCHR). After the decreasing of bivalent ion concentration (0.1 mM Ca2+, 2 mM Mg2+) the main and peripheral parts of the chromatin remained on the contrary as the compact chromatin bodies. The additional ultrasound treatment of isolated nuclei in the presence of 0.1 mM Ca2+ with DNAase II and triton X-100 resulted in the species enriched by the condensed PCHR.

[Chromocenters of interphase nuclei in the mouse liver contain satellite DNA]. / Khromotsentry interfaznykh iader pecheni myshi soderzhat satellitnuiu DNK.

In isolated interphase mouse liver nuclei after hypotonic treatment only the chromocenters belonging to the pericentromeric heterochromatin remain in dense form while the main mass of a chromatin is completely decondensed. The centromeric nature of these chromocenters is demonstrated by their capability for C-banding and for hybridization with a satellite mouse DNA.

Significant impact of behavioral and cognitive impairment on quality of life in patients with myotonic dystrophy type 1.

OBJECTIVE: To assess an impact of cognitive and behavioral impairment on QoL in a larger cohort of patients with DM1. METHODS: Sixty six genetically confirmed DM1 patients (22 with juvenile (jDM1) and 44 with adult form (aDM1) of the disease) were recruited. Following behavioral tests were used: Hamilton scales for depression and anxiety (HamD and HamA), Daytime Sleepiness Scale (DSS), and Krupp's Fatigue Severity Scale (FSS). Patients also underwent detailed classic neuropsychological investigation and Cambridge Neuropsychological Test Automated Battery (CANTAB). Individualized Neuromuscular Quality of Life questionnaire (INQoL) was used as a measure of QoL. RESULTS: Patients with jDM1 scored lower than aDM1 patients regarding total INQoL score and all INQoL subdomains, except for myotonia. Significant predictors of total INQoL score in patients with jDM1 were severity of fatigue (ß=+0.60, p<0.01) and percentage of correct responses on Spatial Recognition Memory test from CANTAB that measures visuospatial abilities (ß=-0.38, p<0.05). The most important predictors of total INQoL score in patients with aDM1 were severity of fatigue (ß=+0.36, p<0.05) and level of education (ß=-0.29, p<0.05). CONCLUSION: Our results showed clear influence of different central manifestations on QoL in patients with both aDM1 and jDM1.

Apathy and depression in Parkinson's disease: the Belgrade PD study report.

Apathy and depression are among the most common psychiatric and behavioral disorders associated with Parkinson's disease (PD). The objective of this study was to examine the prevalence and demographic and clinical correlates of apathy and depression in a clinical population-based sample of patients with PD and to assess whether apathy may present as a primary behavioral disturbance independent from depression and cognitive impairment. A series of 360 PD patients underwent psychiatric investigation with the Starkstein's Apathy Scale (AS), and the 17-item Hamilton Depression Rating Scale (HDRS-17), motor scoring with Hoehn and Yahr (HY) staging, and the Unified Parkinson's Disease Rating Scale (UPDRS); and cognitive screening with the Mini-Mental State Examination (MMSE) on the same day. Apathy coexisted with depression in 133 (36.9%) of PD patients, compared with depression without apathy in 16 (4.4%), apathy without depression in 84 (23%), and neither apathy nor depression in 127 PD patients (35.2%). Apathy was associated with higher axial UPDRS impairment score, lower MMSE score, higher l-dopa dosage, and earlier HY stages, while depression was predicted by the more advanced HY stages and younger age of PD patients. These findings suggest that apathy and depression may be separable in PD, although both are common in patients with PD. Therefore these two conditions should be systematically screened and considered in the care and management of PD.

Pattern of brain tissue loss associated with freezing of gait in Parkinson disease.

OBJECTIVE: To investigate whether a specific pattern of gray matter (GM) tissue loss is associated with freezing of gait (FOG) in patients with Parkinson disease (PD). METHODS: Seventeen patients with PD with FOG (PD-FOG), 20 patients with PD with no FOG (PD-noFOG), and 34 healthy control subjects were recruited. PD-FOG and PD-noFOG patients were matched on an individual basis for age, disease duration, and Hoehn and Yahr stage. Patients were also administered a comprehensive neuropsychological battery focused on executive functions. The extent and distribution of GM atrophy were assessed using voxel-based morphometry. RESULTS: In patients with PD, the severity of FOG correlated with frontal executive deficits. Compared with healthy control subjects, PD-FOG patients showed a distributed pattern of GM atrophy including the dorsolateral prefrontal, medial, and lateral temporal, inferior parietal, and occipital cortices. PD-noFOG patients showed only small regions of GM atrophy in the bilateral frontal and temporal cortex. The left inferior frontal gyrus, left precentral gyrus, and left inferior parietal gyrus were more atrophic in PD-FOG patients relative to both healthy control subjects and PD-noFOG patients. In PD-FOG patients, the severity of FOG was associated with GM volumes of the frontal and parietal cortices bilaterally. CONCLUSIONS: GM frontal and parietal atrophy occur in PD-FOG patients. FOG in PD seems to share with executive dysfunction and perception deficits a common pattern of structural damage to the frontal and parietal cortices.

Vascular risk factors in Alzheimer's disease - preliminary report.

BACKGROUND: The vascular risk factors are associated with an increased risk for vascular cognitive decline (VCD), but also with Alzheimer disease (AD). OBJECTIVE: To investigate vascular risk factors in relation to AD and VCD, with a non-invasive neurosonological methods in a clinical settings. RESULTS: A total of 296 patients with AD and 237 patients with VCD were included in the study. Hypertension, hyperlipidemia, diabetes mellitus, stroke, and white matter changes (p<0.001) were significantly more prevalent in VCD, although they were also present in AD patients. No statistically significant differences were obtained between groups regarding coronary disease, atrial fibrillation, average degree of carotid artery stenosis and carotid intima-media thickness (cITM). However, the patients with AD had carotid artery stenosis ">50%" (p=0.007) and present plaques (p<0.001) more frequently compared to vascular group. The significant associations between robust cognitive measure and vascular factors, diabetes mellitus, carotid stenosis, cITM, and type of plaques were identified only in VCD, but not in AD group. CONCLUSIONS: The vascular risk factors were more prevalent in VCD group, although they were also present in AD. With few treatment options available in AD, it may be important not to neglect the vascular risk factors.

The incidence of and risk factors for HIV-associated cognitive-motor complex among patients on HAART.

BACKGROUND: While highly active antiretroviral therapy (HAART) allows for the considerable decline in the incidence of HIV-related opportunistic infections and tumors, its effect on treating HIV infection of the brain, such as HIV-associated dementias (HADs), remains unclear. METHODS: A cross-sectional study of consecutive series of 96 patients from the Serbian HIV/AIDS cohort, treated with HAART in our HIV unit was performed to evaluate the incidence of and risk factors for cognitive/motor complex during HAART. CD4+T cell counts and pVL values at the time of neurological evaluation were parameters of the response to HAART. The mini-mental test and neurologic examination were performed at one point of time during treatment to reveal cognitive and/or motor disorders. RESULTS: After mean HAART duration of 47 months, unimpaired cognition, minor cognitive impairment, and HIV-associated dementia were recorded in 56 (58.3%), 27 (28.1%), and 13 (13.5%), respectively. Motor abnormalities had 39 (40.6%) patients. Of these, 21, 12, and 6 patients belong to the subgroups with normal cognition, minor cognitive impairment and HAD patients, respectively. Factors predictive for HAD were age over 40 (OR 3.7, 95% CI 1.07-13.28, P=0.039), and AIDS diagnosis prior to HAART initiation (OR 14.19, 95% CI 1.76-114.16, P=0.013). Conversely, factors shown to be protective against HAD were the usage of AZT and NNRTIs, as components of HAART regimens (OR 0.18, 95% CI 0.046-0.76, P=0.019, and OR 0.14, 95% CI 0.034-0.6, P=0.008). CONCLUSION: Cognitive/motor complex has still remained a significant neuropathology among late presenters and elder HIV/AIDS patients. Certain HAART regimens containing AZT, and/or NNRTIs, could be protective for these patients.

Longitudinal PET evaluation of cerebral glucose metabolism in rivastigmine treated patients with mild Alzheimer's disease.

In this study 11 patients with mild Alzheimer's disease (AD) were treated with the cholinesterase inhibitor rivastigmine (mean dose 8.6 +/- 1.3'mg) for 12 months and underwent positron emission tomography (PET) studies of cerebral glucose metabolism (CMRglc) and neuropsychological testing at baseline and after 12 months. An untreated group of 10 AD patients served as control group. While the untreated AD patients showed a significant decline of CMRglc in the temporo-parietal and frontal cortical regions after 12 months follow-up the rivastigmine-treated patients showed no decline in CMRglc in corresponding cortical brain regions. Furthermore, a significant dose-related increase in CMRglc was recorded in the right frontal association region after 12 months rivastigmine treatment. A positive correlation was observed between changes in CMRglc and several cognitive tests in patients receiving higher doses (10.5-12'mg) of rivastigmine. These results suggest a stabilization effect of rivastigmine on CMRglc in mild AD patients receiving long-term rivastigmine treatment.

[Idiopathic normotensive hydrocephalus. Neuropsychologic evaluation after ventriculo-atrial shunt]. / Idiopatski normotenzivni hidrocefalus. Neuropsioholoska procena ishoda ventrikulo-atriumskog santa.

Two patients with normal-pressure hydrocephalus were assessed with Luria Nebraska Neuropsychological Battery, before ventriculo-atrial shunting and six months later. The best improvement was recorded in attention, visuospatial and intellectual functions. It is well documented that normal-pressure hydrocephalus dementia can be reversible if proper selection for neurosurgical treatment is made. Cognitive outcome of ventriculo-atrial shunting in normal-pressure hydrocephalus is best assessed with the appropriate neuropsychological testing.