Cortical ubiquitin-positive inclusions in frontotemporal dementia without motor neuron disease: a quantitative immunocytochemical study

Ubiquitin-positive tau-negative inclusions were initially described in the rare form of frontotemporal dementia (FTD) associated with motor neuron disease. However, recent studies have indicated that these inclusions are also present in typical FTD, which is usually characterized by nonspecific histological changes. To examine the contribution of these inclusions to neuronal loss and to explore their relationship with disease duration, we performed a quantitative immunocytochemical analysis of 38 typical FTD cases. Relationships between neuron and ubiquitin inclusion densities as well as between duration of illness and neuropathological parameters was studied using linear regression in both univariate and multivariate models. Ubiquitin-positive tau-negative intracytoplasmic inclusions were present in 65.8% of cases in the dentate gyrus, 57.9% in temporal cortex and 31.6% in frontal cortex. The highest densities of ubiquitin-positive inclusions were consistently observed in the dentate gyrus, followed by the temporal and frontal cortex. There was no statistically significant relationship between neuron and ubiquitin-positive inclusion densities in any of the areas studied. In contrast, ubiquitin-positive inclusion densities in the dentate gyrus were negatively related to the duration of illness. Our data suggest that the development of ubiquitin-related pathology is the rule and not the exception in typical FTD, yet is not causally related to neuronal loss. They also reveal that the development of ubiquitin-positive inclusion densities in the dentate gyrus may be associated with a more aggressive form of the diseas

A new model for computing the evolution of the extracellular, innercellular and membrane potential simultaneously

Poster Presentation from Nineteenth Annual Computational Neuroscience Meeting: CNS*2010 San Antonio, TX, USA. 24-30 July 2010 In order to model extracellular potentials the Line-Source method provides [1] a very powerful and accurate approach. In this method transmembane fluxes are understood as sources for potential distributions which obey the Poission-equation with zero boundary conditions in the infinity. Its solutions reveal that the waveforms are proportional to local transmembrane net currents. The extracellular potentials are comparable small in amplitude and with the aid of their second special derivatives, it is possible to interpret them as additional fluxes to be included into the cable equation having an impact on the membrane potential of surrounding cells [2]. On this basis ephaptic interactions have been studied and have been considered to play a minor role in the network activity. This modeling study provides a new approach based on the first principle of the conservation of charges which leads to a generalized form of the cable equation taking into account the full three-dimensional detail of the cell’s geometry and the presence of the extracellular potential. So instead of coupling the compartment model and the model for extracellular potentials by means of the transmembrane currents, a non-linear system of partial differential equations is solved. Because the abstraction of deviding the cell’s geometry into compartments falls apart, it is possible to examine the contribution of the precise cell geometry to the signal processing while not neglecting the impact which could result from the extracellular potential. Some simulations of propagating action potentials on ramified geometries are going to be shown as well as the resulting distributions of extracellular action potentials

Effect of music-based multitask training on cognition and mood in older adults

Background: in a secondary analysis of a randomised controlled trial, we investigated whether 6 months of music-based multitask training had beneficial effects on cognitive functioning and mood in older adults. Methods: 134 community-dwellers aged ≥65 years at increased risk for falling were randomly assigned to either an intervention group (n = 66) who attended once weekly 1-h supervised group classes of multitask exercises, executed to the rhythm of piano music, or a control group with delayed intervention (n = 68) who maintained usual lifestyle habits, for 6 months. A short neuropsychological test battery was administered by an intervention-blinded neuropsychologist at baseline and Month 6, including the mini-mental state examination (MMSE), the clock-drawing test, the frontal assessment battery (FAB) and the hospital anxiety (HADS-A) and depression scale. Results: intention-to-treat analysis showed an improvement in the sensitivity to interference subtest of the FAB (adjusted between-group mean difference (AMD), 0.12; 95% CI, 0.00 to 0.25; P = 0.047) and a reduction in anxiety level (HADS-A; AMD, −0.88; 95% CI, −1.73 to −0.05; P = 0.039) in intervention participants, as compared with the controls. Within-group analysis revealed an increase in MMSE score (P = 0.004) and a reduction in the number of participants with impaired global cognitive performance (i.e., MMSE score ≤23; P = 0.003) with intervention. Conclusion: six months of once weekly music-based multitask training was associated with improved cognitive function and decreased anxiety in community-dwelling older adults, compared with non-exercising controls. Studies designed to further delineate whether training-induced changes in cognitive function could contribute to dual-task gait improvements and falls reduction, remain to be conducte

End-of-Life Care of Persons With Dementia

Many clinicians with different training and practice are involved in the care of persons with dementia. Whereas neurologists and psychiatrists focus their attention on the early phase of dementia, geriatricians and palliative care specialists are particularly involved at the end of demented patients' lives. To summarize the progress of knowledge in this field, it seems possible to answer four fundamental questions. When? Several longitudinal studies of cohorts of demented and nondemented patients showed clearly that dementia is a risk factor for early death. There are no survival differences between Alzheimer's and Lewy body disease patients. Patients with vascular dementia have the worst prognosis. These results need to be analyzed with consideration of associated comorbidity, types and intensity of care, and dementia treatment. Why? Studies conducted on the basis of death certificates appear to be biased. A large autopsy study performed in the geriatric department of Geneva University Hospital showed no difference existed in immediate causes of death between demented and nondemented hospitalized old patients. On the other hand, cardiac causes are significantly more frequent in vascular dementia than in Alzheimer's disease or mixed dementia patients. How? Deaths of demented patients raise a lot of ethical considerations. It is always difficult to know demented patients' awareness of the end of life. It is really difficult to accompany these patients, with whom communication is essentially nonverbal. During this delicate phase of the end of life, how can formal health professionals help the family members who are afraid of both death and dementia? And after? Suffering of family members and caregivers has to be strongly considered. This goal includes the improvement of our communication skills with the patient, and the facilitation of interdisciplinary exchanges with the caregiver's team and with the family members to allow acceptance of the deat

Identification of Alzheimer and vascular lesion thresholds for mixed dementia

To explore the pathological substrates of mixed dementia, we performed a detailed analysis of lacunar and microvascular pathology in 156 autopsied, elderly individuals with various degrees of Alzheimer's disease (AD) pathology. Cognitive status was assessed prospectively using the Clinical Dementia Rating (CDR) scale; neuropathological evaluation included Braak neurofibrillary tangle (NFT) and Aß-protein deposition staging and bilateral semi-quantitative assessment of microvascular ischaemic pathology and lacunes; statistics included univariate and multiple regression models controlling for age, and receiver-operating characteristic analysis. Sensitivity analysis was performed in a randomized derivation sub-sample and tested in a validation sub-sample. White matter lacunes, periventricular and diffuse white matter demyelination and focal and diffuse cortical gliosis were not associated with cognition. Braak NFT, Aß deposition, cortical microinfarcts (CMI) and thalamic and basal ganglia lacunes (TBGL) predicted 27% of CDR variability and 49% of the presence of dementia. Braak NFT, CMI and TBGL thresholds determined in a derivation sample yielded 0.88 sensitivity, 0.79 specificity and 0.85 correct classification rate for dementia in a validation sample. The same thresholds distinguished three groups of demented cases consistent with mixed dementia, pure vascular dementia and AD. These findings indicate that the clinical expression of the vascular component in mixed cases is highly dependent on lesion type and location as well as severity of concomitant AD-related pathology. Proposed thresholds for vascular and degenerative lesions predict the presence of dementia with great accuracy and provide a basis for distinguishing pure vascular dementia or AD from mixed case

Early disturbances of gamma band dynamics in mild cognitive impairment

Recent studies have indicated that gamma band oscillations participate in the temporal binding needed for the synchronization of cortical networks involved in short-term memory and attentional processes. To date, no study has explored the temporal dynamics of gamma band in the early stages of dementia. At baseline, gamma band analysis was performed in 29 cases with mild cognitive impairment (MCI) during the n-back task. Based on phase diagrams, multiple linear regression models were built to explore the relationship between the cognitive status and gamma oscillation changes over time. Individual measures of phase diagram complexity were made using fractal dimension values. After 1year, all cases were assessed neuropsychologically using the same battery. A total of 16 MCI patients showed progressive cognitive decline (PMCI) and 13 remained stable (SMCI). When adjusted for gamma values at lag −2, and −3ms, PMCI cases displayed significantly lower average changes in gamma values than SMCI cases both in detection and 2-back tasks. Gamma fractal dimension of PMCI cases displayed significantly higher gamma fractal dimension values compared to SMCI cases. This variable explained 11.8% of the cognitive variability in this series. Our data indicate that the progression of cognitive decline in MCI is associated with early deficits in temporal binding that occur during the activation of selective attention processe

Feasibility and Reliability of Four Pain Self-Assessment Scales and Correlation With an Observational Rating Scale in Hospitalized Elderly Demented Patients

Background. Acute and chronic pain is common in hospitalized demented elderly people, yet there are limited data about the performance of pain assessment tools in this population. The aim of this study was to evaluate the feasibility and reliability of four pain self-assessment scales in this population and compare their performance to an observational pain rating scale. Methods. Our prospective clinical study was conducted in an acute-care and intermediate-care geriatric hospital on 160 consecutive inpatient referrals to the dementia consultation who met Diagnostic and Statistical Manual of Mental Disorders-IV criteria for dementia. Exclusion criteria were delirium, terminal care, and severe sensory impairment. Four unidimensional self-assessment tools—the verbal, horizontal visual, vertical visual, and faces pain scales—were administered in randomized order to mild, moderate, and severely demented patients. An observational pain rating scale was independently completed by the nursing team. Results. Only 12% of the 160 patients (mean age 85 years, 71% women) understood no scale. Respectively, 97%, 90%, and 40% of patients with mild, moderate, and severe dementia understood at least one scale (p <.05). There was a nonsignificant trend toward poorer comprehension of the faces scale. Test-retest reliability was high for all four self-assessment scales, and the correlation between these scales was very strong (Spearman's rs = 0.81-0.95; p <.001). Observational rating correlated moderately with self-assessment and tended to underestimate pain intensity (rs = 0.31-0.40; p <.05). Conclusions. Self-assessment pain scales can be used reliably in the vast majority of older hospitalized patients with mild to moderate dementia and in nearly half of those with severe dementia. Observational pain rating scales correlate only moderately with self-assessment and should be reserved for those few patients who have demonstrated that they cannot complete a self-assessmen

Mild cognitive impairment, degenerative and vascular dementia as predictors of intra-hospital, short- and long-term mortality in the oldest old

Background and aims: The relative weight of various etiologies of dementia and mild cognitive impairment (MCI) as predictors of intra-hospital, short- and long-term mortality in very old acutely ill patients suffering from multiple comorbid conditions remains unclear. We investigated intra-hospital, 1- and 5-year mortality risk associated with dementia and its various etiologies in a very old population after discharge from acute care. Methods: Prospective cohort study of 444 patients (mean age 85 years; 74% female) discharged from the acute geriatric unit of Geneva University Hospital. On admission, each subject underwent standardized evaluation of cognitive and comorbid conditions. Patients were followed yearly by the same team. Predictive variables were age, sex, cognitive diagnosis, dementia etiology and severity. Survival during hospitalization, at 1- and 5-year follow-ups was the outcome of interest evaluated with Cox proportional hazard models. Results: Two hundred and six patients were cognitively normal, 48 had MCI, and 190 had dementia: of these, there were 75 cases of Alzheimer's disease (AD), 20 of vascular dementia (VaD), 82 of mixed dementia (MD) and 13 of other types of dementia. The groups compared were statistically similar in age, sex, education level and comorbidity score. After 5 years of follow-up, 60% of the patients had died. Regarding intra-hospital mortality, none of the predictive variables was associated with mortality. MCI, AD and MD were not predictive of short- or long-term mortality. Features significantly associated with reduced survival at 1 and 5 years were being older, male, and having vascular or severe dementia. When all the variables were added in the multiple model, the dementia effect completely disappeared. Conclusions: Dementia (all etiologies) is not predictive of mortality. The observed VaD effect is probably linked to cardiovascular risk comorbidities: hypertension, stroke and hyperlipidemi