Beyond neuropathy in hereditary sensory and autonomic neuropathy type V: cognitive evaluation

Background and purpose: Hereditary sensory and autonomic neuropathy ( HSAN) type V is a very rare disorder. It is characterized by the absence of thermal and mechanical pain perception caused by decreased number of small diameter neurons in peripheral nerves. Recent genetic studies have pointed out the aetiological role of nerve growth factor beta, which is also involved in the development of the autonomic nervous system and cholinergic pathways in the brain. HSAN type V is usually reported not to cause mental retardation or cognitive decline. However, a structured assessment of the cognitive pro. le of these patients has never been made. Methods and results: We performed a throughout evaluation of four HSAN type V patients and compared their performance with 37 normal individuals. Our patients showed no cognitive deficits, not even mild ones. Discussion and Conclusions: Although newer mutations on this and related disorders are continuously described, their clinical characterization has been restricted to the peripheral aspects of these conditions. A broader characterization of this rare disorder may contribute to better understand the mechanisms of the nociceptive and cognitive aspects of pain.

Effects of Age-Related Cognitive Deficits on EEG Phase Coherence

Body and brain undergo several changes with aging. One of these changes is the loss of neuroplasticity, which leads to the decrease of cognitive abilities. Hence the necessity of stopping or reversing these changes is of utmost importance to contemporary society. In the present work, electroencephalogram (EEG) markers of cognitive decline are sought whilst the subjects perform the Wisconsin Card Sorting Test (WCST). Considering the expected age-related cognitive deficits, WCST was applied to young and elder participants. The results suggest that coherence on theta and alpha EEG rhythms decrease with aging and increase with performance. Additionally, theta phase coherence seems more sensitive to performance, while alpha synchronization appears as a potential ageing marker.

Undrestanding postoperative cognitive dysfunction: novel insights

ABSTRACT: Background: Sleep is integral to biological function and sleep disruption can result in both physiological and psychological dysfunction. The acute cognitive consequences of sleep loss has been an active field of recent investigation, evidence suggests that sleep disruption in critically ill older adults can result in acute decrements in cognitive functioning. Surgery activates the innate immune system, inducing neuroinflammatory changes that interfere with cognition. The fact that patients with sleep disorders have an increased likelihood of exhibiting postoperative delirium encourages us to investigate the contribution of perioperative SF to the neuroinflammatory and cognitive responses of surgery. Methods: The effects of 24h sleep fragmentation (SF) and surgery were explored on adult C57BL/6J male mice. SF procedure started at 7 am with the home-cages being placed on a large platform orbital shaker cycled every 120 seconds (30 sec on/90 sec off). This procedure lasted for 24h. Stabilized tibia fracture was performed either before or after the 24h SF procedure. Separate cohorts of mice were tested for systemic and hippocampal inflammation and cognition. Results: Twenty-four hours of SF induced non-hippocampal memory dysfunction and increase in systemic IL-6. SF and surgery caused hippocampal-dependent memory impairment, although memory impairment was not exacerbated by combining SF with surgery. One day after either SF or surgery there was a significant increase in IL6 mRNA and TNF-alpha mRNA. These increments were more pronounced when either pre or post operative SF was combined with surgery. Conclusions: We show that while SF and surgery can independently produce significant memory impairment, perioperative SF significantly increased hippocampal inflammation without further cognitive impairment. The dissociation between neuroinflammation and cognitive decline may relate to our use of a sole memory paradigm that does not capture other aspects of cognition, especially learning.

Effector memory CD4+ T cells are associated with cognitive performance in a senior population

Objective: Immunosenescence and cognitive decline are common markers of the aging process. Taking into consideration the heterogeneity observed in aging processes and the recently described link between lymphocytes and cognition, we herein explored the possibility of an association between alterations in lymphocytic populations and cognitive performance. Methods: In a cohort of cognitively healthy adults (n = 114), previously characterized by diverse neurocognitive/psychological performance patterns, detailed peripheral blood immunophenotyping of both the innate and adaptive immune systems was performed by flow cytometry. Results: Better cognitive performance was associated with lower numbers of effector memory CD4(+) T cells and higher numbers of naive CD8(+) T cells and B cells. Furthermore, effector memory CD4(+) T cells were found to be predictors of general and executive function and memory, even when factors known to influence cognitive performance in older individuals (e.g., age, sex, education, and mood) were taken into account. Conclusions: This is the first study in humans associating specific phenotypes of the immune system with distinct cognitive performance in healthy aging.

Neurocognitive profile and cognitive intervention in Alzheimer's disease

Tese de Doutoramento em Psicologia (Especialidade de Psicologia Clínica)

Penetrance of marked cognitive impairment in older male carriers of the FMR1 gene premutation.

BACKGROUND: Male carriers of the FMR1 premutation are at risk of developing the fragile X-associated tremor/ataxia syndrome (FXTAS), a newly recognised and largely under-diagnosed late onset neurodegenerative disorder. Patients affected with FXTAS primarily present with cerebellar ataxia and intention tremor. Cognitive decline has also been associated with the premutation, but the lack of data on its penetrance is a growing concern for clinicians who provide genetic counselling. METHODS: The Mattis Dementia Rating Scale (MDRS) was administered in a double blind fashion to 74 men aged 50 years or more recruited from fragile X families (35 premutation carriers and 39 intrafamilial controls) regardless of their clinical manifestation. Based on previous publications, marked cognitive impairment was defined by a score <or=123 on the MDRS. RESULTS: Both logistic and survival models confirmed that in addition to age and education level, premutation size plays a significant (p<0.01 and p<0.03 for logistic and survival model, respectively) role in cognitive impairment. The estimated penetrance of marked cognitive impairment in our sample (adjusted for the mean age 63.4 years and mean education level 9.7 years) for midsize/large (70-200 CGG) and small (55-69 CGG) premutation alleles was 33.3% (relative risk (RR) 6.5; p = 0.01) and 5.9% (RR 1.15; p = 0.9) respectively. Penetrance in the control group was 5.1%. CONCLUSIONS: Male carriers of midsize to large premutation alleles had a sixfold increased risk of developing cognitive decline and the risk increases with allele size. In addition, it was observed that cognitive impairment may precede motor symptoms. These data provide guidance for genetic counselling although larger samples are required to refine these estimates.

Hypertension. Effets du traitement antihypertenseur sur les fonctions cognitives [Hypertension. Effects of antihypertensive therapy on cognitive functions].

A cause and effect relationship between arterial hypertension and decline of cognitive function has long been suspected. In middle-age subjects indeed, an abnormally high blood pressure is a risk factor for the long-term development of dementia. Presently, it seems crucial to treat hypertensive patients in order to better protect them against cognitive decline. However, in the elderly patients the risk of mental deterioration may also be enhanced when diastolic pressure becomes too low, for example below 70 mmHg. Further studies are required to better define the antihypertensive drug regimen and target blood pressure which would be optimal for the prevention of cerebral small vessel disease.

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 1 year, 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 -3 ms, 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 processes.

Polyphenol-rich foods in the Mediterranean diet are associated with better cognitive function in elderly subjects at high cardiovascular risk

Brain oxidative processes play a major role in age-related cognitive decline, thus consumption of antioxidant-rich foods might help preserve cognition. Our aim was to assess whether consumption of antioxidant-rich foods in the Mediterranean diet relates to cognitive function in the elderly. In asymptomatic subjects at high cardiovascular risk (n = 447; 52% women; age 5580 y) enrolled in the PREDIMED study, a primary prevention dietary-intervention trial, we assessed food intake and cardiovascular risk profile, determined apolipoprotein E genotype, and used neuropsychological tests to evaluate cognitive function.We also measured urinary polyphenols as an objective biomarker of intake. Associations between energy-adjusted food consumption, urinary polyphenols, and cognitive scores were assessed by multiple linear regression models adjusted for potential confounders. Consumption of some foods was independently related to better cognitive function. The specific associations [regression coefficients (95% confidence intervals)] were: total olive oil with immediate verbal memory [0.755 (0.1511.358)]; virgin olive oil and coffee with delayed verbal memory [0.163 (0.0100.316) and 0.294 (0.0550.534), respectively];walnuts with working memory [1.191 (0.0612.322)]; and wine with Mini-Mental State Examination scores [0.252 (0.0060.496)]. Urinary polyphenols were associated with better scores in immediate verbal memory [1.208 (0.2362.180)]. Increased consumption of antioxidant-rich foods in general and of polyphenols in particular is associated with better cognitive performance in elderly subjects at high cardiovascular risk. The results reinforce the notion that Mediterranean diet components might counteract age-related cognitive decline.

Prevalence of cognitive disorders in HIV plus patients with long-term suppression of viremia

Background: HAART has contributed to decrease the HIV-related mortality and morbidity. However, the prevalence of HIV-associated neurocognitive disorders (HAND) seems to have increased. The aim of this study was to determine the prevalence of cognitive complaint and of HAND in a cohort of aviremic HIV_patients in the South-western part of Switzerland. Design/Methods: Two hundred HIV_ patients who had (1) undetectable HIV RNA concentrations in the plasma for_3 months, (2) no history of major opportunistic infection of the CNS in the past three years, (3) no current use of IV drugs and (4) no signs of major depression according to the DSM-IV criteria, answered a questionnaire designed to elicit cognitive complaints. Cognitive functions of a subset of HIV_ patients with or without cognitive complaints were assessed using the HIV Dementia scale (HDS) and a battery of neuropsychological tests evaluating the sub-cortical functions. Cognitive impairment was defined according to the revised diagnostic criteria for HAND. Non-parametric tests were used for statistics and a Bonferroni corrected standard p level of pB0.002 was applied for multiple comparisons. Results: The prevalence of cognitive complaints was 27% (54 patients) among the 200 questioned patients. At the time of writing this abstract, cognitive functions of 50 complaining and 28 noncomplaining aviremic patients had been assessed with the HDS and the full neuropsychological battery. The prevalence of HAND producing at least mild interference in daily functioning (mild neurocognitive disorders [MND] or HIV-associated dementia [HAD]) was 44% (34/78 patients) in the group who underwent neuropsychological testing. Objective evidences of HAND were more frequent in complaining than in non-complaining patients (pB0.001). Using a ROC curve, a cut-off of 13 on the HDS was found to have a sensitivity of 74% and a specificity of 71% (p_0.001) for the diagnosis of HAND. A trend for lower CNS Penetrating-Effectiveness scores for HAART in patients with MND or HAD as compared to the others was present (1.59 0.6 vs. 1.990.6; p_0.006 [Bonferroni correction]). Conclusions/Relevance: So far, our results suggest that (1) the prevalence of HAND is high in HIV_ patients with a long-term suppression of viremia, and (2) cognitive complaints expressed by aviremic HIV_ patients should be carefully investigated as they correlate with objective evidences of cognitive decline in a neuropsychological testing. HAART with a high CNS penetrating-effectiveness may contribute to prevent HAND. Funding: Swiss HIV Cohort Study.

Polyphenol-rich foods in the Mediterranean diet are associated with better cognitive function in elderly subjects at high cardiovascular risk

Brain oxidative processes play a major role in age-related cognitive decline, thus consumption of antioxidant-rich foods might help preserve cognition. Our aim was to assess whether consumption of antioxidant-rich foods in the Mediterranean diet relates to cognitive function in the elderly. In asymptomatic subjects at high cardiovascular risk (n = 447; 52% women; age 55-80 y) enrolled in the PREDIMED study, a primary prevention dietary-intervention trial, we assessed food intake and cardiovascular risk profile, determined apolipoprotein E genotype, and used neuropsychological tests to evaluate cognitive function.We also measured urinary polyphenols as an objective biomarker of intake. Associations between energy-adjusted food consumption, urinary polyphenols, and cognitive scores were assessed by multiple linear regression models adjusted for potential confounders. Consumption of some foods was independently related to better cognitive function. The specific associations [regression coefficients (95% confidence intervals)] were: total olive oil with immediate verbal memory [0.755 (0.151-1.358)]; virgin olive oil and coffee with delayed verbal memory [0.163 (0.010-0.316) and 0.294 (0.055-0.534), respectively];walnuts with working memory [1.191 (0.061-2.322)]; and wine with Mini-Mental State Examination scores [0.252 (0.006-0.496)]. Urinary polyphenols were associated with better scores in immediate verbal memory [1.208 (0.236-2.180)]. Increased consumption of antioxidant-rich foods in general and of polyphenols in particular is associated with better cognitive performance in elderly subjects at high cardiovascular risk. The results reinforce the notion that Mediterranean diet components might counteract age-related cognitive decline.

Benzodiazepines and Cognitive Functioning in Older Adults. With Emphasis on Long-Term Use and Withdrawal

Benzodiazepines (BZD) and benzodiazepine related drugs (RD) are the most commonly used psychotropics among the aged. The use of other psychotropics taken concomitantly with BZD/ RD or their cognitive effects with BZD/RD have not been studied frequently. The aim of this academic thesis was to describe and analyse relationships between the use of BZD/RD alone or concomitantly with antipsychotics, antidepressants, opioids, antiepileptics, opioids and anticholinergics in the aged and their health. Especially, the relationships between long-term use of BZD/RD and cognitive decline were studied. Additionally, the effect of melatonin on BZD/RD withdrawal and the cognitive effects of BZD/RD withdrawal were studied. This study used multiple data sets: the first study (I) was based on clinical data containing aged patients (≥65 years; N=164) admitted to Pori City Hospital due to acute disease. The second data set (Studies II and III) was based on population-based data from the Lieto Study, a clinico-epidemiological longitudinal study carried out among the aged (≥65 years) in the municipality of Lieto. Follow-up data was formed by combining the cohort data collected in 1990-1991 (N=1283) and in 1998-1999 (N=1596) from those who participated in both cohorts (N=617). The third data set (Studies IV and V) was based on the Satauni Study’s data. This study was performed in the City of Pori in 2009-2010. In the RCT part of the Satauni Study, ninety-two long-term users of BZD/RD were withdrawn from their drugs using melatonin against placebo. The change of their cognitive abilities was measured during and after BZD/ RD withdrawal. BZD/RD use was related to worse cognitive and functional abilities, and their use may predict worse cognitive outcomes compared with BZD/RD non-users. Hypnotic use of BZD/RD could be withdrawn with psychosocial support in motivated participants, but melatonin did not improve the withdrawal results compared to those with placebo. Cognitive abilities in psychomotor tests did not show, or showed only modest, improvements for up to six months after BZD/RD withdrawal. This suggests that the cognitive effects of BZD/RD may be longlasting or permanent.

Electrocortical indices of cognitive control in working memory : exploring the effects of proactive interference, cognitive load, and aging

Cognitive control involves the ability to flexibly adjust cognitive processing in order to resist interference and promote goal-directed behaviour. Although frontal cortex is considered to be broadly involved in cognitive control, the mechanisms by which frontal brain areas implement control functions are unclear. Furthermore, aging is associated with reductions in the ability to implement control functions and questions remain as to whether unique cortical responses serve a compensatory role in maintaining maximal performance in later years. Described here are three studies in which electrophysiological data were recorded while participants performed modified versions of the standard Sternberg task. The goal was to determine how top-down control is implemented in younger adults and altered in aging. In study I, the effects of frequent stimulus repetition on the interference-related N450 were investigated in a Sternberg task with a small stimulus set (requiring extensive stimulus resampling) and a task with a large stimulus set (requiring no stimulus resampling).The data indicated that constant stimulus res amp ling required by employing small stimulus sets can undercut the effect of proactive interference on the N450. In study 2, younger and older adults were tested in a standard version of the Sternberg task to determine whether the unique frontal positivity, previously shown to predict memory impairment in older adults during a proactive interference task, would be associated with the improved performance when memory recognition could be aided by unambiguous stimulus familiarity. Here, results indicated that the frontal positivity was associated with poorer memory performance, replicating the effect observed in a more cognitively demanding task, and showing that stimulus familiarity does not mediate compensatory cortical activations in older adults. Although the frontal positivity could be interpreted to reflect maladaptive cortical activation, it may also reflect attempts at compensation that fail to fully ameliorate agerelated decline. Furthermore, the frontal positivity may be the result of older adults' reliance on late occurring, controlled processing in contrast to younger adults' ability to identify stimuli at very early stages of processing. In the final study, working memory load was manipulated in the proactive interference Sternberg task in order to investigate whether the N450 reflects simple interference detection, with little need for cognitive resources, or an active conflict resolution mechanism that requires executive resources to implement. Independent component analysis was used to isolate the effect of interference revealing that the canonical N450 was based on two dissociable cognitive control mechanisms: a left frontal negativity that reflects active interference resolution, , but requires executive resources to implement, and a right frontal negativity that reflects global response inhibition that can be relied on when executive resources are minimal but at the cost of a slowed response. Collectively, these studies advance understanding of the factors that influence younger and older adults' ability to satisfy goal-directed behavioural requirements in the face of interference and the effects of age-related cognitive decline.

Cognitive follow up of a small cohort of Huntington's disease patients over a 5 year period

A small group of patients with manifest Huntington's disease (HD) were followed longitudinally to assess cognitive decline in relation to time from disease diagnosis. This article looks at performance on a range of computerised and pencil and paper cognitive tasks in patients 5 years post diagnosis, who were assessed annually for a 5 year follow up period. The almost universal cognitive decline reported in other longitudinal studies of HD was not replicated in this study. It was proposed that longitudinal follow up in HD is complicated by the varying degree to which different tasks are able to withstand repeated administration; a finding which would have significant implications on study design in future trials of cognitive enhansing interventions.

Chronic consumption of flavanone-rich orange juice is associated with cognitive benefits: an 8-wk randomised, double-blind, placebo-controlled trial in healthy older adults

Background: Research indicates that chronic consumption of flavonoids is associated with cognitive benefits in adults with mild cognitive impairment and neurodegenerative disease, although, there has been no such studies in healthy older adults. Furthermore, the effects of commonly consumed orange juice flavanones on cognitive function remain unexplored. Objective: To investigate whether eight weeks of daily flavanone-rich orange juice consumption was beneficial for cognitive function in healthy older adults. Design: High flavanone (HF: 305mg) 100% orange juice and equicaloric low flavanone (LF: 37mg) orange flavored cordial (500ml) were consumed daily for eight weeks by thirty seven healthy older adults (mean age 67 years) according to a crossover, double blind, randomized design separated by a four week washout. Cognitive function, mood and blood pressure were assessed at baseline and follow up with standardized validated tests. Results: Global cognitive function was significantly better following eight week consumption of flavanone-rich juice relative to eight week consumption of the low flavanone control. No significant effects on mood or blood pressure were observed. Conclusions: Chronic daily consumption of flavanone-rich 100% orange juice over eight weeks is beneficial for cognitive function in healthy older adults. The potential for flavanone-rich foods and drinks to attenuate cognitive decline in ageing and the mechanisms which underlie these effects should be investigated.