Effectiveness of a Visual Imagery Training Program to Improve Prospective Memory in Older Adults with and without Mild Cognitive Impairment: A Randomized Controlled Study.

Prospective memory (PM) problems in aging and, to a greater extent, in mild cognitive impairment (MCI), compromise functional independence. This study examined the effectiveness of a cognitive training program based on visual imagery to improve PM among older adults with and without MCI. Participants were older adults, 24 with MCI and 24 cognitively healthy (HOA). Half of them (12 MCI and 12 HOA) were randomly assigned to the PM training program, the other half to the no-training control group. All participants also completed a pre- and post-test evaluation, including neuropsychological tests, questionnaires, and the Ecological Test of Prospective Memory (TEMP). There was no significant effect of the intervention on the TEMP total, event-based or time-based scores for either the MCI or HOA groups. However, the trained MCI group committed fewer false alarms (i.e., more efficient identification of prospective cues) in the event-based condition of the TEMP at post-test. On the other hand, all trained participants performed better than control participants on retrospective memory tests, which suggests that visual imagery-based training is more effective to improve retrospective memory than PM. Possible explanations for these results are explored.

Higher cardiovascular fitness level is associated to better cognitive dual-task performance in Master Athletes: Mediation by cardiac autonomic control.

INTRODUCTION/PURPOSE: This study compared cognitive performances and cardiac autonomic measures of higher fit and lower fit middle-aged and older highly active adults. The working hypotheses were that higher fit (master athletes) would show cognitive benefits in executive control conditions due to a high level of fitness compared to lower fit people and that this effect would be mediated by better cardiac autonomic adaptations in athletes. METHODS: We recruited 39 highly active middle aged and older adults from Master Athletes' organizations. All participants performed a Rockport walking test and a computerized dual-task. Cardiac autonomic control was assessed with a measure of heart rate variability. Based on the V̇O2max estimated by the Rockport test, a median split was performed to assess the influence of fitness level on cognitive performance and the link with heart rate variability. Those with the highest fitness level were considered Master Athletes. RESULTS: Master Athletes showed better dual-task performances than lower fit individuals. A positive relationship between the V̇O2max and dual-task performances was also observed. Master Athletes demonstrated a lower resting HR and higher RR interval than lower fit individuals, and this index was specifically related to the executive conditions of the dual task. CONCLUSION: Our results highlight the role of fitness level on executive function in highly active middle aged and older adults and suggest that the better performances observed in highly fit individuals is mediated by cardiac autonomic control.

The relationship between exercise intensity, cerebral oxygenation and cognitive performance in young adults.

PURPOSE: To assess the relationship between exercise intensity, cerebral HbO2 and cognitive performance (Executive and non-Executive) in young adults. METHODS: We measured reaction time (RT) and accuracy, during a computerized Stroop task, in 19 young adults (7 males and 12 females). Their mean ± SD age, height, body mass and body mass index (BMI) were 24 ± 4 years, 1.67 ± 0.07 m, 72 ± 14 kg and 25 ± 3 kg m(-2), respectively. Each subject performed the Stroop task at rest and during cycling at exercise of low intensity [40% of peak power output (PPO)], moderate intensity (60% of PPO) and high intensity (85% of PPO). Cerebral oxygenation was monitored during the resting and exercise conditions over the prefrontal cortex (PFC) using near-infrared spectroscopy (NIRS). RESULTS: High-intensity exercise slowed RT in both the Naming (p = 0.04) and the Executive condition (p = 0.04). The analysis also revealed that high-intensity exercise was associated with a decreased accuracy when compared to low-intensity exercise (p = 0.021). Neuroimaging results confirm a decrease of cerebral oxygenation during high-intensity exercise in comparison to low- (p = 0.004) and moderate-intensity exercise (p = 0.003). Correlations revealed that a lower cerebral HbO2 in the prefrontal cortex was associated with slower RT in the Executive condition only (p = 0.04, g = -0.72). CONCLUSION: Results of the present study suggest that low to moderate exercise intensity does not alter Executive functioning, but that exercise impairs cognitive functions (Executive and non-Executive) when the physical workload becomes heavy. The cerebral HbO2 correlation suggests that a lower availability of HbO2 was associated with slower RT in the Executive condition only.

Fitness level moderates executive control disruption during exercise regardless of age.

The purpose of this study was to assess the effects of exercise intensity, age, and fitness levels on executive and nonexecutive cognitive tasks during exercise. Participants completed a computerized modified-Stroop task (including denomination, inhibition, and switching conditions) while pedaling on a cycle ergometer at 40%, 60%, and 80% of peak power output (PPO). We showed that a bout of moderate-intensity (60% PPO) to high-intensity (80% PPO) exercise was associated with deleterious performance in the executive component of the computerized modified-Stroop task (i.e., switching condition), especially in lower-fit individuals (p < .01). Age did not have an effect on the relationship between acute cardiovascular exercise and cognition. Acute exercise can momentarily impair executive control equivalently in younger and older adults, but individual's fitness level moderates this relation.

Clinical heterogeneity and a high proportion of novel mutations in a Chinese cohort of patients with dysferlinopathy.

BACKGROUND AND AIMS: Dysferlinopathies are a group of autosomal recessive muscular dystrophies caused by mutations in the dysferlin gene. This study presents clinical features and the mutational spectrum in the largest cohort of Chinese patients analyzed to date. PATIENTS AND METHODS: A total of 36 unrelated Chinese patients with diagnostic suspicion of dysferlinopathy were clinically and genetically characterized. RESULTS: Patients were divided into five phenotypes: 19 patients with limb girdle muscular dystrophy (LGMD) type 2B, 10 with Miyoshi myopathy (MM), 1 with distal anterior compartment myopathy (DACM), 3 with exercise intolerance, and 3 with asymptomatic hypercreatine phosphokinasemia (hyperCPKemia). Thirty-one patients showed an absence or drastic reduction of dysferlin expression by Westernblot. Forty-three mutations were identified in DYSF, including 31 novel. CONCLUSION: Our study underlines clinical heterogeneity and a high proportion of novel mutations in Chinese patients affected with dysferlinopathy.

Decline in executive control during acute bouts of exercise as a function of exercise intensity and fitness level.

Studies on the effects of acute bouts of cardiovascular exercise on cognitive performances show contradictory findings due to methodological differences (e.g., exercise intensity, cognitive function assessed, participants' aerobic fitness level, etc.). The present study assessed the acute effect of exercise intensity on cognition while controlling for key methodological confounds. Thirty-seven participants (M(age)=23. 8 years; SD=2.6) completed a computerized modified-Stroop task (involving denomination, inhibition and switching conditions) while pedalling at 40%, 60% and 80% of their peak power output (PPO). Results showed that in the switching condition of the task, error rates increased as a function of exercise intensity (from 60% to 80% of PPO) in all participants and that lower fit individuals showed increased reaction time variability. This suggests that acute bouts of cardiovascular exercise can momentarily alter executive control and increase performance instability in lower fit individuals.

UMD-DYSF, a novel locus specific database for the compilation and interactive analysis of mutations in the dysferlin gene.

Mutations in the dysferlin gene (DYSF) lead to a complete or partial absence of the dysferlin protein in skeletal muscles and are at the origin of dysferlinopathies, a heterogeneous group of rare autosomal recessive inherited neuromuscular disorders. As a step towards a better understanding of the DYSF mutational spectrum, and towards possible inclusion of patients in future therapeutic clinical trials, we set up the Universal Mutation Database for Dysferlin (UMD-DYSF), a Locus-Specific Database developed with the UMD® software. The main objective of UMD-DYSF is to provide an updated compilation of mutational data and relevant interactive tools for the analysis of DYSF sequence variants, for diagnostic and research purposes. In particular, specific algorithms can facilitate the interpretation of newly identified intronic, missense- or isosemantic-exonic sequence variants, a problem encountered recurrently during genetic diagnosis in dysferlinopathies. UMD-DYSF v1.0 is freely accessible at www.umd.be/DYSF/. It contains a total of 742 mutational entries corresponding to 266 different disease-causing mutations identified in 558 patients worldwide diagnosed with dysferlinopathy. This article presents for the first time a comprehensive analysis of the dysferlin mutational spectrum based on all compiled DYSF disease-causing mutations reported in the literature to date, and using the main bioinformatics tools offered in UMD-DYSF.

Characterization of prospective memory in mild cognitive impairment by using the Ecological test of Prospective Memory.

The objective of this study was to explore the exact nature, extent, and cognitive correlates of prospective memory deficits in mild cognitive impairment (MCI) by using the Ecological Test of Prospective Memory (TEMP). Twenty-five MCI participants and 25 healthy older adults (HOA) performed the TEMP, the Envelope Task, the Comprehensive Assessment of Prospective Memory (CAPM), and a neuropsychological test battery. Results showed that, during the TEMP, MCI participants had difficulty detecting the moment to perform the intentions in the time-based condition (prospective component) and retrieving the associated actions in the event- and time-based conditions (retrospective component). The prospective component of the event-based condition was correlated with retrospective memory, whereas the prospective component of the time-based condition was correlated with executive functions. Finally, the TEMP yielded good sensitivity and specificity for discriminating between MCI and HOA, contrary to the Envelope Task and the CAPM.

Analysis of the DYSF mutational spectrum in a large cohort of patients.

Dysferlinopathies belong to the heterogeneous group of autosomal recessive muscular dystrophies. Mutations in the gene encoding dysferlin (DYSF) lead to distinct phenotypes, mainly Limb Girdle Muscular Dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM). Here, we analysed the mutational data from the largest cohort described to date, a cohort of 134 patients, included based on clinical suspicion of primary dysferlinopathy and/or dysferlin protein deficiency identified on muscle biopsy samples. Data were compiled from 38 patients previously screened for mutations in our laboratory (Nguyen, et al., 2005; Nguyen, et al., 2007), and 96 supplementary patients screened for DYSF mutations using genomic DHPLC analysis, and subsequent sequencing of detected variants, in a routine diagnostic setting. In 89 (66%) out of 134 patients, molecular analysis identified two disease causing mutations, confirming the diagnosis of primary Dysferlinopathy on a genetic basis. Furthermore, one mutation was identified in 30 patients, without identification of a second deleterious allele. We are currently developing complementary analysis for patients in whom only one or no disease-causing allele could be identified using the genomic screening procedure. Altogether, 64 novel mutations have been identified in this cohort, which corresponds to approximately 25% of all DYSF mutations reported to date. The mutational spectrum of this cohort significantly shows a higher proportion of nonsense mutations, but a lower proportion of deleterious missense changes as compared to previous series. (c) 2008 Wiley-Liss, Inc.

Phenotypic study in 40 patients with dysferlin gene mutations: high frequency of atypical phenotypes.

OBJECTIVE: To describe the phenotypic spectrum of dysferlin (DYSF) gene mutations (which cause dysferlinopathies, autosomal recessive muscular dystrophies) in patients with a dysferlin protein deficiency. DESIGN: Clinical, biological, and pathological data from 40 patients were reviewed. The diagnosis of dysferlinopathy was based on the absence or strong reduction of dysferlin in muscle, and confirmed by mutational screening of the DYSF gene. SETTING: Two French neuromuscular diseases centers (in Paris and Marseilles). RESULTS: Two main dysferlinopathy phenotypes are well recognized: Miyoshi myopathy and limb-girdle muscular dystrophy type 2B. Typical Miyoshi myopathy and limb-girdle muscular dystrophy type 2B were found in 20 (50%) patients only. Unusual phenotypes included a mixed phenotype, referred to as "proximodistal," combining distal and proximal onset in 14 (35%) patients, pseudometabolic myopathy in 4 (10%), and asymptomatic hyperCKemia (an increased serum creatine kinase level) in 2 (5%). The disease may worsen rapidly, and 10 (25%) patients were initially misdiagnosed as having polymyositis. We suggest a relationship between proximodistal phenotype, inflammation, and severity. CONCLUSION: In addition to typical Miyoshi myopathy and limb-girdle muscular dystrophy type 2B, dysferlinopathies are a clinically heterogeneous group of disorders ranging from asymptomatism to severe functional disability.

Cognitive function in patients with stable coronary heart disease: Related cerebrovascular and cardiovascular responses.

Chronic exercise has been shown to prevent or slow age-related decline in cognitive functions in otherwise healthy, asymptomatic individuals. We sought to assess cognitive function in a stable coronary heart disease (CHD) sample and its relationship to cerebral oxygenation-perfusion, cardiac hemodynamic responses, and [Formula: see text] peak compared to age-matched and young healthy control subjects. Twenty-two young healthy controls (YHC), 20 age-matched old healthy controls (OHC) and 25 patients with stable CHD were recruited. Cognitive function assessment included short term-working memory, perceptual abilities, processing speed, cognitive inhibition and flexibility and long-term verbal memory. Maximal cardiopulmonary function (gas exchange analysis), cardiac hemodynamic (impedance cardiography) and left frontal cerebral oxygenation-perfusion (near-infra red spectroscopy) were measured during and after a maximal incremental ergocycle test. Compared to OHC and CHD, YHC had higher [Formula: see text] peak, maximal cardiac index (CI max), cerebral oxygenation-perfusion (ΔO2 Hb, ΔtHb: exercise and recovery) and cognitive function (for all items) (P<0.05). Compared to OHC, CHD patients had lower [Formula: see text] peak, CI max, cerebral oxygenation-perfusion (during recovery) and short term-working memory, processing speed, cognitive inhibition and flexibility and long-term verbal memory (P<0.05). [Formula: see text] peak and CI max were related to exercise cerebral oxygenation-perfusion and cognitive function (P<0.005). Cerebral oxygenation-perfusion (exercise) was related to cognitive function (P<0.005). Stable CHD patients have a worse cognitive function, a similar cerebral oxygenation/perfusion during exercise but reduced one during recovery vs. their aged-matched healthy counterparts. In the all sample, cognitive functions correlated with [Formula: see text] peak, CI max and cerebral oxygenation-perfusion.

Cerebral Hemodynamics During Exercise and Recovery in Heart Transplant Recipients.

BACKGROUND: The aims of this work were (1) to compare cerebral oxygenation-perfusion (COP), central hemodynamics, and peak oxygen uptake (V˙o2peak) in heart transplant recipients (HTRs) vs age-matched healthy controls (AMHCs) during exercise and recovery and (2) to study the relationships between COP, central hemodynamics, and V˙o2peak in HTRs and AMHCs. METHODS: Twenty-six HTRs (3 women) and 27 AMHCs (5 women) were recruited. Maximal cardiopulmonary function (gas exchange analysis), cardiac hemodynamics (impedance cardiography), and left frontal COP (near-infrared spectroscopy) were measured continuously during and after a maximal ergocycle (Ergoline 800S, Bitz, Germany) test. RESULTS: Compared with AMHCs, HTRs had lower V˙o2peak, maximal cardiac index (CImax), and maximal ventilatory variables (P < 0.05). COP was lower during exercise (oxyhemoglobin [ΔO2Hb], 50% and 75% of V˙O2peak, total hemoglobin [ΔtHb], 100% of V˙O2peak; P < 0.05), and recovery in HTRs (ΔO2Hb, minutes 2-5; ΔtHb, minutes 1-5; P < 0.05) compared with AMHCs. End-tidal pressure of CO2 was lower during exercise compared with that in AMHCs (P < 0.0001). In HTRs, CImax was positively correlated with exercise cerebral hemodynamics (R = 0.54-0.60; P < 0.01). CONCLUSIONS: In HTRs, COP was reduced during exercise and recovery compared with that in AMHCs, potentially because of a combination of blunted cerebral vasodilation by CO2, cerebrovascular dysfunction, reduced cardiac function, and medication. The impaired V˙O2peak observed in HTRs was mainly caused by reduced maximal ventilation and CI. In HTRs, COP is impaired and is correlated with cardiac function, potentially impacting cognitive function. Therefore, we need to study which interventions (eg, exercise training) are most effective for improving or normalizing (or both) COP during and after exercise in HTRs.

Dysferlin mutations in LGMD2B, Miyoshi myopathy, and atypical dysferlinopathies.

DYSF encoding dysferlin is mutated in Miyoshi myopathy and Limb-Girdle Muscular Dystrophy type 2B, the two main phenotypes recognized in dysferlinopathies. Dysferlin deficiency in muscle is the most relevant feature for the diagnosis of dysferlinopathy and prompts the search for mutations in DYSF. DYSF, located on chromosome 2p13, contains 55 coding exons and spans 150 kb of genomic DNA. We performed a genomic analysis of the DYSF coding sequence in 34 unrelated patients from various ethnic origins. All patients showed an absence or drastic decrease of dysferlin expression in muscle. A primary screening of DYSF using SSCP or dHPLC of PCR products of each of 55 exons of the gene was followed by sequencing whenever a sequence variation was detected. All together, 54 sequence variations were identified in DYSF, 50 of which predicting either a truncated protein or one amino-acid substitution and most of them (34 out of 54) being novel. In 23 patients, we identified two pathogenic mutations, while only one was identified in 11 patients. These mutations were widely spread in the coding sequence of the gene without any mutational "hotspot."

Dysferlinopathy in Iran: Clinical and genetic report.

BACKGROUND: Dysferlinopathy is caused by a very wide range of autosomal recessively inherited mutations of the Dysferlin gene. It causes a spectrum of muscle diseases including limb-girdle muscular dystrophy (LGMD) 2B and Miyoshi myopathy (MM). We describe the clinical course and mutational analyses of 15 Iranian patients with dysferlinopathy from 9 different families. METHODS: Genomic DNA was extracted from peripheral blood and 55 exons and flanking intronic boundaries of the dysferlin gene (DYSF; NM_003494.2) were screened for mutations and analyzed. RESULTS: From 15 studied patients in 9 families, 5 patients were male. Seven families had consanguineous marriage. Median age of onset was 16.8; and the median age of diagnosis was 26.6. The onset was clearly distal in 7 patients, and proximal in 6 patients. Three patients had partial biceps atrophy and 13 showed prominent calf muscle wasting. Foot plantar flexors, deep finger flexors and hip adductors were predominantly involved. Genetic testing showed homozygous mutation of dysferlin gene in 9 probands, 5 of which were not previously reported. CONCLUSION: This work, in fact, may help shed some light on the pattern of this morbidity in Iran, an effort that may have not been attempted so far.

Novel ancestral Dysferlin splicing mutation which migrated from the Iberian peninsula to South America.

Primary dysferlinopathies are a group of recessive heterogeneous muscular dystrophies. The most common clinical presentations are Miyoshi myopathy and LGMD2B. Additional presentations range from isolated hyperCKemia to severe functional disability. Symptomatology begins in the posterior muscle compartment of the calf and its clinical course progresses slowly in Miyoshi myopathy whereas LGMD2B involves predominantly the proximal muscles of the lower limbs. The age of onset ranges from 13 to 60years in Caucasians. We present five patients that carry a novel mutation in the exon12/intron12 boundary: c.1180_1180+7delAGTGCGTG (r.1054_1284del). We provide evidence of a founder effect due to a common ancestral origin of this mutation, detected in heterozygosity in four patients and in homozygosity in one patient.

Exclusion of mutations in the dysferlin alternative exons 1 of DYSF-v1, 5a, and 40a in a cohort of 26 patients.

Mutations in the gene encoding dysferlin (DYSF; MIM# 603009, 2p13, GenBank NM_003494.2) cause primary dysferlinopathies, which are autosomal recessive muscular dystrophies. DYSF has a large mutational spectrum, and genetic diagnosis is complicated by incomplete mutation detection rates. Recently, novel dysferlin transcripts were characterized by identifying alternative exons 1 of DYSF-v1 (GenBank DQ267935), exon 5a (GenBank DQ976379), and exon 40a (GenBank EF015906). To evaluate the frequency of possible mutations in the newly identified DYSF alternative exons, we screened the corresponding genomic regions for mutations in a cohort of 26 patients, carrying only one mutation undoubtedly considered as disease causing in the 55 canonical DYSF exons. No disease-causing mutation was identified in alternative exons 1 of DYSF-v1, exon 5a, and exon 40a, demonstrating a low frequency of disease-causing mutations in these exons.

A naturally occurring human minidysferlin protein repairs sarcolemmal lesions in a mouse model of dysferlinopathy.

Dysferlinopathies are autosomal recessive, progressive muscle dystrophies caused by mutations in DYSF, leading to a loss or a severe reduction of dysferlin, a key protein in sarcolemmal repair. Currently, no etiological treatment is available for patients affected with dysferlinopathy. As for other muscular dystrophies, gene therapy approaches based on recombinant adeno-associated virus (rAAV) vectors are promising options. However, because dysferlin messenger RNA is far above the natural packaging size of rAAV, full-length dysferlin gene transfer would be problematic. In a patient presenting with a late-onset moderate dysferlinopathy, we identified a large homozygous deletion, leading to the production of a natural "minidysferlin" protein. Using rAAV-mediated gene transfer into muscle, we demonstrated targeting of the minidysferlin to the muscle membrane and efficient repair of sarcolemmal lesions in a mouse model of dysferlinopathy. Thus, as previously demonstrated in the case of dystrophin, a deletion mutant of the dysferlin gene is also functional, suggesting that dysferlin's structure is modular. This minidysferlin protein could be used as part of a therapeutic strategy for patients affected with dysferlinopathies.