No abstract

The efficacy of cognitive training was assessed in persons with mild cognitive impairment (MCI) and persons with normal cognitive aging. Forty-seven participants were included in this study: 28 with MCI and 17 controls. Twenty-one participants received intervention (20 MCI and 9 controls) and 16 participants (8 MCI and 8 controls) received no intervention (waiting-list group). The intervention focused on teaching episodic memory strategies. Three tasks of episodic memory (list recall, face-name association, text memory) were used as primary outcome measures. Results were analyzed using analyses of variance. The intervention effect (pre- and post-intervention difference) was significant on two of the primary outcome measures (delayed list recall and face-name association). A significant pre-post-effect was also found on measures of subjective memory and well-being. There was no improvement in the performance of groups of individuals with MCI and normal elderly persons who did not receive the intervention. These results suggest that persons with MCI can improve their performance on episodic memory when provided with cognitive training.

Subjects with mild cognitive impairment are at risk of developing Alzheimer's disease. Cognitive stimulation is an emerging intervention in the field of neurology and allied sciences, having already been shown to improve cognition in subjects with mild cognitive impairment. Yet no studies have attempted to unravel the brain mechanisms that support such improvement. This study uses functional magnetic resonance imaging to measure the effect of memory training on brain activation in older adults with mild cognitive impairment and to assess whether it can reverse the brain changes associated with mild cognitive impairment. Brain activation associated with verbal encoding and retrieval was recorded twice prior to training and once after training. In subjects with mild cognitive impairment, increased activation was found after training within a large network that included the frontal, temporal and parietal areas. Healthy controls showed mostly areas of decreased activation following training. Comparison with pre-training indicated that subjects with mild cognitive impairment used a combination of specialized areas; that is, areas activated prior to training and new alternative areas activated following training. However, only activation of the right inferior parietal lobule, a new area of activation, correlated with performance. Furthermore, the differences between the brain activation patterns of subjects with mild cognitive impairment and those of healthy controls were attenuated by training in a number of brain regions. These results indicate that memory training can result in significant neural changes that are measurable with brain imaging. They also show that the brains of people with mild cognitive impairment remain highly plastic.

Cerebral cavernous malformations (CCM) are hamartomatous vascular malformations characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. They cause seizures and focal neurological deficits due to cerebral hemorrhages. CCM loci have already been assigned to chromosomes 7q (CCM1), 7p (CCM2), and 3q (CCM3) and have been identified in 40%, 20%, and 40%, respectively, of families with CCM. Loss-of-function mutations have been identified in CCM1/KRIT1, the sole CCM gene identified to date. We report here the identification of MGC4607 as the CCM2 gene. We first reduced the size of the CCM2 interval from 22 cM to 7.5 cM by genetic linkage analysis. We then hypothesized that large deletions might be involved in the disorder, as already reported in other hamartomatous conditions, such as tuberous sclerosis or neurofibromatosis. We performed a high-density microsatellite genotyping of this 7.5-cM interval to search for putative null alleles in 30 unrelated families, and we identified, in 2 unrelated families, null alleles that were the result of deletions within a 350-kb interval flanked by markers D7S478 and D7S621. Additional microsatellite and single-nucleotide polymorphism genotyping showed that these two distinct deletions overlapped and that both of the two deleted the first exon of MGC4607, a known gene of unknown function. In both families, one of the two MGC4607 transcripts was not detected. We then identified eight additional point mutations within MGC4607 in eight of the remaining families. One of them led to the alteration of the initiation codon and five of them to a premature termination codon, including one nonsense, one frameshift, and three splice-site mutations. All these mutations cosegregated with the disease in the families and were not observed in 192 control chromosomes. MGC4607 is so far unrelated to any known gene family. Its implication in CCMs strongly suggests that it is a new player in vascular morphogenesis.

Background/Objectives There is no consensus on the efficacy of cognitive training in persons with mild cognitive impairment (MCI) because of the paucity of well‐designed randomized controlled trials. The objective was to assess the effect of memory training on the cognitive functioning of persons with MCI and its durability and to evaluate whether this effect generalizes to daily life and whether positive effects could be obtained from psychosocial intervention. Design Single‐blind randomized controlled trial. Setting Research centers of the Institut Universitaire de Gériatrie de Montréal and Institut Universitaire en Santé Mentale de Québec. Participants Older adults meeting criteria for amnestic MCI (N = 145). Intervention Participants were randomized to cognitive training, a psychosocial intervention, or a no‐contact control condition. Interventions were provided in small groups in eight 2‐hour sessions. Measurement Outcome measures were immediate and delayed composite performance memory scores, psychological health (depression, anxiety, well‐being), and generalization effects of the intervention (strategy use in everyday life, difficulties in complex activities of daily living, memory complaints). Testing was administered before training and immediately, 3 months, and 6 months after training. Results Participants in the cognitive training condition improved on the delayed composite memory score and on strategy use in everyday life. Improvement was maintained at the 3‐ and 6‐month follow‐up assessments. Participants in the psychosocial and no‐contact conditions did not show any significant improvement. Conclusion Cognitive training improves the memory of persons with amnestic MCI. The effect persists over a 6‐month period, and learned strategies are used in everyday life. Cognitive training is a valid way to promote cognition in MCI.

Although screening for large deletions or duplications of the BRCA1 gene is becoming a routine component of the molecular diagnosis of familial breast cancer, little is known about the occurrence of such rearrangements in the BRCA2 gene. Because of the high frequency of BRCA2 mutations in breast cancer families with at least one case of male breast cancer, we selected a cohort of 39 such families, tested negative for mutations in the coding regions of BRCA1 and BRCA2, and developed an assay for BRCA2 rearrangements, based on quantitative multiplex PCR of short fluorescent fragments (QMPSF). We found three rearrangements: (1) a deletion of exons 12 and 13; (2) a duplication of exons 1 and 2; and (3) a complete deletion of BRCA2. We determined the boundaries of the deletion of exons 12 and 13, showing that it resulted from an unequal recombination between Alu sequences. We mapped the complete BRCA2 deletion, which extends over at least 298 kb and showed that it does not affect APRIN/AS3, previously characterized as a tumor suppressor gene, but it comprises several loci corresponding to proven or putative transcripts of unknown functional significance. These data suggest that screening for BRCA2 rearrangements should be done, especially in male breast cancer families tested negative for BRCA1 and BRCA2 mutations.

Diagnostic testing for USH1 is feasible with a high rate of detection and can be made more efficient by selecting a candidate gene by preliminary linkage and haplotype analysis.

Thyroid dysgenesis is the most common cause of congenital hypothyroidism, a relatively frequent disease affecting 1 in 3000-4000 newborns. Whereas most cases are sporadic, mutations in transcription factors implicated in thyroid development have been shown to cause a minority of cases transmitted as monogenic Mendelian diseases. PAX8 is one of these transcription factors, and so far, five mutations have been identified in its paired domain in patients with thyroid dysgenesis. We have identified a novel mutation of PAX8, in the heterozygous state, in a father and his two children both presenting with congenital hypothyroidism associated with an in-place thyroid of normal size at birth. In addition, one of the affected siblings displayed unilateral kidney agenesis. The mutation substitutes a highly conserved serine in position 54 of the DNA-binding domain of the protein (S54G mutation) by a glycine. Functional analyses of the mutant protein (PAX8-S54G) demonstrated that it is unable to bind a specific cis-element of the thyroperoxidase gene promoter in EMSAs and that it has almost completely lost the ability to act in synergy with Titf1 to transactivate transcription from the thyroglobulin promoter/enhancer. These results indicate that loss of function mutations of the PAX8 gene may cause congenital hypothyroidism in the absence of thyroid hypoplasia.