Measuring the impact of cognitive and psychosocial interventions in persons with mild cognitive impairment with a randomized single-blind controlled trial: rationale and design of the MEMO+ study.

BACKGROUND: Several studies have suggested that cognitive training is a potentially effective way to improve cognition and postpone cognitive decline in older adults with mild cognitive impairment (MCI). The MEMO+ study is a randomized, controlled, single-blind trial designed to test the efficacy, specificity, and long-term effect of a cognitive training intervention and a psychosocial intervention in persons with MCI. METHODS: One hundred and sixty-two participants with MCI will be recruited. They will be randomized into three groups: cognitive training, psychosocial intervention, and no-contact. Each intervention will last for eight weeks (one session per week) and a booster training session will be provided three months after the end of the intervention. Various proximal and distal outcomes will be measured at pre-intervention as well as at one week, three months, and six months post-training. Proximal outcomes include memory and psychological health measures. Distal outcomes focus on self-rated functioning in complex daily activities and strategies used in daily life to enhance function. Socio-demographic factors (age, gender, and education), general cognition, personality traits, engagement in activities, and self-efficacy will be used as moderators. Enrolment began in April 2012 and will be completed by December 2014. CONCLUSIONS: This study is likely to have a significant impact on the well-being of persons with MCI by contributing to the development of adapted and scientifically supported cognitive and psychosocial interventions.

The profile of executive functioning in amnestic mild cognitive impairment: disproportionate deficits in inhibitory control.

Amnestic mild cognitive impairment (aMCI) represents a group of individuals who are highly likely to develop Alzheimer's disease (AD). Although aMCI is typically conceptualized as involving predominantly deficits in episodic memory, recent studies have demonstrated that deficits in executive functioning may also be present, and thorough categorization of cognitive functioning in MCI may improve early diagnosis and treatment of AD. We first provide an extensive review of neuropsychology studies that examined executive functioning in MCI. We then present data on executive functioning across multiple sub-domains (divided attention, working memory, inhibitory control, verbal fluency, and planning) in 40 aMCI patients (single or multiple domain) and 32 normal elderly controls (NECs). MCI patients performed significantly worse than NECs in all 5 sub-domains, and there was impairment (>1.0 SD below the mean of NECs) in all sub-domains. Impairment on each test was frequent, with 100% of MCI patients exhibiting a deficit in at least one sub-domain of executive functioning. Inhibitory control was the most frequently and severely impaired. These results indicate that executive dysfunction in multiple sub-domains is common in aMCI and highlights the importance of a comprehensive neuropsychological evaluation for fully characterizing the nature and extent of cognitive deficits in MCI.

Training-related brain plasticity in subjects at risk of developing Alzheimer's disease.

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.

Dual-system Involvement: Exploring the Overlap Between Domestic and Family Violence and Child Maltreatment Perpetration.

This longitudinal population-based study aimed to understand the dual-system involvement of males who engage in domestic and family violence (DFV) and child maltreatment perpetration. Specifically, this study investigates the prevalence of male perpetration of DFV, child maltreatment, and dual-system involvement, and compares the frequency and nature of perpetration by males with single-system contact and males with dual-system contact. The effect of race (Indigenous Australian/non-Indigenous Australian) and parental status on dual-system involvement is also examined. This study utilizes data from the Queensland Cross-sector Research Collaboration repository. These data contain each contact an individual male born in 1983 or 1984 had with the Queensland civil court system as a respondent to a domestic violence order (DVO) and the Queensland statutory child protection system, where, after an investigation, they were identified as the person responsible for substantiated harm to a child. The results from the study show a high level of overlap between males who perpetrate DFV and child maltreatment. Of males identified as being responsible for substantiated harm to a child, 58% have also been a respondent of a DVO, and approximately 16% of male DVO respondents were identified as being responsible for substantiated harm to a child. Differences were found in the frequency and nature of perpetration by males with dual-system involvement compared to those with single-system contact for either DFV or child maltreatment. Our results also show differences for Indigenous status, parental status, number of maltreatment events, harm type, number of DVOs, and number of breaches of a DVO. The implications of this study for both policy and practice are discussed.

Exploring dual-system involvement for domestic violence victimisation and child maltreatment perpetration: An exploration by gender and race/ethnicity.

BACKGROUND: There is an historical separation between system responses to domestic violence (DV) and child maltreatment. Concerns have been noted that DV victims may be over-represented as parents responsible for harm to children in the child protection system. Although there is a growing acknowledgement of the high overlap between DV and child maltreatment within families, little empirical research has been conducted on this relationship. OBJECTIVE: This study aims to longitudinally examine the overlap of being a victim of DV and a perpetrator of child maltreatment, along with the impact of dual-system involvement on the nature and frequency of the violence experienced. METHODS: The data are linked longitudinal administrative data from the Queensland Cross-sector Research Collaboration (QCRC) repository. These data contain each contact every individual born in Queensland in 1983 or 1984 had with the Queensland DV civil court system and the Queensland statutory child protection system. RESULTS: Of individuals identified as a perpetrator of child maltreatment, 45% have also been a victim of DV and approximately 22% of DV victims were identified as a perpetrator of child maltreatment. Our results also show differences based on Indigenous status, gender, parental status, number of substantiations, frequency of violence, harm type, and number of domestic violence orders. CONCLUSIONS: There is considerable overlap between individuals who are victims of DV and individuals who perpetrate child maltreatment. This overlap was influenced by both gender and race/ethnicity. The implications of this study for both policy and practice are discussed.

Development and validation of a quality of life measurement scale specific to hereditary hemorrhagic telangiectasia: the QoL-HHT.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) disease is a rare genetic disorder with symptoms and complications that can significantly affect patients' daily lives. To date, no scale has been validated to assess the specific symptoms of this disease on the quality of life (QOL) of HHT patients. This makes it difficult for clinicians to accurately measure the quality of life of patients with HHT. The present study aims to develop and validate a QOL measurement tool specific to HHT disease: the QOL questionnaire in HHT (QoL-HHT). METHODS: A quantitative, non-interventional, multi-center study involving HHT patients in twenty French HHT expert centers was conducted. A calibration sample of 415 HHT patients and a validation sample of 228 HHT patients voluntarily participated in the study. Data were analyzed using exploratory factor analysis (EFA), confirmatory factor analysis (CFA), Exploratory Structural Equation Modeling (ESEM) analyses, reliability analyses, and correlational analyses. RESULTS: The EFA, CFA and ESEM results allowed us to provide evidence of the factorial structure of a questionnaire composed of 24 items measuring 6 domains of QOL: Physical limitations, social relationships, concern about bleeding, relationship with the medical profession, experience of symptoms, and concern about the evolution of the disease. Cronbach's alpha coefficients (> 0.70) demonstrated reliable internal consistency of all the QoL-HHT scores (dimensions). The results of the test-retest provided further evidence of the reliability of the QOL-HHT scores over time. Correlational analyses provided evidence for the convergent validity of the QoL-HHT scores. CONCLUSIONS: We developed a simple and quick self-assessment tool to measure quality of life specific to HHT disease. This study demonstrated reliability and validity of our QoL-HHT scores. It is a very promising tool to evaluate the impact of HHT disease on all aspects of the quality of life of HHT patients in order to offer them individualized medico-psycho-social support. TRIAL REGISTRATION: ClinicalTrials, NCT03695874. Registered 04 October 2018, https://www. CLINICALTRIALS: gov/ct2/show/NCT03695874.

Smart Home Technology: A New Approach for Performance Measurements of Activities of Daily Living and Prediction of Mild Cognitive Impairment in Older Adults.

BACKGROUND: Functional assessment is of paramount importance when mild cognitive impairment is suspected, but common assessment tools such as questionnaires lack sensitivity. An alternative and innovative approach consists in using sensor technology in smart apartments during scenario-based assessments of instrumental activities of daily living (IADL). However, studies that investigate this approach are scarce and the technology used is not always transposable in healthcare settings. OBJECTIVE: To explore whether simple and wireless technology used in two different smart environments could add value to performance and rater-based measures of IADL when it comes to predicting mild cognitive impairment (MCI) in older adults. METHODS: Twenty-six (26) cognitively healthy older adults (CH) and 22 older adults with MCI were recruited. Functional performance in a set of five scripted tasks was evaluated with sensor-based observations (motion, contact, and electric sensors) and performance-based measures (rated with videotapes). The five tasks could be performed in any order and were detailed on an instruction sheet given to participants. RESULTS: Sensor-based observations showed that participants with MCI spent more time in the kitchen and looking into the fridge and kitchen cabinets than CH participants. Moreover, these measures were negatively associated with memory and executive performances of participants and significantly contributed to the prediction of MCI. CONCLUSION: Simple, wireless, and sensor-based technology holds potential for the detection of MCI in older adults as they perform daily tasks. However, some limits are discussed and we offer recommendations to improve the usefulness of this innovative approach.

MEMO+: Efficacy, Durability and Effect of Cognitive Training and Psychosocial Intervention in Individuals with Mild Cognitive Impairment.

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.

Significant contribution of germline BRCA2 rearrangements in male breast cancer families.

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.

Significant contribution of large BRCA1 gene rearrangements in 120 French breast and ovarian cancer families.

Genetic linkage data have shown that alterations of the BRCA1 gene are responsible for the majority of hereditary breast-ovarian cancers. However, BRCA1 germline mutations are found much less frequently than expected, especially as standard PCR-based mutation detection approaches focus on point and small gene alterations. In order to estimate the contribution of large gene rearrangements to the BRCA1 mutation spectrum, we have extensively analysed a series of 120 French breast-ovarian cancer cases. Thirty-eight were previously found carrier of a BRCA1 point mutation, 14 of a BRCA2 point mutation and one case has previously been reported as carrier of a large BRCA1 deletion. The remaining 67 cases were studied using the BRCA1 bar code approach on combed DNA which allows a panoramic view of the BRCA1 region. Three additional rearrangements were detected: a recurrent 23.8 kb deletion of exons 8-13, a 17.2 kb duplication of exons 3-8 and a 8.6 kb duplication of exons 18-20. Thus, in our series, BRCA1 large rearrangements accounted for 3.3% (4/120) of breast-ovarian cancer cases and 9.5% (4/42) of the BRCA1 gene mutation spectrum, suggesting that their screening is an important step that should be now systematically included in genetic testing surveys.

The 5' region of the MSH2 gene involved in hereditary non-polyposis colorectal cancer contains a high density of recombinogenic sequences.

MSH2 rearrangements are involved in approximately 10% of hereditary non-polyposis colorectal cancer (HNPCC) families, and in most of the rearrangements, exon 1 is deleted. We scanned by quantitative multiplex polymerase chain reaction (PCR) of short fluorescent fragments (QMPSF) 200 kb of genomic sequences upstream of the MSH2 transcription initiation site in 21 HNPCC families with exon 1 deletions. This QMPSF scan revealed 12 distinct 5' breakpoints located up to 200 kb upstream of the MSH2 transcription initiation site. Sequencing analysis of the rearranged allele in 17 families revealed that most of the deletions (15/17) resulted from homologous Alu-mediated recombination. QMPSF and sequencing analysis in these 21 families led us to detect the presence of 20 distinct 5' breakpoints. In 14 out of 15 Alu-mediated recombinations, we found, either within the identical region in which the recombination had probably occurred or in its vicinity, the 26-bp Alu core sequence containing the recombinogenic Chi-like motif. Compared to the equivalent regions of other human genes, the MSH2 upstream region was found to contain a high density of Alu repeats (30% within 228 kb and 43% within 50 kb), most of which belong to the old Alu S subfamilies. In conclusion, this study demonstrates the heterogeneity of the breakpoints within the MSH2 upstream region and reveals the remarkable density of recombinogenic Alu sequences in this region.

Study of verbal working memory in patients with Parkinson's disease.

The authors examined the nature of the working memory deficit in persons with Parkinson's disease (PD). Three hypotheses were tested: a limited storage capacity, an impaired executive component, and a reduction of psychomotor speed. Verbal working memory was assessed in 14 PD patients without dementia and 14 matched control participants. Participants were administered a classical verbal span test, working memory tasks that required either updating or manipulation capacities, and motor and psychomotor speed tasks. Patients' performance was comparable to that of control participants on the verbal span test. However, results on the working memory tasks indicated a deficit in manipulation with normal updating capacities. Motor and psychomotor slowing were found in the patient group, but slowing could not fully account for the impairment observed in the manipulation task. Results indicated that there is a genuine but selective working memory impairment in patients with PD.

Value of microsatellite instability typing in detecting hereditary non-polyposis colorectal cancer. A prospective multicentric study by the Association Aquitaine Gastro.

AIM OF THE STUDY: To detect hereditary non-polyposis colorectal cancer (HNPCC) patients with a strategy combining clinical selection (patient age at onset of cancer less than 50 years or family history of HNPCC tumors) and microsatellite instability typing plus immunohistochemistry, leading to mismatch repair (MMR) germline mutation analysis. METHODS: Tumors were screened for microsatellite instability (MSI) and for hmlh1 and hmsh2 immunohistochemical expression. Germline mutation analysis was performed to search for MLH1 and MSH2 mutations in patients with MSI-High and MSI-Low tumors. RESULTS: 197 adenocarcinomas were studied: 164 patients were< or =50 years old, 33 were older than 50 years but had a family history of HNPCC tumors. Fifty tumors (25.4%) were MSI-High, 10 were MSI-Low (5.1%), and 130 were MS-Stable (66%). MSI typing was inconclusive in 7 (3.5%). Immunohistochemistry screening was performed on 165 tumors: sensitivity was 63.6%, specificity was 99%. Germline mutation analysis was performed in 33/60 MSI-High or Low tumors: 23 mutations were noted (70% of the tested patients). CONCLUSION: This proposed strategy of determining microsatellite instability in young colorectal cancer patients or in patients with a family history of HNPCC tumors led to an increased frequency in the detection of MMR germline mutations.

Characterization of a novel loss of function mutation of PAX8 in a familial case of congenital hypothyroidism with in-place, normal-sized thyroid.

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.

Bilateral anophthalmia and oesophageal atresia in a newborn female: a new case of the anophthalmia-oesophageal-genital (AEG) syndrome.

A newborn female is described with bilateral anophthalmia and oesophageal atresia. This is the seventh reported case of the Anophthalmia-Oesophageal-Genital (AEG) syndrome.

Oculo-ectodermal syndrome: a new tumour predisposition syndrome.

We report a new case of oculo-ectodermal syndrome who developed giant cell granulomas of the jaw, similar to the patient previously described by Toriello et al. (1999). We review reported cases to better delineate the clinical spectrum of this rare condition. Giant cell granulomas developing in childhood seem to be part of the oculo-ectodermal syndrome. This condition appears to be a new tumour predisposition syndrome.

Predicting decline in mild cognitive impairment: a prospective cognitive study.

OBJECTIVE: The primary aim of this study was to identify cognitive tests that differentiate between persons with mild cognitive impairment (MCI) who later develop cognitive decline and those who remain stable. METHOD: This study used a prospective longitudinal design. One hundred twenty-two older adults with single-domain or multiple-domain amnestic MCI were recruited from memory clinics. They completed tests to measure baseline episodic memory, working memory, executive functions, perception, and language. They were then followed annually to determine with criteria independent from those tests whether they had remained stable or had developed dementia or significant cognitive decline. This was used as the reference standard to measure diagnostic test accuracy value. RESULTS: ANOVAs indicated that participants with progressive MCI showed more impaired performance than those with stable MCI at baseline on episodic memory (word and story recall), the Brown-Peterson working memory test, object naming, object decision, and position of gap test. Logistic regression derived a significant model with 87.8% overall predictive value. The model included delayed text memory, free recall, naming, orientation match, object decision, and alpha span. Its sensitivity was 86.2% and its specificity was 88.9%. Positive predictive value was 83.3%, and negative predictive value was particularly high at 90.9%. CONCLUSIONS: Identifying individuals with MCI who will progress to dementia or more severe cognitive impairment is a challenge. This study shows that cognitive measures provide valuable information regarding the predictive diagnosis of persons with MCI. Predictive accuracy of a cognitive battery might be optimized by selecting both memory and nonmemory measures.

Cerebral abscesses in hereditary haemorrhagic telangiectasia: a clinical and microbiological evaluation.

OBJECTIVES: Hereditary haemorrhagic telangiectasia (HHT) is a rare autosomal dominant disorder that can lead to neurological manifestations including strokes and cerebral abscesses. Our objectives were to describe clinical, radiological, bacteriological, and outcome characteristics of patients with cerebral abscess and HHT, and to concurrently compare this group with a control group with cerebral abscess, but without HHT. PATIENTS AND METHODS: Patients with HHT and cerebral abscess in 5 French medical centers were included. Their clinical, radiological, biological data and prognosis were compared to the data of unselected patients with cerebral abscesses but without HHT included during the same period of time. RESULTS: Twenty-six patients (13 men and 13 women; 44.7±17.2; range 12-79 years), with HHT and cerebral abscess were included. A pulmonary arteriovenous malformation (AVM) was present in all cases. Cerebral abscesses were solitary, supratentorial, and mostly lobar. In all cases, pathogens were anaerobic or facultative anaerobic germs (particularly streptococcus). No death was observed, but various sequels were present in up to two-thirds of the patients. We observed a recurrence of the cerebral abscess in 4 patients with a mean delay of 81 months. In comparison with the control group, cerebral abscesses were generally of later recurrence and significantly more often unique and less often due to staphylococcus. CONCLUSION: HHT cerebral abscesses are particularly linked to pulmonary arteriovenous malformations and anaerobic germs. Their clinical, radiological and bacteriological characteristics are quite different than in a control group with more solitary brain localizations, no staphylococcus infection and a significantly longer interval to recurrence.

Executive functions in frontotemporal dementia and Lewy body dementia.

Diagnosis of different types of dementia is often based on clinical symptomatology rather than underlying pathology; therefore, accurate diagnosis depends on a thorough description of cognitive functioning in different dementias. Furthermore, direct comparison of cognitive functions between different types of dementia is necessary for differential diagnosis. Executive dysfunction is common in several types of dementia, including frontotemporal dementia (FTD) and Lewy body dementia (LBD); however, FTD and LBD patients have never been directly compared on measures of executive functioning. The authors compared the performance of 17 FTD and 15 LBD patients on 6 measures of executive functioning in terms of statistical group differences, mean severity of clinical impairment in comparison to normal controls, and frequency of impairment. Results indicated a remarkably similar pattern of performance across all areas examined in terms of mean performance, as well as degree and frequency of impairment. Only the Stroop test produced results that could potentially differentiate the patient groups. These findings suggest that both FTD and LBD should be considered disorders involving executive dysfunction.