Clinical Deep Phenotyping of ABCA7 Mutation Carriers

Background and ObjectivesPutative loss-of-function (pLOF) ABCA7 variants that increase Alzheimer disease (AD) risk were identified; however, deep phenotypic characterization of these variants in mutation carriers is limited. We aimed to obtain deep clinical phenotypes of ABCA7 pLOF mutation carriers from a large retrospectively reviewed series.MethodsGenotypes were determined for 5,353 individuals evaluated at Mayo Clinic for 6 reported ABCA7 pLOF variants (p.E709fs, p.Trp1214X, p.L1403fs, c.4416+2T>G, p.E1679X, and c.5570+5G>C). Medical records of 100 mutation carriers were reviewed for demographics, clinical phenotypes, and diagnoses. Eleven mutation carriers had autopsy-based neuropathologic diagnoses.ResultsWe confirmed that ABCA7 pLOF mutations confer AD risk in our series of 2,495 participants with AD and 2,858 cognitively unaffected participants. Clinical review of 100 mutation carriers demonstrated phenotypic variability of clinical presentations with both memory and nonmemory cognitive impairment and a subset presenting with motor symptoms. There was a wide range of age at onset of cognitive symptoms (ages 56–92 years, mean = 75.6). Ten of the 11 autopsied mutation carriers had AD neuropathology. ABCA7 pLOF mutation carriers had higher rates of depression (41.6%) and first-degree relatives with cognitive impairment (38.1%) compared with the general population.DiscussionOur study provides a deep clinical review of phenotypic characteristics of mutation carriers for 6 ABCA7 pLOF mutations. Although memory impairment was the most common initial symptom, nonmemory cognitive and/or motor symptoms were present in a substantial number of mutation carriers, highlighting the heterogeneity of clinical features associated with these mutations. Likewise, although AD neuropathology is the most common, it is not the only autopsy-based diagnosis. Presence of earlier ages at onset, higher rates of depression, and first-degree relatives with cognitive impairment among mutation carriers suggest that these genetic variants may have more aggressive clinical features than AD in the general population. This deep phenotyping study of ABCA7 pLOF mutation carriers provides essential genotype-phenotype correlations for future precision medicine approaches in the clinical setting.

Development of a questionnaire to identify persons with a family history of aneurysmal subarachnoid hemorrhage

Background: Preventive screening for intracranial aneurysms is effective in persons with a positive family history of aneurysmal subarachnoid hemorrhage (aSAH), but for many relatives of aSAH patients, it can be difficult to assess whether their relative had an aSAH or another type of stroke. Aim: We aimed to develop a family history questionnaire for people in the population who believe they have a first-degree relative who had a stroke and to assess its accuracy to identify relatives of aSAH patients. Methods: A questionnaire to distinguish between aSAH and other stroke types (ischemic stroke and intracerebral hemorrhage) was developed by a team of clinicians and consumers. The level of agreement between the questionnaire outcome and medical diagnosis was pilot tested in 30 previously admitted aSAH patients. Next, the sensitivity and specificity of the questionnaire were assessed in 91 first-degree relatives (siblings/children) of previously admitted stroke patients. Results: All 30 aSAH patients were identified by the questionnaire in the pilot study; 29 of 30 first-degree relatives of aSAH patients were correctly identified. The questionnaire had a sensitivity of 97% (95% confidence interval (CI) = 83–100%) and a specificity of 93% (95% CI = 84–98%) when tested in the first-degree relatives of stroke patients. Conclusion: Our questionnaire can help persons to discriminate an aSAH from other types of stroke in their affected relative. This family history questionnaire is developed in the Netherlands but could also be used in other countries after validation.

Polygenic risk, familial liability and stress reactivity in psychosis: an experience sampling study

Background There is evidence for a polygenic contribution to psychosis. One targetable mechanism through which polygenic variation may impact on individuals and interact with the social environment is stress sensitization, characterized by elevated reactivity to minor stressors in daily life. The current study aimed to investigate whether stress reactivity is modified by polygenic risk score for schizophrenia (PRS) in cases with enduring non-affective psychotic disorder, first-degree relatives of cases, and controls. Methods We used the experience sampling method to assess minor stressors, negative affect, positive affect and psychotic experiences in 96 cases, 79 first-degree relatives, i.e. siblings, and 73 controls at wave 3 of the Dutch Genetic Risk and Outcome of Psychosis (GROUP) study. Genome-wide data were collected at baseline to calculate PRS. Results We found that associations of momentary stress with psychotic experiences, but not with negative and positive affect, were modified by PRS and group (all pFWE<0.001). In contrast to our hypotheses, siblings with high PRS reported less intense psychotic experiences in response to momentary stress compared to siblings with low PRS. No differences in magnitude of these associations were observed in cases with high v. low level of PRS. By contrast, controls with high PRS showed more intense psychotic experiences in response to stress compared to those with low PRS. Conclusions This tentatively suggests that polygenic risk may operate in different ways than previously assumed and amplify reactivity to stress in unaffected individuals but operate as a resilience factor in relatives by attenuating their stress reactivity.

Suicidal Ideations in Patients With Obsessive-Compulsive Disorder

Background: There are many controversies about the frequency and burden of suicidality in patients with Obsessive-Compulsive Disorder (OCD). Objectives: This study was done to determine the prevalence and risk factors of current suicidal ideations in patients with OCD. Materials & Methods: In this cross-sectional study, 258 outpatients with OCD (Yale-Brawn Obsessive Compulsive Scale, Y-BOCS ≥16) referring to two psychiatry clinics in Guilan, Iran, from March 2018 to September 2019 were evaluated. Suicidality score of the Brief Psychiatric Rating Scale (BPRS) ≥4 was considered for current suicidal ideation at the first visit. Beck Scale for Suicidal Ideation (BSSI) was used to evaluate the intensity of suicidal ideations a week before evaluation. Simple linear and binary logistic regression analyses were used to analyze data by SPSS v. 20. Results: Current suicidal ideation was found in 22.1% of patients. The previous history of suicide attempt (BPRS, P<0.0001 and BSSI, P<0.0001), a history of OCD in first-degree relatives (BPRS: P=0.004 and BSSI: P=0.010), a history of suicide attempts in first-degree relatives (BPRS: P=0.013 and BSSI: P<0.0001), comorbid diagnosis of depressive or body dysmorphic disorder (BPRS, P<0.0001 and BSSI, P<0.0001), and higher Y-BOCS score (BPRS: P=0.043 and BSSI: P<0.0001) were associated with a higher risk of having suicidal ideation. Conclusion: Suicidal thoughts are high in Iranian patients with OCD at their first visit to psychiatry clinics. The previous suicide history, positive history of OCD and suicide attempts in their first-degree relatives, the severity of OCD, and some comorbid psychological disorders are associated with a higher risk of suicidal ideation among OCD patients.

Atypical Neural Responses of Cognitive Flexibility in Parents of Children With Autism Spectrum Disorder

Impaired cognitive flexibility has been repeatedly demonstrated in autism spectrum disorder (ASD). There is strong evidence for genetic involvement in ASD. First-degree relatives of individuals with ASD may show mild deficits in cognitive inflexibility. The present study investigated cognitive flexibility and its neuroelectrophysiological mechanisms in first-degree relatives of individuals with ASD to assess its potential familiality. Forty-five biological parents of individuals/children with ASD (pASD) and thirty-one biological parents of typically developing individuals/children (pTD), matched by gender, age, and IQ, were enrolled. The broad autism phenotype questionnaire (BAPQ) and cognitive flexibility inventory (CFI) were used to quantitatively assess autistic traits and cognitive flexibility in daily life, respectively. The task-switching paradigm was used to evaluate the behavioral flexibility in a structured assessment situation. Event-related potentials (ERPs) induced by this paradigm were also collected. Results showed that compared with the pTD group, the pASD group had lower CFI scores (t = −2.756, p &lt; 0.01), while both groups showed an equivalent “switch cost” in the task-switching task (p &gt; 0.05). Compared with the pTD group, the pASD group induced greater N2 amplitude at F3, F4, Fz, and C4 (F = 3.223, p &lt; 0.05), while P3 amplitude and latency did not differ between the two groups. In addition, there was a significant negative correlation between the CFI total scores and BAPQ total scores in the pASD group (r = −0.734, p &lt; 0.01). After controlling for age and IQ, the N2 amplitude in the frontal lobe of pASD was negatively correlated with the CFI total scores under the repetition sequence (r = −0.304, p = 0.053). These results indicated that pASD had deficit in cognitive flexibility at the self-reported and neurological levels. The cognitive flexibility difficulties of parents of children with ASD were related to autistic traits. These findings support that cognitive flexibility is most likely a neurocognitive endophenotype of ASD, which is worthy of further investigation.

Insulin Resistance in Type II Diabetes Mellitus Patients and Their First Degree Relatives- An Observational Study

Type II diabetes (T2DM) is caused by environmental, genetic, metabolic, and unknown variables. In diabetics, insulin resistance is the most of prolonged hyperglycemia. T2DM is induced by insulin resistance and cell dysfunction. The interaction of genetics and environment further complicates T2DM development. Insulin resistance and beta cell dysfunction are two of the most common Type 2 Diabetes Mellitus symptoms. A vicious triangle of cell failure (80% cell function) and insulin resistance in the muscles and liver causes major physiological issues. A group of diabetes patients (Group I), non-diabetic first-degree relatives of diabetic patients (Group II), and a non-diabetic healthy control group (Group III) were studied. The diabetes patients had the greatest systolic and diastolic blood pressures, followed by first degree relatives and healthy controls. We found that people with diabetes had higher fasting (FBS) and postprandial sugar, glycated haemoglobin (HbA1c) than diabetic offsprings and control group. Moreover, fasting insulin levels are higher in first degree relatives than in diabetes patients in the control group. The HOMA-IR (Homeostatic Model Assessment of Insulin Resistance) levels of diabetics and their progeny do not differ much. The HOMA-IR measures insulin resistance severity. Common reference levels for HOMA-IR insulin resistance range from 0.7 - 2. Insulin resistance in diabetics and their first-degree relatives is evident from the results.

Long-Term Mortality in Children With Ischemic Stroke: A Nationwide Register-Based Cohort Study

Background and Purpose: Ischemic stroke is a common cause of death in adults, however, mortality after pediatric ischemic stroke is not well explored. We investigate long-term and cause-specific mortality in children with ischemic stroke and their first-degree relatives. Methods: Through nationwide Swedish registers, we identified 1606 individuals <18 years old with ischemic stroke between 1969 and 2016 and their first-degree relatives (n=5714). Each individual with ischemic stroke was compared with 10 reference individuals (controls) matched for age, sex, and county of residence. Our main analysis examined 1327 children with ischemic stroke still alive 1 week after the event. First-degree relatives to children with ischemic stroke were compared with first-degree relatives to the reference individuals. Using a Cox proportional hazard regression model, the risk of overall and cause-specific mortality was computed in individuals with pediatric ischemic stroke and their first-degree relatives. Results: The mortality rate in the first 6 months was 40.1 (95% CI, 24.7–55.6) per 1000 person-years compared with 1.1/1000 in controls (95% CI, 0.3–1.9). The overall mortality risk was hazard ratio (HR)=10.8 (95% CI, 8.1–14.3) and remained elevated beyond 20 years (HR=3.9 [95% CI, 2.1–7.1]). Children with ischemic stroke were at increased risk of death from neurological diseases (HR=29.9 [95% CI, 12.7–70.3]), cardiovascular diseases (HR=6.2 [95% CI, 1.8–22.2]), cancers (HR=6.5 [95% CI, 2.6–15.9]) and endocrine, nutritional and metabolic diseases (HR=49.2 [95% CI, 5.7–420.8]). First-degree relatives to children with ischemic stroke had an increased mortality risk (HR=1.21 [95% CI, 1.05–1.39]), with the highest risk among siblings (HR=1.52 [95% CI, 1.09–2.11]) and relatives to individuals with ischemic stroke >28 days of age (HR=1.23 [95% CI, 1.06–1.42]) compared with the relatives of the controls. Conclusions: Long-term mortality increased after pediatric ischemic stroke, even 20 years later, with neurological diseases as the most frequent cause of death.