Clinical phenotypic heterogeneity of Alzheimer's disease associated with mutations of the presenilin–1 gene

It is now 10 years since the first report of mutations in the presenilin genes that were deterministic for familial autosomal dominant Alzheimer's disease. The most common of these mutations occurs in the presenilin–1 gene (PSEN1) located on chromosome 14. In the ensuing decade, more than 100 PSEN1 mutations have been described. The emphasis of these reports has largely been on the novelty of the mutations and their potential pathogenic consequences rather than detailed clinical, neuropsychological, neuroimaging and neuropathological accounts of patients with the mutation. This article reviews the clinical phenotypes of reported PSEN1 mutations, emphasizing their heterogeneity, and suggesting that other factors, both genetic and epigenetic,must contribute to disease phenotype.     

Neocortical β-amyloid area is associated with dementia and APOE in the oldest-old

ObjectiveApolipoprotein E (APOE) ε2 carriers may be protected from dementia because of reduced levels of cortical β-amyloid. In the oldest-old, however, APOE ε2 carriers have high β-amyloid plaque scores and preserved cognition. We compared different measures of β-amyloid pathology across APOE genotypes in the oldest-old, and their relationship with dementia.MethodsThe study included 96 participants from The 90+ Study. Using all information, dementia diagnoses were made. Neuropathological examination included staging for amyloid plaques and β-amyloid cortical percent area stained by NAB228 antibody.ResultsBoth APOE ε2 and APOE ε4 carriers had high Consortium to Establish a Registry for Alzheimer’s Disease plaque scores. However, APOE ε2 carriers had low cortical β-amyloid percent areas. β-amyloid percent area was associated with dementia across APOE genotypes.ConclusionsLower levels of percent area in APOE ε2 carriers may reflect lower total β-amyloid and may contribute to APOE ε2 carriers’ decreased risk of dementia, despite high β-amyloid plaque scores. The relationship between β-amyloid plaques and dementia in the oldest-old may vary by APOE genotype.     

Lysosomal β-galactosidase and β-hexosaminidase activities correlate with clinical stages of dementia associated with Alzheimer's disease and type 2 diabetes mellitus

Multiple epidemiological studies have shown that individuals affected by type-2 diabetes mellitus (T2DM) carry a 2-to-5-fold higher risk of developing Alzheimer's disease (AD) when compared to non-diabetic subjects. Thus, biochemical parameters that can be easily and routinely assessed for high-confidence evaluation of diabetic conditions leading to AD (AD-T2DM) are regarded as efficient tools aimed at early diagnosis and, in turn, timely AD treatment. In this regard, the activity of lysosomal glycohydrolases may of use, in light of the implication of these enzymes in early events that underlie AD pathology and an overt correlation, in diabetes, between altered metabolic homeostasis, abnormal glycohydrolase secretion in body fluids, and occurrence of diabetic complications. Based on marked up-regulation previously shown in a peripheral, cell-based model of AD, we selected β-Galactosidase, β-Hexosaminidase, and α-Mannosidase to discriminate T2DM from AD-T2DM subjects. A screen of 109, 114, and 116 patients with T2DM, AD and AD-T2DM, respectively, was performed by testing enzyme activities in both blood plasma and peripheral blood mononuclear cells. Compared to age-matched, healthy controls (n = 122), β-Galactosidase and β-Hexosaminidase activities markedly diverged across the three groups, whereas virtually unchanged values were observed for α-Mannosidase. In particular, plasma β-Galactosidase and β-Hexosaminidase levels were higher in patients with AD-T2DM compared to those with T2DM, suggesting different mechanisms leading to enzyme secretion. Statistical analyses based on ROC curves showed that both β-Galactosidase and β-Hexosaminidase activities, either intracellular or plasma-secreted, may be used to discriminate AD patients from controls and AD-T2DM from T2DM patients.     

APP mutations in the Aβ coding region are associated with abundant cerebral deposition of Aβ38

A?? is the main component of amyloid deposits in Alzheimer disease (AD) and its aggregation into oligomers, protofibrils and fibrils is considered a seminal event in the pathogenesis of AD. A?? with C-terminus at residue 42 is the most abundant species in parenchymal deposits, whereas A?? with C-terminus at residue 40 predominates in the amyloid of the walls of large vessels. A?? peptides with other C-termini have not yet been thoroughly investigated. We analysed A??38 in the brains of patients with A?? deposition linked to sporadic and familial AD, hereditary cerebral haemorrhage with amyloidosis, or Down syndrome. Immunohistochemistry, confocal microscopy, immunoelectron microscopy, immunoprecipitation and the electrophoresis separation of low molecular weight aggregates revealed that A??38 accumulates consistently in the brains of patients carrying APP mutations in the A?? coding region, but was not detected in the patients with APP mutations outside the A?? domain, in the patients with presenilin mutations or in subjects with Down syndrome. In the patients with sporadic AD, A??38 was absent in the senile plaques, but it was detected only in the vessel walls of a small subset of patients with severe cerebral amyloid angiopathy. Our results suggest that APP mutations in the A?? coding region favour A??38 accumulation in the brain and that the molecular mechanisms of A?? deposition in these patients may be different from those active in patients with familial AD associated with other genetic defects and sporadic AD.     

G-protein β3 subunit 825CC genotype is associated with postprandial distress syndrome with impaired gastric emptying and with the feeling of hunger in Japanese

Background G‐protein dysfunction related alteration of intracellular signal transduction might be linked to various abnormalities of functional gastrointestinal (GI) disorders. Serotonin (5‐hydroxytryptamine; 5‐HT) as well as G‐protein is also key signaling molecule sensorimotor functions in the GI tract. Thus, this study aims to evaluate the correlation between gastric emptying and GNβ3 and 5‐HTs polymorphisms in functional dyspepsia (FD) as defined by Rome III classification. Methods Seventy‐four patients presenting with typical symptoms of FD (epigastric pain syndrome: EPS, n = 24; postprandial distress syndrome: PDS, n = 51) and sixty‐four healthy volunteers were enrolled. Gastric motility was evaluated with the T_max value using the ¹³C‐acetate breath test. We used Rome III criteria to evaluate upper abdominal symptoms and SRQ‐D scores to determine depression status. GNβ3‐C825T, 5‐HT_1A‐C1019G, 5‐HT_2A‐G1438A, 5‐HT_3A‐C42T, and 5‐HT_4A‐G353 + 6A polymorphisms were analyzed in DNA from blood samples of enrolled subjects. Genotyping was performed by polymerase chain reaction. Key Results There was a significant relationship (P = 0.045) between GNβ3 825CC genotype and PDS patients without gastro‐esophageal reflux symptoms with impaired gastric emptying. In Japanese, GNβ3 825CC genotype in FD patients was significantly associated (P = 0.0485) with the feeling of hunger compared with GNβ3 825CT and TT genotypes. Conclusions & Inferences Our results suggest that the GNβ3 825CC genotype is significantly associated with PDS patients without gastro‐esophageal reflux with impairments of gastric emptying and also with the feeling of hunger in patients with FD. Further studies are needed to clarify whether the GNβ3 825CC genotype is linked to disturbances of gastric emptying via altered signal transduction responses.     

Horner''s syndrome associated with Guillain-Barré syndrome

Autonomic dysfunctions are classically described during the acute phase of Guillain-Barré syndrome (GBS). This involvement concerns visceral afferent, parasympathetic and/or sympathetic efferent fibers and is closely related to sudden deaths in the acute phase of the disease. We report a case of a patient suffering from a GBS associated with a transient Horner syndrome without extraocular muscle involvement. Pharmacological tests of the pupils pointed to an orthosympathetic pre-ganglionic disturbance. Neither clinical nor electrophysiological parameter suggested a broader involvement of the autonomic nervous system.     

Meningioma associated with Gorlin’s syndrome

Gorlin’s syndrome or naevoid basal cell carcinoma syndrome is a rare autosominal dominant condition characterised by a variety of congenital anomalies and various malignancies. The chief manifestations include multiple basal cell naevi, mandibular cysts, plantar and palmar pits, vertebral and rib abnormalities and intracranial calcifications. We report a patient with Gorlin’s syndrome associated with meningioma treated at our institution. The clinical and radiological features together with the management strategies of this unusual disease entity are discussed.     

Is COPD associated with suicide behavior?

Background

The goal of this study is to examine the relationship between chronic obstructive pulmonary disease (COPD) and suicidal ideation and suicide attempt among adults in the United States.

Methods

Data were drawn from the National Comorbidity Study-Replication (NCS-R), a household probability sample of adults ages 18 and older in the United States.

Results

COPD is associated with significantly increased odds of suicidal ideation and suicide attempt, compared with those without COPD. The association between COPD and suicide attempt remained statistically significant after adjusting for demographics, depression, panic disorder, substance use and nicotine dependence. The association between COPD and suicidal ideation was no longer significant after adjusting for nicotine dependence.

Conclusions

Our findings provide initial evidence that there is a relationship between COPD and suicidal behavior among adults in the community. Future studies that can examine the relationship between COPD and completed suicide, as well as replication of these results, would improve our understanding of whether and to what degree COPD confers an increased vulnerability for suicide behavior.     

Is parenthood associated with mental health?

BACKGROUND: Despite some reports on a potential link between parenthood and mental health, associations have not been systematically investigated yet. The present article provides prevalence rates of the most common mental disorders for parents and non-parents. Interactions between demographic and socio-economic variables, parental status and mental health are explored. METHODS: Data from the 1998/99 German Health Survey (GHS) and its Mental Health Supplement (GHS-MHS) were analysed using logistic regression models. Analyses were restricted to participants in the age group 18 to 49 (N=2,801). Mental disorders and syndromes were assessed with a standardized diagnostic interview (M-CIDI). RESULTS: Parenthood was associated with lower rates of psychiatric morbidity in general, and depressive and substance use disorders, in particular. The association between parental status and mental health was more distinct in men than in women, whereas partnership status moderated this relationship: An absence of partnership was associated with increased rates of all common mental disorders. Among non-parents, such a difference could not be found. Full-time employment, compared to part-time employment or unemployment, was linked to lower rates of the common mental disorders among fathers but not among mothers and non-parents. Age, education and income had no effects on the association between parental status and mental health. CONCLUSION: Parenthood is positively associated with mental health, particularly for men. Most differences can be found for depressive and substance use disorders. Partnership seems especially important for parents since it does not affect prevalence rates of mental disorders among non-parents.     

Narcolepsy with cataplexy associated with H1N1 vaccination

IntroductionIt has been suggested that the H1N1 vaccine may be a trigger for the onset of narcolepsy-cataplexy, a rare disease whose autoimmune origin is suspected.ObservationsWe report two patients (a 9-year-old boy and an 18-year-old man) with severe narcolepsy-cataplexy, in whom the illness appeared within 3–4 weeks after H1N1 vaccination. In both cases, symptoms developed unusually abruptly and they presented with severe daytime sleepiness and multiple daily cataplexy attacks. Other similar cases have been recently reported associated with H1N1 vaccine.ConclusionAlthough no formal link can be established, the unusual characteristics of the reported cases and the striking temporal relationship suggests that narcolepsy may be the result of an autoimmune reaction triggered by H1N1 vaccination in susceptible individuals.     

Is bipolar disorder specifically associated with aggression?

Ballester J, Goldstein T, Goldstein B, Obreja M, Axelson D, Monk K, Hickey MB, Iyengar S, Farchione T, Kupfer DJ, Brent D, Birmaher B. Is bipolar disorder specifically associated with aggression? Bipolar Disord 2012: 14: 283–290. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objective: Several studies have suggested that bipolar disorder (BP) in adults is associated with aggressive behaviors. However, most studies have included only inpatients and have not taken into consideration possible confounding factors. The goal of the present study was to compare the prevalence of aggression in subjects with BP compared to subjects with other, non‐BP psychopathology and healthy controls. Methods: Subjects with bipolar I disorder (BP‐I) and bipolar II disorder (BP‐II) (n = 255), non‐BP psychopathology (n = 85), and healthy controls (n = 84) were recruited. Aggression was measured using the Aggression Questionnaire (AQ). Group comparisons were adjusted for demographic and clinical differences (e.g., comorbid disorders) and multiple comparisons. The effects of the subtype of BP, current versus past episode, polarity of current episode, psychosis, the presence of irritable mania/hypomania only, and pharmacological treatment were examined. Results: Subjects with BP showed significantly higher total and subscale AQ scores (raw and T‐scores) when compared to subjects with non‐BP psychopathology and healthy controls. Exclusion of subjects with current mood episodes and those with common comorbid disorders yielded similar results. There were no effects of BP subtype, polarity of the current episode, irritable manic/hypomanic episodes only, or current use of pharmacological treatments. Independent of the severity of BP and polarity of the episode, those in a current mood episode showed significantly higher AQ scores than those not in a current mood episode. Subjects with current psychosis showed significantly higher total AQ score, hostility, and anger than those without current psychosis. Conclusions: Subjects with BP display greater rates of anger and aggressive behaviors, especially during acute and psychotic episodes. Early identification and management of these behaviors is warranted.     

Is preeclampsia associated with restless legs syndrome?

ObjectiveRestless legs syndrome (RLS) is a common neurologic disorder. Secondary RLS includes pregnancy and iron deficiency. Prevalence of RLS in pregnancy ranges from 11% to 27%. We aimed to assess the frequency and characteristics of RLS in pregnancy in a Peruvian population and to evaluate the possible pregnancy or delivery complications due to RLS.MethodsWe assessed 218 consecutive expectant mothers at the inpatient clinic of the Hospital San Bartolome in Lima, Peru. Assessment was performed by using the standard diagnostic criteria for RLS and by using a clinical and diagnostic interview. Questionnaires for RLS severity, idiopathic RLS (IRLS), and excessive daytime sleepiness (EDS) according to the Epworth sleepiness scale (ESS) were used. Blood examination was performed for hemoglobin and hematocrit. For comparison, RLS patients were matched for age and body mass index (BMI) with pregnant women without RLS.ResultsOut of 218 patients, 40 (18.4%) fulfilled diagnostic criteria for RLS. In RLS patients, prophylactic iron supplementation therapy during pregnancy was less frequently taken (P = .02). Pregnant women with RLS had a higher ESS score than pregnant controls (10.6 +/− 3.1 vs 7.6. +/− 3.6; P < .001). Preeclampsia was more frequent in RLS (7/40 vs 1/39; P = .03).ConclusionsIn our study, RLS was frequent in pregnant Peruvian women, especially in those without prophylactic iron supplementation. RLS patients described more EDS. Preeclampsia was more common in RLS. Our study is the first study to indicate a possible association between RLS and preeclampsia.