A novel V272D presenilin mutation associated with logopenia, disorientation, and apraxia in an autosomal-dominant Alzheimer's disease family.

In the present study, a novel mutation in the presenilin 1 gene was discovered in an Iraq-native patient with early-onset Alzheimer's disease, who presented with speech impairment and memory decline at age 46 years. Magnetic resonance imaging showed a frontotemporal atrophy. Sanger sequencing identified a heterozygous T to A transversion at position 815 (c.815T>A) in the presenilin 1 gene (PSEN1), resulting in a novel missense mutation at codon 272 from valine to aspartate (V272D). We tested this PSEN1 mutation in vitro and found V272D resulted in an altered Aß42/40 ratio.

Self-reported confusion is related to global and regional ß-amyloid: data from the Women's healthy ageing project.

Disease-modifying treatments for Alzheimer's disease (AD) may require implementation during early stages of ß-amyloid accumulation, well before patients have objective cognitive decline. In this study we aimed to assess the clinical value of subjective cognitive impairment (SCI) by examining the cross-sectional relationship between ß-amyloid load and SCI. Cerebral ß-amyloid and SCI was assessed in a cohort of 112 cognitively normal subjects. Subjective cognition was evaluated using specific questions on memory and cognition and the MAC-Q. Participants had cerebral ß-amyloid load measured with 18F-Florbetaben Positron Emission Tomography (PET). No associations were found between measures of subjective memory impairment and cerebral ß-amyloid. However, by self-reported confusion was predictive of a higher global ß-amyloid burden (p = 0.002), after controlling for confounders. Regional analysis revealed significant associations of confusion with ß-amyloid in the prefrontal region (p = 0.004), posterior cingulate and precuneus cortices (p = 0.004) and the lateral temporal lobes (p = 0.001) after controlling for confounders. An in vivo biomarker for AD pathology was associated with SCI by self-reported confusion on cross-sectional analysis. Whilst there has been a large body of research on SMC, our results indicate more research is needed to explore symptoms of confusion.

Dazed and confused: a molecular genetic approach to everyday cognitive failure.

An individual's susceptibility to everyday cognitive failure constitutes a risk factor for physical and mental health. Different factors such as inefficiency of executive functioning and high trait impulsivity have been shown to affect this susceptibility. Furthermore, twin studies indicate a high heritability of failure susceptibility revealing genetic variables as an important biological influence. We tested for a molecular genetic association between variants on the dopamine D2 receptor gene (DRD2), which relate to executive control and impulsivity, and susceptibility to everyday cognitive failure as assessed by the cognitive failure questionnaire (CFQ) in a sample of N=500 (n=140 male, n=360 female, mean age M=24.62, SD=7.98) healthy participants of central European descent. Moreover, we assessed whether trait impulsivity as measured by the Barratt impulsiveness scale (BIS-11) qualifies as a mediator between DRD2 variants and CFQ scores. We found a positive association between DRD2 variants and the CFQ. This effect was in part yet not completely mediated by trait impulsivity. The DRD2 C/C variant constitutes a protective factor for the susceptibility to everyday cognitive failure. Results point towards at least two biopsychological pathways that may explain the observed effect.

A lifetime of hypercalcemia and hypercalciuria, finally explained.

CONTEXT: Hypercalcemia, hypercalciuria, and recurrent nephrolithiasis are all common clinical problems. This case report illustrates a newly described but possibly not uncommon cause of this presenting complex. OBJECTIVE: We report on a patient studied for over 30 years, with the diagnosis finally made with modern biochemical and genetic tools. DESIGN AND SETTING: This study consists of a case report and review of literature conducted in a University Referral Center. PATIENT AND INTERVENTION: A single patient with hypercalcemia, hypercalciuria, and recurrent nephrolithiasis was treated with low-calcium diet, low vitamin D intake, prednisone, and ketoconazole. MAIN OUTCOME MEASURE: We measured the patient's clinical and biochemical response to interventions above. RESULTS: Calcium absorption measured by dual isotope absorptiometry was elevated at 37.4%. Serum levels of 24,25-dihydroxyvitamin D were very low, as measured in two laboratories (0.62 ng/mL [normal, 3.49 ± 1.57], and 0.18 mg/mL). Genetic analysis of CYP24A1 revealed homozygous mutation E143del previously described. The patient's serum calcium and renal function improved markedly on treatment with ketoconazole but not with prednisone. CONCLUSIONS: Chronic hypercalcemia, hypercalciuria, and/or nephrolithiasis may be caused by mutations in CYP24A1 causing failure to metabolize 1,25-dihydroxyvitamin D.

Frontal motor seizure following non-convulsive status epilepticus in ring chromosome 20 syndrome.

The ring chromosome 20 syndrome is a rare syndrome characterized by intractable epilepsy with particular electro clinical features including episodes of prolonged confusional state and nocturnal frontal lobe seizures. We report a 17-year-old girl who had intractable epilepsy with frontal seizure and prolonged confusional state secondary to non-convulsive status epilepticus. The diagnosis of ring chromosome 20 was suspected and confirmed by karyotype. The cytogenetic study of CHRNA4 and KCNQ2 genes did not detect deletion in the ring chromosome 20. During video-EEG recording, this girl presented a non-convulsive status epilepticus that lasted more than 20 minutes followed by typical frontal lobe seizure. This association was not previously described, and was probably caused by chromosomal instability.

Link between confusional migraine, hemiplegic migraine and episodic ataxia type 2: hypothesis, family genealogy, gene typing and classification.

An association between hemiplegic migraine (HM) and episodic ataxia type 2 (EA2) has been described; both disorders are linked to mutations in the CACNA1A gene. Although confusion occurs in 21% of patients with HM, we found only one case in the literature of confusional episodes associated with ataxia without hemiplegia. These findings raise the possibility of confusional episodes being part of both the HM and EA2 phenotype. However, a patient with episodic ataxia, confusional spells and CACNA1A gene mutations has not been identified. We describe four individuals, spanning three generations of a family, with episodic ataxia without hemiplegia and confusion, in association with a CACNA1A mutation. We follow with a description of the relationship between the CACNA1A mutations and the three syndromes, suggesting a potential need for a new classification in which the conditions can be subsumed.

ApoE epsilon4 is not associated with posictal confusion in patients with mesial temporal lobe epilepsy with hippocampal sclerosis.

A previous report found an association between ApoE isoforms and postictal confusion in medically intractable temporal lobe epilepsy (TLE). We performed a molecular epidemiology study in an independent sample of 77 TLE patients. We failed to replicate the original allelic association between ApoE epsilon4 allele and postictal confusion in our population (chi(2)=1.67; d.f.=1; p=0.2). Thus, the association between ApoE epsilon4 allele and postictal confusion still needs to be fully investigated in different and independent populations.

APOE epsilon4 is associated with postictal confusion in patients with medically refractory temporal lobe epilepsy.

This study examined the relationship between the APOE epsilon4 allele and postictal confusion in patients with medically intractable temporal lobe epilepsy (TLE). Patients with at least one epsilon4 allele (n=22) were three times more likely to exhibit postictal confusion (68%) than the 63 patients without epsilon4 (43%). These preliminary results demonstrate that APOE epsilon4 is associated with an increased risk of postictal confusion in patients with medically intractable TLE, suggesting possible dysfunction in neuronal recovery mechanisms.

Source monitoring for actions in adolescents with 22q11.2 deletion syndrome (22q11DS).

BACKGROUND: Source monitoring consists in identifying the origin of mental events. Recent research suggests that confusions over internally generated mental events may represent a cognitive marker for increased proneness to psychotic symptoms and disorders. We have examined source monitoring for actions in adolescents with the 22q11.2 deletion syndrome (22q11DS), a neurogenetic disease associated with high rates of schizophrenia during adulthood, and expected to observe source monitoring deficits in comparison to IQ-matched and typically developing controls. METHOD: Eighteen adolescents with 22q11DS, 17 adolescents matched for age and IQ, and also 17 adolescents matched for age participated in this study. Our adapted action monitoring paradigm asked subjects to visualize a series of actions in three different conditions: (1) visualize themselves performing the action; (2) visualize the experimenter performing the action; or (3) simply repeat the action statements without visualization of the action performer. RESULTS: The adolescents with 22q11DS performed adequately in terms of recognition (hits), but in comparison to both control groups, they committed more source confusions on correctly recognized items. Further examination revealed that the adolescents were more likely to demonstrate confusions between exterior sources in which the self was not involved. CONCLUSIONS: Source monitoring deficits can be observed in adolescents with 22q11DS, a syndrome putting them at high risk for developing schizophrenia. These deficits are discussed in terms of early cognitive processes associated with genetic risk for schizophrenia.

Apolipoprotein epsilon4 allele and problems with orientation are associated with a persistent decline in cognition in community-dwelling elderly persons.

BACKGROUND: A decline in cognitive test scores in elderly persons can signal the beginning of a descent into dementia or may indicate only a short-term cognitive disturbance. It would be clinically useful to distinguish between the two outcomes and to identify characteristics of each. METHODS: Four hundred thirty-seven community-dwelling elderly persons were given the Mini-Mental State Examination (MMSE) annually for an average of 7 years. A low score between baseline and final MMSE was identified. A low score 3 or more points lower than baseline score indicated cognitive decline. This decline was called persistent if the final MMSE score was also at least 3 points lower than baseline MMSE score; otherwise, the decline was considered transient. RESULTS: Twenty participants (4.6%) experienced a persistent cognitive decline, 67 participants (15.3%) experienced a transient cognitive decline. Presence of the apolipoprotein epsilon4 allele was significantly associated with persistent cognitive decline (age-adjusted odd ratio [OR] = 11.46, p < .0001) but not with transient cognitive decline (age-adjusted OR = 1.53, p = .219). Incorrect answers on the orientation part of the MMSE at the time of cognitive decline was associated with persistent decline compared to transient decline (age-adjusted OR = 3.58, p = .058). CONCLUSIONS: Persistent cognitive decline is an infrequent occurrence in community-dwelling elderly persons. Presence of the epsilon4 allele and errors made by the subject on questions of orientation may be useful in determining whether a cognitive decline is likely to be persistent.

Bipolar mood disorders: an affected sibling study. II. Symptom correlations.

Part II of the affected sibling study raises questions of symptom correlation (incidence of delusions, states of confusion, suicide tendencies and attempts, hallucinatory episodes, hypochondriac attitudes, angry manias, and depressive stupor) in mood disorders. The investigated sample (307 sibling groups, 701 hospitalized patients; selection principle: at least 1 sibling showing a bipolar or manic axial syndrome) directs our attention to the possibility that the multiplicity of specific manic and depressive syndromes derives not only from the genetic complexity of the mood-producing system but mirrors the full range of human behavior. Moods must be conceptualized as interpretative metalanguages with respect to the entire wealth of behavioral object languages.