Annalisa Davin

SOD1 mRNA expression in sporadic amyotrophic lateral sclerosis

The mutated Cu,Zn-superoxide dismutase gene (SOD1) (E.C. No. 1.15.1.1) is generally recognized as a pathological cause of 20% of the familial form of Amyotrophic Lateral Sclerosis (ALS). However, several pieces of evidence also show that wild-type SOD1, under conditions of cellular stress, is implicated in a significant fraction of sporadic ALS cases, which represent 90% of ALS patients. Herein, we describe an abnormally high level of SOD1 transcript in spinal cord, brain stem and lymphocytes of sporadic ALS patients. Protein expression studies show a similar or lower amount of SOD1 in affected brain areas and lymphocytes, respectively. No differences are found in brain regions (cerebellum and non-motor cerebral cortex) not involved in the ALS neurodegenerative processes. In this report, cell and disease specificity are shown since no mRNA SOD1 increase is observed in sporadic ALS fibroblasts or in lymphocytes of patients affected by Alzheimers disease. These findings provide new insight and understanding of the pathologic causes of sporadic forms of ALS and allow a possible explanation for the molecular involvement of wild-type SOD1.

The Prevalence of Mild Cognitive Impairment in Diverse Geographical and Ethnocultural Regions: The COSMIC Collaboration

Background Changes in criteria and differences in populations studied and methodology have produced a wide range of prevalence estimates for mild cognitive impairment (MCI). Methods Uniform criteria were applied to harmonized data from 11 studies from USA, Europe, Asia and Australia, and MCI prevalence estimates determined using three separate definitions of cognitive impairment. Results The published range of MCI prevalence estimates was 5.0%–36.7%. This was reduced with all cognitive impairment definitions: performance in the bottom 6.681% (3.2%–10.8%); Clinical Dementia Rating of 0.5 (1.8%–14.9%); Mini-Mental State Examination score of 24–27 (2.1%–20.7%). Prevalences using the first definition were 5.9% overall, and increased with age (P < .001) but were unaffected by sex or the main races/ethnicities investigated (Whites and Chinese). Not completing high school increased the likelihood of MCI (P ≤ .01). Conclusion Applying uniform criteria to harmonized data greatly reduced the variation in MCI prevalence internationally.

The SIRT2 polymorphism rs10410544 and risk of Alzheimer’s disease in two Caucasian case–control cohorts

Human sirtuins are a current hotspot for research in neurodegenerative disorders, including Alzheimers disease (AD). This study investigated whether genetic variants in two members of the sirtuin family, SIRT2 and SIRT3, affected AD susceptibility.

G93A SOD1 alters cell cycle in a cellular model of Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative multifactorial disease characterized, like other diseases such as Alzheimers disease (AD), Parkinsons disease (PD) or frontotemporal dementia (FTD), by the degeneration of specific neuronal cell populations. Motor neuron loss is distinctive of ALS. However, the causes of onset and progression of motor neuron death are still largely unknown. In about 2% of all cases, mutations in the gene encoding for the Cu/Zn superoxide dismutase (SOD1) are implicated in the disease. Several alterations in the expression or activation of cell cycle proteins have been described in the neurodegenerative diseases and related to cell death. In this work we show that mutant SOD1 can alter cell cycle in a cellular model of ALS. Our findings suggest that modifications in the cell cycle progression could be due to an increased interaction between mutant G93A SOD1 and Bcl-2 through the cyclins regulator p27. As previously described in post mitotic neurons, cell cycle alterations could fatally lead to cell death.

Comparison of three methods for genotyping of prothrombotic polymorphisms

Several methods have been developed to detect common prothrombotic mutations, including factor V Leiden (G1691), prothrombin G20210A, and methylenetetrahydrofolate reductase (MTHFR) C677C. In this study, we compared the accuracy of three different molecular techniques, i.e.: (1) restriction enzyme digestion (RFLP), (2) real time with hybridization probes and final melting curve (Fluorescence Resonance Energy Transfer, FRET), and (3) real time with hydrolysis probes (TaqMan®). Sequencing was used as the reference standard. Our data showed that RFLPs analysis for the detection of prothrombotic mutations, albeit easy-to-perform, had a limited reliability for assessing correct genotypes. FRET analysis displayed higher resolution than RFLPs. Additionally, FRET analysis was faster and less tedious than sequencing.

Serotonin transporter polymorphism modifies the association between depressive symptoms and sleep onset latency complaint in elderly people: results from the ‘InveCe.Ab’ study

Previous studies have documented the involvement of the central nervous system serotonin in promoting wakefulness. There are few and conflicting results over whether there is an actual association between bearing the short allele of serotonin transporter promoter polymorphism (5‐HTTLPR) and worse sleep quality. This study examined whether sleep onset latency complaint is associated with the 5‐HTTLPR triallelic polymorphism in the SLC6A4 gene promoter and whether this polymorphism influences the relationship between sleep onset latency complaint and depressive symptoms in elderly people. A total of 1321 community‐dwelling individuals aged 70–74 years were interviewed for sleep onset latency complaint and for sleep medication consumption. Participants’ genomic DNA was typed for 5‐HTTLPR and rs25531 polymorphisms. Depressive symptoms were evaluated with the Geriatric Depression Scale Short form and general medical comorbidity was assessed by the Cumulative Illness Rating Scale. The presence of a past history of depression was recorded. The S′ allele of the 5‐HTTLPR triallelic polymorphism was associated with sleep onset latency complaint. This association was maintained after adjusting for depressive symptoms, sex, age, history of depression and medical comorbidity. After stratification for 5‐HTTLPR/rs25531, only in S′S′ individuals high depressive symptoms were actually associated with sleep onset latency complaint. These data indicate that the low‐expressing 5‐HTTLPR triallelic polymorphism is an independent risk factor for sleep onset latency disturbance. Furthermore, the 5‐HTTLPR genotype influences the association between depressive symptoms and sleep onset latency complaint.

Flavin-Containing Monooxygenase mRNA Levels are Up-Regulated in ALS Brain Areas in SOD1-Mutant Mice

Flavin-containing monooxygenases (FMOs) are a family of microsomal enzymes involved in the oxygenation of a variety of nucleophilic heteroatom-containing xenobiotics. Recent results have pointed to a relation between Amyotrophic Lateral Sclerosis (ALS) and FMO genes. ALS is an adult-onset, progressive, and fatal neurodegenerative disease. We have compared FMO mRNA expression in the control mouse strain C57BL/6J and in a SOD1-mutated (G93A) ALS mouse model. Fmo expression was examined in total brain, and in subregions including cerebellum, cerebral hemisphere, brainstem, and spinal cord of control and SOD1-mutated mice. We have also considered expression in male and female mice because FMO regulation is gender-related. Real-Time TaqMan PCR was used for FMO expression analysis. Normalization was done using hypoxanthine–guanine phosphoribosyl transferase (Hprt) as a control housekeeping gene. Fmo genes, except Fmo3, were detectably expressed in the central nervous system of both control and ALS model mice. FMO expression was generally greater in the ALS mouse model than in control mice, with the highest increase in Fmo1 expression in spinal cord and brainstem. In addition, we showed greater Fmo expression in males than in female mice in the ALS model. The expression of Fmo1 mRNA correlated with Sod1 mRNA expression in pathologic brain areas. We hypothesize that alteration of FMO gene expression is a consequence of the pathological environment linked to oxidative stress related to mutated SOD1.

Cognitive stimulation in cognitively impaired individuals and cognitively healthy individuals with a family history of dementia: short‐term results from the “Allena‐Mente” randomized controlled trial

We evaluated the short‐term efficacy of a protocol of cognitive stimulation (CS), compared with a sham intervention, on cognitive performance in cognitively healthy individuals with a family history of dementia (NDFAM) and in non‐demented individuals with cognitive impairment (CI).

A new GLUT-1 mutation in a family with glucose transporter 1 deficiency syndrome.

Glucose transporter 1 deficiency syndrome (GLUT1-DS) is characterized by movement disorders, including paroxysmal exercise-induced dystonia, seizures, mental retardation, and hypoglycorrhachia. Patients present with early-onset epilepsy resistant to anticonvulsants, developmental delay, and a complex movement disorder. GLUT1-DS results from heterozygous mutation of the glucose transporter type 1 gene (GLUT1/SLC2A1). Most commonly these mutations arise de novo, although several familial cases reported with apparent autosomal dominant inheritance have been described. Here we report a novel mutation, Gly91Ala, in the SLC2A1 gene in a family affected by GLUT1-DS. A 48-year-old man with a history of paroxysmal abnormal movements, III-1 (Fig. 1A), at age 12 developed episodes of choreoathetosic movements affecting the feet and arms lasting 15–30 minutes if induced by intense physical exercise. He showed episodes of déjà vu, confusion, mild cognitive decline, anxiety, mood disturbances, and dysmorphic features (downslanting palpebral fissures, microcephaly, and micrognathia). The patient had a pontomesenchephalic ischemic stroke at age 42, and an aneurysm of the atrial septum was detected by echocardiography. Brain CT scans showed mild bilateral frontal lobe atrophy. His mother (II-2), his maternal grandfather (I-1), his 2 brothers (III-2 and III-3), and his son experienced the same movement disorder. His brothers (III-2 and III-3) presented with seizures, mild cognitive impairment, psychotic behavior, and epilepsy. His sister (III-4) died of unknown causes. His son (IV2) showed normal psychomotor development. He showed epilepsy and since age 4 had developed paroxysmal choreoathetosic movements induced by physical exercise. He presented with dyskinetic attacks every 1–4 weeks, lasting about 30 minutes. In infancy and adolescence he presented with absence seizures, recurrent migraine attacks, and episodes of hemiplegic migraine. He showed the same dysmorphic features as his father. Cerebrospinal fluid analysis detected mild hypoglycorrhachia. In both individuals, father and son, carbamazepine administration decreased the frequency of paroxysmal dyskinesias. His daughter did not present with any of these symptoms. In patients III-1, -2, -3; IV-1, -2; and II-1, the exons of the SLC2A1 gene were sequenced by direct sequencing. In members III-1, -2, -3 and IV-2, DNA analysis showed 1 novel heterozygous mutation (c.797 G>C) in exon 3 (Fig. 1B), a substitution of glycine for alanine at codon 91 in the SLC2A1 protein (Gly91Ala). Sequencing of exon 3 in 100 healthy controls did not detect the G91A mutation. The functional activity of the Gly91Ala mutation has already been described in vitro, showing significant reduction of its functional activity compared with the protein encoded by the wild-type gene. These amino acid changes affect a highly conserved motif whose position is crucial for glucose transport. Because GLUT1-DS is characterized by a variety of neurological and psychiatric symptoms associated with SLC2A1 gene mutations, this case presentation confirms the multiplicity of clinical features such as anxiety, mood disturbances, and facial dysmorphia described here in an adult subject and in a child. This work reveals a new pathologic mutation in GLUT1-DS, but the study of additional affected individuals is essential for understanding the high intrafamilial variability of the mutation associated with a pathological phenotype.

Subthreshold Depression and Clinically Significant Depression in an Italian Population of 70–74-Year-Olds: Prevalence and Association with Perceptions of Self

Estimates of depressive disorders in the elderly vary depending on how cases are defined. We estimated the prevalence of subthreshold depression (SD) and clinically significant depression (D) in a population of 70–74-year-olds. We also looked for associations with sociodemographic factors and perceptions of self. Participants underwent a multidimensional assessment (social, medical, and neuropsychological). The estimated prevalence of SD was 15.71% (95% CI: 13.70–17.72), while that of D was 5.58% (95% CI: 4.31–6.85). Multinomial logistic regression analysis revealed that female gender and dissatisfaction with family relationships were related to SD and D. A self-perception of physical age as older than actual age (but not comorbidity) and greater self-perceived stress caused by negative life events both increased the probability of SD. The likelihood of D was decreased in those who perceived their own health as good, whereas a self-perception of mental age as older than actual age and dissatisfaction with relationships with friends were both significantly associated with D. Both SD and D emerged as key problems in our population. Female gender and self-perceptions of various characteristics, which can be explored through simple questions, are associated with late-life depression in elderly people independently of their actual physical condition and other characteristics.