Chiara Costanzi

Role of BDNF Val66Met functional polymorphism in Alzheimer's disease-related depression

BACKGROUND The gene encoding brain-derived neurotrophic factor (BDNF) has been suggested as a candidate for major depression, and for depression susceptibility in different neurological and psychiatric diseases. No study has investigated the role of BDNF genetic variation and depressive symptoms in Alzheimers disease (AD). OBJECTIVE The aim of this study was to assess the genetic contribution of BDNF Val66Met functional polymorphism to AD-related depression. METHODS Two-hundred and sixty-four AD patients underwent clinical and neuropsychological examination as well as an evaluation of behavioral and psychiatric disturbances. They were subsequently divided into two subgroups according to the presence (AD-D) or the absence (AD-nD), based on DSM-IV criteria for depression in AD. In each subject, BDNF Val66Met functional polymorphism and apolipoprotein E (APOE) genotype were evaluated. RESULTS In our sample, 35.2% of patients (n=93) reported AD-related depressive symptoms. Compared to patients bearing no polymorphisms (BDNF G/G), BDNF G/A carriers showed more than twofold-time risk (OR=2.38; 95%CI=1.38-4.13), and BDNF A/A carriers had a threefold-time risk (OR=3.04; 95%CI=1.15-8.00) for depression in AD. Accordingly, considering the allele frequencies, BDNF A allele was significantly over-represented in AD-D (32.8%) compared to AD-nD (19.0%) (OR=2.08; 95%CI=1.38-3.13). An association between the number of carried A allele and the severity of depressive symptoms was observed (P<0.002). No effect of APOE genotype on risk for depression was found. CONCLUSIONS The present findings provide evidence of BDNF genetic variation role in the susceptibility to AD-related depression. This study puts emphasis on the usefulness of considering genetic background for better defining individualized risk profiles in AD.

Catechol-O-methyltransferase gene polymorphism is associated with risk of psychosis in Alzheimer Disease.

There is emerging evidence that psychosis in Alzheimer Disease (AD) represents a clinically relevant phenotype with a distinct biological process. It has been reported that a functional polymorphism of the catechol-O-methyltransferase (COMT) gene predisposes to an increased risk for schizophrenia and likely to psychosis susceptibility. Aim of this study was to evaluate functional COMT genetic variation as a risk factor for psychosis in Alzheimer Disease. One hundred eighty-one AD patients and 208 age-matched controls underwent clinical and neuropsychological examination, behavioural and psychiatric disturbances evaluation, and ApoE and COMT genotyping. The distribution of COMT genotypes did not significantly differ in AD compared to controls. Among patients with psychosis (32.6%), 88.1% were COMT*H carriers (COMT H/H or COMT H/L, p < .01). The Odds Ratio (OR) for risk of psychosis in COMT*H carriers was 2.66 (confidence interval, CI 95%: 1.6-6.62), taking into account possible confounding factors. A comparable influence of COMT polymorphism on psychosis over the course of the disease was reported. These findings suggest that COMT polymorphism influences on the risk of psychosis since the early stages, and claims for the possibility to identify distinct phenotypes on genetic basis among AD patients.

Parkinson's disease and dementia

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, affecting about 1% of the population over the age of 60. In addition to motor abnormalities, there are several non-motor signs and symptoms that may create a considerable burden for patients and care-givers. Dementia is common and affects approximately 40% of PD patients during the course of the disease, the risk for the development of dementia being 6 times higher than in non-PD age-matched controls. In most cases, PD patients with dementia (PDD) display a dysexecutive syndrome and visuospatial deficits, while memory is relatively unaffected. The overlap between PDD and dementia with Lewy bodies suggests that they likely share similar underlying neuropathological processes.

BDNF genetic variations increase the risk of Alzheimer's disease-related depression

The gene encoding the brain-derived neurotrophic factor (BDNF) has been demonstrated as a candidate for Alzheimers disease-related depression (AD-D) susceptibility. Additionally, an association between AD-D and the functional valine to methionine (Val66Met) polymorphism has been reported. The aim of this study was to assess the genetic contribution of other BDNF variants to AD-D. Two-hundred forty-five AD patients were divided into two subgroups according to the presence (AD-D) or the absence (AD-nD) of depressive symptoms. Four single-nucleotide polymorphisms within BDNF gene were considered, i.e., C270T, rs2049045 C/G, G196A (Val66Met), and G11757C. In our sample, 35.5% of patients (n = 87) reported AD-related depressive symptoms. The individual SNP analysis showed an association between G196A and G11757C genotypes and AD-D. Accordingly, considering the allele frequencies, BDNF 196*A allele was significantly overrepresented in AD-D compared to AD-nD (OR = 1.80, 95% CI = 1.19-2.72), as well as BDNF 11757*C allele (OR = 1.90, 95% CI = 1.25-2.90). Haplotype analyses revealed that the alleles at four loci (C270T, rs2049045 C/G, G196A, G11757C) interacted to further increase the risk of AD-D. Compared to the most common not-at-risk C-C-G-G haplotype, C-G-A-C (OR = 3.55, 95% CI = 1.44-8.76, P = 0.006) and C-C-A-C haplotypes (OR = 1.72, 95% CI = 1.03-2.87, P = 0.037) were overrepresented in AD-D. This study suggests that BDNF genetic variations play a role in the susceptibility to AD-related depression.

ELOVL5 Mutations Cause Spinocerebellar Ataxia 38

Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal-dominant neurodegenerative disorders involving the cerebellum and 23 different genes. We mapped SCA38 to a 56 Mb region on chromosome 6p in a SCA-affected Italian family by whole-genome linkage analysis. Targeted resequencing identified a single missense mutation (c.689G>T [p.Gly230Val]) in ELOVL5. Mutation screening of 456 independent SCA-affected individuals identified the same mutation in two further unrelated Italian families. Haplotyping showed that at least two of the three families shared a common ancestor. One further missense variant (c.214C>G [p.Leu72Val]) was found in a French family. Both missense changes affect conserved amino acids, are predicted to be damaging by multiple bioinformatics tools, and were not identified in ethnically matched controls or within variant databases. ELOVL5 encodes an elongase involved in the synthesis of polyunsaturated fatty acids of the ω3 and ω6 series. Arachidonic acid and docosahexaenoic acid, two final products of the enzyme, were reduced in the serum of affected individuals. Immunohistochemistry on control mice and human brain demonstrated high levels in Purkinje cells. In transfection experiments, subcellular localization of altered ELOVL5 showed a perinuclear distribution with a signal increase in the Golgi compartment, whereas the wild-type showed a widespread signal in the endoplasmic reticulum. SCA38 and SCA34 are examples of SCAs due to mutations in elongase-encoding genes, emphasizing the importance of fatty-acid metabolism in neurological diseases.

APOE Genotype and Cholesterol Levels in Lewy Body Dementia and Alzheimer Disease: Investigating Genotype–Phenotype Effect on Disease Risk

BACKGROUND APOE is the most recognized genetic risk factor for sporadic late-onset Alzheimer disease (AD). The role of APOE genotype in Lewy body dementia (LBD) is still unknown as well as the relationship between APOE genotype and cholesterol levels. OBJECTIVE The objective of this study was to explore the association between APOE genotype and cholesterol levels in patients with LBD and those with AD. METHODS Eighty-two patients with LBD were consecutively enrolled as well as a comparable number of patients with AD and comparison group. Each subject underwent a clinical and neuropsychologic evaluation and APOE genotyping. RESULTS The distribution of APOE genotypes significantly differed between AD and LBD cases compared with the comparison group, with the APOE epsilon4+ (epsilon4+/epsilon4 + or epsilon4+/epsilon4-) genotype more frequent in patient subgroups. Different models have been fitted, and total APOE epsilon4-hypercholesterolemia complete interaction effect was claimed in predicting their relationship on disease outcome. Subjects with hypercholesterolemia and heterozygous for APOE epsilon4 allele had more than threefold risk to develop AD compared both with the comparison group and with those with LBD. The risk to develop AD in hypercholesterolemic and APOE epsilon4 homozygous subjects was 13-fold compared with the comparison group and those with LBD. Conversely, there was not evidence for APOE epsilon4-hypercholesterolemia complete interaction effect in LBD and in the comparison group. CONCLUSIONS This study highlighted that APOE is a risk factor not only for AD, but also for LBD, and that the APOE-cholesterol pathway differently affects AD and LBD. This approach may aid the search for the identification of an interactive effect of APOE genotype and modifiable risk factors, i.e., hypercholesterolemia, eventually resulting in individualized and effective cholesterol-lowering therapy in at-risk subjects.

Primitive reflex evaluation in the clinical assessment of extrapyramidal syndromes

The aim of the present study was to evaluate the role of primitive reflexes (PRs) as additional alert sign in routine clinical practice in patients with extrapyramidal syndrome. We considered glabellar, snout, palmomental and grasp reflexes in patients with mild stage of Lewy body dementia (LBD), corticobasal degeneration, progressive supranuclear palsy or Parkinson disease (PD). We also enrolled mild Alzheimer disease (AD) patients, and healthy subjects, as controls. LBD patients showed the highest prevalence of PRs compared with the other groups. The odds ratio of the risk of LBD in PRs ≥ 2 was 27.9 (95% CI 2.9–269.0) compared with control group, 14.6 (95% CI 2.7–79.6) compared with mild AD, and 19.7 (95% CI 3.7–104.3) compared with PD. These data suggest that the occurrence of combination of PRs might be an useful additional warning sign of possible diffuse Lewy body pathology more than other causes of extrapyramidal syndrome.

Docosahexaenoic acid is a beneficial replacement treatment for spinocerebellar ataxia 38

Spinocerebellar ataxia 38 (SCA38) is caused by mutations in the ELOVL5 gene, which encodes an elongase involved in the synthesis of polyunsaturated fatty acids, including docosahexaenoic acid (DHA). As a consequence, DHA is significantly reduced in the serum of SCA38 subjects. In the present study, we evaluated the safety of DHA supplementation, its efficacy for clinical symptoms, and changes of brain functional imaging in SCA38 patients.

Clinical and neuroradiological features of spinocerebellar ataxia 38 (SCA38)

Introduction SCA38 (MIM 611805) caused by mutations within the ELOVL5 gene, which encodes an enzyme involved in the synthesis of long-chain fatty acids with a high and specific expression in Purkinje cells, has recently been identified. Objective The present study was aimed at describing the clinical and neuroimaging features, and the natural history of SCA38. Methods We extended our clinical and brain neuroimaging data on SCA38 including 21 cases from three Italian families. All had the ELOVL5 c.689G > T (p.Gly230Val) missense mutation. Results Age at disease onset was in the fourth decade of life. The presenting features were nystagmus (100% of cases) and slowly progressive gait ataxia (95%). Frequent signs and symptoms included pes cavus (82%) and hyposmia (76%); rarer symptoms were hearing loss (33%) and anxiety disorder (33%). The disease progressed with cerebellar symptoms such as limb ataxia, dysarthria, dysphagia, and ophtalmoparesis followed in the later stages by ophtalmoplegia. Peripheral nervous system involvement was present in the last phase of disease with sensory loss. Dementia or extrapyramidal signs were not detected. Significant loss of abilities of daily living was reported only after 20 years of the disease. Brain imaging documented cerebellar atrophy with sparing of cerebral cortex and no white matter disease. Conclusions SCA38 is a rare form of inherited ataxia with characteristic clinical features, including pes cavus and hyposmia, that may guide genetic screening and prompt diagnosis in light of possible future therapeutic interventions.

Docosahexaenoic acid (DHA) is a beneficial replacement treatment for Spinocerebellar Ataxia 38 (SCA38)

Spinocerebellar ataxia 38 (SCA38) is caused by mutations in the ELOVL5 gene, which encodes an elongase involved in the synthesis of polyunsaturated fatty acids, including docosahexaenoic acid (DHA). As a consequence, DHA is significantly reduced in the serum of SCA38 subjects. In the present study, we evaluated the safety of DHA supplementation, its efficacy for clinical symptoms, and changes of brain functional imaging in SCA38 patients.