Spinocerebellar ataxia 38: structure-function analysis shows ELOVL5 G230V is proteotoxic, conformationally altered and a mutational hotspot.

Fatty acid elongase ELOVL5 is part of a protein family of multipass transmembrane proteins that reside in the endoplasmic reticulum where they regulate long-chain fatty acid elongation. A missense variant (c.689G>T p.Gly230Val) in ELOVL5 causes Spinocerebellar Ataxia subtype 38 (SCA38), a neurodegenerative disorder characterized by autosomal dominant inheritance, cerebellar Purkinje cell demise and adult-onset ataxia. Having previously showed aberrant accumulation of p.G230V in the Golgi complex, here we further investigated the pathogenic mechanisms triggered by p.G230V, integrating functional studies with bioinformatic analyses of protein sequence and structure. Biochemical analysis showed that p.G230V enzymatic activity was normal. In contrast, SCA38-derived fibroblasts showed reduced expression of ELOVL5, Golgi complex enlargement and increased proteasomal degradation with respect to controls. By heterologous overexpression, p.G230V was significantly more active than wild-type ELOVL5 in triggering the unfolded protein response and in decreasing viability in mouse cortical neurons. By homology modelling, we generated native and p.G230V protein structures whose superposition revealed a shift in Loop 6 in p.G230V that altered a highly conserved intramolecular disulphide bond. The conformation of this bond, connecting Loop 2 and Loop 6, appears to be elongase-specific. Alteration of this intramolecular interaction was also observed when comparing wild-type ELOVL4 and the p.W246G variant which causes SCA34. We demonstrate by sequence and structure analyses that ELOVL5 p.G230V and ELOVL4 p.W246G are position-equivalent missense variants. We conclude that SCA38 is a conformational disease and propose combined loss of function by mislocalization and gain of toxic function by ER/Golgi stress as early events in SCA38 pathogenesis.

Docosahexaenoic acid is a beneficial replacement treatment for spinocerebellar ataxia 38.

OBJECTIVE: 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. METHODS: We enrolled 10 SCA38 patients, and carried out a double-blind randomized placebo-controlled study for 16 weeks, followed by an open-label study with overall 40-week DHA treatment. At baseline and at follow-up visit, patients underwent standardized clinical assessment, brain 18-fluorodeoxyglucose positron emission tomography, electroneurography, and ELOVL5 expression analysis. RESULTS: After 16 weeks, we showed a significant pre-post clinical improvement in the DHA group versus placebo, using the Scale for the Assessment and Rating of Ataxia (SARA; mean difference [MD] = +2.70, 95% confidence interval [CI] = +0.13 to + 5.27, p = 0.042). At 40-week treatment, clinical improvement was found significant by both SARA (MD = +2.2, 95% CI = +0.93 to + 3.46, p = 0.008) and International Cooperative Ataxia Rating Scale (MD = +3.8, 95% CI = +1.39 to + 6.41, p = 0.02) scores; clinical data were corroborated by significant improvement of cerebellar hypometabolism (statistical parametric mapping analyses, false discovery rate corrected). We also showed a decreased expression of ELOVL5 in patients' blood at 40 weeks as compared to baseline. No side effect was recorded. INTERPRETATION: DHA supplementation is a safe and effective treatment for SCA38, showing an improvement of clinical symptoms and cerebellar hypometabolism. Ann Neurol 2017;82:615-621.

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.

Clinical-radiological-pathological spectrum of central nervous system-idiopathic inflammatory demyelinating disease in the elderly.

BACKGROUND: The spectrum of central nervous system-idiopathic inflammatory demyelinating disease (CNS-IIDD) in the elderly is uncertain. OBJECTIVE: To describe the clinical, radiological, and pathological features of a cohort of 30 pathologically proven CNS-IIDD patients ⩾65 years. METHODS: Elderly multiple sclerosis (MS)/clinically isolated syndrome (CIS) patients were compared to a cohort of 125 patients with pathologically proven MS/CIS and symptom onset <65 years. RESULTS: Median age at symptom onset was 69 years (interquartile range (IQR) = 68-75). Median follow-up was 1.9 years (IQR = 1.0-5.6). Diagnoses were MS (14/30), CIS (11/30), neuromyelitis optica (NMO; 4/30), and acute disseminated encephalomyelitis (ADEM; 1/30). Disability was higher in patients with MS/CIS ⩾65 compared to patients <65 (median Expanded Disability Status Scale (EDSS) 4 (IQR = 2.5-7) vs 2.5 (IQR = 1.5-4); p = 0.002). When compared to patients <65 years, there was no difference in the lesion size, number of patients fulfilling Barkhof's criteria, edema, or mass effect. Confluent demyelination was observed in 27 patients (MS/CIS (23/25), NMO (4)), 2 had a mixed perivenular/confluent pattern (MS (1), ADEM (1)), and 1 patient with MS had a mixed confluent/perivenular/coalescent pattern. Early active lesions were found in 19/30 patients ((MS (4), CIS (13), NMO (2); 53%). Cortical demyelination was present in 7/12 (58%) patients (MS (3), CIS(3), ADEM (1)). CONCLUSION: A spectrum of CNS-IIDD can develop in the elderly, with presenting symptoms similar to younger patients. Early diagnosis of CNS demyelinating disease is essential to avoid invasive and disabling procedures.

Erenumab Discontinuation After 12-Month Treatment: A Multicentric, Observational Real-Life Study.

OBJECTIVE: To assess migraine outcome after 12-month treatment with erenumab and compare patients who underwent 3-month erenumab discontinuation following the first treatment cycle with those who continued monthly administrations. METHODS: This is a multicentric observational study in patients with migraine in treatment with erenumab. After a full 12-month treatment cycle (T12), patients could either continue or discontinue erenumab for at least 3 months. Patients who underwent treatment discontinuation were assessed after 3 months (T15) to decide whether to start retreatment. Patients were then assessed following at T16 and T18. RESULTS: Thirty consecutive patients were enrolled. Nineteen patients underwent treatment suspension at T12 up to T15, whereas 11 continued prophylaxis. At T15, patients who discontinued treatment documented significantly more migraine days (17.06 ± 6.5 vs 4.8 ± 2.5; p < 0.0001) and analgesics consumption (14.8 ± 9.2 vs 4.6 ± 2.5; p = 0.002), compared with those who continued treatment. After retreatment, at T16, patients who had previously undergone discontinuation documented a significant improvement in terms of migraine days (9.01 ± 4.4 vs 17.06 ± 6.5; p < 0.0001) and analgesics consumption (9.6 ± 7.3 vs 14.8 ± 9.2; p = 0.004). Such improvement was even greater at T18, comparable with T12. CONCLUSION: After treatment discontinuation, a rapid migraine worsening was found, despite the high clinical response during treatment and at retreatment, which might be secondary to an untimely interruption of a potentially disease-modifying pharmacologic intervention. Although clinical improvement was documented after retreatment, given the high frequency and degree of worsening during discontinuation, it seems plausible-even ethical-to re-evaluate current timing of discontinuation. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that people with migraine discontinuing erenumab migraine prophylaxis after 12 months were more likely to have an increase in nonresponder status and migraine days than those who continued treatment.

Canakinumab as treatment for COVID-19-related pneumonia: A prospective case-control study.

OBJECTIVES: Canakinumab is an IL-1ß antibody that neutralises the activity of IL-1ß. This study examined the efficacy and safety of canakinumab in patients with moderate COVID-19-related pneumonia. DESIGN: This study aimed to evaluate the reduction in duration of hospitalisation with adequate oxygen status. Forty-eight patients with moderate COVID-19-related pneumonia were asked to participate in the prospective case-control study: 33 patients (cases) signed informed consent and received canakinumab (Cohort 1) and 15 patients (Controls) refused to receive the experimental drug and received institutional standard of care (Cohort 2). RESULTS: Hospital discharge within 21 days was seen in 63% of patients in Cohort 1 vs. 0% in Cohort 2 (median 14 vs. 26 days, respectively; p < 0.001). There was significant clinical improvement in ventilation regimes following administration of canakinumab compared with Cohort 2 (Stuart-Maxwell test for paired data, p < 0.001). Patients treated with canakinumab experienced a significant increase in PaO2:FiO2 (p < 0.001) and reduction in lung damage by CT (p = 0.01), along with significant decreases in immune/inflammation markers that were not observed in Cohort 2. Only mild side-effects were seen in patients treated with canakinumab; survival at 60 days was 90.0% (95% CI 71.9-96.7) in patients treated with canakinumab and 73.3% (95% CI 43.6-89.1) for Cohort 2. CONCLUSIONS: Treatment with canakinumab in patients with COVID-19-related pneumonia rapidly restored normal oxygen status, decreased the need for invasive mechanical ventilation, and was associated with earlier hospital discharge and favourable prognosis versus standard of care.

Behavioral dimensions and acetylcholinesterase inhibitor-related effect in Alzheimer disease over time: a latent trajectory modeling.

OBJECTIVE: To evaluate whether treatment with acetylcholinesterase inhibitors (AChEIs) exerts a favorable effect on the behavioral dimensions in Alzheimer disease (AD) over time. METHODS: Two hundred AD patients entered the study and underwent clinical and neuropsychologic examination. Neuropsychiatry Inventory (NPI) total scores and 4 behavioral factor scores, termed "psychosis," "moods," "apathy," and "frontal" were also evaluated. Of this large sample, 107 completed the 6-month follow-up and 83 were followed through for 1 year. Latent Trajectory Modeling analysis was applied, which allows for the estimation of a developmental trajectory over time for each case in the sample adjusting for confounders. These trajectories can be modeled to better understand individual differences in rates of change of behavioral dimensions and the relationship with AChEIs dose therapy. RESULTS: The behavioral phenotypes and NPI total scores were differently expressed, the most prevalent being the mood and the less prevalent being frontal endophenotype over time. The development relationship between the baseline and trend levels of behavioral phenotypes, or NPI total scores and the differences of AChEIs, adjusting for disease severity, concurrent drugs, and demographic data did not "travel together" through time, that is, the correlations of individual trajectories could be estimated equal to zeros. CONCLUSIONS: These data confirm that behavioral dimensions are variably represented in AD and change over time. However, AChEIs could not influence the behavioral disturbance pattern, both measured as total behavioral abnormality burden or as behavioral defined clusters.

Long-term efficacy of docosahexaenoic acid (DHA) for Spinocerebellar Ataxia 38 (SCA38) treatment: An open label extension study.

INTRODUCTION: Spinocerebellar Ataxia 38 (SCA38) is caused by ELOVL5 gene mutation, with significant reduction of serum docosahexaenoic acid (DHA) levels. DHA supplementation has been proven effective at short-term follow-up. In the present paper, we evaluated long-term safety and efficacy of 600 mg/day oral DHA in SCA38 by a 2-year open label extension study. METHODS: Nine SCA38 patients underwent standardised clinical assessment at 62 (T1), 82 (T2) and 104 (T3) weeks, and compared to pre-treatment scores (T0). Brain 18-Fluorodeoxyglucose Positron Emission Tomography and electroneurography were performed at T0 and T3. RESULTS: We found a significant maintenance of clinical symptom improvement at each follow-up time-point (p < 0.001) as compared to T0, a sustained increase of cerebellar metabolism at T3 as compared to T0 (p = 0.013), and no worsening of neurophysiological parameters. No side effect was recorded. CONCLUSIONS: Long-term DHA supplementation is an eligible treatment for SCA38.

"Por causa da liberdade que eu tenho": trabalho e cotidiano de mulheres pipoqueiras / "For the freedom I have": work and daily life of female popcorn makers / "Por la libertad que tengo": trabajo y vida cotidiana de mujeres fabricantes de palomitas

Esta pesquisa buscou compreender, por meio dos discursos que atravessam o fazer pipoca, como se (re)produzem as identidades de gênero no cotidiano de mulheres pipoqueiras em Belo Horizonte. Para tanto, foi realizada uma análise do discurso de vinte e oito entrevistas semiestruturadas com mulheres pipoqueiras, além da observação participante e do diário de campo. Em consonância com as teorias discutidas, notamos que a divisão sexual do trabalho faz com que essas sujeitas sofram duplamente as consequências do cenário de precarização e informalidade do trabalho. À guisa de conclusão, estratégias de liberação e resistência caracterizadas por táticas singulares no cotidiano do fazer pipoca foram observadas e analisadas.

This work sought to understand how gender identities are (re)produced in the daily lives of female popcorn makers in Belo Horizonte through the conversations that surround the popcorn making. For this purpose, a discourse analysis of twenty-eight semi-structured interviews with female popcorn makers was carried out, in addition to participant observation and a field diary. In line with the theories discussed, it was noted that the gender division of labor makes them suffer twice the consequences of the precarious and informal work scenario. By way of conclusion, strategies of liberation and resistance characterized by singular tactics in the daily life of making popcorn were observed and analyzed.

Este trabajo buscó comprender, a través de los discursos que atraviesan la elaboración de las palomitas de maíz, cómo se (re)producen las identidades de género en la vida cotidiana de las mujeres fabricantes de palomitas en Belo Horizonte. Para ello, se realizó un análisis del discurso de veintiocho entrevistas semiestructuradas con mujeres fabricantes de palomitas, además de la observación participante y un diario de campo. En línea con las teorías discutidas, se observó que la división sexual del trabajo les hace sufrir el doble de las consecuencias del escenario de precarización e informalidad del trabajo. A modo de conclusión, se observaron y analizaron estrategias de liberación y resistencia caracterizadas por tácticas singulares en la vida cotidiana de hacer palomitas de maíz.

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.

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.

Updated estimate of AQP4-IgG serostatus and disability outcome in neuromyelitis optica.

OBJECTIVE: To 1) determine, using contemporary recombinant antigen-based assays, the aquaporin-4 (AQP4)-immunoglobulin G (IgG) detection rate in sequential sera of patients assigned a clinical diagnosis of neuromyelitis optica (NMO) but initially scored negative by tissue-based indirect immunofluorescence (IIF) assay; and 2) evaluate the impact of serostatus on phenotype and outcome. METHODS: From Mayo Clinic records (2005-2011), we identified 163 patients with NMO; 110 (67%) were seropositive by IIF and 53 (33%) were scored seronegative. Available stored sera from 49 "seronegative" patients were tested by ELISA, AQP4-transfected cell-based assay, and in-house fluorescence-activated cell sorting assay. Clinical characteristics were compared based on final serostatus. RESULTS: Thirty of the 49 IIF-negative patients (61%) were reclassified as seropositive, yielding an overall AQP4-IgG seropositivity rate of 88% (i.e., 12% seronegative). The fluorescence-activated cell sorting assay improved the detection rate to 87%, cell-based assay to 84%, and ELISA to 79%. The sex ratio (female to male) was 1:1 for seronegatives and 9:1 for seropositives (p < 0.0001). Simultaneous optic neuritis and transverse myelitis as onset attack type (i.e., within 30 days of each other) occurred in 32% of seronegatives and in 3.6% of seropositives (p < 0.0001). Relapse rate, disability outcome, and other clinical characteristics did not differ significantly. CONCLUSIONS: Serological tests using recombinant AQP4 antigen are significantly more sensitive than tissue-based IIF for detecting AQP4-IgG. Testing should precede immunotherapy; if negative, later-drawn specimens should be tested. AQP4-IgG-seronegative NMO is less frequent than previously reported and is clinically similar to AQP4-IgG-seropositive NMO.

Crystal-storing histiocytosis: An unusual relapsing inflammatory CNS disorder.

The differential diagnosis of acute leukoencephalopathy often focuses on central nervous system idiopathic inflammatory demyelinating diseases (IIDDs) such as multiple sclerosis (MS). However, a spectrum of conditions mimic IIDDs, therefore it is critical to consider whether symptoms, signs, imaging and/or response to therapies are compatible with the diagnosis. We describe a 32-year-old previously healthy woman presenting with a 2 year history of steroid-responsive relapsing episodes lasting 2-10 days characterized by transient visual blurring, right-hemiparesis, and spells of aphasia. MRI demonstrated multifocal, relapsing, predominantly white matter enhancing brain lesions, a longitudinally extensive cord lesion, and abnormal visual evoked potentials. Notably, some lesions persistently enhanced whereas others demonstrated progressive T2W hypointensity. Brain biopsy revealed an atypical plasma cell infiltrate and crystal-storing histiocytosis, which by mass spectrometry confirmed the presence of macrophages containing intracellular kappa-light chain restricted crystals. Bone marrow was negative. The patient did well for several years on pulse dexamethasone, however subsequent scans demonstrated increasing enhancement. Repeat biopsy demonstrated a clonal plasma cell proliferation. She was treated with melphalan, and has remained stable. Although this patient initially met McDonald criteria, atypical imaging prompted further workup, and advanced proteomic technology helped secured an accurate diagnosis. Crystal-storing histiocytosis should be considered in the differential diagnosis of inflammatory CNS disorders.

Effects of age and sex on aquaporin-4 autoimmunity.

OBJECTIVE: To determine the sex and age distribution of aquaporin-4 (AQP4) autoimmunity using data derived from clinical service laboratory testing of 56,464 patient samples. DESIGN: Observational analysis. SETTING: Mayo Clinic Neuroimmunology Laboratory. PATIENTS: Between October 1, 2005, and January 4, 2011, 56,464 patients were tested for AQP4-IgG; 2960 (5.2%) patients were seropositive. MAIN OUTCOME MEASURE: Seropositivity for AQP4-IgG. RESULTS: Patients seropositive for AQP4-IgG were older than seronegative patients (mean [SD] age, 46 [16] vs 42 [15] years, respectively; P < .001). More females than males were tested (37,662 vs 16,810, respectively; P < .001). Among 2743 seropositive patients, 146 (5.3%) were pediatric (aged ≤18 years) and 333 (12.1%) were elderly (aged ≥65 years). The sex distribution of seropositive patients was 2465 females and 306 males (absolute female:male ratio, 8.1:1; P < .001). After adjusting for the number of females tested, an excess of females persisted (adjusted female:male ratio, 3.6:1). Female predominance for AQP4-IgG was more striking in adults (absolute female:male ratio, 8.4:1; adjusted female:male ratio, 3.5:1) than in pediatric patients (absolute female:male ratio, 4.3:1; adjusted female:male ratio, 2.9:1) (P < .001). Elderly women were more likely to be seropositive than individuals in other age categories (13.1% vs 6.0%, respectively; P < .001). The proportion of AQP4-IgG-seropositive individuals (detection rate), defined by decade of age, increased exponentially in women after age 50 years. CONCLUSIONS: Seropositivity for AQP4-IgG occurs predominantly in females, particularly in individuals older than 18 years. Among seropositive patients, 1 in 6 is in the extremes of age. The detection rate of AQP4-IgG increased in women after age 50 years.

Genetic susceptibility to behavioural and psychological symptoms in Alzheimer disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline including loss of memory, orientation and reasoning. However, a relevant aspect of AD is the presence of a variety of behavioural and psychological symptoms in dementia (BPSD), beyond the well-known progressive cognitive impairment. Approximately 50% to 80% of patients diagnosed with AD present behavioural or psychiatric disturbances such as psychosis, depression, agitation, disinhibition, aggression, hyperactivity, and socially intrusive behaviours. These symptoms may be burdensome for physicians and caregivers and lead to earlier institutionalization and increased social and economic costs. In this view, recent literature has considered the likely genetic component of BPSD in AD, defining different clusters. Several studies have investigated whether the main recognised genetic risk factor for late-onset AD, namely the apolipoprotein E (APOE) gene, is associated with BPSD, with conflicting results. The involvement of dopamine- or serotonin-related pathways and associated genetic variabilities has been demonstrated as being interesting candidates for the neuropsychiatry manifestations of dementia. Moreover, genetic variations of neurotrophins, such as brain-derived neurotrophic factor (BDNF), have been related to depression susceptibility in AD. In the present review, we summarise the current literature on genetic risk factors to BPSD susceptibility in AD and discuss future possible treatment strategies.

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 Alzheimer's 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.

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.

Cumulative effect of COMT and 5-HTTLPR polymorphisms and their interaction with disease severity and comorbidities on the risk of psychosis in Alzheimer disease.

OBJECTIVE: The objective of this study was to investigate the cumulative effect of the genes likely involved in Alzheimer disease (AD)-related psychosis and their interaction with disease stage and environmental factors. METHODS: Two hundred thirty-four patients with AD underwent clinical and neuropsychologic examination, behavioral and psychiatric disturbances evaluation, and were subsequently divided into two subgroups according to the presence (AD-P) or the absence (AD-nP) of psychotic symptoms. Cathecol-O-methyltransferase (COMT), serotonin gene-linked promoter region (5-HTTLPR), and Apolipoprotein E (ApoE) genotypes were performed. RESULTS: COMT*H (H/H or H/liter; odds ratio [OR]: 2.4; 95% confidence interval [CI]: 1.13-5.11) and 5-HTTLPR*S (S/S or S/liter, OR: 2.14; 95% CI: 1.13-4.07) were associated with AD-P. A gene dose effect was observed; in fact, carriers of both polymorphisms showed a fivefold risk for psychosis compared with patients bearing no polymorphisms. An interaction between these two genetic variations with disease stage and ischemic cardiomyopathy was found, the latter influencing AD-P risk only if "at-risk" genetic polymorphisms were present. The combined trend effect of COMT*H plus 5-HTTLPR*S and advance disease stage on AD-P risk was approximately 200% greater than that predicted by assuming additive effects, whereas the one obtained by COMT*H plus 5-HTTLPR*S and ischemic cardiomyopathy was 50% greater. ApoE genotype did not influence AD-P risk. CONCLUSIONS: These findings claim for a synergic effect of COMT*H and 5-HTTLPR*S polymorphisms on the risk of psychosis in AD and for their interaction with disease stage and ischemic cardiomyopathy. This study suggests that considering both the genetic background and the environmental correlates might provide new insight for understanding psychosis mechanisms related to AD.