Cathepsin B p.Gly284Val Variant in Parkinson's Disease Pathogenesis.

Parkinson's disease (PD) is generally considered a sporadic disorder, but a strong genetic background is often found. The aim of this study was to identify the underlying genetic cause of PD in two affected siblings and to subsequently assess the role of mutations in Cathepsin B (CTSB) in susceptibility to PD. A typical PD family was identified and whole-exome sequencing was performed in two affected siblings. Variants of interest were validated using Sanger sequencing. CTSB p.Gly284Val was genotyped in 2077 PD patients and 615 unrelated healthy controls from the Czech Republic, Ireland, Poland, Ukraine, and the USA. The gene burden analysis was conducted for the CTSB gene in an additional 769 PD probands from Mayo Clinic Florida familial PD cohort. CTSB expression and activity in patient-derived fibroblasts and controls were evaluated by qRT-PCR, western blot, immunocytochemistry, and enzymatic assay. The CTSB p.Gly284Val candidate variant was only identified in affected family members. Functional analysis of CTSB patient-derived fibroblasts under basal conditions did not reveal overt changes in endogenous expression, subcellular localization, or enzymatic activity in the heterozygous carrier of the CTSB variant. The identification of the CTSB p.Gly284Val may support the hypothesis that the CTSB locus harbors variants with differing penetrance that can determine the disease risk.

Metabolism and the Effect of Animal-Derived Oxysterols in the Diet on the Development of Alzheimer's Disease.

BACKGROUND: The rapid worldwide increase in the incidence of Alzheimer's disease is associated with changing nutrition patterns. Recently, some articles have highlighted the link between Alzheimer's disease and dietary cholesterol. It was found that elevated levels of some of its fractions in the brain and circulation affect metabolism. SUMMARY: Previous studies have considered the relationship between Alzheimer's disease and oxidized cholesterol molecules in the brain. To date, there are limited data available on the relationship between oxidized cholesterol in the brain and Alzheimer's disease. There is a link between a diet high in cholesterol and its oxidized forms, leading to hypercholesterolemia, which is one of significant risk factors of dementia, and Alzheimer's disease. Oxidized cholesterol can be absorbed in the small intestine and cross the blood-brain barrier, leading to increased inflammation and endogenous oxidative process. Animal-origin foods are sources of oxidized cholesterol, with cholesterol oxidation beginning already after slaughter and occurring during storage and processing. KEY MESSAGES: High-heat food preparation and storage of cooked products in the refrigerator followed by subsequent heating may significantly increase the amount of oxidized cholesterol products. Therefore, a diet low in cholesterol oxidation products and high in plants with antioxidative properties seems to be most preventable and should be implemented as early as possible.

Frequency of mutations in PRKN, PINK1, and DJ1 in Patients With Early-Onset Parkinson Disease from neighboring countries in Central Europe.

INTRODUCTION: Approximately 10% of patients with Parkinson disease (PD) present with early-onset disease (EOPD), defined as diagnosis before 50 years of age. Genetic factors are known to contribute to EOPD, with most commonly observed mutations in PRKN, PINK1, and DJ1 genes. The aim of our study was to analyze the frequency of PRKN, PINK1, and DJ1 mutations in an EOPD series from 4 neighboring European countries: Czech Republic, Germany, Poland, and Ukraine. METHODS: Diagnosis of PD was made based on UK Brain Bank diagnostic criteria in departments experienced in movement disorders (1 from Czech Republic, 1 from Germany, 9 from Poland, and 3 from Ukraine). EOPD was defined as onset at or before 50 years of age. Of the 541 patients recruited to the study, 11 were Czech, 38 German, 476 Polish, and 16 Ukrainian. All cohorts were fully screened with Sanger sequencing for PRKN, PINK1, and DJ1 and multiplex ligation-dependent probe amplification for exon dosage. RESULTS: PRKN homozygous or double heterozygous mutations were identified in 17 patients: 1 Czech (9.1%), 1 German (2.6%), 14 Polish (2.9%), and 1 Ukrainian (6.3%). PINK1 homozygous mutations were only identified in 3 Polish patients (0.6%). There were no homozygous or compound heterozygous DJ1 mutations in analyzed subpopulations. One novel variant in PRKN was identified in the Ukrainian series. CONCLUSION: In the analyzed cohorts, mutations in the genes PRKN, PINK1, and DJ1 are not frequently observed.

The Erlangen Score Algorithm in the diagnosis and prediction of the progression from subjective cognitive decline and mild cognitive impairment to Alzheimer-type dementia.

The evaluation of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) (ß-amyloid, t-tau, p-tau) can be used to estimate the risk of developing dementia in patients at the pre-clinical stages of AD, i.e. subjective cognitive decline (SCD) and mild cognitive impairment (MCI). Erlangen Score Algorithm allows interpretation of CSF biomarker concentrations and is cut-off value independent. The aim of this study was to establish if this algorithm can be applied for routine diagnostic testing in clinical and preclinical subjects and has prognostic value. We analysed 217 patients from the memory clinic with the diagnosis of SCD (n = 31), MCI (n = 104), and AD (n = 82) with clinical follow-up amounting to 14.33 months (SD = 6.82). It was found that the highest Erlangen Score dominated in the AD group and was the rarest in the SCD group. In the group of patients with progression of symptoms during our period of observation, the AD pathology was confirmed in 93.75% of cases. Among the non-progressing subjects (n = 119) the algorithm indicated the risk of developing AD as possible in 40.34% and probable in 15.97% of cases. To conclude, the Erlangen Score Algorithm is a useful tool to determinate the risk of developing AD before the onset of dementia or to confirm the AD diagnosis. It is extremely valuable in preclinical stages of AD for planning purposes and early intervention as well as for future clinical trials.

Plasma adiponectin array in women with Alzheimer's disease.

Introduction Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease. Typical features of AD include memory loss, social dysfunction and physical impairment. Although the pathological findings in the central nervous system are well established, the etiological factors are poorly known. Recent studies suggested the role of metabolic disturbances in the development of AD neurodegeneration. Adiponectin, an anti-inflammatory and metabolism regulating factor, was linked to AD. Aim The aim was to examine whether adiponectin fractions combined with insulin/insulin resistance-associated metabolic parameters correlate with AD progression. Material and methods The study comprised 98 women: 27 with moderate to severe AD, 31 with AD at early stage and 40 healthy controls, matched for age and BMI. To evaluate memory impairment, the MMSE was performed. Plasma total adiponectin and its high-, medium- and low molecular weights were measured with ELISA. Anthropometric, clinical and metabolic parameters were assessed. Correlations between adiponectin array and measured parameters were evaluated. Results In comparison to the controls, enhanced levels of total and medium molecular weight adiponectin characterized AD individuals. In AD, we found correlations between adiponectin array, and anthropometric and biochemical parameters. After adjustment to BMI, a significant increase of the total adiponectin and high- and medium molecular weight fractions was observed. A negative correlation between low molecular weight adiponectin and MMSE was found. Conclusions Our results indicate a possible link between adiponectin variations and AD. We hypothesize that changes in adiponectin profile observed in AD result from compensatory mechanism against neuropathological processes, as well as from adiponectin homeostasis impairment.

TREM2 variants in neurodegenerative disorders in the Polish population. Homozygosity and compound heterozygosity in FTD patients.

Activation of the TREM2 receptor on microglia stimulates phagocytosis and decreases the microglial proinflammatory response. Mutations in exon 2 of the TREM2 gene have been reported to be associated with various neurodegenerative diseases characterized by chronic inflammation. The aim of our study was to evaluate exon 2 of TREM2 gene variants as a putative genetic risk factor for Alzheimer's disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) in the Polish population. The results were interpreted using previously published data, especially highlighting differences in the prevalence of the variants among Caucasian subpopulations across different geographic regions. The DNA sequence of exon 2 of TREM2 was analyzed in 811 subjects (274 AD, 135 FTD, 194 ALS patients, and 208 neurologically healthy controls). Nine heterozygous variants were detected, including two novel ones: p.G29 = and c.41-2_3insA, found respectively in a control and an ALS patient. Additionally, we identified one homozygous and two compound heterozygous FTD patients. We confirm previous data that homozygous and compound heterozygous TREM2 mutations can be causative for FTD.

Assessment of Olfactory Function in MAPT-Associated Neurodegenerative Disease Reveals Odor-Identification Irreproducibility as a Non-Disease-Specific, General Characteristic of Olfactory Dysfunction.

Olfactory dysfunction is associated with normal aging, multiple neurodegenerative disorders, including Parkinson's disease, Lewy body disease and Alzheimer's disease, and other diseases such as diabetes, sleep apnea and the autoimmune disease myasthenia gravis. The wide spectrum of neurodegenerative disorders associated with olfactory dysfunction suggests different, potentially overlapping, underlying pathophysiologies. Studying olfactory dysfunction in presymptomatic carriers of mutations known to cause familial parkinsonism provides unique opportunities to understand the role of genetic factors, delineate the salient characteristics of the onset of olfactory dysfunction, and understand when it starts relative to motor and cognitive symptoms. We evaluated olfactory dysfunction in 28 carriers of two MAPT mutations (p.N279K, p.P301L), which cause frontotemporal dementia with parkinsonism, using the University of Pennsylvania Smell Identification Test. Olfactory dysfunction in carriers does not appear to be allele specific, but is strongly age-dependent and precedes symptomatic onset. Severe olfactory dysfunction, however, is not a fully penetrant trait at the time of symptom onset. Principal component analysis revealed that olfactory dysfunction is not odor-class specific, even though individual odor responses cluster kindred members according to genetic and disease status. Strikingly, carriers with incipient olfactory dysfunction show poor inter-test consistency among the sets of odors identified incorrectly in successive replicate tests, even before severe olfactory dysfunction appears. Furthermore, when 78 individuals without neurodegenerative disease and 14 individuals with sporadic Parkinson's disease were evaluated twice at a one-year interval using the Brief Smell Identification Test, the majority also showed inconsistency in the sets of odors they identified incorrectly, independent of age and cognitive status. While these findings may reflect the limitations of these tests used and the sample sizes, olfactory dysfunction appears to be associated with the inability to identify odors reliably and consistently, not with the loss of an ability to identify specific odors. Irreproducibility in odor identification appears to be a non-disease-specific, general feature of olfactory dysfunction that is accelerated or accentuated in neurodegenerative disease. It may reflect a fundamental organizational principle of the olfactory system, which is more "error-prone" than other sensory systems.

Association between Cerebrospinal Fluid Biomarkers for Alzheimer's Disease, APOE Genotypes and Auditory Verbal Learning Task in Subjective Cognitive Decline, Mild Cognitive Impairment, and Alzheimer's Disease.

In the course of Alzheimer's disease (AD), early pathological changes in the brain start decades before any clinical manifestation. The concentration levels of AD cerebrospinal fluid (CSF) biomarkers, such as amyloid-ß1-42 (Aß1-42), total tau (T-tau), and phosphorylated tau (P-tau), may reflect a cerebral pathology facilitating an early diagnosis of the disease and predicting a cognitive deterioration. The aim of this study was to estimate the prevalence of AD CSF biomarkers in those individuals with a subjective cognitive decline (SCD), a mild cognitive impairment (MCI), and Alzheimer's dementia (AD-D), together with the relationships between the biomarkers, an APOE ɛ4 presence, and a verbal episodic memory performance. We included 252 patients from the memory clinic with a diagnosis of SCD (n = 85), MCI (n = 87), and AD-D (n = 80). A verbal episodic memory performance level was assessed and was based on a delayed recall trial from the 10-word list of an auditory verbal learning task (AVLT). We found that the patients with more severe cognitive impairments had significantly lower levels of Aß1-42 and higher levels of T-tau and P-tau. This pattern was also typical for the APOE ɛ4 carriers, who had lower levels of Aß1-42 than the noncarriers in the AD-D and MCI groups. The levels of T-tau and P-tau were significantly higher in the APOE ɛ4 carriers than in the noncarriers, but only in the MCI patients. The AVLT performance in the whole study samples was predicted by age, Aß1-42, and the T-tau CSF biomarkers, but not by the APOE genotyping.

Combined use of biochemical and volumetric biomarkers to assess the risk of conversion of mild cognitive impairment to Alzheimer's disease.

INTRODUCTION: The aim of our study was to evaluate the usefulness of several biomarkers in predicting the conversion of mild cognitive impairment (MCI) to Alzheimer's disease (AD): ß-amyloid and tau proteins in cerebrospinal fluid and the volumetric evaluation of brain structures including the hippocampus in magnetic resonance imaging (MRI). MATERIAL AND METHODS: MRI of the brain with the volumetric assessment of hippocampus, entorhinal cortex, posterior cingulate gyrus, parahippocampal gyrus, superior, medial and inferior temporal gyri was performed in 40 patients diagnosed with mild cognitive impairment. Each patient had a lumbar puncture to evaluate ß-amyloid and tau protein (total and phosphorylated) levels in the cerebrospinal fluid. The observation period was 2 years. RESULTS: Amongst 40 patients with MCI, 9 (22.5%) converted to AD within 2 years of observation. Discriminant analysis was conducted and sensitivity for MCI conversion to AD on the basis of volumetric measurements was 88.9% and specificity 90.3%; on the basis of ß-amyloid and total tau, sensitivity was 77.8% and specificity 83.9%. The combined use of the results of volumetric measurements with the results of proteins in the cerebrospinal fluid did not increase the sensitivity (88.9%) but increased specificity to 96.8% and the percentage of correct classification to 95%.

Mitochondrial targeting sequence variants of the CHCHD2 gene are a risk for Lewy body disorders.

OBJECTIVE: To assess the role of CHCHD2 variants in patients with Parkinson disease (PD) and Lewy body disease (LBD) in Caucasian populations. METHODS: All exons of the CHCHD2 gene were sequenced in a US Caucasian patient-control series (878 PD, 610 LBD, and 717 controls). Subsequently, exons 1 and 2 were sequenced in an Irish series (355 PD and 365 controls) and a Polish series (394 PD and 350 controls). Immunohistochemistry and immunofluorescence studies were performed on pathologic LBD cases with rare CHCHD2 variants. RESULTS: We identified 9 rare exonic variants of unknown significance. These variants were more frequent in the combined group of PD and LBD patients compared to controls (0.6% vs 0.1%, p = 0.013). In addition, the presence of any rare variant was more common in patients with LBD (2.5% vs 1.0%, p = 0.050) compared to controls. Eight of these 9 variants were located within the gene's mitochondrial targeting sequence. CONCLUSIONS: Although the role of variants of the CHCHD2 gene in PD and LBD remains to be further elucidated, the rare variants in the mitochondrial targeting sequence may be a risk factor for Lewy body disorders, which may link CHCHD2 to other genetic forms of parkinsonism with mitochondrial dysfunction.

Role for the microtubule-associated protein tau variant p.A152T in risk of α-synucleinopathies.

OBJECTIVE: To assess the importance of MAPT variant p.A152T in the risk of synucleinopathies. METHODS: In this case-control study, we screened a large global series of patients and controls, and assessed associations between p.A152T and disease risk. We included 3,229 patients with clinical Parkinson disease (PD), 442 with clinical dementia with Lewy bodies (DLB), 181 with multiple system atrophy (MSA), 832 with pathologically confirmed Lewy body disease (LBD), and 2,456 healthy controls. RESULTS: The minor allele frequencies (MAF) in clinical PD cases (0.28%) and in controls (0.2%) were not found to be significantly different (odds ratio [OR] 1.37, 95% confidence interval [CI] 0.63-2.98, p = 0.42). However, a significant association was observed with clinical DLB (MAF 0.68%, OR 5.76, 95% CI 1.62-20.51, p = 0.007) and LBD (MAF 0.42%, OR 3.55, 95% CI 1.04-12.17, p = 0.04). Additionally, p.A152T was more common in patients with MSA compared to controls (MAF 0.55%, OR 4.68, 95% CI 0.85-25.72, p = 0.08) but this was not statistically significant and therefore should be interpreted with caution. CONCLUSIONS: Overall, our findings suggest that MAPT p.A152T is a rare low penetrance variant likely associated with DLB that may be influenced by coexisting LBD and AD pathology. Given the rare nature of the variant, further studies with greater sample size are warranted and will help to fully explain the role of p.A152T in the pathogenesis of the synucleinopathies.

Hypertension in patients with Alzheimer's disease--prevalence, characteristics, and impact on clinical outcome. Experience of one neurology center in Poland.

The aim of the study was to evaluate hypertension (HT) prevalence, characteristics, and impact on clinical outcome in patients with Alzheimer's disease (AD). We evaluated 701 patients with AD (249 males, 452 females, and mean age 74.9 ± 7.5 years). As a group representing general population matched with regard to age, education level, and place of residence, we included 762 subjects (438 males, 324 females, and mean age 74.7 ± 4.4 years) from the Polish National Multicenter Health Survey (WOBASZ) studies. The patients with AD were characterized by lower systolic blood pressure (BP) and diastolic BP values (134 ± 21 vs. 151 ± 23 mm Hg, P < .001 and 77 ± 11 vs. 86 ± 12 mm Hg, P < .001, respectively) as well as lower HT prevalence (66% vs. 78.6%, P < .001) compared with the WOBASZ group. In long-term follow-up of AD group, HT and BP levels were not associated with the decline in cognitive functions nor the increased risk of death. Patients with AD were characterized by lower prevalence of HT and other vascular risk factors. BP levels and HT had no impact on clinical outcome.

Writing in Richardson variant of progressive supranuclear palsy in comparison to progressive non-fluent aphasia.

BACKGROUND: The overlap between progressive supranuclear palsy (PSP) and progressive non-fluent aphasia (PNFA) is being increasingly recognized. In this paper descriptive writing in patients with Richardson syndrome of progressive supranuclear palsy (PSP-RS) is compared to writing samples from patients with PNFA. METHODS: Twenty-seven patients participated in the study: 17 with the clinical diagnosis of PSP-RS and 10 with PNFA. Untimed written picture description was administered during neuropsychological assessment and subsequently scored by two raters blinded to the clinical diagnosis. Lexical and syntactic content, as well as writing errors (e.g. omission and perseverative errors) were analyzed. RESULTS: In patients with PSP-RS both letter and diacritic mark omission errors were very frequent. Micrographia was present in 8 cases (47%) in PSP-RS group and in one case (10%) with PNFA. Perseverative errors did not differentiate between the groups. CONCLUSIONS: As omission errors predominate in writing of patients with PSP-RS, writing seems to be compromised mainly because of oculomotor deficits, that may alter visual feedback while writing.

Is descriptive writing useful in the differential diagnosis of logopenic variant of primary progressive aphasia, Alzheimer's disease and mild cognitive impairment?

Current classification of primary progressive aphasia (PPA) encompasses three variants: non-fluent (nfvPPA), semantic (svPPA) and logopenic (lvPPA). Previously lvPPA was regarded as aphasic form of Alzheimer's disease (AD). However, not all patients with lvPPA phenotype present with AD pathology. Despite abundant literature on differentiation of lvPPA from svPPA and nfvPPA, studies comparing lvPPA with AD and mild cognitive impairment (MCI) are scarce. This study aimed at analyzing written descriptive output in lvPPA, AD and MCI. Thirty-five patients participated in the study: 9 with lvPPA, 13 with AD and 13 with MCI. Most aspects of writing performance were comparable in three groups. However, letter insertion errors appeared in 44% patients with lvPPA, while they were absent in AD and MCI. Patients with lvPPA used more verbs than patients with AD. Writing profile may complement other neuropsychological assessment results in the differential diagnosis of lvPPA. Letter insertion errors and frequent verb use may raise a query of lvPPA.

Plasma leptin levels and free leptin index in women with Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by irreversible and progressive loss of memory and other cognitive functions. Controversies still exist on the precise mechanisms contributing to neurodegeneration. Obesity and disturbances in metabolic homeostasis are thought to be AD risk factors. Adipokine leptin has receptors in the brain, also in the regions related to AD. Leptin may protect against AD. The aim was to assess leptin and soluble leptin receptor levels in plasma as well as free leptin index (FLI) in correlation with metabolic status of women diagnosed with Alzheimer's disease. Eighteen women with moderate to severe stage of AD, 40 women with AD at early stage, and 42 female controls, matched for age and body mass index, participated in the study. Leptin and soluble leptin receptor levels were measured with RIA and IRMA, respectively. Then, FLI was calculated. In addition, metabolic parameters (lipid profile, glucose and insulin concentrations, HOMA-IR) were estimated. Clinical and anthropometric data were collected. The Mini-Mental State Examination (MMSE) as a cognitive impairment measurement was performed. Correlations with both leptin and FLI, and MMSE, clinical and biochemical parameters were evaluated. Leptin levels and FLI were significantly lower and leptin receptor concentrations were higher in AD subjects when compared with the controls. In AD group leptin, soluble leptin receptor and FLI correlated with selected metabolic parameters but not with MMSE. We conclude that alterations in leptin, leptin receptor, and FLI were the most intensified in advanced AD. However, these results did not correlate with dementia stage measured with MMSE. Therefore, further intensive research is needed to explain the mechanisms involved in this phenomenon.

Exonic Re-Sequencing of the Chromosome 2q24.3 Parkinson's Disease Locus.

Genome-wide association studies (GWAS) in Parkinson's disease (PD) have identified over 20 genomic regions associated with disease risk. Many of these loci include several candidate genes making it difficult to pinpoint the causal gene. The locus on chromosome 2q24.3 encompasses three genes: B3GALT1, STK39, and CERS6. In order to identify if the causal variants are simple missense changes, we sequenced all 31 exons of these three genes in 187 patients with PD. We identified 13 exonic variants including four non-synonymous and three insertion/deletion variants (indels). These non-synonymous variants and rs2102808, the GWAS tag SNP, were genotyped in three independent series consisting of a total of 1976 patients and 1596 controls. Our results show that the seven identified 2q24.3 coding variants are not independently responsible for the GWAS association signal at the locus; however, there is a haplotype, which contains both rs2102808 and a STK39 exon 1 6bp indel variant, that is significantly associated with PD risk (Odds Ratio [OR] = 1.35, 95% CI: 1.11-1.64, P = 0.003). This haplotype is more associated than each of the two variants independently (OR = 1.23, P = 0.005 and 1.10, P = 0.10, respectively). Our findings suggest that the risk variant is likely located in a non-coding region. Additional sequencing of the locus including promoter and regulatory regions will be needed to pinpoint the association at this locus that leads to an increased risk to PD.

Genetic variation of the retromer subunits VPS26A/B-VPS29 in Parkinson's disease.

We recently showed that mutation of the VPS35 gene can cause late-onset Parkinson's disease. In the present study we sequenced 702 affected subjects from the Mayo Clinic Parkinson's disease patient-control series for the VPS29 and VPS26A/B genes. We identified only 2 rare nonsynonymous variants in the VPS26A p.K93E and VPS29 p.N72H. The results show that mutations in the genes composing the retromer cargo recognition subunit are not a common cause of Parkinson's disease.

ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer's disease.

Recent genome-wide association studies (GWAS) of late-onset Alzheimer's disease (LOAD) have identified single nucleotide polymorphisms (SNPs) which show significant association at the well-known APOE locus and at nineteen additional loci. Among the functional, disease-associated variants at these loci, missense variants are particularly important because they can be readily investigated in model systems to search for novel therapeutic targets. It is now possible to perform a low-cost search for these "actionable" variants by genotyping the missense variants at known LOAD loci already cataloged on the Exome Variant Server (EVS). In this proof-of-principle study designed to explore the efficacy of this approach, we analyzed three rare EVS variants in APOE, p.L28P, p.R145C and p.V236E, in our case control series of 9114 subjects. p.R145C proved to be too rare to analyze effectively. The minor allele of p.L28P, which was in complete linkage disequilibrium (D' = 1) with the far more common APOE ϵ4 allele, showed no association with LOAD (P = 0.75) independent of the APOE ϵ4 allele. p.V236E was significantly associated with a marked reduction in risk of LOAD (P = 7.5 × 10⁻°5; OR = 0.10, 0.03 to 0.45). The minor allele of p.V236E, which was in complete linkage disequilibrium (D' = 1) with the common APOE ϵ3 allele, identifies a novel LOAD-associated haplotype (APOE ϵ3b) which is associated with decreased risk of LOAD independent of the more abundant APOE ϵ2, ϵ3 and ϵ4 haplotypes. Follow-up studies will be important to confirm the significance of this association and to better define its odds ratio. The ApoE p.V236E substitution is the first disease-associated change located in the lipid-binding, C-terminal domain of the protein. Thus our study (i) identifies a novel APOE missense variant which may profitably be studied to better understand how ApoE function may be modified to reduce risk of LOAD and (ii) indicates that analysis of protein-altering variants cataloged on the EVS can be a cost-effective way to identify actionable functional variants at recently discovered LOAD loci.

Agraphia in patients with frontotemporal dementia and parkinsonism linked to chromosome 17 with P301L MAPT mutation: dysexecutive, aphasic, apraxic or spatial phenomenon?

OBJECTIVES: Patients with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) may be agraphic. The study aimed at characterizing agraphia in individuals with a P301L MAPT mutation. METHODS: Two pairs of siblings with FTDP-17 were longitudinally examined for agraphia in relation to language and cognitive deficits. RESULTS: All patients presented with dysexecutive agraphia. In addition, in the first pair of siblings one sibling demonstrated spatial agraphia with less pronounced allographic agraphia and the other sibling had aphasic agraphia. Aphasic agraphia was also present in one sibling from the second pair. CONCLUSION: Agraphia associated with FTDP-17 is very heterogeneous.

GWAS risk factors in Parkinson's disease: LRRK2 coding variation and genetic interaction with PARK16.

Parkinson's disease (PD) is a multifactorial movement disorder characterized by progressive neurodegeneration. Genome-wide association studies (GWAS) have nominated over fifteen distinct loci associated with risk of PD, however the biological mechanisms by which these loci influence disease risk are mostly unknown. GWAS are only the first step in the identification of disease genes: the specific causal variants responsible for the risk within the associated loci and the interactions between them must be identified to fully comprehend their impact on the development of PD. In the present study, we first attempted to replicate the association signals of 17 PD GWAS loci in our series of 1381 patients with PD and 1328 controls. BST1, SNCA, HLA-DRA, CCDC62/HIP1R and MAPT all showed a significant association with PD under different models of inheritance and LRRK2 showed a suggestive association. We then examined the role of coding LRRK2 variants in the GWAS association signal for that gene. The previously identified LRRK2 risk mutant p.M1646T and protective haplotype p.N551K-R1398H-K1423K did not explain the association signal of LRRK2 in our series. Finally, we investigated the gene-gene interaction between PARK16 and LRRK2 that has previously been proposed. We observed no interaction between PARK16 and LRRK2 GWAS variants, but did observe a non-significant trend toward interaction between PARK16 and LRRK2 variants within the protective haplotype. Identification of causal variants and the interactions between them is the crucial next step in making biological sense of the massive amount of data generated by GWAS studies. Future studies combining larger sample sizes will undoubtedly shed light on the complex molecular interplay leading to the development of PD.