The PINK1 p.Asn521Thr Variant Is Associated with Earlier Disease Onset in GRN/C9orf72 Frontotemporal Lobar Degeneration.

Genetic frontotemporal lobar degeneration (FTLD) is characterized by heterogeneous phenotypic expression, with a disease onset highly variable even in patients carrying the same mutation. Herein we investigated if variants in lysosomal genes modulate the age of onset both in FTLD due to GRN null mutations and C9orf72 expansion. In a total of 127 subjects (n = 74 GRN mutations and n = 53 C9orf72 expansion carriers), we performed targeted sequencing of the top 98 genes belonging to the lysosomal pathway, selected based on their high expression in multiple brain regions. We described an earlier disease onset in GRN/C9orf72 pedigrees in subjects carrying the p.Asn521Thr variant (rs1043424) in PTEN-induced kinase 1 (PINK1), a gene that is already known to be involved in neurodegenerative diseases. We found that: (i) the PINK1 rs1043424 C allele is significantly associated with the age of onset; (ii) every risk C allele increases hazard by 2.11%; (iii) the estimated median age of onset in homozygous risk allele carriers is 10-12 years earlier than heterozygous/wild type homozygous subjects. A replication study in GRN/C9orf72 negative FTLD patients confirmed that the rs1043424 C allele was associated with earlier disease onset (-5.5 years in CC versus A carriers). Understanding the potential mechanisms behind the observed modulating effect of the PINK1 gene in FTLD might prove critical for identifying biomarkers and/or designing drugs to modify the age of onset, especially in GRN/C9orf72-driven disease.

Feasibility of Leukemia-Derived Exosome Enrichment and Co-isolated dsDNA Sequencing in Acute Myeloid Leukemia Patients: A Proof of Concept for New Leukemia Biomarkers Detection.

Exosomes are extracellular vesicles playing a pivotal role in the intercellular communication. They shuttle different cargoes, including nucleic acids from their cell of origin. For this reason, they have been studied as carriers of tumor markers in different liquid biopsy approaches, in particular for solid tumors. Few data are available concerning exosomes as markers of myeloid neoplasia. To better understand their real potential and the best approach to investigate leukemic exosomes, we present the results of a pilot feasibility study evaluating the application of next-generation sequencing analysis of dsDNA derived from exosomes isolated in 14 adult patients affected by acute myeloid leukemias. In particular, leukemia-derived exosome fractions have been analyzed. The concentration of dsDNA co-extracted with exosomes and the number and types of mutations detected were considered and compared with ones identified in the Bone Marrow (BM) and Peripheral Blood (PB) cells. Exosomal DNA concentration, both considering the cargo and the DNA surrounding the lipid membrane resulted in a linear correlation with leukemic burden. Moreover, exosomal DNA mutation status presented 86.5% of homology with BM and 75% with PB. The results of this pilot study confirmed the feasibility of a leukemia-derived exosome enrichment approach followed by exosomal dsDNA NGS analysis for AML biomarker detection. These data point to the use of liquid biopsy in myeloid neoplasia for the detection of active leukemic cells resident in the BM via a painless procedure.

The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence.

Cellular senescence is an irreversible state of cell cycle arrest occurring in response to stressful stimuli, such as telomere attrition, DNA damage, reactive oxygen species, and oncogenic proteins. Although beneficial and protective in several physiological processes, an excessive senescent cell burden has been involved in various pathological conditions including aging, tissue dysfunction and chronic diseases. Oxidative stress (OS) can drive senescence due to a loss of balance between pro-oxidant stimuli and antioxidant defences. Therefore, the identification and characterization of antioxidant compounds capable of preventing or counteracting the senescent phenotype is of major interest. However, despite the considerable number of studies, a comprehensive overview of the main antioxidant molecules capable of counteracting OS-induced senescence is still lacking. Here, besides a brief description of the molecular mechanisms implicated in OS-mediated aging, we review and discuss the role of enzymes, mitochondria-targeting compounds, vitamins, carotenoids, organosulfur compounds, nitrogen non-protein molecules, minerals, flavonoids, and non-flavonoids as antioxidant compounds with an anti-aging potential, therefore offering insights into innovative lifespan-extending approaches.

Investigating the Endo-Lysosomal System in Major Neurocognitive Disorders Due to Alzheimer's Disease, Frontotemporal Lobar Degeneration and Lewy Body Disease: Evidence for SORL1 as a Cross-Disease Gene.

Dysfunctions in the endo-lysosomal system have been hypothesized to underlie neurodegeneration in major neurocognitive disorders due to Alzheimer's disease (AD), Frontotemporal Lobar Degeneration (FTLD), and Lewy body disease (DLB). The aim of this study is to investigate whether these diseases share genetic variability in the endo-lysosomal pathway. In AD, DLB, and FTLD patients and in controls (948 subjects), we performed a targeted sequencing of the top 50 genes belonging to the endo-lysosomal pathway. Genetic analyses revealed (i) four previously reported disease-associated variants in the SORL1 (p.N1246K, p.N371T, p.D2065V) and DNAJC6 genes (p.M133L) in AD, FTLD, and DLB, extending the previous knowledge attesting SORL1 and DNAJC6 as AD- and PD-related genes, respectively; (ii) three predicted null variants in AD patients in the SORL1 (p.R985X in early onset familial AD, p.R1207X) and PPT1 (p.R48X in early onset familial AD) genes, where loss of function is a known disease mechanism. A single variant and gene burden analysis revealed some nominally significant results of potential interest for SORL1 and DNAJC6 genes. Our data highlight that genes controlling key endo-lysosomal processes (i.e., protein sorting/transport, clathrin-coated vesicle uncoating, lysosomal enzymatic activity regulation) might be involved in AD, FTLD and DLB pathogenesis, thus suggesting an etiological link behind these diseases.

Promising Intervention Approaches to Potentially Resolve Neuroinflammation And Steroid Hormones Alterations in Alzheimer's Disease and Its Neuropsychiatric Symptoms.

Neuroinflammation is a biological process by which the central nervous system responds to stimuli/injuries affecting its homeostasis. So far as this reactive response becomes exacerbated and uncontrolled, it can lead to neurodegeneration, compromising the cognitive and neuropsychiatric domains. Parallelly, modifications in the hypothalamic signaling of neuroprotective hormones linked also to the inflammatory responses of microglia and astrocytes can exacerbate these processes. To complicate the picture, modulations in the gut microbiota (GM) can induce changes in neuroinflammation, altering cognitive and neuropsychiatric functioning. We conducted a web-based search on PubMed. We described studies regarding the cross-talk among microglia and astrocytes in the neuroinflammation processes, along with the role played by the steroid hormones, and how this can reflect on cognitive decline/neurodegeneration, in particular on Alzheimer's Disease (AD) and its neuropsychiatric manifestations. We propose and support the huge literature showing the potentiality of complementary/alternative therapeutic approaches (nutraceuticals) targeting the sustained inflammatory response, the dysregulation of hypothalamic system and the GM composition. NF-κB and Keap1/Nrf2 are the main molecular targets on which a list of nutraceuticals can modulate the altered processes. Since there are some limitations, we propose a new intervention natural treatment in terms of Oxygen-ozone (O2-O3) therapy that could be potentially used for AD pathology. Through a meta-analytic approach, we found a significant modulation of O3 on inflammation-NF-κB/NLRP3 inflammasome/Toll-Like Receptor 4 (TLR4)/Interleukin IL-17α signalling, reducing mRNA (p<0.00001 Odd Ratio (OR)=-5.25 95% CI:-7.04/-3.46) and protein (p<0.00001 OR=-4.85 95%CI:-6.89/-2.81) levels, as well as on Keap1/Nrf2 pathway. Through anti-inflammatory, immune, and steroid hormones modulation and anti-microbial activities, O3 at mild therapeutic concentrations potentiated with nutraceuticals and GM regulators could determine combinatorial effects impacting on cognitive and neurodegenerative domains, neuroinflammation and neuroendocrine signalling, directly or indirectly through the mediation of GM.

Copper Imbalance in Alzheimer's Disease: Meta-Analysis of Serum, Plasma, and Brain Specimens, and Replication Study Evaluating ATP7B Gene Variants.

Evidence indicates that patients with Alzheimer's dementia (AD) show signs of copper (Cu) dyshomeostasis. This study aimed at evaluating the potential of Cu dysregulation as an AD susceptibility factor. We performed a meta-analysis of 56 studies investigating Cu biomarkers in brain specimens (pooled total of 182 AD and 166 healthy controls, HC) and in serum/plasma (pooled total of 2929 AD and 3547 HC). We also completed a replication study of serum Cu biomarkers in 97 AD patients and 70 HC screened for rs732774 and rs1061472 ATP7B, the gene encoding for the Cu transporter ATPase7B. Our meta-analysis showed decreased Cu in AD brain specimens, increased Cu and nonbound ceruloplasmin (Non-Cp) Cu in serum/plasma samples, and unchanged ceruloplasmin. Serum/plasma Cu excess was associated with a three to fourfold increase in the risk of having AD. Our replication study confirmed meta-analysis results and showed that carriers of the ATP7B AG haplotype were significantly more frequent in the AD group. Overall, our study shows that AD patients fail to maintain a Cu metabolic balance and reveals the presence of a percentage of AD patients carrying ATP7B AG haplotype and presenting Non-Cp Cu excess, which suggest that a subset of AD subjects is prone to Cu imbalance. This AD subtype can be the target of precision medicine-based strategies tackling Cu dysregulation.

Intermediate lengths of the C9ORF72 hexanucleotide repeat expansion may synergistically contribute to attention deficit hyperactivity disorder in child and his father: case report.

We have summarized the abstract section as follows: "We report a son and his father affected by Attention Deficit Hyperactivity Disorder (ADHD). They belonged to a larger cohort (116 ADHD children, 20 related parents, 77 controls) wholly genotyped forC9ORF72 expansion. Ten ADHD susceptibility genes were further investigated in the family. We revealed that son and father shared an intermediateC9ORF72 expansion and common variants inCDH23, ITGAE and MTRR. Bioinformatics highlighted aC9ORF72-MTRR interaction. This case-report underlines that in relatives with ADHD, carrying variants in ADHD susceptibility genes, the intermediateC9ORF72 repeats might have a potentially pathogenetic synergistic effect, supporting the multifactorial polygenic aetiopathogenetic profile of disease".

Genetic counselling and testing for inherited dementia: single-centre evaluation of the consensus Italian DIAfN protocol.

BACKGROUND: A consensus protocol for genetic counselling and testing of familial dementia, the Italian Dominantly Inherited Alzheimer's and Frontotemporal Network (IT-DIAfN) protocol, has been developed in Italy by a network of expert dementia centres. The aim of this study is to evaluate feasibility and acceptability of the genetic counselling and testing process, as undertaken according to the IT-DIAfN protocol in one of the IT-DIAfN dementia research centres. METHODS: The protocol was tested by a multidisciplinary team at the IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy, on affected individuals with suspected inherited forms of Alzheimer's disease (AD) or frontotemporal dementia (FTD), and to healthy at-risk relatives. The genetic counselling and testing process consisted of (i) pre-test consultation and psychological assessment (ii) genetic testing, (iii) genetic test result disclosure and (iv) follow-up consultation and psychological assessment. RESULTS: Twenty affected individuals from 17 families fulfilled the family history criteria of the IT-DIAfN protocol for suspected inherited dementia (17 for AD, 2 for FTD, 1 for inclusion body myopathy with Paget disease of bone and frontotemporal dementia) and were included in the protocol. Nineteen out of 20 affected individuals received the genetic test result (one left after the pre-test consultation being not ready to cope with an unfavourable outcome). A pathogenic mutation was found in 6 affected individuals (1 in PSEN1, 2 in PSEN2, 1 in GRN, 1 in MAPT, 1 in VCP). Eleven healthy at-risk relatives asked to undergo predictive testing and were included in the protocol. Three completed the protocol, including follow-up; one did not ask for the genetic test result after genetic testing; and eight withdrew before the genetic testing, mainly due to an increased awareness about the possible consequences of an unfavourable test result. To date, no catastrophic reactions were reported at the follow-up. CONCLUSIONS: Our case series shows that a structured genetic counselling and testing protocol for inherited dementia can be implemented in both affected individuals and at-risk relatives in a research setting. The procedure was shown to be safe in terms of occurrence of catastrophic events. A formal validation in larger cohorts is needed.

Behavioral and Psychological Symptoms of Dementia (BPSD): Clinical Characterization and Genetic Correlates in an Italian Alzheimer's Disease Cohort.

BACKGROUND: The occurrence of Behavioral and Psychological Symptoms of Dementia (BPSD) in Alzheimer's Disease (AD) patients hampers the clinical management and exacerbates the burden for caregivers. The definition of the clinical distribution of BPSD symptoms, and the extent to which symptoms are genetically determined, are still open to debate. Moreover, genetic factors that underline BPSD symptoms still need to be identified. PURPOSE: To characterize our Italian AD cohort according to specific BPSD symptoms as well as to endophenotypes. To evaluate the associations between the considered BPSD traits and COMT, MTHFR, and APOE genetic variants. METHODS: AD patients (n = 362) underwent neuropsychological examination and genotyping. BPSD were assessed with the Neuropsychiatric Inventory scale. RESULTS: APOE and MTHFR variants were significantly associated with specific single BPSD symptoms. Furthermore, "Psychosis" and "Hyperactivity" resulted in the most severe endophenotypes, with APOE and MTHFR implicated as both single risk factors and "genexgene" interactions. CONCLUSIONS: We strongly suggest the combined use of both BPSD single symptoms/endophenotypes and the "genexgene" interactions as valid strategies for expanding the knowledge about the BPSD aetiopathogenetic mechanisms.

Ozone: a natural bioactive molecule with antioxidant property as potential new strategy in aging and in neurodegenerative disorders.

Systems medicine is founded on a mechanism-based approach and identifies in this way specific therapeutic targets. This approach has been applied for the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Nrf2 plays a central role in different pathologies including neurodegenerative disorders (NDs), which are characterized by common pathogenetic features. We here present wide scientific background indicating how a natural bioactive molecule with antioxidant/anti-apoptotic and pro-autophagy properties such as the ozone (O3) can represent a potential new strategy to delay neurodegeneration. Our hypothesis is based on different evidence demonstrating the interaction between O3 and Nrf2 system. Through a meta-analytic approach, we found a significant modulation of O3 on endogenous antioxidant-Nrf2 (p < 0.00001, Odd Ratio (OR) = 1.71 95%CI:1.17-2.25) and vitagene-Nrf2 systems (p < 0.00001, OR = 1.80 95%CI:1.05-2.55). O3 activates also immune, anti-inflammatory signalling, proteasome, releases growth factors, improves blood circulation, and has antimicrobial activity, with potential effects on gut microbiota. Thus, we provide a consistent rationale to implement future clinical studies to apply the oxygen-ozone (O2-O3) therapy in an early phase of aging decline, when it is still possible to intervene before to potentially develop a more severe neurodegenerative pathology. We suggest that O3 along with other antioxidants (polyphenols, mushrooms) implicated in the same Nrf2-mechanisms, can show neurogenic potential, providing evidence as new preventive strategies in aging and in NDs.

Association study between HTR2A rs6313 polymorphism and early response to risperidone and olanzapine in schizophrenia patients.

Antipsychotic drugs are the preferred choice for schizophrenia treatment; however, response is highly variable. In the context of the search for predictors of antipsychotic treatment effectiveness, the evaluation of response within 2 weeks has been indicated to predict long-term outcome. Moreover, a focus on symptomatological domains could be helpful to better characterize antipsychotic response, identifying more specific predictors. Pharmacogenetic studies have indicated a role for rs6313 in the serotonin receptor gene HTR2A in affecting response to antipsychotics, with heterogeneous results. With the aim to test for the first time the application of a dimensional approach for the evaluation of early response, we carried out a genetic association study between rs6313 and antipsychotic response in two groups of schizophrenia patients in monotherapy with risperidone (n = 121) and olanzapine (n = 100). Patients were evaluated at the baseline and after 1 and 2 weeks of treatment. When comparing early responders versus early nonresponders, no association was detected for the two drugs separately, whereas by taking into consideration the two drugs together it was observed that carriers of the T allele had a higher response probability compared to noncarriers. Considering 2-week improvements, changes in PANSS total scores, subscores and in PANSS Emsley's symptomatological dimensions were associated with rs6313 for both risperidone and olanzapine. Moreover, the repeated measures analysis indicated an association of rs6313 with the disorganized thought dimension for risperidone, and with the depressive and anxiety dimensions for olanzapine. These data add support to the hypothesis that the HTR2A gene is involved in antipsychotic treatment outcome.

Neurodevelopmental disorders: Metallomics studies for the identification of potential biomarkers associated to diagnosis and treatment.

BACKGROUND: Diagnosis and treatment of complex diseases such as Neurodevelopmental Disorders (NDDs) can be resolved through the identification of biomarkers. Metallomics (research on biometals) and metallomes (metalloproteins/metalloenzymes/chaperones) along with genomics, proteomics and metabolomics, can contribute to accelerate and improve this process. AIM: This review focused on four NDDs pathologies (Schizophrenia, SZ; Attention Deficit Hyperactivity Disorder, ADHD; Autism, ADS; Epilepsy), and we reported, for the first time, different studies on the role played by the principal six essential trace elements (Cobalt, Co; Copper, Cu; Iron, Fe; Manganese, Mn; Selenium, Se; Zinc, Zn) that can influence diagnosis/treatment. RESULTS: in light of the literature presented, based on meta-analyses, we suggest that Zn (glutamatergic neurotransmission, inflammation, neurodegeneration, autoimmunity alterations), could be a potential diagnostic biomarker associated to SZ. Moreover, considering the single association studies going in the same direction, increased Cu (catecholamine alterations, glucose intolerance, altered lipid metabolism/oxidative stress) and lower Fe (dopaminergic dysfunctions) levels were associated with a specific negative symptomatology. Lower Mn (lipid metabolism/oxidative stress alterations), and lower Se (metabolic syndrome) were linked to SZ. From the meta-analyses in ADHD, it is evidenced that Fe (and ferritin in particular), Mn, and Zn (oxidative stress dysfunctions) could be potential diagnostic biomarkers, mainly associated to severe hyperactive or inattentive symptoms; as well as Cu, Fe, Zn in ADS and Zn in Epilepsy. Fe, Zn and Mn levels seem to be influenced by antipsychotics treatment in SZ; Mn and Zn by methylphenidate treatment in ADHD; Cu and Zn by antiepileptic drugs in Epilepsy. CONCLUSIONS: Although there is controversy and further studies are needed, this work summarizes the state of art of the literature on this topic. We claim to avoid underreporting the impact of essential trace elements in paving the way for biomarkers research for NDDs.

Genetic determinants of circulating VEGF levels in major depressive disorder and electroconvulsive therapy response.

Alterations in peripheral vascular endothelial growth factor (VEGF) levels were observed in major depressive disorder and relative treatments and were shown to be influenced by genetic variants. The study objective was to explore, at a genome-wide level, possible interplaying effects between the genetic background and major depressive disorder in regulating VEGF levels. Moreover, we aimed to investigate the association between these variants and response to electroconvulsive therapy. A genome-wide association study was carried out both on controls and patients with major depressive disorder (n = 145; n = 121) in correlation with serum VEGF levels determined by ELISA. Five SNPs not included in SNP arrays were additionally genotyped. Seventy-one patients with treatment-resistant depression underwent electroconvulsive therapy and were evaluated as responders/nonresponders. An association between VEGF levels and a locus in 6p21.1, downstream the VEGF gene, was evidenced both in controls (best SNP: FDR-corrected p = 2.4 × 10-5 ) and in patients with major depressive disorder (best SNP: FDR-corrected p = 2.6 × 10-3 ). The alleles associated with lower VEGF concentrations in patients were also associated with nonresponse to electroconvulsive therapy (p = .01). These results confirm a role of SNPs in 6p21.1 locus as major influencers of circulating VEGF levels also in patients affected by major depressive disorder and indicate a possible implication in response to electroconvulsive therapy.

DRD4 48 bp multiallelic variants as age-population-specific biomarkers in attention-deficit/hyperactivity disorder.

The identification of biomarkers to support the diagnosis and prediction of treatment response for attention-deficit/hyperactivity disorder (ADHD) is still a challenge. Our previous works highlighted the DRD4 (dopamine receptor D4) as the best potential genetic marker for childhood diagnosis and methylphenidate (MPH) response. Here, we aimed to provide additional evidence on biomarkers for ADHD diagnosis and treatment response, by using more specific approaches such as meta-analytic and bioinformatics tools. Via meta-analytic approaches including over 3000 cases and 16,000 controls, we demonstrated that, among the different variants studied in DRD4 gene, the 48-base pair, Variable Tandem Repeat Polymorphism, VNTR in exon 3 showed an age/population-specificity and an allelic heterogeneity. In particular, the 7R/"long" allele was identified as an ADHD risk factor in European-Caucasian populations (d = 1.31, 95%CI: 1.17-1.47, Z = 4.70/d = 1.36, 95%CI: 1.20-1.55, Z = 4.78, respectively), also, from the results of last meta-analysis, linked to the poor MPH efficacy. The 4R/"short" allele was a protective factor in European-Caucasian and South American populations (d = 0.83, 95%CI: 0.75-0.92, Z = 3.58), and was also associated to positive MPH response. These results refer to children with ADHD. No evidence of such associations was detected for adults with persistent ADHD (data from the last meta-analysis). Moreover, we found evidence that the 4R allele leads to higher receptor expression and increased sensitivity to dopamine, as compared with the 7R allele (d = 1.20, 95%CI: 0.71-1.69, Z = 4.81), and this is consistent with the ADHD protection/susceptibility effects of the respective alleles. Using bioinformatics tools, based on the latest genome-wide association (GWAS) meta-analysis of the Psychiatry Genomic Consortium (PGC), we demonstrated that the 48 bp VNTR is not in Linkage Disequilibrium with the DRD4 SNPs (Single Nucleotide Polymorphisms), which were not found to be associated with ADHD. Moreover, a DRD4 expression downregulation was found in ADHD specific brain regions (Putamen, Z score = -3.02, P = 0.00252). Overall, our results suggest that DRD4 48 bp VNTR variants should be considered as biomarkers to support the diagnosis of ADHD and to predict MPH response, although the accuracy of such a biomarker remains to be further elucidated.

Molecular mechanisms in cognitive frailty: potential therapeutic targets for oxygen-ozone treatment.

In the last decade, cognitive frailty has gained great attention from the scientific community. It is characterized by high inflammation and oxidant state, endocrine and metabolic alterations, mitochondria dysfunctions and slowdown in regenerative processes and immune system, with a complex and multifactorial aetiology. Although several treatments are available, challenges regarding the efficacy and the costs persist. Here, we proposed an alternative non-pharmacological, non-side-effect, low cost therapy based on anti-inflammation, antioxidant, regenerative and anti-pathogens properties of ozone, through the activation of several molecular mechanisms (Nrf2-ARE, NF-κB, NFAT, AP-1, HIFα). We highlighted how these specific processes could be implicated in cognitive frailty to identify putative therapeutic targets for its treatment. The oxigen-ozone (O2-O3) therapy has never been tested for cognitive frailty. This work provides thus wide scientific background to build a consistent rationale for testing for the first time this therapy, that could modulate the immune, inflammatory, oxidant, metabolic, endocrine, microbiota and regenerative processes impaired in cognitive frailty. Although insights are needed, the O2-O3 therapy could represent a faster, easier, inexpensive monodomain intervention working in absence of side effects for cognitive frailty.

Age at onset reveals different functional connectivity abnormalities in prodromal Alzheimer's disease.

Age at symptom onset (AAO) underlies different Alzheimer's disease (AD) clinical variants: late-onset AD (LOAD) is characterized by memory deficits, while early-onset AD (EOAD) presents predominantly with non-memory symptoms. The involvement of different neural networks may explain these distinct clinical phenotypes. In this study, we tested the hypothesis of an early and selective involvement of neural networks based on AAO in AD. Twenty memory clinic patients with prodromal AD (i.e., mild cognitive impairment with an AD-like cerebrospinal fluid profile) and 30 healthy controls underwent a cognitive evaluation and a resting state functional MRI exam. Independent component analysis was performed to assess functional connectivity (FC) in the following networks: default mode, frontoparietal, limbic, visual, and sensorimotor. Patients were stratified into late-onset (pLOAD) and early-onset (pEOAD) prodromal AD according to the AAO and controls were stratified into younger and older groups accordingly. Decreased FC within the default mode and the limbic networks was observed in pLOAD, while pEOAD showed lower FC in the frontoparietal and visual networks. The sensorimotor network did not show differences between groups. A significant association was found between memory and limbic network FC in pLOAD, and between executive functions and frontoparietal network FC in pEOAD, although the latter association did not survive multiple comparison correction. Our findings indicate that aberrant connectivity in memory networks is associated with pLOAD, while networks underlying executive and visuo-spatial functions are affected in pEOAD. These findings are in line with the hypothesis that the pathophysiological mechanisms underlying EOAD and LOAD are distinct.

The Missing Heritability of Sporadic Frontotemporal Dementia: New Insights from Rare Variants in Neurodegenerative Candidate Genes.

Frontotemporal dementia (FTD) is a common form of dementia among early-onset cases. Several genetic factors for FTD have been revealed, but a large proportion of FTD cases still have an unidentified genetic origin. Recent studies highlighted common pathobiological mechanisms among neurodegenerative diseases. In the present study, we investigated a panel of candidate genes, previously described to be associated with FTD and/or other neurodegenerative diseases by targeted next generation sequencing (NGS). We focused our study on sporadic FTD (sFTD), devoid of disease-causing mutations in GRN, MAPT and C9orf72. Since genetic factors have a substantially higher pathogenetic contribution in early onset patients than in late onset dementia, we selected patients with early onset (<65 years). Our study revealed that, in 50% of patients, rare missense potentially pathogenetic variants in genes previously associated with Alzheimer's disease, Parkinson disease, amyotrophic lateral sclerosis and Lewy body dementia (GBA, ABCA7, PARK7, FUS, SORL1, LRRK2, ALS2), confirming genetic pleiotropy in neurodegeneration. In parallel, a synergic genetic effect on FTD is suggested by the presence of variants in five different genes in one single patient. Further studies employing genome-wide approaches might highlight pathogenic variants in novel genes that explain the still missing heritability of FTD.

Genome Wide Association Study and Next Generation Sequencing: A Glimmer of Light Toward New Possible Horizons in Frontotemporal Dementia Research.

Frontotemporal Dementia (FTD) is a focal neurodegenerative disease, with a strong genetic background, that causes early onset dementia. The present knowledge about the risk loci and causative mutations of FTD mainly derives from genetic linkage analysis, studies of candidate genes, Genome-Wide Association Studies (GWAS) and Next-Generation Sequencing (NGS) applications. In this review, we report recent insights into the genetics of FTD, and, specifically, the results achieved thanks to GWAS and NGS approaches. Linkage studies of large FTD pedigrees have prompted the identification of causal mutations in different genes: mutations in C9orf72, MAPT, and GRN genes explain the large majority of cases with a high family history of the disease. In cases with a less clear inheritance, GWAS and NGS have contributed to further understand the genetic picture of FTD. GWAS identified several common genetic variants with a modest risk effect. Of interest, many of these variants are in genes belonging to the endo-lysosomal pathway, the immune response and neuronal survival. On the opposite, the NGS approach allowed the identification of rare variants with a strong risk effect. These variants were identified in known FTD-associated genes and again in genes involved in the endo-lysosomal pathway and in the immune response. Interestingly, both approaches demonstrated that several genes are associated to multiple neurodegenerative disorders including FTD. Thanks to these complementary approaches, the genetic picture of FTD is becoming more clear and novel key molecular processes are emerging. This will foster opportunities to move toward prevention and therapy for this incurable disease.

Next Generation Sequencing Analysis in Early Onset Dementia Patients.

BACKGROUND: Early onset dementias (EOD) are rare neurodegenerative dementias that present before 65 years. Genetic factors have a substantially higher pathogenetic contribution in EOD patients than in late onset dementia. OBJECTIVE: To identify known and/or novel rare variants in major candidate genes associated to EOD by high-throughput sequencing. Common-risk variants of apolipoprotein E (APOE) and prion protein (PRNP) genes were also assessed. METHODS: We studied 22 EOD patients recruited in Memory Clinics, in the context of studies investigating genetic forms of dementia. Two methodological approaches were applied for the target-Next Generation Sequencing (NGS) analysis of these patients. In addition, we performed progranulin plasma dosage, C9Orf72 hexanucleotide repeat expansion analysis, and APOE genotyping. RESULTS: We detected three rare known pathogenic mutations in the GRN and PSEN2 genes and eleven unknown-impact mutations in the GRN, VCP, MAPT, FUS, TREM2, and NOTCH3 genes. Six patients were carriers of only common risk variants (APOE and PRNP), and one did not show any risk mutation/variant. Overall, 69% (n = 9) of our early onset Alzheimer's disease (EAOD) patients, compared with 34% (n = 13) of sporadic late onset Alzheimer's disease (LOAD) patients and 27% (n = 73) of non-affected controls (ADNI, whole genome data), were carriers of at least two rare/common risk variants in the analyzed candidate genes panel, excluding the full penetrant mutations. CONCLUSION: This study suggests that EOD patients without full penetrant mutations are characterized by higher probability to carry polygenic risk alleles that patients with LOAD forms. This finding is in line with recently reported evidence, thus suggesting that the genetic risk factors identified in LOAD might modulate the risk also in EOAD.