Differential levels of Neurofilament Light protein in cerebrospinal fluid in patients with a wide range of neurodegenerative disorders.

Cerebrospinal fluid (CSF) biomarkers are useful in the diagnosis and the prediction of progression of several neurodegenerative diseases. Among them, CSF neurofilament light (NfL) protein has particular interest, as its levels reflect neuroaxonal degeneration, a common feature in various neurodegenerative diseases. In the present study, we analyzed NfL levels in the CSF of 535 participants of the SPIN (Sant Pau Initiative on Neurodegeneration) cohort including cognitively normal participants, patients with Alzheimer disease (AD), Down syndrome (DS), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). We evaluated the differences in CSF NfL accross groups and its association with other CSF biomarkers and with cognitive scales. All neurogenerative diseases showed increased levels of CSF NfL, with the highest levels in patients with ALS, FTD, CBS and PSP. Furthermore, we found an association of CSF NfL levels with cognitive impairment in patients within the AD and FTD spectrum and with AD pathology in DLB and DS patients. These results have implications for the use of NfL as a marker in neurodegenerative diseases.

Fused in Sarcoma (FUS) gene mutations are not a frequent cause of essential tremor in Europeans.

FUS/TLS (denoting fused in sarcoma/translocated in liposarcoma [MIM 137070]) codifies an RNA binding protein. Mutations in this gene cause amyotrophic lateral sclerosis (ALS; MIM 608030). Essential tremor (ET [MIM 190300]) is the most frequent movement disorder. Despite its strong familiar aggregation, recently a whole exome sequencing study has identified FUS mutations as a cause of familial ET. To determine whether mutations in FUS are also common in other populations, we sequenced FUS gene in 178 unrelated Spanish subjects with ET. We detected only an intronic single-pair nucleotide deletion (c.1293-37delC), which was predicted to affect mRNA splicing. However, leukocyte mRNA analysis showed no changes in FUS expression. In conclusion, coding or splicing FUS mutations are not a frequent cause of ET in the Spanish population.

Genetic risk score predicting accelerated progression from mild cognitive impairment to Alzheimer's disease.

Aside from APOE, the genetic factors that influence the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) remain largely unknown. We assessed whether a genetic risk score (GRS), based on eight non-APOE genetic variants previously associated with AD risk in genome-wide association studies, is associated with either risk of conversion or with rapid progression from MCI to AD. Among 288 subjects with MCI, follow-up (mean 26.3 months) identified 118 MCI-converters to AD and 170 MCI-nonconverters. We genotyped ABCA7 rs3764650, BIN1 rs744373, CD2AP rs9296559, CLU rs1113600, CR1 rs1408077, MS4A4E rs670139, MS4A6A rs610932, and PICALM rs3851179. For each subject we calculated a cumulative GRS, defined as the number of risk alleles (range 0-16) with each allele weighted by the AD risk odds ratio. GRS was not associated with risk of conversion from MCI to AD. However, MCI-converters to AD harboring six or more risk alleles (second and third GRS tertiles) progressed twofold more rapidly to AD when compared with those with less than six risk alleles (first GRS tertile). Our GRS is a first step toward development of prediction models for conversion from MCI to AD that incorporate aggregate genetic factors.

PICOGEN: experiencia de 5 años de un programa de asesoramiento genético en demencia / PICOGEN: Five years experience with a genetic counselling program for dementia

Introducción: Describimos la experiencia del Programa de Información y Consejo Genético para demencias familiares (PICOGEN) en sus 5 a˜nos de funcionamiento. Métodos: Todos los sujetos fueron asesorados por un neurólogo que seleccionó los candidatos a estudio genético según la historia familiar y el diagnóstico (enfermedad de Alzheimer [EA], degeneración lobular frontotemporal [DLFT] o enfermedad priónica). Los sujetos asintomáticos que decidieron conocer su estatus genético siguieron un protocolo estructurado de evaluación antes y después de la realización del test genético. Resultados: Ochenta y siete pacientes de 72 familias fueron candidatos a estudio genético, 20 de 72 familias presentaban historia familiar autosómica dominante de inicio precoz (HADp). En 22 se detectó una mutación patogénica (8 PSEN1, 1 PSEN2, 1 APP, 4 MAPT, 8 PRNP), 5 no descritas previamente. Todos los casos con mutación, excepto uno PSEN1 (12,5%) y 4 PRNP (50%) presentaban HADp. En 3 casos con HADp (15%) no se encontró ninguna mutación. 24 de 54 sujetos asintomáticos de familias con mutación conocida decidieron realizarse el estudio presintomático, 10 resultaron portadores. En el seguimiento de los sujetos que realizaron el estudio predictivo no se observó ninguna complicación psiquiátrica mayor. Conclusiones: En nuestra serie la HADp resultó un criterio sensible para la detección de mutaciones patogénicas en EA y DLFT, pero no en enfermedades priónicas. Un 15% de los casos HADp no presentaron alteraciones genéticas causales en estudios diagnósticos convencionales. El 43% de los sujetos en riesgo que recibieron asesoramiento genético individual realizaron el estudio presintomático. El estudio presintomático resultó seguro en este contexto (AU)

Introduction: We describe the 5 year experience of a genetic counselling program for familial dementias (the PICOGEN program). Methods: The neurologist selected the candidates for genetic testing in the screening visit based on family history and phenotype (Alzheimer disease-AD, frontotemporal lobar degeneration-FTLD, or prion disease). Asymptomatic subjects who decided to know their genetic status were evaluated within a structured protocol by the psychiatrist and psychologist prior to entering the program and followed up afterwards. Results: A total of 87 patients from 72 families were candidates for the genetic study, 20 of the 72 families had a family history of autosomal dominant early-onset dementia (ADEOD). A pathogenic mutation was found in 22 patients (8 PSEN1, 1 PSEN2, 1 APP, 4 MAPT, 8 PRNP), 5 of which had not been previously described. All positive cases, except for 1 PSEN1 (12.5%) and 4 PRNP (50%) showed ADEOD. In 3 ADEOD cases (15%) no pathogenic mutation was found. After individual genetic counselling, 24/54 asymptomatic subjects at risk decided to have the presymptomatic study, of whom 10 (42%) were carriers of the pathogenic mutation. In the follow up, no major psychiatric complication was observed. Conclusions: In our series, family history of ADEOD was a sensitive criterion for the detection of pathogenic mutations in AD and FTLD but not in prion diseases. No genetic anomalies were detected in 15% of the ADEOD cases using conventional diagnostic procedures, and 43% of presymptomatic subjects at risk who received individual genetic counselling decided to have the study. The pre-symptomatic diagnosis proved to be safe under these conditions (AU)

PICOGEN: five years experience with a genetic counselling program for dementia.

INTRODUCTION: We describe the 5 year experience of a genetic counselling program for familial dementias (the PICOGEN program). METHODS: The neurologist selected the candidates for genetic testing in the screening visit based on family history and phenotype (Alzheimer disease-AD, frontotemporal lobar degeneration-FTLD, or prion disease). Asymptomatic subjects who decided to know their genetic status were evaluated within a structured protocol by the psychiatrist and psychologist prior to entering the program and followed up afterwards. RESULTS: A total of 87 patients from 72 families were candidates for the genetic study, 20 of the 72 families had a family history of autosomal dominant early-onset dementia (ADEOD). A pathogenic mutation was found in 22 patients (8 PSEN1, 1 PSEN2, 1 APP, 4 MAPT, 8 PRNP), 5 of which had not been previously described. All positive cases, except for 1 PSEN1 (12.5%) and 4 PRNP (50%) showed ADEOD. In 3 ADEOD cases (15%) no pathogenic mutation was found. After individual genetic counselling, 24/54 asymptomatic subjects at risk decided to have the pre-symptomatic study, of whom 10 (42%) were carriers of the pathogenic mutation. In the follow up, no major psychiatric complication was observed. CONCLUSIONS: In our series, family history of ADEOD was a sensitive criterion for the detection of pathogenic mutations in AD and FTLD but not in prion diseases. No genetic anomalies were detected in 15% of the ADEOD cases using conventional diagnostic procedures, and 43% of pre-symptomatic subjects at risk who received individual genetic counselling decided to have the study. The pre-symptomatic diagnosis proved to be safe under these conditions.

A novel PSEN1 mutation (K239N) associated with Alzheimer's disease with wide range age of onset and slow progression.

OBJECTIVE: To describe a novel mutation (K239N) in the PSEN1 associated with familial Alzheimer's disease (AD). METHODS AND RESULTS: The proband was a man who developed cognitive decline with marked behavioural abnormalities at age 57. At age 70, he was admitted into a psychiatric facility because of aggressiveness and a suicide attempt. Family history was consistent with autosomal dominant AD. One of the two other family members studied presented also with prominent behavioural symptoms at age 42 and has also been forced into a psychiatric facility because of aggressiveness at age 56. The remainder patient has presented a prototypical AD, but starting at age 71. Direct sequencing of PSEN1 in the three living affected members disclosed a heterozygous G to C transition in exon 7 of PSEN1 leading to the K239N mutation. CONCLUSION: The K239N mutation is associated with autosomal dominant AD with a wide range of age of onset and incomplete penetrance at the age of 65, prominent behavioural features and slow progression.

Triflusal reduces dense-core plaque load, associated axonal alterations and inflammatory changes, and rescues cognition in a transgenic mouse model of Alzheimer's disease.

Inflammation has been associated with the two classic lesions in the Alzheimer's (AD) brain, amyloid deposits and neurofibrillary tangles. Recent data suggest that Triflusal, a compound with potent anti-inflammatory effects in the central nervous system in vivo, might delay the conversion from amnestic mild cognitive impairment to a fully established clinical picture of dementia. In the present study, we investigated the effect of Triflusal on brain Abeta accumulation, neuroinflammation, axonal curvature and cognition in an AD transgenic mouse model (Tg2576). Triflusal treatment did not alter the total brain Abeta accumulation but significantly reduced dense-cored plaque load and associated glial cell proliferation, proinflammatory cytokine levels and abnormal axonal curvature, and rescued cognitive deficits in Tg2576 mice. Behavioral benefit was found to involve increased expression of c-fos and BDNF, two of the genes regulated by CREB, as part of the signal transduction cascade underlying the molecular basis of long-term potentiation. These results add preclinical evidence of a potentially beneficial effect of Triflusal in AD.

A novel GSK-3beta inhibitor reduces Alzheimer's pathology and rescues neuronal loss in vivo.

Amyloid deposits, neurofibrillary tangles, and neuronal cell death in selectively vulnerable brain regions are the chief hallmarks in Alzheimer's (AD) brains. Glycogen synthase kinase-3 (GSK-3) is one of the key kinases required for AD-type abnormal hyperphosphorylation of tau, which is believed to be a critical event in neurofibrillary tangle formation. GSK-3 has also been recently implicated in amyloid precursor protein (APP) processing/Abeta production, apoptotic cell death, and learning and memory. Thus, GSK-3 inhibition represents a very attractive drug target in AD and other neurodegenerative disorders. To investigate whether GSK-3 inhibition can reduce amyloid and tau pathologies, neuronal cell death and memory deficits in vivo, double transgenic mice coexpressing human mutant APP and tau were treated with a novel non-ATP competitive GSK-3beta inhibitor, NP12. Treatment with this thiadiazolidinone compound resulted in lower levels of tau phosphorylation, decreased amyloid deposition and plaque-associated astrocytic proliferation, protection of neurons in the entorhinal cortex and CA1 hippocampal subfield against cell death, and prevention of memory deficits in this transgenic mouse model. These results show that this novel GSK-3 inhibitor has a dual impact on amyloid and tau alterations and, perhaps even more important, on neuronal survival in vivo further suggesting that GSK-3 is a relevant therapeutic target in AD.

Whole genome analysis in a consanguineous family with early onset Alzheimer's disease.

Early-onset Alzheimer's disease (EOAD) is a clinically and genetically heterogeneous condition in which the typical features appear significantly earlier in life (before 65 years). Mutations in three genes (PSEN1, PSEN2, and APP) have been identified in autosomal dominant forms of EOAD. However, in about 50% of Mendelian cases and in most of the sporadic EOAD patients, no mutations have been found. We present clinical characteristics of an Israeli family comprising two affected siblings with EOAD born to neurologically healthy parents who were first cousins (both parents died after 90 years old). Sequence analysis of PSEN1, PSEN2, APP, TAU, PGRN, and PRNP failed to reveal any mutations in the affected siblings. Because the disease in this family is consistent with an autosomal recessive mode of inheritance we identified all homozygous regions identical by descent (IBD) in both siblings, by high-density SNP genotyping. We provide here the first catalog of autozygosity in EOAD and suggest that the regions identified are excellent candidate loci for a recessive genetic lesion causing this disease.

Association of phosphodiesterase 4D gene G0 haplotype and ischaemic stroke in a Greek population.

We have examined the association of phosphodiesterase 4D (PDE4D) single nucleotide polymorphism (SNP45) and microsatellite marker AC008818-1 with ischaemic stroke, in an independent cohort of Greek patients and control individuals with no clinical manifestations of vascular disease. Significantly different distributions were observed with respect to the AC008818-1 alleles, with allele 148 associating with an increased risk of stroke incidence, and allele 144 with a protective effect. In addition, the haplotype defined by allele 148 and G allele of SNP45 was found to be significantly increased in patients even though no statistically significant differences emerged with respect to SNP45 alone. The previously established association of a PDE4D gene haplotype with ischaemic stroke in a population from Iceland was independently confirmed in our Greek population, suggesting that PDE4D may be involved in the aetiology and pathogenesis of stroke.

Alpha-synuclein in blood and brain from familial Parkinson disease with SNCA locus triplication.

The authors recently demonstrated that genetic triplication of the SNCA locus causes Parkinson disease. Here it is shown that SNCA triplication results in a doubling in the amount of alpha-synuclein protein in blood. Examination of brain tissue showed a doubling in the level of SNCA message. However, at the protein level in brain, there was a greater effect on deposition of aggregated forms into insoluble fractions than on net expression of soluble alpha-synuclein.

Possible increased risk for Alzheimer's disease associated with neprilysin gene.

Neprilysin has recently been reported to be the major physiological Abeta-degradating enzyme. In this study we describe a new biallelic polymorphism in the 3'UTR of the neprilysin gene in a representative population sample. The (*)159C/C genotype was found to be associated with an increased risk for Alzheimer's disease in an age-dependent manner. Adjusting for sex and APOE status, an odds ratio of 2.74 (p < 0.05) was observed among patients under 75 years old.

Allele frequencies of 13 short tandem repeats in population samples from the Iberian Peninsula and northern Africa.

The 13 short tandem repeat (STR) loci D3S1358, vWA, FGA, D16S539, TH01, TPOX, CSF1PO, D8S1179, D21S11, D18S51, D5S818, D13S317 and D7S820 as well as the amelogenin locus, contained in AmpFlSTR Profiler Plus and/or AmpFlSTR Cofiler and/or AmpFlSTR Green I PCR amplification kits, were studied in four populations from the Iberian Peninsula, Basques, Catalans, Andalusians and Portuguese and two North African populations (Moroccan Arabs and Berbers). The aim of the study was to obtain accurate allele frequency data and other genetic parameters of forensic interest on the main representative human groups living in Iberia and Morocco using an automated method and commercial amplification kits.