Alzheimer's Disease CSF Biomarkers as Possible Indicators of Tap-Test Response in Idiopathic Normal Pressure Hydrocephalus.

The aim of the present study is the evaluation of established Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in patients with idiopathic normal-pressure hydrocephalus (iNPH), both individually and as a total profile, and the investigation of their use as potential predictors of Tap-test responsiveness. Fifty-three patients with iNPH participated in the study. Aß42, Aß40, total Tau and phospho-Tau proteins were measured in duplicate with double-sandwich ELISA assays. Clinical evaluation involved a 10 m timed walk test before an evacuative lumbar puncture (LP) and every 24 h for three consecutive days afterwards. Neuropsychological assessment involved a mini-mental state examination, frontal assessment battery, 5-word test and CLOX drawing test 1 and 2, which were also performed before and 48 h after LP. Response in the Tap-test was defined as a 20% improvement in gait and/or a 10% improvement in neuropsychological tests. The Aß42/Aß40 ratio was found to be significantly higher in Tap-test responders than non-responders. Total Tau and phospho-Tau CSF levels also differed significantly between these two groups, with Tap-test responders presenting with lower levels compared to non-responders. Regarding the AD CSF biomarker profile (decreased amyloid and increased Tau proteins levels), patients with a non-AD profile were more likely to have a positive response in the Tap-test than patients with an AD profile.

Subclinical atherosclerosis profiles in rheumatoid arthritis and primary Sjögren's syndrome: the impact of BAFF genetic variations.

OBJECTIVES: RA and primary SS carry increased atherosclerotic risk, while B-cell activating factor holds a vital role in disease pathogenesis and atherosclerosis. We aimed to compare subclinical atherosclerosis profiles between the two clinical entities and define whether BAFF genetic variants alter atherosclerotic risk. METHODS: DNA from 166 RA, 148 primary SS patients and 200 healthy controls of similar age and sex distribution was subjected to PCR-based assay for the detection of five single nucleotide polymorphisms of the BAFF gene (rs1224141, rs12583006, rs9514828, rs1041569 and rs9514827). Genotype and haplotype frequencies were determined by SNPStats software and statistical analysis was performed by SPSS and Graphpad Software. Subclinical atherosclerosis was defined by the presence of carotid/femoral plaque formation and arterial wall thickening. RESULTS: Atherosclerotic plaque formation was more frequently detected in the RA vs primary SS group (80.7% vs 62.2%, P-value <0.001), along with higher rates of family CVD history, current steroid dose and serum inflammatory markers. The TT genotype of the rs1224141 variant was more prevalent in RA but not primary SS patients with plaque and arterial wall thickening vs their counterparts without. Regarding the rs1014569 variant, among RA patients the TT genotype increased the risk for plaque formation while in primary SS patients the AT genotype conferred increased risk. Haplotype GTTTT was protective in the RA cohort, while TATTT and TTCTT haplotypes increased susceptibility for arterial wall thickening in the primary SS cohort. CONCLUSIONS: Increased inflammatory burden, higher steroid doses and distinct BAFF gene variations imply chronic inflammation and B-cell hyperactivity as key contributors for the augmented atherosclerotic risk among autoimmune patients.

Cerebrospinal Fluid Biomarkers in iNPH: A Narrative Review.

Idiopathic normal pressure hydrocephalus (iNPH) is a neurological syndrome characterized by the clinical triad of gait disorder, cognitive impairment and urinary incontinence. It has attracted interest because of the possible reversibility of symptoms, especially with timely treatment. The main pathophysiological theory is based on a vicious circle of disruption in circulation of cerebrospinal fluid (CSF) that leads to the deceleration of its absorption. Data regarding CSF biomarkers in iNPH are contradictory and no definite CSF biomarker profile has been recognized as in Alzheimer's disease (AD), which often co-exists with iNPH. In this narrative review, we investigated the literature regarding CSF biomarkers in iNPH, both the established biomarkers total tau protein (t-tau), phosphorylated tau protein (p-tau) and amyloid peptide with 42 amino acids (Aß42), and other molecules, which are being investigated as emerging biomarkers. The majority of studies demonstrate differences in CSF concentrations of Aß42 and tau-proteins (t-tau and p-tau) among iNPH patients, healthy individuals and patients with AD and vascular dementia. iNPH patients present with lower CSF Aß42 and p-tau concentrations than healthy individuals and lower t-tau and p-tau concentrations than AD patients. This could prove helpful for improving diagnosis, differential diagnosis and possibly prognosis of iNPH patients.

From Cerebrospinal Fluid Neurochemistry to Clinical Diagnosis of Alzheimer's Disease in the Era of Anti-Amyloid Treatments. Report of Four Patients.

Analysis of classical cerebrospinal fluid biomarkers, especially when incorporated in a classification/diagnostic system such as the AT(N), may offer a significant diagnostic tool allowing correct identification of Alzheimer's disease during life. We describe four patients with more or less atypical or mixed clinical presentation, in which the classical cerebrospinal fluid biomarkers amyloid peptide with 42 and 40 amino acids (Aß42 and Aß40, respectively), phospho-tau (τP-181) and total tau (τΤ) were measured. Despite the unusual clinical presentation, the biomarker profile was compatible with Alzheimer's disease in all four patients. The measurement of classical biomarkers in the cerebrospinal fluid may be a useful tool in identifying the biochemical fingerprints of Alzheimer's disease, especially currently, due to the recent approval of the first disease-modifying treatment, allowing not only typical but also atypical cases to be enrolled in trials of such treatments.

TOPORS, implicated in retinal degeneration, is a cilia-centrosomal protein.

We recently reported that mutations in the widely expressed nuclear protein TOPORS (topoisomerase I-binding arginine/serine rich) are associated with autosomal dominant retinal degeneration. However, the precise localization and a functional role of TOPORS in the retina remain unknown. Here, we demonstrate that TOPORS is a novel component of the photoreceptor sensory cilium, which is a modified primary cilium involved with polarized trafficking of proteins. In photoreceptors, TOPORS localizes primarily to the basal bodies of connecting cilium and in the centrosomes of cultured cells. Morpholino-mediated silencing of topors in zebrafish embryos demonstrates in another species a comparable retinal problem as seen in humans, resulting in defective retinal development and failure to form outer segments. These defects can be rescued by mRNA encoding human TOPORS. Taken together, our data suggest that TOPORS may play a key role in regulating primary cilia-dependent photoreceptor development and function. Additionally, it is well known that mutations in other ciliary proteins cause retinal degeneration, which may explain why mutations in TOPORS result in the same phenotype.

Mutations in TOPORS cause autosomal dominant retinitis pigmentosa with perivascular retinal pigment epithelium atrophy.

We report mutations in the gene for topoisomerase I-binding RS protein (TOPORS) in patients with autosomal dominant retinitis pigmentosa (adRP) linked to chromosome 9p21.1 (locus RP31). A positional-cloning approach, together with the use of bioinformatics, identified TOPORS (comprising three exons and encoding a protein of 1,045 aa) as the gene responsible for adRP. Mutations that include an insertion and a deletion have been identified in two adRP-affected families--one French Canadian and one German family, respectively. Interestingly, a distinct phenotype is noted at the earlier stages of the disease, with an unusual perivascular cuff of retinal pigment epithelium atrophy, which was found surrounding the superior and inferior arcades in the retina. TOPORS is a RING domain-containing E3 ubiquitin ligase and localizes in the nucleus in speckled loci that are associated with promyelocytic leukemia bodies. The ubiquitous nature of TOPORS expression and a lack of mutant protein in patients are highly suggestive of haploinsufficiency, rather than a dominant negative effect, as the molecular mechanism of the disease and make rescue of the clinical phenotype amenable to somatic gene therapy.

Y-chromosomal evidence for a limited Greek contribution to the Pathan population of Pakistan.

Three Pakistani populations residing in northern Pakistan, the Burusho, Kalash and Pathan claim descent from Greek soldiers associated with Alexander's invasion of southwest Asia. Earlier studies have excluded a substantial Greek genetic input into these populations, but left open the question of a smaller contribution. We have now typed 90 binary polymorphisms and 16 multiallelic, short-tandem-repeat (STR) loci mapping to the male-specific portion of the human Y chromosome in 952 males, including 77 Greeks in order to re-investigate this question. In pairwise comparisons between the Greeks and the three Pakistani populations using genetic distance measures sensitive to recent events, the lowest distances were observed between the Greeks and the Pathans. Clade E3b1 lineages, which were frequent in the Greeks but not in Pakistan, were nevertheless observed in two Pathan individuals, one of whom shared a 16 Y-STR haplotype with the Greeks. The worldwide distribution of a shortened (9 Y-STR) version of this haplotype, determined from database information, was concentrated in Macedonia and Greece, suggesting an origin there. Although based on only a few unrelated descendants, this provides strong evidence for a European origin for a small proportion of the Pathan Y chromosomes.

A new locus (RP31) for autosomal dominant retinitis pigmentosa maps to chromosome 9p.

Retinitis pigmentosa (RP) is a debilitating disease of the retina affecting approximately 1.5 million people worldwide. RP shows remarkable heterogeneity both clinically and genetically, with more than 40 genetic loci implicated, 12 of which account for the autosomal dominant form (adRP) of inheritance. We have recently identified a French Canadian family that presents with early onset adRP. After exclusion of all known loci for adRP, a genome-wide search established firm linkage with a marker from the short arm of chromosome 9 (LOD score of 6.3 at recombination fraction theta=0). The linked region is flanked by markers D9S285 and D9S1874, corresponding to a genetic distance of 31 cM, in the region 9p22-p13.

Investigation of the Greek ancestry of populations from northern Pakistan.

Three populations from northern Pakistan, the Burusho, Kalash, and Pathan, claim descent from soldiers left behind by Alexander the Great after his invasion of the Indo-Pak subcontinent. In order to investigate their genetic relationships, we analyzed nine Alu insertion polymorphisms and 113 autosomal microsatellites in the extant Pakistani and Greek populations. Principal component, phylogenetic, and structure analyses show that the Kalash are genetically distinct, and that the Burusho and Pathan populations are genetically close to each other and the Greek population. Admixture estimates suggest a small Greek contribution to the genetic pool of the Burusho and Pathan and demonstrate that these two northern Pakistani populations share a common Indo-European gene pool that probably predates Alexander's invasion. The genetically isolated Kalash population may represent the genetic pool of ancestral Eurasian populations of Central Asia or early Indo-European nomadic pastoral tribes that became sequestered in the valleys of the Hindu Kush Mountains.

Reconstruction of human evolutionary tree using polymorphic autosomal microsatellites.

Allelic frequencies of 182 tri- and tetra-autosomal microsatellites were used to examine phylogenetic relationships among 19 extant human populations. In particular, because the languages of the Basques and Hunza Burusho have been suggested to have an ancient relationship, this study sought to explore the genetic relationship between these two major language isolate populations and to compare them with other human populations. The work presented here shows that the microsatellite allelic diversity and the number of unique alleles were highest in sub-Saharan Africans. Neighbor-joining trees based on genetic distances and principal component analyses separated populations from different continents, and are consistent with an African origin for modern humans. For the first time, with biparentally transmitted markers, the microsatellite tree also shows that the San are the first branch of the human tree before the branch leading to all other Africans. In contrast to an earlier study, these results provided no evidence of a genetic relationship among the two language isolate groups. Genetic relationships, as ascertained by these microsatellites, are dictated primarily by geographic proximity rather than by remote linguistic origin, Mantel test, R(0) = 0.484, g = 3.802 (critical g value = 1.645; P = 0.05).

Mutations in HPRP3, a third member of pre-mRNA splicing factor genes, implicated in autosomal dominant retinitis pigmentosa.

Retinitis pigmentosa (RP), the commonest form of inherited retinal dystrophies is a clinically and genetically heterogeneous disorder. It is characterized by progressive degeneration of the peripheral retina leading to night blindness and loss of peripheral visual field. RP is inherited either in an autosomal dominant, autosomal recessive or X-linked mode. A locus (RP18) for autosomal dominant RP was previously mapped by linkage analysis in two large pedigrees to chromosome 1p13-q21. The human HPRP3 gene, the orthologue of the yeast pre-mRNA splicing factor (PRP3), localizes within the RP18 disease interval. The recent identification of mutations in human splicing factors, PRPF31 and PRPC8, led us to screen HPRP3 as a candidate in three chromosome 1q-linked families. So far, two different missense mutations in two English, a Danish family and in three RP individuals have been identified. Both mutations are clustered within a two-codon stretch in the 11th exon of the HPRP3 gene. Interestingly, one of the mutations (T494M) is seen repeatedly in apparently unlinked families raising the possibility of a mutation hot spot. This has been confirmed by haplotype analysis using SNPs spanning the HPRP3 gene region supporting multiple origins of the mutation. The altered HPRP3 amino acids, which are highly conserved in all known HPRP3 orthologues, indicate a major function of that domain in the splicing process. The identification of mutations in a third pre-mRNA splicing factor gene further highlights a novel mechanism of photoreceptor degeneration due to defects in the splicing process.