PRND 3'UTR polymorphism may be associated with behavioral disturbances in Alzheimer disease.

The etiology of behavioral and psychological symptoms of dementia (BPSD) is complex, including putative biological, psychological, social and environmental factors. Recent years have witnessed accumulation of data on the association between genetic factors and behavioral abnormalities in Alzheimer disease (AD). In this research paper, our aim is to evaluate the association between the APOE, CYP46, PRNP and PRND genes and the profile of neuropsychiatric symptoms in Polish subjects with AD and mild cognitive impairment (MCI). We studied 99 patients with AD and 48 subjects with MCI. The presence and profile of BPSD were evaluated at baseline and prospectively with the Neuropsychiatric Inventory (NPI). Patients were dichotomized into those having ever experienced a particular symptom and those who did not over the whole disease period. Genotyping was performed using previously described standard protocols. The prevalence of comorbid behavioral symptoms and the overall level of behavioral burden were significantly greater in AD compared with the MCI group. In AD patients, carrier status of the T allele of the 3'UTR (untranslated region) PRND polymorphism was associated with an increased cumulative behavioral load and an elevated risk for delusions, anxiety, agitation/aggression, apathy and irritability/emotional ability. Among MCI subjects, APOE ε4 carriers demonstrated a reduced risk for nighttime behavior change. No other statistically significant genotype-phenotype correlations were observed, including the APOE, CYP46 and PRNP genes. A precise estimation of the exact significance of particular polymorphisms in BPSD etiology requires future studies on large populations.

Behavioural genetics of Alzheimer's disease: a comprehensive review.

Behavioural and psychological symptoms of dementia (BPSD) are present in the course of the illness in up to 90% of patients with Alzheimer's disease (AD). They are the main source of caregiver burden and one of the major factors contributing to early institutionalization. The involvement of a genetic component in BPSD aetiology seems beyond controversy, though the exact significance of particular polymorphisms is uncertain in the majority of cases. Multiple genes have been assessed for their putative influence on BPSD risk. In this paper we review the behavioural genetics of AD, particularly the importance, with respect to BPSD risk, of genes coding for apolipoprotein E and proteins involved in the process of neurotransmission: serotonin receptors, serotonin transporter, COMT, MAO-A, tryptophan hydroxylase and dopamine receptors. A general conclusion is the striking inconsistency of the findings, unsurprising in the field of psychiatric genetics. The potential reasons for such discrepancy are exhaustively discussed.

Predictors of long-term treatment effect of rivastigmine in Alzheimer's disease: a role for beta-amyloid plasma levels?

BACKGROUND AND PURPOSE: Cholinesterase inhibitors (ChEI) are currently the mainstream symptomatic treatment of patients with Alzheimer's disease (AD). To this end, the response to the treatment with ChEI is clinically difficult to predict. Several demographic, clinical and biological variables have been proposed as pre-treatment predictors of long-term therapy efficacy. The aim of the study was to confirm our initial observations of the significance of a change in plasma levels of beta-amyloid (Abeta) peptides after initial treat-ment with rivastigmine for predicting clinical response to ChEI. MATERIAL AND METHODS: Fifty-four carefully selected subjects (37 females) satisfying criteria for mild (n = 25) or moderate (n = 29) AD were included in the study. Rivastigmine was prescribed at the initial dose of 3 mg/day b.i.d.; the dose was escalated to the maximum tolerated one in at least 4-week intervals. The response to treatment was assessed using the ADAS-Cog and CDR scales. Whole blood samples were collected twice: before the first rivastigmine dose and at the 2nd week on active treatment. Levels of Abeta(1-40) and Abeta(1-42) were measured in plasma using a commercially available ELISA. RESULTS: We confirmed that higher initial disease severity (higher ADAS-Cog scores) and the increase in the con-centration of plasma Abeta(1-42) peptide following 2 weeks of treatment with an initial dose of rivastigmine increased the chance of a clinically meaningful response to ChEI therapy in AD patients after 2 years of follow-up. CONCLUSIONS: A change in plasma Abeta(1-42) level might constitute a novel biochemical predictor of long-term rivastigmine treatment efficacy in AD.

Plasma Abeta levels as predictors of response to rivastigmine treatment in Alzheimer's disease.

Cholinesterase inhibitors are currently the mainstream of symptomatic treatment of patients with Alzheimer's disease. The response to treatment with cholinesterase inhibitors is clinically difficult to predict. Several demographic, clinical and biological variables have been proposed as pretreatment predictors of long-term therapy efficacy. In this paper, consistently with previous reports, we confirm that higher initial disease severity and faster progression of cognitive impairment increase the chance of a clinically meaningful response to cholinesterase inhibitor therapy in a carefully selected population of patients with Alzheimer's disease. Moreover, for the first time we demonstrate the association between the increase in the concentration of plasma Abeta(1-42) peptide after 2 weeks of treatment with an initial dose of rivastigmine and the likelihood of a positive response to treatment after 6 months. A change in plasma Abeta(1-42) level might constitute a novel biochemical predictor of rivastigmine treatment efficacy in Alzheimer's disease.

Biochemical markers and risk factors of Alzheimer's disease.

As the spectrum of therapeutic options broadens, the possibility of an early and accurate diagnosis of Alzheimer's disease (AD), or even isolation of a group at high risk of subsequent cognitive decline, is focusing widespread attention. Therefore, biological markers or risk factors of AD are highly desirable. In this work, we give an overview of the most extensively studied AD biomarkers, namely beta-amyloid, tau protein, and phosphorylated tau-protein, alone or in combination. Moreover, we describe the role of inflammatory markers (cytokines, acute phase proteins), oxidative stress markers (isoprostanes, 8-hydroxyguanine, 3-nitrotyrosine, plasma antioxidants, redox transition metals), homocysteine and related vitamins, cholesterol and 24S-hydroxycholesterol in the diagnostic process or prediction of AD. We briefly review less popular, though promising markers of AD - markers of apoptosis, neuronal thread protein, acetyl- and butyrylcholinesterase, sulfatide, kallikreins, matrix-degrading metalloproteinases, and novel isoforms of beta-amyloid and tau. Finally, we discuss the clinical applicability of AD-related biological markers.

Plasma levels of alpha beta peptides are altered in amnestic mild cognitive impairment but not in sporadic Alzheimer's disease.

Plasma alpha beta levels have been examined in sporadic Alzheimer's disease yielding conflicting results; both no difference and an increase in plasma concentrations of alpha beta42 and alpha beta40 in sporadic cases of AD as compared to controls have been reported. Elevated plasma alpha beta42 levels may be detected several years before the onset of symptoms (in mild cognitive impairment stadium). Levels of alpha beta40 and alpha beta42 were measured in plasma from 54 patients with AD, 39 subjects with MCI and 35 controls using a commercially available ELISA. Mean plasma alpha beta42 levels were significantly higher in MCI as compared to both AD (P < 0.001) and control subjects (P < 0.001), while alpha beta40 did not differ between the groups. No correlations were observed between alpha beta levels and age, MMSE scores or gender. According to ROC curve analysis the maximum accuracy in discriminating MCI versus both controls and AD subjects has been achieved using a cut-off value of 3.8.

Doppel: the prion's double.

Doppel (Dpl) is a PrP-like protein, coded by a gene named PRND, located near the PRNP (prion proten coding gene) locus. Human Dpl is a 179-amino acid protein showing approximately 25% sequence identity with the carboxyproximal two thirds of the human cellular prion protein (PrPC). A comparison of the structures of Dpl and PrP(C) reveals similarities in the secondary structure and topology. Apart from their structural similarities, the PrP and Dpl proteins seem to have different functions. The Prnd gene is expressed in mouse embryos; in adult mice its transcripts are present in heart, mammary gland, spleen, testes and, in contrast to Prnp, only at very low levels in the adult CNS. Moreover, the Dpl protein is not capable of enhancing the propagation of the pathological prion protein (PrP(Sc)). The Dpl protein has been identified as a regulator of acrosome function and male gametogenesis. The human PRND open reading frame has been shown to contain polymorphic codons, but research on a correlation between the PRND polymorphic sequences and neurodegenerative disorders carried out to date in different populations have shown contradictory results. Therefore, the role of the PRND gene in CJD and other diseases still remains unexplained.

Amyloid-beta and tau proteins as biochemical markers of Alzheimer's disease.

With the development of new therapeutic strategies, and the concept of mild cognitive impairment (MCI) as an early stage of Alzheimer's disease (AD), there is an increasing need for an early and accurate diagnosis of sporadic AD. Therefore, biological markers allowing a positive diagnosis early in the course of the disease are highly desirable. The most extensively evaluated markers of sporadic AD are amyloid-beta proteins and levels of both total and phosphorylated microtubule-associated protein tau. In this study, we review the currently available data on the aforementioned markers assessed in the cerebrospinal fluid or plasma, alone and in combinations, focusing on their clinical applicability including sensitivity in the diagnosis of AD and mild cognitive impairment, specificity in discriminating AD from other dementias and correlations with the disease progression and apolipoprotein E genotype. We also analyze advantages and potential drawbacks of using biomarkers in the laboratory diagnosis of AD.