Pharmacotherapy, clinical pharmacology and biomarker research in geriatric patients

Evaluation of pharmacotherapy and diagnosis and treatment of dementia are important subjects within geriatric medicine. Geriatric patients are more vulnerable for adverse events and pharmacokinetic interactions. Polypharmacy should be reduced, however, undertreatment of conditions or illnesses is also recognised in geriatric populations. Pharmacotherapy was evaluated in geriatric patients attending the diagnostic day-clinic and the geriatric ward of a general hospital. Vitamin supplementation, treatment of urinary tract infections and proton-pump-inhibitor therapy were the most frequently started therapies after evaluation. Although less frequent, medication was discontinued mostly because diagnoses were not longer relevant. Patients aged above 65 years are often excluded from clinical pharmacological research. We showed selected polymorphism in exon 12, 21 and 26 of the ABCB1 gene, encoding for the efflux pump P-glycoprotein, to be unrelated to the steady-state digoxin clearance in geriatric patients. Rivastigmine, an acetylcholinesterase inhibitor, is registered for the indication mild-to-moderate severe Alzheimer's Disease. In clinical practice patients discontinue therapy because of adverse events and only a subset of patients is identified as a responder to therapy. Rivastigmine was primarily discontinued within the first 6 months of therapy because of adverse events, after 6 months mainly for therapy ineffectiveness. Absence of nurse support and not tolerating the minimal effective daily dose of twice daily 3 mg resulted in an increased risk for discontinuation of rivastigmine within 6 months after starting therapy. Rivastigmine shows a modest effect on cognition, activities of daily living and memory-related behaviour. Rivastigmine does not have clinically relevant treatment effects on disruptive behaviour, and depressive behaviour worsened during the first 6 months of treatment. Patients with a baseline Mini Mental State Examination score ?19 showed significant and larger responses to rivastigmine therapy. Differences in pharmacokinetics were not related to treatment outcome in Alzheimer’s disease patients and could not explain treatment variability in individuals. With the future possibilities of disease-modifying therapies it is becoming important to diagnose dementia preferably in a pre-clinical stadium or as early as possible in the clinical process, when pathological mechanisms have already been started. We showed that selected genotypes in exon 12, 21 and 26 of the ABCB1 gene, encoding for the efflux drug-transporter P-glycoprotein, are not useful as biological markers for different types of dementia. These ABCB1 single nucleotide polymorphism were not significantly different between dementia patients and age-matched non-demented control patients, or between different types of dementia. Furthermore, we used Surface-Enhanced Laser Desorption/Ionisation-Time of Flight Mass Spectrometry (SELDI-TOF MS) to investigate amyloid ? profiles in cerebrospinal fluid and serum of patients with Alzheimer’s disease, vascular dementia and non-demented control patients. Certain peaks in cerebrospinal fluid, as obtained with SELDI-TOF MS, were significantly different between those patient groups. In serum, however, no significantly different peaks intensities were obtained between the three patient groups. Investigations in serum showed that the ABCB1 polymorphism in exon 21 (G2677T/A) was significantly related to the peak intensity of amyloid ?-40 and the SNP in exon 12 (C1236T) was significantly related to a peak at molecular mass 3891, corresponding to an unidentified amyloid-peptide

Amyloid beta protein and tau in cerebrospinal fluid and plasma as biomarkers for dementia: a review of recent literature.

Item does not contain fulltextThis review addresses recent developments in amyloid beta (Abeta), total tau (t-tau), and phosporylated tau (p-tau) protein analysis, in cerebrospinal fluid (CSF) and plasma as biomarkers for dementia. Recent research focused on the protection of patients with mild cognitive impairment (MCI) into dementia and the differential diagnosis of Alzheimer's Disease (AD). A combination of Abeta42 and t-tau in CSF can discriminate between patients with stable MCI and patients with progressive MCI into AD or other types of dementia with a sufficient sensitivity and specificity. Regression analyses demonstrated that pathological CSF (with decreased Abeta42 and and increased tau levels) is a very strong predictor for the progression of MCI into AD. Furthermore, CSF measurements of p-tau and Abeta42 can assist in diagnosing vascular dementia or frontotemporal dementia in the differential diagnosis of AD indicated by a reasonable sensitivity and specificity. Whether tau in combination with Abeta42 or in combination with the Abeta37/Abeta42 or Abeta38/Abeta42 ratio aids in the discrimination between AD and Lewy Body dementia remains to be elucidated. Cross-sectional research could not demonstrate significant differences for Abeta40 and Abeta42 in plasma between AD and controls. However, a recently published longitudinal study showed high baseline Abeta40 levels, especially when combined with low baseline Abeta 42 levels, are a strong risk factor for the development of dementia. This emphasizes the importance of performing longitudinal studies in addition to cross-sectional ones. The origin of plasma Abeta and its transport between CSF and plasma, however, needs further clarification. In conclusion, progress has been made regarding Abeta and tau as biomarkers for dementia, both for differentiation between stable MCI and progressive MCI patients and for the differential diagnosis of AD. Future research should aim to validate these recently published results, preferably in pathologically confirmed AD patients. In addition, it is important to standardise research in terms of study design (longitudinal, minimal follow-up period of 5 years), type of researched parameters ( total or p-tau, type of Abeta peptides), type of matrix (CSF and plasma) and data analysis (establishment of predefined cut-off values, type of ratio, type of marker combination)