A novel seven-octapeptide repeat insertion in the prion protein gene (PRNP) in a Dutch pedigree with Gerstmann–Sträussler–Scheinker disease phenotype: comparison with similar cases from the literature

Human prion diseases can be sporadic, inherited or acquired by infection and show considerable phenotypic heterogeneity. We describe the clinical, histopathological and pathological prion protein (PrPSc) characteristics of a Dutch family with a novel 7-octapeptide repeat insertion (7-OPRI) in PRNP, the gene encoding the prion protein (PrP). Clinical features were available in four, neuropathological features in three and biochemical characteristics in two members of this family. The clinical phenotype was characterized by slowly progressive cognitive decline, personality change, lethargy, depression with anxiety and panic attacks, apraxia and a hypokinetic-rigid syndrome. Neuropathological findings consisted of numerous multi- and unicentric amyloid plaques throughout the cerebrum and cerebellum with varying degrees of spongiform degeneration. Genetic and molecular studies were performed in two male family members. One of them was homozygous for valine and the other heterozygous for methionine and valine at codon 129 of PRNP. Sequence analysis identified a novel 168 bp insertion [R2–R2–R2–R2–R3g–R2–R2] in the octapeptide repeat region of PRNP. Both patients carried the mutation on the allele with valine at codon 129. Western blot analysis showed type 1 PrPSc in both patients and detected a smaller ~8 kDa PrPSc fragment in the cerebellum in one patient. The features of this Dutch kindred define an unusual neuropathological phenotype and a novel PRNP haplotype among the previously documented 7-OPRI mutations, further expanding the spectrum of genotype–phenotype correlations in inherited prion diseases

No Effect of One-Year Treatment with Indomethacin on Alzheimer's Disease Progression: A Randomized Controlled Trial

Contains fulltext : 71117.pdf (publisher's version ) (Open Access)BACKGROUND: The objective of this study was to determine whether treatment with the nonselective nonsteroidal anti-inflammatory drug (NSAID) indomethacin slows cognitive decline in patients with Alzheimer's disease (AD). METHODOLOGY/PRINCIPAL FINDINGS: This double-blind, randomized, placebo-controlled trial was conducted between May 2000 and September 2005 in two hospitals in the Netherlands. 51 patients with mild to moderate AD were enrolled into the study. Patients received 100 mg indomethacin or placebo daily for 12 months. Additionally, all patients received omeprazole. The primary outcome measure was the change from baseline after one year of treatment on the cognitive subscale of the AD Assessment Scale (ADAS-cog). Secondary outcome measures included the Mini-Mental State Examination, the Clinician's Interview Based Impression of Change with caregiver input, the noncognitive subscale of the ADAS, the Neuropsychiatric Inventory, and the Interview for Deterioration in Daily life in Dementia. Considerable recruitment problems of participants were encountered, leading to an underpowered study. In the placebo group, 19 out of 25 patients completed the study, and 19 out of 26 patients in the indomethacin group. The deterioration on the ADAS-cog was less in the indomethacin group (7.8+/-7.6), than in the placebo group (9.3+/-10.0). This difference (1.5 points; CI -4.5-7.5) was not statistically significant, and neither were any of the secondary outcome measures. CONCLUSIONS/SIGNIFICANCE: The results of this study are inconclusive with respect to the hypothesis that indomethacin slows the progression of AD

Study protocol: EXERcise and Cognition In Sedentary adults with Early-ONset dementia (EXERCISE-ON)

<p>Abstract</p> <p>Background</p> <p>Although the development of early-onset dementia is a radical and invalidating experience for both patient and family there are hardly any non-pharmacological studies that focus on this group of patients. One type of a non-pharmacological intervention that appears to have a beneficial effect on cognition in older persons without dementia and older persons at risk for dementia is exercise. In view of their younger age early-onset dementia patients may be well able to participate in an exercise program. The main aim of the EXERCISE-ON study is to assess whether exercise slows down the progressive course of the symptoms of dementia.</p> <p>Methods/Design</p> <p>One hundred and fifty patients with early-onset dementia are recruited. After completion of the baseline measurements, participants living within a 50 kilometre radius to one of the rehabilitation centres are randomly assigned to either an <it>aerobic exercise program in a rehabilitation centre</it> or a <it>flexibility and relaxation program in a rehabilitation centre</it>. Both programs are applied three times a week during 3 months. Participants living outside the 50 kilometre radius are included in a feasibility study where participants join in a <it>daily physical activity program set at home making use of pedometers</it>. Measurements take place at baseline (entry of the study), after three months (end of the exercise program) and after six months (follow-up). Primary outcomes are cognitive functioning; psychomotor speed and executive functioning; (instrumental) activities of daily living, and quality of life. Secondary outcomes include physical, neuropsychological, and rest-activity rhythm measures.</p> <p>Discussion</p> <p>The EXERCISE-ON study is the first study to offer exercise programs to patients with early-onset dementia. We expect this study to supply evidence regarding the effects of exercise on the symptoms of early-onset dementia, influencing quality of life.</p> <p>Trial registration</p> <p>The present study is registered within The Netherlands National Trial Register (ref: NTR2124)</p

The Comparative Risk of Delirium with Different Opioids:A Systematic Review

There is substantial evidence that the use of opioids increases the risk of adverse outcomes such as delirium, but whether this risk differs between the various opioids remains controversial. In this systematic review, we evaluate and discuss possible differences in the risk of delirium from the use of various types of opioids in older patients. We performed a search in MEDLINE by combining search terms on delirium and opioids. A specific search filter for use in geriatric medicine was used. Quality was scored according to the quality assessment for cohort studies of the Dutch Cochrane Institute. Six studies were included, all performed in surgical departments and all observational. No study was rated high quality, one was rated moderate quality, and five were rated low quality. Information about dose, route, and timing of administration of the opioid was frequently missing. Pain and other important risk factors of delirium were often not taken into account. Use of tramadol or meperidine was associated with an increased risk of delirium, whereas the use of morphine, fentanyl, oxycodone, and codeine were not, when compared with no opioid. Meperidine was also associated with an increased risk of delirium compared with other opioids, whereas tramadol was not. The risk of delirium appeared to be lower with hydromorphone or fentanyl, compared with other opioids. Numbers used for comparisons were small. Some data suggest that meperidine may lead to a higher perioperative risk for delirium; however, high-quality studies that compare different opioids are lacking. Further comparative research is neede

Alzheimer's disease - input of vitamin D with mEmantine assay (AD-IDEA trial): study protocol for a randomized controlled trial

BACKGROUND: Current treatments for Alzheimer\u27s disease and related disorders (ADRD) are symptomatic and can only temporarily slow down ADRD. Future possibilities of care rely on multi-target drugs therapies that address simultaneously several pathophysiological processes leading to neurodegeneration. We hypothesized that the combination of memantine with vitamin D could be neuroprotective in ADRD, thereby limiting neuronal loss and cognitive decline. The aim of this trial is to compare the effect after 24 weeks of the oral intake of vitamin D3 (cholecalciferol) with the effect of a placebo on the change of cognitive performance in patients suffering from moderate ADRD and receiving memantine. METHODS: The AD-IDEA Trial is a unicentre, double-blind, randomized, placebo-controlled, intent-to-treat, superiority trial. Patients aged 60 years and older presenting with moderate ADRD (i.e., Mini-Mental State Examination [MMSE] score between 10-20), hypovitaminosis D (i.e., serum 25-hydroxyvitamin D [25OHD] &lt; 30 ng/mL), normocalcemia (i.e., serum calcium &lt; 2.65 mmol/L) and receiving no antidementia treatment at time of inclusion are being recruited. All participants receive memantine 20 mg once daily -titrated in 5 mg increments over 4 weeks- and each one is randomized to one of the two treatment options: either cholecalciferol (one 100,000 IU drinking vial every 4 weeks) or placebo (administered at the same pace). One hundred and twenty participants are being recruited and treatment continues for 24 weeks. Primary outcome measure is change in cognitive performance using Alzheimer\u27s Disease Assessment Scale-cognition score. Secondary outcomes are changes in other cognitive scores (MMSE, Frontal Assessment Battery, Trail Making Test parts A and B), change in functional performance (Activities of Daily Living scale, and 4-item Instrumental Activities of Daily Living scale), posture and gait (Timed Up &amp; Go, Five Time Sit-to-Stand, spatio-temporal analysis of walking), as well as the between-groups comparison of compliance to treatment and tolerance. These outcomes are assessed at baseline, 12 and 24 weeks, together with the serum concentrations of 25OHD, calcium and parathyroid hormone. DISCUSSION: The combination of memantine plus vitamin D may represent a new multi-target therapeutic class for the treatment of ADRD. The AD-IDEA Trial seeks to provide evidence on its efficacy in limiting cognitive and functional declines in ADRD. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01409694

Early Onset Prion Disease from Octarepeat Expansion Correlates with Copper Binding Properties

Insertional mutations leading to expansion of the octarepeat domain of the prion protein (PrP) are directly linked to prion disease. While normal PrP has four PHGGGWGQ octapeptide segments in its flexible N-terminal domain, expanded forms may have up to nine additional octapeptide inserts. The type of prion disease segregates with the degree of expansion. With up to four extra octarepeats, the average onset age is above 60 years, whereas five to nine extra octarepeats results in an average onset age between 30 and 40 years, a difference of almost three decades. In wild-type PrP, the octarepeat domain takes up copper (Cu2+) and is considered essential for in vivo function. Work from our lab demonstrates that the copper coordination mode depends on the precise ratio of Cu2+ to protein. At low Cu2+ levels, coordination involves histidine side chains from adjacent octarepeats, whereas at high levels each repeat takes up a single copper ion through interactions with the histidine side chain and neighboring backbone amides. Here we use both octarepeat constructs and recombinant PrP to examine how copper coordination modes are influenced by octarepeat expansion. We find that there is little change in affinity or coordination mode populations for octarepeat domains with up to seven segments (three inserts). However, domains with eight or nine total repeats (four or five inserts) become energetically arrested in the multi-histidine coordination mode, as dictated by higher copper uptake capacity and also by increased binding affinity. We next pooled all published cases of human prion disease resulting from octarepeat expansion and find remarkable agreement between the sudden length-dependent change in copper coordination and onset age. Together, these findings suggest that either loss of PrP copper-dependent function or loss of copper-mediated protection against PrP polymerization makes a significant contribution to early onset prion disease

Preoperative cerebrospinal fluid cytokine levels and the risk of postoperative delirium in elderly hip fracture patients

Aging and neurodegenerative disease predispose to delirium and are both associated with increased activity of the innate immune system resulting in an imbalance between pro- and anti-inflammatory mediators in the brain. We examined whether hip fracture patients who develop postoperative delirium have altered levels of inflammatory mediators in cerebrospinal fluid (CSF) prior to surgery. Patients were 75 years and older and admitted for surgical repair of an acute hip fracture. CSF samples were collected preoperatively. In an exploratory study, we measured 42 cytokines and chemokines by multiplex analysis. We compared CSF levels between patients with and without postoperative delirium and examined the association between CSF cytokine levels and delirium severity. Delirium was diagnosed with the Confusion Assessment Method; severity of delirium was measured with the Delirium Rating Scale Revised-98. Mann-Whitney U tests or Student t-tests were used for between-group comparisons and the Spearman correlation coefficient was used for correlation analyses. Sixty-one patients were included, of whom 23 patients (37.7%) developed postsurgical delirium. Concentrations of Fms-like tyrosine kinase-3 (P=0.021), Interleukin-1 receptor antagonist (P=0.032) and Interleukin-6 (P=0.005) were significantly lower in patients who developed delirium postoperatively. Our findings fit the hypothesis that delirium after surgery results from a dysfunctional neuroinflammatory response: stressing the role of reduced levels of anti-inflammatory mediators in this process. The Effect of Taurine on Morbidity and Mortality in the Elderly Hip Fracture Patient.Registration number: NCT00497978. Local ethical protocol number: NL16222.094.0