Analyzing the impact of 23 mg/day donepezil on language dysfunction in moderate to severe Alzheimer\u27s disease

INTRODUCTION: Progressive language impairment is among the primary components of cognitive decline in Alzheimer\u27s disease (AD). Because expressive and receptive language help to maintain emotional connections to caregivers and support the management of AD patients\u27 functional needs, language plays a critical role in patients\u27 emotional and physical health. Using data from a large prospective clinical trial comparing two doses of donepezil in patients with moderate to severe AD, we performed a post hoc analysis to determine whether a higher dose of donepezil was associated with greater benefits in language function. METHODS: In the original randomized, double-blind clinical trial, 1,467 patients with moderate to severe AD (baseline Mini-Mental State Examination (MMSE) score 0 to 20) were randomized 2:1 to receive donepezil 23 mg/day or to continue on donepezil 10 mg/day for 24 weeks. In this post hoc analysis, the Severe Impairment Battery-Language scale (SIB-L) and a new 21-item SIB-derived language scale (SIB[lang]) were used to explore differences in language function between the treatment groups. Correlations between SIB-L and SIB[lang] scores and scores on the severe version of the Alzheimer\u27s Disease Cooperative Study-Activities of Daily Living inventory (ADCS-ADL-sev), the Clinician\u27s Interview-Based Impression of Severity-plus caregiver input/Clinician\u27s Interview-Based Impression of Change-plus caregiver input (CIBIS-plus/CIBIC-plus) and the MMSE were also investigated. RESULTS: At week 24, treatment with donepezil 23 mg/day was associated with an improvement in language in the full intention-to-treat population, whereas language function declined in the group treated with donepezil 10 mg/day (SIB-L treatment difference 0.8, P = 0.0013; SIB[lang] treatment difference 0.8, P = 0.0009). Similar results were observed in a cohort of patients with more severe baseline disease (MMSE score 0 to 16). At baseline and week 24, correlations between the SIB-derived language scales and the ADCS-ADL-sev and CIBIC-plus were moderate, but the correlations were stronger between the language scales and the MMSE scores. CONCLUSIONS: Patients with moderate to severe AD receiving donepezil 23 mg/day showed greater language benefits than those receiving donepezil 10 mg/day as measured by SIB-derived language assessments. Increasing the dose of donepezil to 23 mg/day may provide language benefits in patients with moderate to severe AD, for whom preservation of language abilities is especially critical. ClinicalTrials.gov identifier: NCT00478205

Analyzing the impact of 23 mg/day donepezil on language dysfunction in moderate to severe Alzheimer's disease

Introduction\ud Progressive language impairment is among the primary components of cognitive decline in Alzheimer's disease (AD). Because expressive and receptive language help to maintain emotional connections to caregivers and support the management of AD patients' functional needs, language plays a critical role in patients' emotional and physical health. Using data from a large prospective clinical trial comparing two doses of donepezil in patients with moderate to severe AD, we performed a post hoc analysis to determine whether a higher dose of donepezil was associated with greater benefits in language function.\ud \ud Methods\ud In the original randomized, double-blind clinical trial, 1,467 patients with moderate to severe AD (baseline Mini-Mental State Examination (MMSE) score 0 to 20) were randomized 2:1 to receive donepezil 23 mg/day or to continue on donepezil 10 mg/day for 24 weeks. In this post hoc analysis, the Severe Impairment Battery-Language scale (SIB-L) and a new 21-item SIB-derived language scale (SIB[lang]) were used to explore differences in language function between the treatment groups. Correlations between SIB-L and SIB[lang] scores and scores on the severe version of the Alzheimer's Disease Cooperative Study-Activities of Daily Living inventory (ADCS-ADL-sev), the Clinician's Interview-Based Impression of Severity-plus caregiver input/Clinician's Interview-Based Impression of Change-plus caregiver input (CIBIS-plus/CIBIC-plus) and the MMSE were also investigated.\ud \ud Results\ud At week 24, treatment with donepezil 23 mg/day was associated with an improvement in language in the full intention-to-treat population, whereas language function declined in the group treated with donepezil 10 mg/day (SIB-L treatment difference 0.8, P = 0.0013; SIB[lang] treatment difference 0.8, P = 0.0009). Similar results were observed in a cohort of patients with more severe baseline disease (MMSE score 0 to 16). At baseline and week 24, correlations between the SIB-derived language scales and the ADCS-ADL-sev and CIBIC-plus were moderate, but the correlations were stronger between the language scales and the MMSE scores.\ud \ud Conclusions\ud Patients with moderate to severe AD receiving donepezil 23 mg/day showed greater language benefits than those receiving donepezil 10 mg/day as measured by SIB-derived language assessments. Increasing the dose of donepezil to 23 mg/day may provide language benefits in patients with moderate to severe AD, for whom preservation of language abilities is especially critical.\ud \ud ClinicalTrials.gov identifier: NCT0047820

Genetic Risk Score Predicts Late-Life Cognitive Impairment

Introduction. A family history of Alzheimer's disease is a significant risk factor for its onset, but the genetic risk associated with possessing multiple risk alleles is still poorly understood. Methods. In a sample of 95 older adults (Mean age = 75.1, 64.2% female), we constructed a genetic risk score based on the accumulation of risk alleles in BDNF, COMT, and APOE. A neuropsychological evaluation and consensus determined cognitive status (44 nonimpaired, 51 impaired). Logistic regression was performed to determine whether the genetic risk score predicted cognitive impairment above and beyond that associated with each gene. Results. An increased genetic risk score was associated with a nearly 4-fold increased risk of cognitive impairment (OR = 3.824, P = .013) when including the individual gene polymorphisms as covariates in the model. Discussion. A risk score combining multiple genetic influences may be more useful in predicting late-life cognitive impairment than individual polymorphisms

Loss-of-Function Mutations in PTPN11 Cause Metachondromatosis, but Not Ollier Disease or Maffucci Syndrome

Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a “second hit,” that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier disease or Maffucci syndrome

Mass entrainment and turbulence-driven acceleration of ultra-high energy cosmic rays in Centaurus A

Observations of the FR I radio galaxy Centaurus A in radio, X-ray, and gamma-ray bands provide evidence for lepton acceleration up to several TeV and clues about hadron acceleration to tens of EeV. Synthesising the available observational constraints on the physical conditions and particle content in the jets, inner lobes and giant lobes of Centaurus A, we aim to evaluate its feasibility as an ultra-high-energy cosmic-ray source. We apply several methods of determining jet power and affirm the consistency of various power estimates of ~1 × 10⁴³ erg s⁻¹. Employing scaling relations based on previous results for 3C 31, we estimate particle number densities in the jets, encompassing available radio through X-ray observations. Our model is compatible with the jets ingesting ~3 × 10²¹ g s⁻¹ of matter via external entrainment from hot gas and ~7 × 10²² g s⁻¹ via internal entrainment from jet-contained stars. This leads to an imbalance between the internal lobe pressure available from radiating particles and magnetic field, and our derived external pressure. Based on knowledge of the external environments of other FR I sources, we estimate the thermal pressure in the giant lobes as 1.5 × 10⁻¹² dyn cm⁻², from which we deduce a lower limit to the temperature of ~1.6 × 10⁸ K. Using dynamical and buoyancy arguments, we infer ~440−645 Myr and ~560 Myr as the sound-crossing and buoyancy ages of the giant lobes respectively, inconsistent with their spectral ages. We re-investigate the feasibility of particle acceleration via stochastic processes in the lobes, placing new constraints on the energetics and on turbulent input to the lobes. The same “very hot” temperatures that allow self-consistency between the entrainment calculations and the missing pressure also allow stochastic UHECR acceleration models to work.Sarka Wykes, Judith H. Croston, Martin J. Hardcastle, Jean A. Eilek, Peter L. Biermann, Abraham Achterberg, Justin D. Bray, Alex Lazarian, Marijke Haverkorn, Ray J. Protheroe, and Omer Bromber

Public policy in two-way cable : Difficult issues for a developing technology

The technological development of two-way cable communication has advanced rapidly without concurrent public policy development. In an effort to bring the policy issues to light, the authors describe existing US policy in two-way cable communication, identify definitional problems, suggest policies for implementing two-way service, and outline some of the responsibilities of local franchising authorities peculiar to two-way services, particularly in the area of upstream spectrum allocation.

Association between Cognitive Decline in Older Adults and Use of Primary Care Physician Services in Pennsylvania

Objective : To assess the relationship between cognitive decline of older patients (≥ 65 y) and use of primary care physician (PCP) services over 24 months. Design : Retrospective analysis of prospectively collected data from a cluster randomized trial that took place from 2006-2010 and investigated the relationship between formal neuropsychological evaluation and patient outcomes in primary care. Setting : Twenty-four PCPs in 11 practices in southwestern Pennsylvania. Most practices were suburban and included more than 5 PCPs. Participants : A sample of 423 primary care patients 65 years old or older. Measurements : The association between the number of PCP visits and a decline in cognitive status, as determined by multivariable analyses that controlled for patient-level, physician-level, and practice-level factors (eg, patient age, comorbidities, and symptoms of depression; practice location and size; PCP age and sex) and used a linear mixed model with a random intercept to adjust for clustering. Results : Over a 2-year follow-up, 199 patients (47.0%) experienced a decline in cognitive status. Patients with a cognitive decline had a mean of 0.69 more PCP visits than did patients without a cognitive decline ( P < .05). Conclusions : Early signs of cognitive decline may be an indicator of greater use of primary care. Given the demographic trends, more PCPs are likely to be needed to meet the increasing needs of the older population