Journal of Alzheimer's disease : JAD
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Randomized Controlled Trial Multicenter Study
PBT2 rapidly improves cognition in Alzheimer's Disease: additional phase II analyses.
PBT2 is a copper/zinc ionophore that rapidly restores cognition in mouse models of Alzheimer's disease (AD). A recent Phase IIa double-blind, randomized, placebo-controlled trial found that the 250 mg dose of PBT2 was well-tolerated, significantly lowered cerebrospinal fluid (CSF) levels of amyloid-beta42, and significantly improved executive function on a Neuro-psychological Test Battery (NTB) within 12 weeks of treatment in patients with AD. In the post-hoc analysis reported here, the cognitive, blood marker, and CSF neurochemistry outcomes from the trial were subjected to further analysis. ⋯ Receiver-operator characteristic analyses revealed that the probability of an improver at any level coming from the PBT2 250 mg group was significantly greater, compared to placebo, for Composite z-scores (Area Under the Curve [AUC] =0.76, p=0.0007), Executive Factor z-scores (AUC =0.93, p=1.3 x 10(-9)), and near-significant for the ADAS-cog (AUC =0.72, p=0.056). There were no correlations between changes in CSF amyloid-beta or tau species and cognitive changes. These findings further encourage larger-scale testing of PBT2 for AD.
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Death with dementia is increasingly common. Although prognostication is difficult, it is an incurable life-limiting illness for which palliative care for the patient is often appropriate. Dementia patients are otherwise at risk of overtreatment with burdensome and possibly non-beneficial interventions and undertreatment of symptoms. ⋯ Guidelines for care and treatment, still mostly consensus-based, support the benefits of advance care planning, continuity of care, and family and practitioner education. Assessment tools for pain, prognosis, and family evaluations of care have been developed and some have been shown to be effective in clinical practice. With increasing numbers of well-designed, large-scale studies, research in the next decade may result in better evidence-based guidelines and practice.
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Randomized Controlled Trial
Effect of donepezil on cognition in severe Alzheimer's disease: a pooled data analysis.
To better characterize response to donepezil in patients with severe AD, Severe Impairment Battery (SIB) data were pooled from four donepezil clinical trials (N=904). Changes in SIB total and domain scores from baseline to week 24 were compared between placebo and donepezil treatment groups (observed case analysis). Analyses were stratified by baseline severity (Mini-Mental State Examination [MMSE] scores 1-5, 6-9, 10-12 and 13-17) to allow investigation of responses at different stages of cognitive impairment. ⋯ Change in total SIB score correlated significantly with change in measures of activities of daily living and global status. These results indicate that donepezil provides cognitive benefits in patients with severe AD, including those most markedly impaired. The treatment effect size and correlation between improvements in SIB scores and functional and global outcome measures suggest the drug-placebo differences are clinically meaningful.
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We first proposed the mitochondrial cascade hypothesis of sporadic Alzheimer's disease (AD) in 2004. Our core assumptions were a person's genes determine baseline mitochondrial function and durability, this durability determines how mitochondria change with advancing age, and critical changes in mitochondrial function initiate other pathologies characteristic of AD. Since then several lines of investigation report data consistent with or supportive of our hypothesis. ⋯ As predicted, AD therapies designed to reduce Abeta thus far have had at best very limited clinical benefits; our hypothesis identifies alternative therapeutic targets. While placing mitochondria at the apex of an AD cascade certainly remains controversial, it is increasingly accepted by the AD research community that mitochondria play an important role in the late-onset forms of the disease. Even if the mitochondrial cascade hypothesis proves incorrect, considering its assumptions could potentially advance our understanding of sporadic, late-onset AD.
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Review
Postoperative cognitive dysfunction: toward the Alzheimer's disease pathomechanism hypothesis.
Alzheimer's disease (AD), a chronic and progressive deterioration of memory and other cognitive domains, is the most common form of dementia. Because of related health and social impact, there is growing interest in assessing potential relationship between anesthesia and the onset and progression of chronic neurodegenerative disorders, including AD. ⋯ Preclinical studies are providing an increasing body of evidences on some of the mechanisms that link anesthetics to neuronal programmed cell death (apoptosis) and accumulation of misfolded proteins in the aging brain. Therefore, risk factors and pathomechanisms of chronic neurodegenerative disorders, including AD, and persistent postoperative-postanesthesia cognitive dysfunction may overlap.