Beneficial effects of pharmacological treatment in post-stroke dynamic aphasia: a behavioural and neuroimaging study

Introduction : Dynamic Aphasia (DA) is a rare form of language disorder characterized by reduced spontaneous speech with preservation of other language functions. Two types of DA have been described: language-specific type (type I DA) and domain-general type (type II DA). In type I DA, deficits are selective for word and sentence generation, whereas in type II DA impairments affect discourse generation, narrative, fluency, and non-verbal generation tasks. There is little information on the treatment of DA. Although treatment with a cognitive enhancing drug (bromocriptine) improved outcome in previous studies, pharmacological interventions combining two drugs acting on other neurotransmitter systems in DA have not been reported so far. Methods : We report an open-label pharmacological single case study (n = 1) in a male patient with a chronic type I/II DA secondary to an ischemic infarction in the left fronto-opercular and insular regions. After baseline evaluation, the patient received donepezil 5 mg/day (2 months), donepezil 10 mg/day (2 months), donepezil 10 mg/day plus memantine 20 mg/day (4½ months) followed by a washout period (1½ months). No speech-language therapy was used. A comprehensive cognitive and language evaluation was carried out at baseline and at different endpoints. 18FDG-PET was performed at the four timepoints. Results : Donepezil (5 mg/day) significantly improved type I DA features (normalization of verbs generation, p = 0.01), whereas donepezil (10 mg/day) improved some type II features (normalizing spontaneous speech, verbal fluency and improving generation of novel thoughts, p = 0.004), along with improvement of executive-attentional functioning. Combined therapy further enhanced cognitive function, but did not additionally improved DA. 18 FDG-PET revealed significant reductions of perilesional hypometabolic activity mainly after donepezil (10 mg/day) and washout. Discussion : Treatment with donepezil improved language deficits in a patient with chronic post-stroke type I/II DA. Combined therapy (donepezil plus memantine) further enhanced executive-attentional functioning. Beneficial changes were associated with improvements in perilesional metabolic activity. References : Luria AR et al.Acta Neurologica et Psychiatrica (1967). Robinson G et al. Brain (1998). Keywords : Language; patients; single case study; adults; cerebrovascular; behavioural, functional imaging.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

The effects of donepezil in Alzheimer's disease - Results from a multinational trial

Donepezil has been shown to be well tolerated and to improve cognition and global function in patients with mild to moderately severe Alzheimer's disease (AD). The current trial was undertaken to investigate further the efficacy and safety of donepezil, in a multinational setting, in patients with mild to moderately severe AD. This 30-week, placebo-controlled, parallel-group study consisted of a 24-week, double-blind treatment phase followed by a 6-week, single-blind, placebo washout. Eight hundred and eighteen patients with mild to moderately severe AD were randomly allocated to treatment with single, daily doses of 5 or 10 mg donepezil, or placebo. The two primary efficacy measures were: a cognitive performance test, the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and a global evaluation, the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC plus). Secondary outcome measures included the Sum of the Boxes of the Clinical Dementia Rating Scale (CDR-SB), a modified Interview for Deterioration in Daily living activities in Dementia (IDDD) and a patient-rated quality of life assessment. Statistically significant improvements in cognitive and global function were observed, as evaluated by ADAS-cog and CIBIC plus, respectively, in both the 5 and 10 mg/day donepezil groups, compared with placebo. Treatment-associated changes were also observed in functional skills, as shown by improved scores on the CDR-SB and the complex-tasks component of the IDDD. A dose-response effect was evident, with the 10 mg/day donepezil group demonstrating greater benefits in all outcome measures than the 5 mg/day group. Donepezil was well tolerated by this patient population and did not produce any clinically significant laboratory test abnormalities. The results of this study confirm that donepezil is effective and well tolerated in treating the symptoms of mild to moderately severe AD

Beyond Cholinesterase Inhibition. Anti-Inflammatory Role and Pharmacological Profile of Current Drug Therapy for Alzheimer's Disease

Inflammation is a common response of an individual against either exogenous or endogenous damage. The role of inflammation and of inflammatory cells recently emerged also in the pathogenesis of neurodegenerative disorders. Experimental evidences show how neurotransmitters, besides their role in the synapses, play a modulatory role during immune response. Drugs used for treatment of dementia symptoms are able to increase neurotransmitters levels, and likely to have a modulatory role during immune response. Aim of this review is to discuss the most recent advances on inflammation role during neurodegeneration and also to individuate the potential anti-inflammatory role played by drugs currently used for Alzheimer's disease treatment

Adherence and Tolerability of Alzheimer's Disease Medications: A Pragmatic Randomized Trial

BACKGROUND/OBJECTIVES: Post-marketing comparative trials describe medication use patterns in diverse, real-world populations. Our objective was to determine if differences in rates of adherence and tolerability exist among new users to acetylcholinesterase inhibitors (AChEI's). DESIGN: Pragmatic randomized, open label comparative trial of AChEI's currently available in the United States. SETTING: Four memory care practices within four healthcare systems in the greater Indianapolis area. PARTICIPANTS: Eligibility criteria included older adults with a diagnosis of possible or probable Alzheimer's disease (AD) who were initiating treatment with an AChEI. Participants were required to have a caregiver to complete assessments, access to a telephone, and be able to understand English. Exclusion criteria consisted of a prior severe adverse event from AChEIs. INTERVENTION: Participants were randomized to one of three AChEIs in a 1:1:1 ratio and followed for 18 weeks. MEASUREMENTS: Caregiver-reported adherence, defined as taking or not taking study medication, and caregiver-reported adverse events, defined as the presence of an adverse event. RESULTS: 196 participants were included with 74.0% female, 30.6% African Americans, and 72.9% who completed at least twelfth grade. Discontinuation rates after 18 weeks were 38.8% for donepezil, 53.0% for galantamine, and 58.7% for rivastigmine (P = .063) in the intent to treat analysis. Adverse events and cost explained 73.1% and 25.4% of discontinuation. No participants discontinued donepezil due to cost. Adverse events were reported by 81.2% of all participants; no between-group differences in total adverse events were statistically significant. CONCLUSIONS: This pragmatic comparative trial showed high rates of adverse events and cost-related non-adherence with AChEIs. Interventions improving adherence and persistence to AChEIs may improve AD management. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01362686 (https://clinicaltrials.gov/ct2/show/NCT01362686)

Adverse Effects of Cholinesterase Inhibitors in Dementia, According to the Pharmacovigilance Databases of the United-States and Canada.

This survey analyzes two national pharmacovigilance databases in order to determine the major adverse reactions observed with the use of cholinesterase inhibitors in dementia. We conducted a statistical analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) and the Canada Vigilance Adverse Reaction Database (CVARD) concerning the side effects of cholinesterase inhibitors. The statistics calculated for each adverse event were the frequency and the reporting odds ratios (ROR). A total of 9877 and 2247 reports were extracted from the FAERS and CVARD databases, respectively. A disproportionately higher frequency of reports of death as an adverse event for rivastigmine, compared to the other acetylcholinesterase inhibiting drugs, was observed in both the FAERS (ROR = 3.42; CI95% = 2.94-3.98; P<0.0001) and CVARD (ROR = 3.67; CI95% = 1.92-7.00; P = 0.001) databases. While cholinesterase inhibitors remain to be an important therapeutic tool against Alzheimer's disease, the disproportionate prevalence of fatal outcomes with rivastigmine compared with alternatives should be taken into consideration

Nootropics use in the workplace. Psychiatric and ethical aftermath towards the new frontier of bioengineering

OBJECTIVE: The authors have sought to expound upon and shed a light on the rise of nootropics, which have gradually taken on a more and more relevant role in workplaces and academic settings. MATERIALS AND METHODS: Multidisciplinary databases have been delved into by entering the following keys: "nootropics", "cognitive enhancement", "workplace", "productivity", "ethics", "bioengineering". In addition, a broad-ranging search has been undertaken on institutional websites in order to identify relevant analysis and recommendations issued by international institutions and agencies. Papers and reports have been independently pored over by each author. This search strategy has led to the identification of 988 sources but only 64 were considered appropriate for the purposes of the paper after being selected by at least 3 of the authors, independently. RESULTS: The notion of an artificially enhanced work performance - carried out by the 'superworker' - is particularly noteworthy and resonates with the conception of contemporary work on so many different levels: the rising need and demands for higher degrees of flexibility and productivity on the job, the implications of a '24/7' society, where more and more services are available at any time, the ever greater emphasis on entrepreneurial spirit, individual self-reliance and self-improvement, and last but not least, the impact of an ageing society on economic standards and performance. CONCLUSIONS: Moreover, it is worth mentioning that human enhancement technologies will predictably and increasingly go hand in hand with gene editing, bioengineering, cybernetics and nanotechnology. Applications are virtually boundless, and may ultimately affect all human traits (physical strength, endurance, vision, intelligence and even personality and mood)

Intellectual autonomy, epistemic dependence and cognitive enhancement

Intellectual autonomy has long been identified as an epistemic virtue, one that has been championed influentially by (among others) Kant, Hume and Emerson. Manifesting intellectual autonomy, at least, in a virtuous way, does not require that we form our beliefs in cognitive isolation. Rather, as Roberts and Wood (Intellectual virtues: an essay in regulative epistemology, OUP Oxford, Oxford, pp. 259–260, 2007) note, intellectually virtuous autonomy involves reliance and outsourcing (e.g., on other individuals, technology, medicine, etc.) to an appropriate extent, while at the same time maintaining intellectual self-direction. In this essay, I want to investigate the ramifications for intellectual autonomy of a particular kind of epistemic dependence: cognitive enhancement. Cognitive enhancements (as opposed to therapeutic cognitive improvements) involve the use of technology and medicine to improve cognitive capacities in healthy individuals, through mechanisms ranging from smart drugs to brain-computer interfaces. With reference to case studies in bioethics, as well as the philosophy of mind and cognitive science, it is shown that epistemic dependence, in this extreme form, poses a prima facie threat to the retention of intellectual autonomy, specifically, by threatening to undermine our intellectual self-direction. My aim will be to show why certain kinds of cognitive enhancements are subject to this objection from self-direction, while others are not. Once this is established, we’ll see that even some extreme kinds of cognitive enhancement might be not merely compatible with, but constitutive of, virtuous intellectual autonomy

Donepezil Combined with Natural Hirudin Improves the Clinical Symptoms of Patients with Mild-to-Moderate Alzheimer's Disease: A 20-Week Open-Label Pilot Study

Aim:To evaluate the efficacy and safety of donepezil plus natural hirudin in patients with mild-to-moderate Alzheimer's Disease. Methods: In the 20-week, randomized, open-label and controlled study, 84 patients received either donepezil (5 mg/day for the first 4 weeks and 10 mg/day thereafter) or donepezil plus natural hirudin (3 g/day) treatment. Efficacy was reflected by the change of the total scores of Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-Cog), Activities of Daily Life (ADL) and Neuropsychiatric Inventory (NPI). Results: The patients with the donepezil plus natural hirudin treatment showed more significant improvement in the daily activities and the decline of the cognition than those with donepezil treatment. Significant difference was present in the groups since the 8th week. No group difference was found in the NPI change. However, within the hirudin treatment group, more powerful efficacy including NPI assessment was found in the patients with vascular risk factors (VRF) as comparing to with those without VRF. The combination of donepezil and natural hirudin was well tolerated. The dropout rate was greater in the donepezil and natural hirudin (50%) treatment group than in the donepezil (39%) treatment group. Similar result was found in the incidence of adverse events (23.8% vs 19.0%), but there was no statistical difference between the two groups. Adverse events were the most common reason for the dropout. Although hemorrhage and hypersensitiveness were more common in donepezil plus Maixuekang treatment (11.9% and 7.1%) group than in donepezil treatment (2.4% and 2.4%) group, no significant difference was present between the two groups. Economic problem was another important reason for the patients' withdrawal. Conclusions: Compared with the donepezil treatment in the patients with mild-to-moderate AD, our results suggest that donepezil combined with natural hirudin may improve the treatment effects in the ADL, BPSD and cognition of the patients. Furthermore, this joint treatment is safe

NICE 2011 recommendations on the management of Alzheimer’s disease by acetylcholinesterase inhibitors and memantine

The National Institute of Clinical Excellence (NICE) has lately overturned its decision to restrict the use of acetycholinesterase inhibitors and memantine in patients diagnosed with Alzheimer’s disease (AD). It is estimated that such a policy U-turn will offer access to a significant number of individuals who were previously denied these medications. This short article will focus on the latest developments and recommendations by NICE on the use of these pharmacological agents in the managment of AD.peer-reviewe

Cost-effectiveness of donepezil and memantine in moderate to severe Alzheimer's disease (the DOMINO-AD trial).

OBJECTIVE: Most investigations of pharmacotherapy for treating Alzheimer's disease focus on patients with mild-to-moderate symptoms, with little evidence to guide clinical decisions when symptoms become severe. We examined whether continuing donepezil, or commencing memantine, is cost-effective for community-dwelling, moderate-to-severe Alzheimer's disease patients. METHODS: Cost-effectiveness analysis was based on a 52-week, multicentre, double-blind, placebo-controlled, factorial clinical trial. A total of 295 community-dwelling patients with moderate/severe Alzheimer's disease, already treated with donepezil, were randomised to: (i) continue donepezil; (ii) discontinue donepezil; (iii) discontinue donepezil and start memantine; or (iv) continue donepezil and start memantine. RESULTS: Continuing donepezil for 52 weeks was more cost-effective than discontinuation, considering cognition, activities of daily living and health-related quality of life. Starting memantine was more cost-effective than donepezil discontinuation. Donepezil-memantine combined is not more cost-effective than donepezil alone. CONCLUSIONS: Robust evidence is now available to inform clinical decisions and commissioning strategies so as to improve patients' lives whilst making efficient use of available resources. Clinical guidelines for treating moderate/severe Alzheimer's disease, such as those issued by NICE in England and Wales, should be revisited. © 2016 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd