Current and Emerging Pharmacological Treatment Options for Dementia

Behavioural Neurology, Jul 2018

Treatments for the symptomatic relief of Alzheimer’s disease are available but despite advances in our ability to treat persons with various forms of dementia, more effective treatments are needed. The cholinesterase inhibitors donepezil, rivastigmine, and galantamine have demonstrated efficacy in improving cognition and global status and to a lesser extent, behavioral abnormalities relative to placebo in patients with mild-to-moderate Alzheimer’s disease. Rivastigmine has been shown to benefit patients with dementia with Lewy Bodies and with dementia associated with Parkinson's disease. Donepezil and galantamine have also been shown to be mildly effective in dementia due to cerebral ischemia. Memantine has a distinct mechanism of action and is effective in moderate-to-severe AD. The benefits from these drugs, however, are limited and their long-term effectiveness has not been well-demonstrated. Their clinical utility is controversial. Many novel approaches that promise to provide more effective treatments are currently being pursued.

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Current and Emerging Pharmacological Treatment Options for Dementia

Behavioural Neurology 0953-4180 Current and emerging pharmacological treatment options for dementia John M. Ringman 0 Jeffrey L. Cummings 0 0 Department of Neurology, Alzheimer's Disease Research Center; University of California , Los Angeles, CA , USA Treatments for the symptomatic relief of Alzheimer's disease are available but despite advances in our ability to treat persons with various forms of dementia, more effective treatments are needed. The cholinesterase inhibitors donepezil, rivastigmine, and galantamine have demonstrated efficacy in improving cognition and global status and to a lesser extent, behavioral abnormalities relative to placebo in patients with mild-to-moderate Alzheimer's disease. Rivastigmine has been shown to benefit patients with dementia with Lewy Bodies and with dementia associated with Parkinson's disease. Donepezil and galantamine have also been shown to be mildly effective in dementia due to cerebral ischemia. Memantine has a distinct mechanism of action and is effective in moderate-to-severe AD. The benefits from these drugs, however, are limited and their long-term effectiveness has not been well-demonstrated. Their clinical utility is controversial. Many novel approaches that promise to provide more effective treatments are currently being pursued. Dementia; treatment; Alzheimer's disease; vascular dementia; frontotemporal dementia; dementia with Lewy Bodies; Parkinson's disease; acetylcholinesterase inhibitors; memantine; review 1. Introduction Between the years 1900 and 2000, life expectancy at birth in the US increased from 47 to 77 years (www.cdc. gov/nchs/datawh.htm) and for many individuals health and productivity extend into these additional years. Unfortunately, the prevalence of dementia increases geometrically after the age of 65 years [ 31 ], resulting in diminished quality of life for affected persons as well as their loved ones and an increased financial burden to individuals and society. The development of efficacious interventions to prevent, slow the progression of, diminish the symptoms of, or even reverse the pathology of dementing conditions is therefore a priority. Though we have a long way to go, some advances have been made and are the topics of this review. In most autopsy series, Alzheimer?s disease (AD) is the most common form of dementia, accounting for approximately two-thirds of cases [ 34 ]. Alternative pathological processes that contribute to dementia, however, are not uncommon and may be the sole cause of dementia or co-exist with AD or each other to induce cognitive deficits [ 42 ]. Other neurodegenerative processes such as those associated with the intracellular formation of Lewy bodies and those underlying the clinical phenotypes of frontotemporal dementia are not uncommon. Cerebrovascular ischemia can cause dementia as well and its contribution to the clinical status of a specific patient may be difficult to estimate. Because of its prevalence, treatment of AD has been emphasized over that of other dementing conditions in drug development. Importantly, however, there have been efforts to develop medications for and test therapies in these other dementing illnesses as well. We will review these. 2. Alzheimer?s disease 2.3. Donepezil AD has many pathological manifestations including extracellular amyloid plaque deposition, intracellular neurofibrillary tangle formation, and ultimately neuronal and synaptic loss with consequent impairment of neurotransmission [ 13 ]. Treatments targeting all of these processes have either been developed or are currently under investigation. 2.1. Acetylcholinergic neurotransmission Though the neuronal loss occurring in AD is widespread and ultimately involves many cell groups, early neurochemical studies of the brains of persons dying with AD revealed a relatively greater extent of loss of neurons employing acetylcholine as a neurotransmitter [ 14,71 ]. As these networks were known to be involved in memory and attention, aspects of cognition that are affected in AD, chemically enhancing the function of remaining cholinergic neurons became a focus of treatment development. Attempts were made to enhance cholinergic neurotransmission by increasing the availability of precursors for acetylcholine [49] and by oral and intraventricular administration of direct muscarinic receptor agonists [ 53 ]. Progress was eventually made with medications that inhibit the enzyme that degrades acetylcholine (acetylcholinesterase or simply cholinesterase) and four of these have now received Food and Drug Administration (FDA) approval in the US. Despite their limited efficacy, they have become the cornerstone of AD treatment. 2.2. Tacrine Tacrine was the first medication to be approved by the US FDA for the treatment of AD. It was demonstrated to be effective in improving cognition and global status compared to placebo in persons with mild-to-moderate probable AD in a 12-week randomized doubleblind, placeb (...truncated)


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John M. Ringman, Jeffrey L. Cummings. Current and Emerging Pharmacological Treatment Options for Dementia, Behavioural Neurology, 17, DOI: 10.1155/2006/315386