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)