Description of the condition
Dementia is a syndrome characterised by disturbances of multiple cognitive domains, including memory, orientation, thinking and behaviour. Most cases of dementia are due to progressive, degenerative disease of the brain. There were estimated to be 24 million people with dementia in the world in 2001, and this is predicted to rise to 42.3 million in 2020, and to 81.1 million by 2040 (Ballard 2011; Ferri 2005). Dementia due to Alzheimer's disease (AD) is the most common (Cacabelos 2008), accounting for 50% to 70% of the cases, followed by vascular dementia (30% to 40%) and mixed Alzheimer's/vascular cases (15% to 20%). Lewy body dementia (LBD) and Parkinson's disease dementia (PDD) together account for 5% to 10% of dementia cases (Mollenhauer 2010). There are also various rarer dementias due to other neurodegenerative disease. These include frontotemporal dementias (FTDs), Huntington's disease (HD), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), dementia in multiple sclerosis (MS) and progressive supranuclear palsy (PSP).
Frontotemporal dementias (FTDs) are a group of disorders with a variety of underlying pathologies, characterised by a progressive decline in behaviour or language associated with degeneration of frontal and anterior temporal lobes. Some FTDs are familial disorders associated with single gene mutation. The prevalence of FTD in population-based studies has varied between 2.7 per 100,000 inhabitants in the Netherlands to 17.6 per 100,000 inhabitants in Northern Italy (Premi 2012). Behavioural variant frontotemporal dementia (bvFTD) is the most common clinical presentation, with prominent personality changes and impaired social behaviour. The most common symptoms of cognitive decline are poor judgement, inattentiveness and distractibility, loss of planning ability and disorganisation (Rabinovici 2010).
Huntington's Disease (HD) is a hereditary neurodegenerative disorder caused by an expansion of a repeating CAG triplet series in the Huntingdon gene. It is characterised by chorea, behavioural and psychiatric manifestations and cognitive dysfunction. The worldwide service-based prevalence of HD, based on a meta-analysis (including 13 studies), was 2.71 per 100,000 (95% confidence interval (CI) 1.55 to 4.72) (Pringsheim 2012). The cognitive and behavioural symptoms and signs of HD have been shown to be evident at least 15 years prior to the time at which motor diagnosis is typically given (Paulsen 2011). Thus, the cognitive and behavioural impairments have been growing in prominence in HD diagnosis and treatment.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a single-gene disorder (mutation in NOTCH3) directly affecting the cerebral small blood vessels. The main clinical manifestations of CADASIL are migraine, recurrent stroke or stepwise deterioration of motor ability and subcortical ischaemic vascular dementia. Estimates of the population prevalence of CADASIL vary from 1.98 per 100,000 in West Scotland to 4.10 per 100,000 in North-East England (Narayan 2012; Razvi 2005). Cognitive deficits can be found in about 60% of people with CADASIL. Typically these are frontal-lobe cognitive deficits, including problems with executive function, working memory, and verbal fluency (Choi 2010; Fukutake 2011). As the disease progresses, people begin to show cognitive deficits typical of subcortical vascular dementia (Choi 2010).
Multiple sclerosis (MS) is a chronic inflammatory neurological condition characterised by focal and diffuse neurodegeneration and demyelination throughout the central nervous system (CNS). Depending on the extent and location of damage in the CNS, people with MS may experience a wide variety of symptoms, including motor, cognitive, and neuropsychiatric problems (Chiaravalloti 2008). MS affects more than 600,000 people in the United States and more than 2 million people worldwide, and 40% to 65% of these people experience some degree of cognitive impairment (Rahn 2012). MS detrimentally affects various aspects of cognitive functioning, including attention, information processing efficiency, executive functioning, processing speed and long-term memory. Processing speed, visual learning and memory seem to be most commonly affected (Chiaravalloti 2008).
Progressive supraneuclear palsy (PSP) is a neurodegenerative disease which falls in the general class of tauopathies. It classically presents with early postural instability and falls; a peculiar wide-based, slow and unsteady gait; Parkinsonism characterised by axial more than limb rigidity and by symmetrical limb involvement; early dysarthria and dysphagia; and early cognitive and behavioural frontal lobe-type disturbances (Boeve 2012; Litvan 2001). The prevalence of PSP ranges from 3.1 to 6.5 per 100,000 in the United Kingdom (Hoppitt 2011). The age-standardised incidence of PSP in Sweden (2004 to 2007) is 1.2 (95% CI 0.4 to 2.6) per 100,000 (Linder 2010).
Description of the intervention
The first cholinesterase inhibitors were introduced into clinical practice in 1993 and the three currently licensed cholinesterase inhibitors - donepezil, rivastigmine and galantamine - are now considered to be the first-line medicines for dementia due to AD. They are usually recommended for dementia of mild to moderate severity. Cholinesterase inhibitors inhibit the enzyme acetylcholinesterase which breaks down acetylcholine (a neurotransmitter in the peripheral and central nervous systems). The cholinergic system is known to play an important role in cognition.
Donepezil is a selective reversible inhibitor of acetylcholinesterase. It is given orally, usually starting at a dose of 5 mg per day, increased after several weeks to 10 mg per day. Rivastigmine is an inhibitor of both acetylcholinesterase and butylcholinesterase. It can be administered orally or transdermally. Rivastigmine treatment is initiated at 1.5 mg twice daily, and is increased gradually over weeks to 6 mg twice daily. Galantamine can stimulate nicotinic acetylcholine receptors as well as inhibiting cholinesterase activity. It is administered orally in once- or twice-daily formulations. Galantamine treatment is usually initiated at 8 mg daily, and can be increased gradually up to 24 mg daily (Lanctôt 2009). Side effects of all the cholinesterase inhibitors include gastrointestinal symptoms, including nausea, diarrhoea and vomiting, as well as leg cramps, abnormal dreams, dizziness and weight loss (Hansen 2008; Tayeb 2012).
There is evidence for the efficacy of cholinesterase inhibitors in dementias due to conditions other than AD. These medications significantly improved the global assessment, cognitive function, behavioural disturbance and activities of daily living in people with dementia or cognitive impairment in Parkinson's disease (Rolinski 2012). They are also reported to produce small cognitive improvements in people with vascular dementia (Baskys 2012) and vascular cognitive impairment (Levine 2011). Based on these findings, cholinesterase inhibitors have also been used in the treatment of rarer dementias.
How the intervention might work
The cholinesterase inhibitors are thought to work primarily by preventing the breakdown of acetylcholine and hence boosting cholinergic neurotransmission in forebrain regions (Tayeb 2012).
CADASIL is a genetic form of subcortical ischaemic vascular dementia. Several recent studies have suggested that subcortical ischaemic lesions disrupt cholinergic pathways. Hence, cholinergic deficits may play a role in the dementia of CADASIL (Keverne 2007; Mesulam 2003 ). Reductions in cerebrospinal fluid (CSF) markers of cholinergic activity, which may reflect reductions in global brain cholinergic activity, have been found in MS, possibly due to disruption of cholinergic pathways by demyelination and axonal transection (Ruberg 1987). Depletions of postsynaptic cholinoreceptors have been found in the temporal cortex of people with FTD (Odawara 2003). Cholinergic neurons may also be indirectly affected in other neurodegenerative conditions associated with cognitive decline and dementia, including HD (Cubo 2006) and PSP (Litvan 2001). The cholinesterase inhibitors may therefore have an impact on cognitive impairment in these rarer dementias.
Why it is important to do this review
Cognitive impairment is one of the major causes of disability in those neurological conditions in which it occurs, resulting in a serious burden for individuals and their carers (Nunnemann 2012; Rahn 2012). In the United States, the estimated yearly monetary cost per person attributable to dementia was USD 41,000 to USD 56,000 in 2010 (Hurd 2013). It is therefore important to evaluate the treatment of the rarer dementias. Some studies have suggested that cholinesterase inhibitors might be associated with improved cognition in people with rarer dementias, but there are conflicting reports in the literature. A systematic review to focus on the efficacy of cholinesterase inhibitors is therefore needed for rarer dementias.