Ethiopian Review

CLINICAL FOCUS: DEMENTIADr Sean Kennelly looks at the diagnostic methods of determining Alzheimer’s disease, treatment options and emerging disease-modifying agents that aim to enhance the lives of patients and carers

Alzheimer’s disease (AD) is a progressive neurodegenerative dementia, resulting in cognitive and behavioural impairment of sufficient severity that markedly interferes with social and occupational functioning. Generally, it is diagnosed in people over 65 years of age, although the less-prevalent early-onset Alzheimer’s can occur much earlier.

An estimated 26.6 million people worldwide had Alzheimer’s in 2006; this number may quadruple by 2050, making it the most common form of dementia. There are currently 40,000 people with dementia in Ireland, with the number expected to be in excess of 104,000 by 2037.

The anatomic pathology of Alzheimer’s disease includes neurofibrillary tangles (NFTs) of hyperphosphorylated tau protein and senile plaques (SPs) of β-amyloid (Aβ) at the microscopic level; and cerebrocortical atrophy, which particularly involves the medial aspect of the temporal lobe on gross pathology. NFTs and SPs were described in by Alois Alzheimer in his original report on the disorder in 1907, and they are now universally accepted as a hallmark of the disease.

Cause is unknown
The cause of AD is unknown. Many investigators believe that converging risk factors, which include advancing age, ApoE epsilon 4 genotype, obesity, insulin resistance, dyslipidemia, hypertension and inflammatory markers, trigger a pathophysiologic cascade that over decades leads to Alzheimer pathology and dementia. Familial forms of Alzheimer’s disease account for less than 7 per cent of all cases of Alzheimer’s disease, with most cases being sporadic (i.e. not inherited).

Although the course of AD progression is different for each individual, there are common features that suggest the onset of AD. The most commonly recognised symptom is memory loss, in particular short-term memory loss. After memory loss occurs, patients may also have language disorders (e.g. anomia) and impairment in their visuospatial skills and executive functions.

As the disease advances further, symptoms may include confusion, irritability and aggression, mood swings and long-term memory loss. AD cannot be diagnosed in patients with clouded consciousness or delirium. The main focus of many of the diagnostic guidelines for AD is the exclusion of other possible causes of dementia (e.g. metabolic causes, vascular disease, neoplasms).

Diagnostic work-up
The diagnosis of AD is largely based on a detailed history. Many of the investigations performed are to out-rule other causes of dementia. All patients in whom the diagnosis is considered should have vitamin B12 levels and thyroid function tests taken. Brain neuro-imaging (MRI/CT) in most instances may be normal, or demonstrate cerebral atrophy.

SPECT or PET scans are rarely required. Recent advances in neuro-imaging have seen the use of specialised amyloid binding compounds that enable the detection and measurement of cerebral amyloid burden directly using PET scanning.

A lumbar puncture measuring cerebrospinal fluid levels of Aβ, total tau and hyperphosphorylated tau may be performed with a sensitivity and specificity of almost 90 per cent. The use of specialist neuro-imaging and lumbar puncture analysis will become more commonplace as we attempt to diagnose AD earlier in the course of the disease, as disease-modifying treatments come on line.

Mild cognitive impairment
The neuropathological changes of AD typically begin many years before its clinical signs are apparent. Most patients pass through a pre-dementia phase called mild cognitive impairment (MCI), with early memory loss (or impairment of one or more cognitive domains on neuropsychological testing) but with relatively well preserved activities of daily living.

Approximately 6-25 per cent of patients with MCI, especially amnestic variant MCI, progress to dementia annually, a rate far higher than the 0.3-3.9 per cent incidence of the general population. It can be difficult to distinguish MCI from minor memory complaints associated with normal ageing, as the two often overlap.

For that reason, the concept of MCI is controversial in that it is a transitional state between normal ageing and dementia in some individuals, whilst other patients diagnosed with MCI will revert to normal cognitive function.

Serial neuropsychological evaluation over several months or years is often required to distinguish those patients who are likely to progress from those who will not. What the diagnosis of MCI does offer us, however, is an opportunity to identify some patients with AD early in the course of the disease, which may be of critical importance when disease-modifying treatments become available in the future. Even current treatments appear to offer better outcomes when used early on.

Screening tests
Memory can be tested simply with a three-or-four-word recall test and a clock-drawing task during a brief examination. Several composite cognitive tests are also available, the most popular of which is the Mini-Mental State Examination (MMSE). This is a 30-point scale that briefly examines orientation, recall, attention, visuospatial ability and language skills.

A score of 23 or less is suggestive of cognitive impairment; however care should be taken in interpreting the results in that a score of 27 (or indeed higher) in a person with ‘high education’ may only be a reflection of their education status, and not reflect any cognitive decline. One should also be aware of any physical or sensory deficits that might limit a person’s performance on the test.

Another commonly used test is the Montreal Cognitive Assessment Battery (MOCA). This is also a 30-point assessment tool that incorporates a five-word recall, clock-drawing and executive and visuospatial items that make it more sensitive for MCI and vascular dementia. These screening tolls are most useful when measured serially, with a decline in scores over time (e.g. three months) being suggestive of a significant cognitive deficit.

Treatment
Four drugs are currently licensed for the treatment of AD: three cholinesterase inhibitors approved for mild/moderate disease and a glutamate N-methyl D-aspartate (NMDA) antagonist approved for moderate to severe disease.

Cholinesterase inhibitors for mild/moderate disease

The cholinesterase inhibitors tend to stabilise memory during the first year of treatment and they may make the subsequent decline more gradual. The three drugs have similar efficacy, so the choice is usually based on tolerability.

1. Donepezil is taken once daily, and its starting dose of 5mg is a therapeutic dose. It has recently been approved for the treatment of severe AD on the basis of positive results in patients with moderate to severe AD.

2. Galantamine is also available in an extended release formulation that can be taken once daily. Galantamine is approved for the treatment of ‘mixed’ AD/vascular dementia.

3. Rivastagmine is taken twice a day with food to reduce the risk of gastrointestinal adverse effects. It is now available as a daily patch, which has a more favourable side-effect profile than the oral preparation.

Memantine for moderate to severe disease

Memantine is approved for moderate to severe disease. The approval was based on a trial in which patients with advanced AD who received memantine showed less decline in cognitive function after six months versus placebo, and another trial in which patients treated with memantine and donepezil showed more benefit than those treated with donepezil alone.

Recent guidelines have recommended a treatment strategy that involves the commencement of a cholinesterase inhibitor soon after the diagnosis has been made, and to slowly titrate up the dose as tolerated. Once patients have progressed into the moderate range of the disease (MMSE 10-20), memantine should be started and titrated upward to 10mg twice a day.

It is reasonable to continue these medications as long as they are tolerated, and the physician and family feel they are of benefit. Patients and their families should be advised prior to the commencement of these medications that their main effect is the attenuation of cognitive decline over time, rather than an improvement in symptoms.

Currently no medications are approved for the treatment of MCI, and on the whole trials on the use of cholinesterase inhibitors in patients with MCI have had no effect on primary end points. None of the medications reduced transition rates from MCI to AD.

Behavioural symptoms
Behavioural problems are often the most disturbing symptom in dementia, requiring higher levels of care. Apathy is the most common behavioural complaint, often increasing in severity with disease progression. There is no approved treatment for apathy, though current trials are examining the efficacy of methylphenidate and modafanil.

Depression and irritability may respond well to low-dose serotonin reuptake inhibitors.

Agitation and psychosis may often be the symptom that overwhelms a carer’s ability to cope. Recent studies have raised concerns about the safety and efficacy of atypical neuroleptics in patients with dementia, and suggest these drugs should be used in the lowest dose necessary with careful monitoring. Risperidone and quetiapine are among the more commonly used atypical neuroleptics.

Future directions
New disease-modifying agents are being developed and tested to see if they delay disability, promote independence and improve the quality of life of patients and carers. Chief among these are compounds that reduce brain amyloid levels.

The ‘amyloid cascade hypothesis’ is the prevailing view of the pathogenesis of AD.

This hypothesis states that a cascade of events that may be triggered by a number of intrinsic risk factors result in the accumulation of Aβ within the brain and subsequent neurodegeneration. Exciting immunotherapeutic (active and passive) approaches that target the toxic fragment of Aβ have been developed, and are being trialled.

Trials are also under way examining the efficacy of gamma secretase inhibitors, a class of drug that blocks the specific cleavage site on the amyloid precursor protein responsible for toxic Aβ production. Several agents that prevent tau hyperphosphorylation are also being developed. These compounds may add significantly to our armory to fight the disease.

Prognosis
Unfortunately, AD is incurable using current approved medications. Gradually, bodily functions are lost, ultimately leading to death. Individual prognosis is difficult to assess, as the duration of the disease varies. The mean life-expectancy following diagnosis is approximately seven years.

Fewer than three per cent of individuals live more than 14 years after diagnosis. Hopefully over the coming years, the outlook for patients diagnosed with AD and their carers will be greatly enhanced by emerging treatments.

References on request.

Dr Sean Kennelly,
Roskamp Research Fellow, Department of Medical Gerontology,
Trinity College Dublin.

- By Dr Sean Kennelly | IMT

- Bin Du