Definition and diagnosis

The new Diagnostic and Statistical Manual of Mental Disorders (DSM-5), renamed dementia as a major neurocognitive disorder (NCD). The two terms are in essence different labels for the same condition and the use of the term dementia is still acceptable.⁶
DSM-5 defines NCD or dementia as significant acquired cognitive impairment in one or more cognitive domains that represents a significant decline from previous baseline and interferes with independence in daily activities.⁶ The following six cognitive domains are listed in DSM-5 as being affected by dementia:⁶

• Memory and learning - including free recall, cued recall, recognition memory, implicit learning, semantic and autobiographical long-term memory
• Executive function - including planning, decision making, responding to feedback, working memory, inhibition and mental flexibility
• Complex attention - including sustained attention, divided attention, selective attention and information processing speed
• Language - including word finding, object naming, fluency, grammar and syntax and receptive language
• Social cognition - including recognition of emotions, theory of mind and insight
• Perceptual-motor function - including visual perception, visuoconstructional reasoning and perceptual-motor coordination

These cognitive deficits should not be due to any other major psychiatric disorder such as depression or delirium.^6,7

Detection of dementia is essential for improving the lives of patients and early diagnosis improves prognosis.^a However, some studies have shown that up to half and even more than 90% of people living with dementia in the community are not detected.^a Symptoms should be further explored when the patient, caregiver or family raises concerns and should not be dismissed as "just a part of ageing".³

A systematic approach to diagnosing dementia is recommended and includes taking a history from both patient and the caregiver, cognitive assessment, medication review, blood tests and computed tomography (CT) or magnetic resonance imaging (MRI) to exclude other cerebral pathologies.³

Cognitive assessment

Cognitive assessment should include the use of a screening tool with established validity and reliability.³ A number of tools are available and recommended in several guidelines and include, but are not limited to, the Mini-Mental State Examination (MMSE)³, the Kokmen Short Test of Mental Status and the ?-minute screen.⁵ Interview-based techniques include the Blessed Dementia Rating Scale, Clinical Dementia Rating (CDR) and Informative Questionnaire on Cognitive Decline in the Elderly (IQCODE).⁵ Brief cognitive assessment instruments include the Clock Drawing Test and the Time and Change test; however these should be used with caution due to their limited scope.⁵ According to South African Dementia guidelines, an MMSE score of 27 out of 30 indicates mild cognitive impairment (MCI), while a range of 21-26 is indicative of mild Alzheimer's disease (AD) with short-term memory impairment, often accompanied by symptoms of anxiety and depression.² An MMSE score of 11-20 (moderate AD) is associated with neuropsychiatric symptoms and severe AD (MMSE score 0-10) is characterised by prominent cognitive decline, motor signs and an onset of loss of sphincter control.²

Due to the progressive nature of dementia, repeat testing at 3-6 month intervals can be used as a tracking tool.² Patients with MCI convert to AD at a rate of close to 10% per year and patients with AD experience an average annual loss of 2-3 points on the MMSE test.^2,3

Laboratory tests and neuroimaging

Patients with abnormal screening tests should undergo further laboratory testing with or without imaging studies to rule out secondary causes of dementia and identify reversible causes of memory loss.⁹ The number of tests and investigations that can be performed are often determined by cost restraints and other practicalities.²

The following routine tests are recommended in the evaluation of patients with dementia:^2,5

• Complete blood cell count
• Urea/Creatinine
• Glucose
• Serum Vitamin B12 levels
• Thyroid function test
• Liver function tests
• Serum electrolytes/Calcium
• Total cholesterol
• Syphilis serology
• Urine dipsticks

Testing for neurosyphilis or HIV is indicated if the patient has a history of risk factors for sexually transmitted diseases.⁹ Although the yield for neuroimaging is low, it may be useful in some symptomatic patients.⁹

Neuroimaging is recommended for the following patients:⁹

• Onset of symptoms before 60 years of age
• Abrupt onset or rapid cognitive decline (over weeks to months)
• Focal neurologic symptoms
• Predisposing conditions such as malignancy, HIV disease or concurrent anticoagulation
• Suspicion of vascular disease, normal pressure hydrocephalus, infection or subdural haematoma

Neuropsychiatric assessment

Over 90% of patients with dementia will experience at least one neuropsychiatric symptom (NPS) at some point in the course of their illness.² Neuropsychiatric symptoms are those that are most disturbing to the family and caregivers and are more likely to prompt entry into long-term care than cognitive decline.^2A The most common symptoms include agitation, aggression, mood disorders/behavioural disturbance, depression, apathy, psychosis and hallucinations. Less frequently occurring symptoms include sexual disinhibition, euphoria/elation, appetite and eating disturbances and abnormal vocalisations.⁴ Patients with dementia with Lewy bodies tend to experience visual hallucinations while patients with frontotemporal dementia display inappropriate disinhibition.⁹

Behavioural disturbances commonly peak in the late afternoon or evening and are closely related to disturbed circadian rhythms.¹⁰ This phenomenon is referred to as "sundown effect" or "sundowning" and affects up to 1 in 5 patients with dementia.¹⁰ Risk factors include fading light and disturbed sleep.¹⁰

NPS's become more prominent with disease progression and may seriously impact the patient's well-being and increase the stress and burden on caregivers, both emotionally and financially.⁴ Patients should be screened for NPS's at regular follow-up visits and adjustments should be made over time with new emerging behaviours.⁴ Behavioural domains are best assessed and tracked against the Neuropsychiatric Inventory (NPI) to quantify treatment response.²

Causes and types of dementia

Alzheimer's disease (AD) is the most common cause of dementia worldwide and especially in the elderly.^4,5 Most patients with dementia before 65 years have AD. The remainder are likely to have vascular dementia, frontotemporal dementia (FTD), head injury, alcohol intoxication or metabolic disorder.¹¹ In South Africa, dementia due to HIV/AIDS complex is common and occurs mostly in the younger age group.² Among the elderly in South Africa, vascular dementia (VaD) is the most prevalent, followed by AD.² Table I provides a summary of diseases and conditions that can cause dementia. Many of these conditions have specific treatments available.¹² Therefore, it is important to perform a thorough diagnostic evaluation in order to make an accurate diagnosis and provide the correct treatment.^2,13

Abnormalities linked to more than one cause of dementia can occur simultaneously in the brain and this is referred to as mixed dementia.¹⁴

Management of dementia

Non-pharmacological management

Non-pharmacological interventions are recommended as the initial strategy for managing problematic behaviours, to improve quality of life and reduce the need to restrain.^3-4 Therapy is now directed at person-centered care (PCC) and efforts are made to understand the individual's experience of dementia.⁴ Role-appropriate dementia-specific training is recommended for caregivers.³ This involves teaching caregivers how to understand a patient with dementia, how to read body language and behaviour as signs of communication and to respond appropriately.³

Cognitive, memory and functional disabilities

Individualised interventions to improve cognitive function, memory and functioning problems may include self-affirming exercises (e.g. reminiscence therapy) and structured socialisation (e.g. viewing family videos or pet therapy).⁴ Patients with dementia should be encouraged to continue with exercise and other activities that they find meaningful, interesting and enjoyable.³

Several nutrient deficiencies are known to be risk factors for AD and although there are no clinical trials to support dietary supplementation, evidence suggests that consumption of fish with high fat content and marine omega-3 polyunsaturated fatty acid decreases the risk of cognitive impairment and dementia.⁴ It may therefore be worthwhile to encourage consumption of fatty fish.⁴ This dietary modification may also reduce the risk of stroke and heart disease.⁴ Studies have suggested that Vitamin D deficiency may be associated with an increased risk of cognitive impairment in the elderly.⁴ Some spices that could be potentially beneficial and that warrant further study include turmeric (contains curcumin), saffron, ginger, cinnamon and the pepper family.¹⁶ It is also important to maintain adequate nourishment and hydration and to monitor the weight of the patient.³

The level of disease progression impacts on functionality in terms of activities of daily living and determines whether the patient is able to perform complicated tasks such as managing their own medication, shopping, cooking and finances or only has the ability to perform basic functions such as wash, dress, feed and toilet themselves.² Whenever possible, it is important to discuss with patients factors such as handing over financial responsibility and last will and testaments while competency is still preserved.² Similarly, it is important to discuss the living circumstances, availability of family or other caregivers and additional social support to ensure that both the patient and caregiver are able to cope.²

Other factors that require regular evaluation are the ability to drive or keep a firearm.² While still competent, patients should be warned to drive only when a caregiver is present, on quiet roads under good visibility conditions and only during the daytime. Both driver's licenses and firearm licenses should be revoked once the patient becomes incapable of safely operating a vehicle or firearm.²

Managing Neuropsychiatric symptoms (NPS)

Managing mood disorders and behavioural problems with non-pharmacological interventions is preferred, as this can avoid possible medicine adverse effects and drug interactions and may also address and improve the underlying reasons for the behaviour.⁴ If patients with dementia cannot express their needs through verbal communication, they may communicate through their actions and behaviours.³ It is therefore important to follow the ABC approach for assessment and analysis of behaviour.^2,3 This entails observing for and noting environmental Antecedents (triggers) as well as the details of Behaviour (description, time, duration) and the Consequences.^2,3 Common triggers of agitation and aggression include medical illness, pain, faecal impaction, boredom, loneliness, depression and social and environmental stressors.⁴

Creating a safe, calm and predictable environment can be effective in alleviating or preventing behavioural problems in patients with dementia.⁴ Maintaining a predictable routine, for instance regular scheduled toileting or prompted voiding, may avert or reduce problematic behaviour - in this instance urinary incontinence.⁴

One strategy that can reduce anxiety and agitation in the patient utilises the three Rs approach - Repeat, Reassure and Redirect.⁴ Using this strategy, caregivers can repeat questions, instructions or responses when necessary, reassure the patient or redirect the patient's focus to something less stressful.⁴ In addition, activities that trigger agitation (functions the patient can no longer perform) should be avoided or altered (for instance, allow the patient to bath instead of shower if this relieves agitation).⁴ Rewarding successes (positive reinforcement), validation therapy, creative diversion and reminiscence therapy are all non-pharmacological interventions that can be used very effectively.²

Cognitive behavioural therapy or cognitive stimulation therapy affords the opportunity to understand the patient's unique distressing experiences and allows interventions specific to the patient's needs.⁴

Pharmacological Management

Since dementia is a progressive disease and the processes are irreversible, the aim of pharmacotherapy is to preserve cognitive and functional ability, minimise behavioural disturbances, and to slow disease progression.⁴ Maintaining quality of life and the highest level of patient functionality for as long as possible, enables delay of enrolment into institutional care.²

Cognitive, Memory and Functional Disabilities

Alzheimer's disease is associated with progressive loss of cholinergic neurons and decreasing levels of acetylcholine in the brain.² Acetylcholinesterase is the enzyme responsible for hydrolysis of acetylcholine.¹⁷ Inhibition of this enzyme is expected to increase the concentrations of acetylcholine that are available for synaptic transmission.¹⁷ In South Africa, there are currently three acetylcholinesterase inhibitors (AChEI) registered for symptomatic treatment of dementia due to AD and include donepezil, galantamine and rivastigmine.¹⁸ Rivastigmine is also registered for treatment of dementia in patients with idiopathic Parkinson's disease.¹⁸ Despite minor variations in their mode of action, there is no evidence to suggest any difference in efficacy between these three cholinesterase inhibitors.^{4, 19} AChEI's with memantine may also be beneficial in the treatment of AD patients with cerebrovascular disease, mild cognitive impairment, diffuse Lewy body dementia, Parkinson's disease dementia and mixed dementia.^{2, 3} Table II provides a summary of the doses recommended to treat cognitive impairment.

In addition to their effects on cognition, AChEI's have also demonstrated benefit in measures of activities of daily living, measures of behaviour and global patient function.⁴ Caregivers experience an immediate relief in stress burden.² Treatment effects may be diminished when treatment is delayed and treatment should ideally be started in the prodromal/symptomatic phase of dementia (patients with mild AD).^2,4

The most common adverse events reported with the use of AChEI's in general include diarrhoea, nausea and vomiting.¹⁹ Patients with AD mainly experience nausea and diarrhoea with the use of donepezil.¹⁹ Patients with vascular dementia have a greater risk of muscle and leg cramps, but also experience abnormal dreams, diarrhoea and nausea¹⁹, while patients with MCI experience similar side effects but with the addition of insomnia.¹⁹

Adverse effects reported with the use of galantamine include nausea, vomiting and diarrhoea, eating disorders/anorexia/weight loss and dizziness with the risk being greatest for anorexia.¹⁹ Side-effects for rivastigmine are similar to those reported with galantamine with the addition of headache and the greatest risk being for vomiting.¹⁹

Lowering the dose or a short pause in treatment is usually successful in overcoming adverse events.² If treatment is re-initiated after a prolonged period, re-challenge may be successful.² Abdominal cramps, excessive sweating and urinary incontinence may indicate the need to switch to a different agent.²

AChEI's may cause bradycardia and should be used with caution in patients with cardiovascular disease and those taking other medication such as beta-blockers, digoxin, amiodarone and calcium channel blockers that also slow the heart rate.²

N-methyl-D-aspartate (NMDA) receptors play a role in physiological processes such as learning and memory.²⁰ Persistent activation of NMDA receptors by glutamate has been implicated as a possible cause of neurodegeneration in various types of dementia.²⁰ Memantine is a low- to moderate-affinity, noncompetitive NMDA receptor antagonist.²⁰ It is thought to act by blocking glutamate (the principal excitatory neurotransmitter in the central nervous system).²⁰ It has been postulated that low- to moderate-affinity NMDA receptor antagonists may prevent neurotoxicity due to glutamate without interfering with the physiologic processes mediated by activation of NMDA receptors.²⁰ In South Africa, memantine is registered for treatment of moderate to severe Alzheimer's disease.¹⁸

Side-effects commonly reported with the use of memantine include confusion, dizziness, headache, agitation and vomiting and are usually transient in nature.^2,19

At least two thirds of patients can be expected to derive modest benefit from treatment in terms of improved cognition, behaviour and activities of daily living.² The decision to initiate therapy to manage patients with dementia should be based on individual assessment and should balance harms against modest or even no benefit.¹⁹ Initial treatment should be with an AChEI and memantine should be added when patients progress from mild to moderate AD.^3-4 Combination therapy appears to be more effective than each agent on its own and there are no pharmacodynamic or pharmacokinetic interactions between these two agents.² Global guidelines recommend that patients on treatment should be reviewed every 6 months and treatment should only be continued while the MMSE score remains above 10 points and the patient's functional, global and behavioural condition indicates that the drug is having a worthwhile effect.⁴ Patients with moderate to severe AD (MMSE score <12) may be treated with memantine alone or in combination with an AChEI.⁴

Neuropsychiatric symptoms (NPS) and behavioural problems.

It is important to identify and treat all reversible causes of agitation and aggression such as pain or constipation.⁴ In patients where non-pharmacological management does not reduce behavioural problems sufficiently⁴, pharmacological intervention may be indicated if the person is severely distressed or if there is an immediate risk of harm.³ Patients treated with AChEI's or memantine may experience a reduction in severity of agitation/aggression and irritability, but anxiety, depression and apathy are not reduced by these agents.⁴

In patients where agitation and aggression are not sufficiently reduced by AChEI's and/or memantine, treatment with a psychotropic agent may be necessary.⁴ A trial of a selective serotonin reuptake inhibitor (SSRI) is recommended for treatment of agitation and the strongest evidence is for citalopram which has the additional benefit of sedation.^2,3 Due to the risk of QT-prolongation, the dose should not exceed 20 mg per day in patients older than 60 years.² Trazodone, carbamazepine and valproate may be considered for treatment of mild agitation.⁴ Antipsychotics are not usually recommended for treatment of aggression and agitation due to the risk of cerebrovascular adverse events and increased mortality in elderly patients with dementia-related psychosis.^3,4 However, in severe cases antipsychotic use may be considered but family members and caregivers should be informed of the possible benefits and harms.³ Additional adverse events such as sedation, falls, extrapyramidal signs and even possible acceleration of cognitive decline, warrant careful consideration before prescribing antipsychotics to this frail population.⁴ If antipsychotics are prescribed, olanzapine or risperidone may be considered at the lowest effective dose and treatment should be reviewed every 4-12 weeks, considering the possibilities of dose reductions or treatment cessation.^3,4 The use of tricyclic antidepressants is avoided in this population due to their anticholinergic and cardiovascular adverse events.²

Benzodiazepines should not be used to treat agitation due to the frequent occurrences of daytime somnolence, confusion, incoordination, memory impairment, incontinence and emotional liability.^2,4

Although major depression may precede the onset of AD, it occurs less frequently as the disease progresses and once dementia is established, apathy (frequently misinterpreted as depression) is the most common NPS.² The role of antidepressant use in dementia is uncertain and larger trials conducted in people with dementia have not shown a benefit with antidepressants for treatment of depression per se.³ Patients with an MMSE score below 20 tend to not benefit from the antidepressants for treatment of depression.² If there is uncertainty about the diagnosis of depression vs. apathy, a trial of antidepressant medication should be given.² Dementia patients tend to fare better on the "sedating" antidepressants such as citalopram (20 mg), sertraline (50-150 mg), mirtazapine (15-30 mg) and agomelatine (25-50 mg) at night.²

General principles of treatment

Medication should be individualised, taking into consideration the constellation of symptoms, side-effect profile of the medicine, stage of the disease and caregiver availability.² Treatment should, in general, be started using low doses, slowly increasing to minimum effective doses with frequent reviews, particularly during the first month after starting therapy.² It may be necessary to check whether the medication is having the desired effect by occasionally withholding treatment for approximately 2 weeks.² Recurrence in severity of NPS and behavioural symptoms will be an indication to continue treatment.² It is important to assess the patient regularly with regards to response to treatment and to determine the need for treatment continuation.²

Treatment is holistic, multifaceted and more often than not, multidisciplinary.² Teamwork is essential and family members and caregivers should be included during consultations and treatment planning.² Treatment aims to maximise cognition, functionality and quality of life to delay institutional care.²

A glance into the future

Challenges experienced in diagnosing and monitoring disease progression and response to treatment have sparked interest in finding reliable biomarkers of Alzheimer's disease.²⁴ Amyloidbeta deposition correlates with memory impairment and a higher risk for cognitive decline in the aging population and mild cognitive impairment subjects.²¹ The evaluation of amyloidbeta deposition is accepted as a measurable outcome in clinical trials and is currently being used for patient recruitment.²¹ Other tests under evaluation include cerebrospinal fluid (CSF) and other biomarkers for AD, Tau mutations in patients with Frontotemporal dementia (FTD) (normal tau protein helps maintain the structure of a neuron²²) and AD gene mutations in patients with FTD.⁵

The other field of research focuses on finding multiple targets in the neurotoxic cascade for effective treatment of dementia. At present key targets under investigation include:

• Reduction of brain amyloid levels⁴ (monoclonal antibody solanezumab and beta-secretase inhibitor verubecestat)²²
• Abnormal tau proteins (AADvac1 that stimulates the immune system to make antibodies against abnormal tau proteins)²²
• Inflammation (microglial modulater CSP-1103 that aims to reduce inflammation in the brain)²²
• 5HT6 receptor (5HT6 antagonist intepirdine that blocks the ability of the receptor to decrease acetylcholine levels)²²

Conclusion

Dementia is a chronic, debilitating disease for which there is currently no cure.^Y Non-pharmacological management should be the first line of approach in managing behavioural problems.^3,4 It is important to maintain a calm, organised environment and a predictable routine in those with dementia to reduce agitation and anxiety.^4,22 It is also important to manage possible medical causes for agitation such as pain and constipation.⁴ A person-centered care approach is recommended, incorporating personal knowledge of the patient in order to understand and provide support for the unmet needs of the individual.²³ It is also essential to provide the caregiver with sufficient training and ongoing support.⁴ Education of family members and caregivers on the progressive nature of the disease will prepare them and help them realise that decline is not due to a lack of proper care.⁴ Referral of the caregiver to support groups is recommended.⁴

Treatment should start in the prodromal/symptomatic/mild cognitive impairment stage of AD.² Combined treatment with AChEls and memantine are more effective and should be considered in patients with moderate to severe AD.^2,3 Neuropsychiatric symptoms should only be treated with medication if non-pharmacological management does not control symptoms sufficiently and symptoms are severe, causing distress to the patient and caregivers.^3,4

A trial of a suitable SSRI may be effective to manage agitation.³ Trazodone, carbamazepine or valproate may also be considered for mild agitation.⁴ Antipsychotics should generally be avoided, although they may be considered where symptoms are severe.³ Treatment should follow the general principles of "start low, go slow, monitor frequently".² The overall goal of treatment is to slow cognitive decline, improve quality of life and delay institutional care.² While current treatment strategies address symptoms of dementia, many of the new drugs in development aim to modify the disease process itself and many researchers believe that in future, successful treatment will involve the use of a "cocktail" of medications aimed at multiple targets.²²

References:

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