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Alzheimer's Disease - Clinical Features, Diagnosis and Treatment

by Dr Smita Pandey Bhat PhD(more info)

listed in alzheimer's, originally published in issue 180 - March 2011

Definition

Alzheimer's disease (AD), also known simply as Alzheimer's, is a neurodegenerative disease. It is characterized by progressive cognitive deterioration, together with declining activities of daily living and neuropsychiatric symptoms or behavioural changes. It is the most common type of dementia.[1]

Early Symptoms

The most striking early symptom is the loss of memory (amnesia), which usually manifests as minor forgetfulness that becomes steadily more pronounced with the progression of the illness, with relative preservation of older memories.[2,3].

 

Alzheimer's Disease  - Clinical Features, Diagnosis and Treatment

Symptoms as the Disorder Progresses

As the disorder progresses, cognitive (intellectual) impairment extends to the domains of language (aphasia), skilled movements (apraxia), recognition (agnosia),[4] and those functions closely related to the frontal and temporal lobes of the brain (such as decision-making and planning)[5] as they become disconnected from the limbic system, reflecting extension of the underlying pathological process.[6]

Pathological Process

This pathological process consists principally of neuronal loss or atrophy, principally in the temporoparietal cortex, but also in the frontal cortex, together with an inflammatory response to the deposition of amyloid plaques and neurofibrillary tangles.[7]

History

In 1901, Dr Alois Alzheimer, a German psychiatrist, interviewed a patient named Mrs Auguste D, age 51 .He would initially record her behaviour as "amnesic writing disorder," but Mrs Auguste D would be the first patient to be identified with Alzheimer's disease.

On November 3, 1906, he presented Auguste D's case to the 37th Assembly of Southwest German Psychiatrists and described the neurofibrillary tangles and amyloid plaques that have come to be considered the hallmark of the disease

Kraepelin would later write about this case and others in his Textbook for Students and Doctors and index them under 'Alzheimer's disease'. By 1910, this denomination for the disease was well established among the specialist community (Maurer et al, 2003).

In the 1970s and early-1980s, because the symptoms and brain pathology were identical for Alzheimer victims older and younger than age 65, the name 'Alzheimer's disease' began to be used, within and outside the medical profession, equally for afflicted individuals of all ages.[8]

Clinical Features

The usual first symptom noticed is short term memory loss which progresses from seemingly simple and often fluctuating forgetfulness (with which the disease should not be confused) to a more pervasive loss of short-term memory, then of familiar and well-known skills or objects or persons.[2,3] Aphasia, disorientation and disinhibition often accompany the loss of memory.[4] Alzheimer's disease may also include behavioural changes, such as outbursts of violence or excessive passivity in people who have no previous history of such behaviour[9].

In the later stages, deterioration of musculature and mobility, leading to bedfastness, inability to feed oneself, and incontinence, will be seen if death from some external cause (e.g. heart attack or pneumonia) does not intervene.[9]

Course of the Disease

The course of the disease varies from person to person. Some people have the disease only for the last 5 years of life, while others may have it for as many as 20 years.[10]

Stages and Symptoms

Stage 1 (Mild): This stage can last from 2 to 4 years. Early in the illness, those with Alzheimer's tend to be less energetic and spontaneous. They exhibit minor memory loss and mood swings, and are slow to learn and react. They may become withdrawn, avoid people and new places and prefer the familiar. Individuals become confused, have difficulty organizing and planning, get lost easily and exercise poor judgment. They may have difficulty performing routine tasks, and have trouble communicating and understanding written material. If the person is employed, memory loss may begin to affect job performance. They can become angry and frustrated.[11]

Some specific examples of behaviours that people exhibit in this mild stage include:

  • Getting lost;
  • Difficulty managing money and paying bills;
  • Repetitive questions and conversations;
  • Taking longer than usual to finish routine daily tasks;
  • Poor judgment;
  • Losing things or misplacing them in odd places;
  • Noticeable changes in personality or mood.

Stage 2 (Moderate): This is generally the longest stage and can last 2 to 10 years. In this stage, the person with Alzheimer's is clearly becoming disabled. Individuals can still perform simple tasks independently, but may need assistance with more complicated activities. They forget recent events and their personal history, and become more disoriented and disconnected from reality. Memories of the distant past may be confused with the present, and affect the person's ability to comprehend the current situation, date and time. They may have trouble recognizing familiar people. Speech problems arise and understanding, reading and writing are more difficult, and the individual may invent words. They may no longer be safe alone and can wander. As Alzheimer's patients become aware of this loss of control, they may become depressed, irritable and restless or apathetic and withdrawn. They may experience sleep disturbances and have more trouble eating, grooming and dressing;[11]

Stage 3 (Severe): This stage may last 1 to 3 years. During this final stage, people may lose the ability to feed themselves, speak, recognize people and control bodily functions, such as swallowing or bowel and bladder control. Their memory worsens and may become almost non-existent. They will sleep often and grunting or moaning can be common. Constant care is typically necessary. In a weakened physical state, patients may become vulnerable to other illnesses, skin infections, and respiratory problems, particularly when they are unable to move around.[11]

Diagnosis

The diagnosis is made primarily on the basis of history, clinical observation, memory tests and intellectual functioning over a series of weeks or months, with various physical tests (blood tests [12]and neuroimaging[13]) being performed to rule out alternative diagnoses.

Interviews with family members and/or caregivers are extremely important in the initial assessment,[14] along with  neuropsychological assessments,[15] as the sufferer him/herself may tend to minimize his symptomatology or may undergo evaluation at a time when his/her symptoms are less apparent, as quotidian fluctuations ('good days and bad days') are a fairly common feature.

Initial suspicion of dementia may be strengthened by performing the mini mental state examination [16], after excluding clinical depression.

Psychological testing generally focuses on memory, attention, abstract thinking, the ability to name objects, visuospatial abilities, and other cognitive functions.[15]

 

Pathology

Biochemical Characteristics
Alzheimer's disease has been identified as a protein misfolding disease, or proteopathy, due to the accumulation of abnormally folded amyloid beta protein and tau protein in the brains of AD patients.[17]

Neuropathology
Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in AD brains.[18]

At an anatomical level, AD is characterized by gross diffuse atrophy of the brain and loss of neurons, neuronal processes and synapses in the cerebral cortex and certain subcortical regions.[19]

This results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.[19]

Levels of the neurotransmitter acetylcholine are reduced. Levels of the neurotransmitters serotonin, norepinephrine, and somatostatin are also often reduced. Glutamate levels are usually elevated.[20]

Disease mechanism
Three major competing hypotheses exist to explain the cause of the disease.

  1. The oldest, on which most currently available drug therapies are based, is known as the 'cholinergic hypothesis' and suggests that AD is due to reduced biosynthesis of the neurotransmitter acetylcholine;[20]
  2. Research after 2000 includes hypotheses centred on the effects of the misfolded and aggregated proteins, amyloid beta and tau;[21;22]
  3. The amyloid hypothesis is initially compelling because the gene for the amyloid beta precursor APP is located on chromosome 21, and patients with trisomy 21 - better known as Down syndrome - who thus have an extra gene copy almost universally exhibit AD-like disorders by 40 years of age.[23,24]

Genetics
Rare cases of Alzheimer's are caused by dominant genes that run in families. These cases often have an early age of onset.[25] Mutations in presenilin-1 or presenilin-2 genes have been documented in some families.[26] Mutations of presenilin 1 (PS1) lead to the most aggressive form of familial Alzheimer's disease (FAD).[27]

Genetic linkage
Alzheimer's disease is definitely linked to the 1st, 14thand 21st chromosomes, but other linkages are controversial and not yet confirmed. While some genes predisposing to AD have been identified , such as ApoE4 on chromosome 19, sporadic AD also involves other risk and protective genes still awaiting confirmation.[28,29]

Epidemiology
Alzheimer's disease is the most frequent type of dementia in the elderly and affects almost half of all patients with dementia. Correspondingly, advancing age is the primary risk factor for Alzheimer's. Among people aged 65, 2-3% show signs of the disease, while 25-50% of people aged 85 have symptoms of Alzheimer's and an even greater number have some of the pathological hallmarks of the disease without the characteristic symptoms. Every five years after the age of 65, the probability of having the disease doubles.[30]

Prevention

Some proposed preventive measures are even based on studies conducted solely in animals or in cell cultures but are not listed here:

  • Intellectual stimulation (e.g., playing chess or doing crosswords;[31]
  • Regular physical exercise;[32]
  • Regular social interaction;[33]
  • A Mediterranean diet with fruits and vegetables and low in saturated fat, supplemented in particular with:
  • B vitamins and Omega-3 fatty acids, especially Docosahexaenoic acid;[34,35]
  • Fruit and vegetable juice[35,36] and high doses of the antioxidant Vitamin E (in combination with vitamin C) seem to reduce Alzheimer's risk in cross sectional studies but not in a randomized trial and so are not currently a recommended preventive measure because of reported observed increases in overall mortality;[37,38] [Editor's Note: this has been strongly disputed. See www.positivehealth.com/article-view.php?articleid=2445; www.positivehealth.com/article-view.php?articleid=2251];
  • Cholesterol-lowering drugs (statins) reduce Alzheimer's risk in observational studies but so far not in randomized controlled trials;[39]
  • Female Hormone replacement therapy is no longer thought to prevent dementia based on data from the Women's Health Initiative;[40]
  • Long-term usage of non-steroidal anti-inflammatory drugs (NSAIDs), used to reduce joint inflammation and pain, is associated with a reduced likelihood of developing AD, according to some observational studies.[41] The risks appear to outweigh the drugs' benefit as a method of primary prevention

Risk Factors

There are various risk factors, the major ones are as given below:

  • Advancing age;
  • ApoE epsilon 4 genotype (in some populations);
  • Head injury;[42]
  • Poor cardiovascular health (including smoking, diabetes,[43] hypertension,[44] high cholesterol and strokes.

General Healthy Ageing

Other lines of evidence suggest that strategies for overall healthy aging may help keep the brain healthy and may even offer some protection against developing Alzheimer's or related diseases[45] .Try to keep your weight within recommended guidelines, avoid tobacco[46] and excess alcohol, stay socially connected, and exercise both your body and mind.[47]

Treatment

There is currently no cure for Alzheimer's disease. Currently available medications offer relatively small symptomatic benefit for some patients but do not slow disease progression. It helps a little for the memory. The American Association for Geriatric Psychiatry published a consensus statement on Alzheimer's treatment in 2006.

Acetylcholinesterase Inhibitors

Acetylcholinesterase (AChE) inhibition was thought to be important because there is a reduction in activity of the cholinergic neurons. AChE-inhibitors reduce the rate at which acetylcholine (ACh) is broken down and hence increase the concentration of ACh in the brain (combating the loss of ACh caused by the death of the cholinergic neurons). Acetylcholinesterase-inhibitors seemed to modestly moderate symptoms but do not alter the course of the underlying dementing process. The examples include:

  • Tacrine - no longer clinically used;
  • Donepezil - (marketed as Aricept); [48]
  • Galantamine - (marketed as Razadyne in the U.S.A. Marketed as Reminyl or Nivalin in the rest of the world);[49]
  • Rivastigmine - (marketed as Exelon).[50]

There is significant doubt as to the effectiveness of cholinesterase inhibitors. A number of recent articles have criticized the design of studies reporting benefit from these drugs, concluding that they have doubtful clinical utility, are costly, and confer many side effects. The pharmaceutical companies, but also some independent clinicians, dispute the conclusions of these articles.

Ginkgo Biloba

Examining over 50 studies conducted on Ginkgo for the treatment of "cognitive impairment and dementia," a Cochrane Review concludes that "there is promising evidence of improvement in cognition and function associated with Ginkgo." According to this review the two randomized controlled studies that focused on Alzheimer's patients both showed significant improvement in these areas.[51]

NMDA Antagonists

Recent evidence of the involvement of glutamatergic neuronal excitotoxicity causing Alzheimer's disease led to the development and introduction of memantine. Memantine is a novel NMDA receptor antagonist, and has been shown to be moderately clinically efficacious. Memantine is marketed as Akatinol, Axura, Ebixa and Namenda.[52]

Psychosocial Interventions

Supportive therapy is essential.[47] Cognitive[53] and behavioural[54] interventions strategies may be used as an adjunct to pharmacologic treatment, especially in the early to moderately advanced stages of disease. Treatment modalities include counselling, psychotherapy (if cognitive functioning is adequate), reminiscent therapy, reality orientation therapy, and behavioural reinforcements as well as cognitive rehabilitation training. Cognitive retraining along with other recreational techniques is really helpful to overcome the cognitive deficits.[55] Reality orientation techniques must be used significantly to reorient the individual suffering from the disease.[56]

Treatments in Clinical Development

A large number of potential treatments for Alzheimer's disease are currently under investigation, including four compounds being studied in phase 3 clinical trials.

  • Leuprolide has also been studied for Alzheimer's. It is hypothesized to work by reducing leutenizing hormone levels which may be causing damage in the brain as one ages;[57]
  • Vaccines or immunotherapy for Alzheimer's, unlike typical vaccines, would be used to treat diagnosed patients rather than for disease prevention. Ongoing efforts are based on the idea that, by training the immune system to recognize and attack beta-amyloid, the immune system might reverse deposition of amyloid and thus stop the disease. Initial results using this approach in animals were promising, and clinical trials of the drug candidate AN-1792 showed results in 20% of patients. However, in 2002 it was reported that 6% of multi-dosed participants (18 of 300) developed symptoms resembling meningoencephalitis;[58]
  • However, in 2002 it was reported that 6% of multi-dosed participants (18 of 300) developed symptoms resembling meningoencephalitis, and the trials were stopped. Participants in the halted trials continued to be followed, and 20% "developed high levels of antibodies to beta-amyloid" and some showed slower progression of the disease, maintaining memory-test levels while placebo-patients worsened;[59]
  • Proposed alternative treatments for Alzheimer's include a range of herbal compounds and dietary supplements;[60]
  • In the AAGP review from 2006 Vitamin E in doses below 400 IU was mentioned as having conflicting evidence in efficacy to prevent AD. Higher doses were discouraged as these may be linked with higher mortality related to cardiac events;[60] [Editor's Note: this has been strongly disputed. See www.positivehealth.com/article-view.php?articleid=2445; www.positivehealth.com/article-view.php?articleid=2251];
  • Recent clinical trials for Phase 2 and Phase 3 in this category have taken 12 to 18 months under study drug, plus additional months for patient enrolment and analysis. Compounds that are just entering into human trials or are in pre-clinical trials would be at least 4 years from being available to the public and would be available only if they can demonstrate safety and efficacy in human trials;

Occupational and Lifestyle Therapies

  • Modifications to the living environment and lifestyle of the Alzheimer's patient can improve functional performance and ease caretaker burden. Assessment by an occupational therapist like music and art therapy is often indicated. Adherence to simplified routines and labelling of household items to cue the patient can aid with activities of daily living, while placing safety locks on cabinets, doors, and gates and securing hazardous chemicals and guns can prevent accidents and wandering;[61,62]
  • Changes in routine or environment can trigger or exacerbate agitation, whereas well-lit rooms, adequate rest, and avoidance of excess stimulation all help prevent such episodes. Appropriate social and visual stimulation, however, can improve function by increasing awareness and orientation. For instance, boldly coloured tableware aids those with severe AD, helping people overcome a diminished sensitivity to visual contrast to increase food and beverage intake.[63]

Social Issues

Alzheimer's is a major public health challenge since the median age of the industrialized world's population is increasing gradually. Indeed, much of the concern about the solvency of governmental social safety nets is founded on estimates of the costs of caring for baby boomers, assuming that they develop Alzheimer's in the same proportions as earlier generations. For this reason, money spent informing the public of available effective prevention methods may yield disproportionate benefits.

The role of family caregivers has also become more prominent, as care in the familiar surroundings of home may delay onset of some symptoms and delay or eliminate the need for more professional and costly levels of care.[64]However, home-based care may entail tremendous economic, emotional, and even psychological costs as well (see elderly care).[65]

Family caregivers often give up time from work and forego pay to spend 47 hours per week on average with an affected loved one who frequently cannot be left alone.[64]

Conclusion

Alzheimer's is a progressively disabling disorder and researchers are making constant efforts for the prevention and cure of the disease which is yet not been successful.  Let us hope that in future scientists and researchers would be able to have effective prevention and cure of the disease.

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About Dr Smita Pandey Bhat PhD

Dr Smita Pandey Bhat PhD is a Clinical Psychologist (served as project manager and neuro-scientist for a CRO) currently practising Cognitive- behavioural management principles and cognitive remediation programs for mentally ill and patients with neuropsychological abnormalities.

She also creates awareness on these issues as an expert orator in workshops, seminars, newspapers, magazines and television shows. Currently, she resides and practises in Gurgaon, Delhi-NCR, India. Also, she works as consultant to various research agencies where her major role is to provide them authentic scientific content for clinical research / trials, educational research, market research and analyses, Writing RFPs and also scientific  protocols, statistical analyses plans and analyses itself, report writing, poster writing, paper writing etc. She may be contacted via dr.smitapandey@gmail.com 

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