Alzheimer's Disease

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Diagnosis and reasoning

Confusion and disorientation are two symptoms commonly encountered in the primary care setting; unfortunately, they are also non-specific, being caused by a broad range of disorders. A detailed history is key to the evaluation of these patients, as this can rapidly rule out many of the potential differentials. Considering the lady in this case, note the presence of confusion, disorientation, forgetfulness, and wandering off alone; these symptoms were of insidious onset, are progressive, and have lasted for a prolonged period of time. The above constellation is most suggestive of dementia; her MMSE (Mini Mental State Examination) supports this possibility, given the score of 20/30 (i.e. moderate dementia). That said, it is essential to consider and exclude several potential mimics. First of all, organic conditions such as vitamin B12 deficiency and thyroid disorders can present in this manner; the American Academy of Neurology recommends their exclusion via targeted investigations. In this patient, a thyroid profile and serum B12 levels are both within normal parameters, excluding the above possibilities. Secondly, both age-related cognitive decline and mild cognitive disorder can present with memory loss; however, confusion and severe disorientation are rare in these patients, making these diagnoses unlikely. Depression can both mimic dementia, and co-exist along with it. However, she has insufficient symptoms to meet the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for depression; in addition, her Geriatric Depression Scale (GDS) score is within normal limits. Following exclusion of these differentials, dementia remains the likely cause of her symptoms; the next step should be determination of the likely underlying form. As Alzheimer's Disease is the commonest cause of dementia, it is logical to consider this diagnosis first. In fact, this lady does meet the DSM-5 criteria for diagnosis of the condition. However, it is still rational to consider and exclude the other key forms of dementia, as their treatment is markedly different. The presence of hypertension and dyslipidemia indicates that multi-infarct dementia should be considered. However, such patients usually experience a sudden onset of symptoms, with subsequent stepwise progression; focal neurological signs may also be present. Dementia with Lewy Bodies (DLB) is another important possibility; however, visual hallucinations are usually prominent, as are sleep disturbances. Parkinson's disease may also result in a progressive dementia; however, this is a late feature of the condition, with motor symptoms usually appearing long before. Thus, in summary, Alzheimer's Disease is indeed the likely diagnosis. An important question is whether imaging of the brain should be performed; while the routine use of neuroimaging in the workup of dementia is controversial, the presence of vascular risk factors in this patient suggests that magnetic resonance imaging (MRI) might indeed be justifiable. However, the MRI only reveals medial temporal and hippocampal atrophy, which is a characteristic imaging feature encountered in the early stages of Alzheimer's Disease. Donepezil is the first-line agent in patients with moderate dementia (such as this lady); it is known to improve both the quality of life and cognitive functions. While Memantine is also used in the treatment of Alzheimer's Disease, it is typically reserved for individuals with severe dementia (i.e. an MMSE score < 10). Aspirin therapy would have been indicated if vascular dementia were present; Ropinirole is used in the management of individuals with Parkinson's disease.


Discussion

Alzheimer's Disease is a progressive neurodegenerative condition; it is the most common cause of dementia worldwide, with over 35 million individuals affected. The underlying pathophysiology appears be deposition of β-amyloid plaques, neuronal inflammation in the neocortical terminal fields, and development of neurofibrillary tangles in medial temporal-lobe structures; deficiencies in cholinergic transmission have also been identified. Note that the cerebral cortex becomes progressively atrophic as the disease progresses. Known risk factors for the condition include increasing age, a family history of the disease, Down syndrome, obesity, dyslipidemia, hypertension, insulin resistance, and certain genetic variants. Affected individuals commonly present with deterioration of memory, the inability to perform activities of daily living (ADL), and behavioral disturbances. Confusion and disorientation with respect to time and place, loss of judgment, and impairment of executive functions are important and easily identifiable components of Alzheimer's Disease. Associated features such as nominal aphasia, apraxia and agnosia may also be identified. Rapid fluctuations of mood may become apparent as the disease progresses, with the patient suddenly becoming anxious or tearful. Note that hallucinations and delusions are uncommon. Individuals who progress to severe dementia usually become completely dependent on their caregivers, and may show significant weight loss, difficulty in swallowing, and loss of bladder and bowel control. The Diagnostic and Statistical Manual of mental disorders, 5th edition (DSM-5), has specific diagnostic criteria for Alzheimer's Disease; these include: - Evidence of cognitive decline from a previous level in one or more cognitive domains (complex attention, executive function, learning and memory, language, perceptual-motor, or social cognition), based on the concern of the patient, a knowledgeable informant or a clinician, and standardized neuropsychological testing - Cognitive deficits interfering with independence in everyday activities - The cognitive deficits do not occur exclusively in the context of delirium - The cognitive deficits are not better explained by another mental disorder (e.g., major depressive disorder, schizophrenia). - Insidious onset and gradual progression of impairment in one or more of the above mentioned cognitive domains Apart from the above, separate sets of criteria are defined for categorization of 'possible' or 'probable' Alzheimer's Disease. Note that alternate conditions which can mimic dementia should also be excluded. These include hearing and visual defects, age-related cognitive impairment, organic conditions such as hypo/hyperthyroidism and vitamin B12 deficiency, and depression. Imaging studies of the central nervous system are not routinely indicated, unless focal neurological signs are present. Syphilis serology, lumbar puncture, electroencephalography (EEG), and genetic testing are also only indicated if there is suspicion of an alternate illness. Alzheimer's Disease is currently incurable; the management is aimed at slowing progression, and alleviating symptoms. Cholinesterase inhibitors such as donepezil, galantamine and rivastigmine are useful in the management of mild to moderate dementia; they both alleviate symptoms and improve cognitive functions. The N-methyl-D-aspartate (NMDA) antagonist Memantine is of use in patients with severe dementia, either alone, or in combination with cholinesterase inhibitors. Non-pharmacological measures are mainly of use in managing coexisting behavioral disturbances such as agitation, psychosis and depression; these include behavioral therapy, cognitive stimulation, environmental modification, multisensory stimulation therapies involving aromas, light and music, and caregiver training programs. Structured exercises and conversation should be incorporated into daily activities in order to preserve the patient's mobility and speech. In general, Alzheimer's Disease progresses from mild cognitive impairment to complete dependency and death over a period averaging 10 years. Note that early diagnosis is critical for slowing the rate of progression of the disease.


Take home messages

  1. Alzheimer's Disease is the commonest cause of dementia worldwide.
  2. A range of organic and psychiatric causes can mimic Alzheimer's Disease, and should be excluded prior to arriving at this diagnosis.
  3. While is Alzheimer's Disease is incurable, early diagnosis and treatment has a significant impact on the disease progression.

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