Alzheimer’s Disease

Alzheimer’s Disease.

Carl Stuart

Stuart Medical Series.

 Alzheimer’s Disease.

 Introduction.

Alzheimer’s disease (abbreviated AD) is a pathological condition of insidious onset that is characterized by gradual memory loss and progressive dementia lasting for a period of several years (Wenk, 2003). It causes more than 50% of the incidence of dementia in the geriatric population. Statistics show that about 10% of individuals who are 70 years old or over are affected by dementia. However, AD can also occur at any age in adulthood. Demographic analysis show that AD affects about 26 million people worldwide, with statistical projections forecasting that the global prevalence rate of AD will increase to 1.17% by 2040. Currently, the cost of managing AD is high and is further increased by the unpredictability of its variable prognosis. The symptoms of AD do cause impairment in social and occupational functioning thus leading the patient to suffer social exclusion, and this precipitates depression. The duration of lifespan after a positive confirmation of AD diagnosis is about 7 years with the less than 3% of the patients living for more than 14 year (Mayeux & Stern, 2012)s. The following literature review of 8 articles aims to demonstrate that AD is caused by multiple etiologies and that it shows variation in the pathogenesis, and this necessitates the specification of the diagnostic criteria and management protocols.

Causes of AD.

A study on the etiologies of AD was done by Dr. Howard Feldman and David G. Munoz and their findings were published as a peer-reviewed article entitled Causes of Alzheimer’s Disease in the Canadian Medical Association Journal (2006). This research studied the following: the role of 3 genes in the pathogenesis of early-onset AD, the role of apoliprotein E gene polymorphism in the development of late-onset AD and the risk factors for AD. The study showed that neuronal structural abnormalities are the hallmarks of AD. These abnormalities are diagnosed using different neuroimaging modalities of the brain. The resulting images have shown that AD is characterized by cerebral atrophy whose distribution pattern is multifocal. This is illustrated by the fact that the cerebral atrophy occurs throughout the lateral frontal cortex, medial temporal lobes and both the medial and lateral regions of the parietal lobes. Also, histopathological studies did show that AD is characterized by two events: multiple neuritic plaques made up of Aβ neurofibrillary tangles of tau filaments that have undergone hyperphosphorylation; and, amyloid accumulation in both cortical blood vessel walls and leptomeninges (Munoz & Feldman, 2000).

This research also studied the role that senile plaques have in the pathogenesis of AD. Senile plaques are complex extracellular amyloid deposits that are associated with dystrophic neurites. The study showed that the specificity of amyloids for the cerebral cortices is determined by their β-amyloid component. The study also showed that senile plaques begin to develop in the fifth decade of life, and thereafter there is a rapid progression in the rate of senile plaque formation. The insidious onset of the initial plaque formation from the nonaggregated innocuous deposits of putatively non-neurotoxic β-amyloid does show that senile plaques development occurs in an orderly sequential process. This process is mediated by butyrycholinesterase. The study also showed that a regional distribution of both neurofibrillary tangles and senile neuritic plaques in both normal individual and AD patients. The results also showed that both tangles and neuritic plaques are associated with mild cognitive impairment and dementia (Munoz & Feldman, 2000). This study thus was not able to clearly demarcate the line were cognitive impairment ends and AD begins.

In the same study, the results showed that point mutations in genes located on chromosome 21 did cause autosomal dominant early-onset AD. This clinical phenotype exhibited complete penetrance. The genes affected coded for β-APP, and the mutations caused excess production of the protein or the production of the dysfunctional long-variant form of β-amyloid which has a predisposition to self-aggregate. Results also showed that mutations in the coding region for presenilin 1 and presenilin 2 proteins do predispose an individual to a familial variant of early-onset AD. The proteins presenilin 1, β-APP and presenilin 2 do organize intraneuronal vesicular traffic, and its associated dysfunction causes neuronal loss due to neurotransmitter deficit and accumulation of β-APP metabolism products (β-amyloids) (Munoz & Feldman, 2000).

Genetic polymorphism of the APOE (apolipoprotein E) gene predisposes an individual to AD. The implicated allelic form of APOE is ε4 as the study showed that ε4/ε4 genotype is associated with a 95% chance of developing AD by the eighth decade of life. Apo-lipoprotein E participates in cholinergic transmission, synaptic repair after injury and maintenance of neuronal structure (Munoz & Feldman, 2000).

The same study also showed that the environmental factors described below do contribute to the pathogenesis of AD. According to the research, clinicopathological studies done on brains of individuals affected by AD do show signs of active chronic inflammation as demonstrated by raised CSF(cerebrospinal fluid) levels of inflammatory cytokines, complement activations products and the persistent activation of microglial cells. This finding is also supported by the fact that anti-inflammatory drugs do reduce the severity of the symptoms associated with AD. Also, the study showed that the incidence of AD in women taking hormonal replacement therapy is low. This finding is also supported by the fact that a combination therapy containing tacrine and estrogen does reduce the severity of AD symptoms. Moreover, based on the findings of clinic-pathological correlation studies, the severity of AD lesions do determine the severity of the dementia. Furthermore, the study also showed that age does predispose an individual to AD.

Alzheimer's disease and Inflammation.

Tony Wyss-Coray and Joseph Rogers have done a study entitled Inflammation in Alzheimer Disease—A Brief Review of the Basic Science and Clinical Literature which aimed at elucidating the neurophysiological effects of inflammation, and how inflammation contributes to the pathogenesis of AD (2012). This research utilized the findings of neuropathological and biochemical studies of brains of AD patients. The study concluded that there was a correlation between an activated inflammatory cascade and AD. The study revealed that inflammation does initiate a complex molecular mechanism which interacts with the cellular machinery and this interaction induces pathological processes which eventually lead to AD. The study also revealed that potent anti-inflammatory drugs do reduce the incidence of AD. The study revealed that these pathological processes are mediated by both cellular and molecular mediators. The cellular mediators are astrocytes, microglial cells, oligodendrocytes and neurons; while the molecular mediators are cytokines, the complement system, soluble signaling molecules, toll-like receptors, other pattern recognition receptors, arachidonic acid metabolites and cyclooxygenases (Wyss-Coray & Rogers, 2012).

Microglias are macrophages that reside in the brain tissue, and as such they survey the entire brain, and also express inflammatory mediators and their corresponding receptors. This enables them to attack potential pathogens and also remove detritus. They are distributed homogenously within the brain. The study also showed that microglia participates in synaptic remodeling especially after synaptic loss. Microglial dysfunction leads to the loss of regulation of the inflammatory cascade, thus causing neuronal necrosis. In contrast to microglia, astrocytes are neurosupportive cells which maintain neuronal homeostasis by regulating energy metabolism, synaptic transmission, ion homeostasis, secretion and modulating oxidative stress. They also express inflammatory mediators and reactive astrocytes tend to overexpress such receptors thus leading to an inflammation cascade that destroys cerebral tissue at a rate that exceeds the restoration rate, thus leading to overall neuronal loss and its consequent dementia (Wyss-Coray & Rogers, 2012).

Pathophysiology of Alzheimer's disease.

According to a study entitled Neuropathologic changes in Alzheimer's disease which was authored by Gary.L.Wenk,  the degenerative effects of AD leads to derangements in the neurotransmitter system which results in neuronal and synaptic losses (2003). These losses predominate in the some specific cortical areas such as the lateral frontal cortex, medial temporal lobe cortex and both the medial and lateral cortices of the parietal lobes. The losses do also occur in some subcortical regions. The resulting cortical atrophy and degeneration of the locus coeruleus can be visualized using specific neuroimaging modalities such as MRI (magnetic resonance imaging) and PET (positron emission tomography) scans. This atrophy and degeneration leads to impairment in cognitive and social functions thus resulting in memory impairment and poor inter-personal relationships. Also, the losses results in the formation of insoluble plaques from the accumulated amyloid deposits in the brain. Senile plaque formation occurs as a consequence of aging, and the plaques are usually localized in the temporal lobes. Lewy bodies also forms in brains of AD patients (Wenk, 2003).

Monica Gheorghita et al did a study entitled Pathophysiology of Alzheimer’s Disease that aimed at elucidating the underlying cellular events that leads to the development of AD. This study revealed that enzymes do degrade the amyloid precursor protein (APP) into its respective fragments via a process of proteolysis. However, two of the fragments; beta and tau amyloids are abnormally folded and this results in AD. Hence, AD can be considered as both a proteopathy and taupathy. APP is vital for the survival, growth and repair of neurons. However, in AD there is excess APP proteolysis thus impairing neuronal functions. Tau proteins stabilize the microtubule framework of the neuron, and its dysfunction results in disintegration of the neuronal transport system (Gheorghita, 2010).

The exact disease mechanism of AD is unknown but several hypotheses have been formulated to explain its pathophysiology. Amyloid hypothesis postulates that accumulation of abnormally folded beta-pleated sheets of proteins is the trigger for neuronal degeneration. This aggregation is toxic to the cell since it disrupts cellular calcium ion homeostasis.  Such disruptions lead to the activation of caspaces which initiate the process of apoptosis which eventually results in cell death. Moreover, accumulation of Aβ protein fibrils in neuronal mitochondria does inhibit enzyme function which impairs several enzymatic processes with a consequent inhibition of glucose metabolism. This causes the mitochondria to release pro-apoptotic molecules which trigger apoptosis which leads to neuronal loss. The cholinergic hypothesis postulates that decreased synthesis of acetylcholine within neurons leads to the development of AD. This effect is caused by acetylcholine depletion which induces widespread aggregation of amyloid thus resulting in neuro-inflammation (Klafki, 2006).

Diagnosis of Alzheimer's disease.

In 2006, Hans-Wolfgang Klafki et al did a study entitled Therapeutic approaches to Alzheimer’s disease whose aim was to assess the current diagnostic modalities and management of AD. Conventionally, AD is diagnosed using both imaging modalities and laboratory studies. However, the mainstay of diagnosis is the history of the illness and the physical examination. This is done as per the neurological and psychological features of the presenting illness, and the consideration of possible differential diagnoses. The most useful imaging modalities are CT (computed tomography), MRI, PET and SPECT (single-photon emission computed tomography) scans. These modalities have excellent resolution which facilitates the exclusion of other probable cerebral pathologies or dementia. Moreover, these modalities could be used to monitor the progress of the disease, and as such they could predict the possible conversion of the disease from its pre-dementia phase to candid AD. Since AD affects cognitive function, cognitive tests should be done to evaluate intellectual functioning especially memory (Klafki, 2006).

AD can be diagnosed conveniently used the updated NINCDS-ADRDA Alzheimer’s diagnostic criteria. In 2006, Bruno Dubois et al carried out a research entitled Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS—ADRDA criteria whose aim was to study the utility of diagnostic criteria. The criteria used are significant cognitive impairment and dementia syndrome which is confirmed by a standard psychological test. Definitive diagnosis is made after histopathological studies of brain biopsy. The cognitive domains assessed are memory, ability to solve problems, perception, attention span, functional capabilities, language, constructional abilities, and orientation (Dubois, 2007).

Several studies have shown that AD is a preventable disease. Epidemiological studies have shown a correlation between AD and intellectual activities and social interactions. The findings show that the risk of AD is decreased in people who constantly engage in intellectually challenging tasks or those who participate in social functions. This supports the postulates of cognitive reserve theory that state that neuronal functioning is improved by intellectual tasks, and the resulting cognitive reserve does delay the development of dementia and AD.  Moreover, education and physical activities also delay the development of AD. Language learning has also been shown to reduce the incidence of AD (Klafki, 2006).

Epidemiology of Alzheimer's disease.

In 2012, Richard Mayeux and Yaakov Stern did a study entitled Epidemiology of Alzheimer Disease whose aim was to study the epidemiological parameters and factors influencing such parameters. Other epidemiological study have shown that there is an association between AD and certain risk factors such as drug use, cardiovascular  status, diet, intellectual activities and the prevalence rate of AD in the population. It has been shown that diets rich in vitamins and minerals do reduce the risk of development of AD. It has been postulated that this risk reduction is due to the cardio-protective effects of the diet. Studies have also shown an association between AD and certain cardiovascular risk factors. The risk factors implicated in increasing the risk of early-onset AD are diabetes mellitus, hypertension, smoking and hypercholesterolaemia (or generalized hyperlipidemia).  Also, long-term use of NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) is correlated with a reduced incidence of AD development. This has been shown to be due to the anti-inflammatory properties of the drugs which prevent neuronal attrition. Immunosuppression is known to accelerate the development of AD. It has been shown that curcumin, gingko and cannabinoids have no protective effects against development of AD. However, there is an association between regular caffeine consumption and a low incidence of AD (Mayeux & Stern, 2012).

Management of Alzheimer's disease.

According to Hans-Wolfgang Klafki et al, management of AD is palliative in nature. Currently, management modalities can be categorized as pharmacological, psychotherapy and caregiving (2006).

According to the research entitled, Therapeutic approaches to Alzheimer’s disease; the drugs used to manage AD do belong to two drug groups: acetylcholinesterase inhibitors and NMDA (N-methyl-d-aspartate or glutamate) receptor antagonists. The acetylcholinesterase inhibitors prolongs the duration of action of acetylcholine in the synaptic junction thus averting neuronal death.  The recommended regimen is donezepil, tacrine, galantamine, rivastigmine and memantine. Due to a predominance of acetylcholinesterase inhibitors in this regimen, its main adverse effect is vomiting, and the other rare side effects are myalgia (muscle cramps), bradycardia (low heart rate), dyspepsia (stomach upset) and loss of appetite.  Studies have shown that antipsychotic medication such as Huperzine can be used to manage the psychosis and aggression associated with AD (Klafki, 2006).

Glutamate is an excitatory CNS (central nervous system) neurotransmitter and excess amounts results in excitotoxicity which leads to neuronal loss. Excitotoxicity is a feature of AD, and the drug memantine blocks the glutamate receptor thus averting excitotoxicity-mediated neuronal cell death. However, memantine causes headache, hallucinations, fatigue and clouding of consciousness (Klafki, 2006).

Psychosocial interventions are used concurrently with pharmacotherapy. It is classified into four basic approaches: behavioral, stimulation-oriented, emotion-oriented and cognition-oriented approach.

The behavioral approach is used to manage problematic behaviors such as incontinence and aggressiveness. It does not improve the overall functioning. Emotion-oriented therapy has not been studied formally, but psychologists have stated that it alleviates symptoms associated with mild AD. Cognition-oriented therapy is used to minimize the cognitive deficits and prevent over-excitation. However, studies have shown that this approach is associated with transitory frustration. Stimulation-oriented therapy is used to manage mood swings but no conclusive study has yet been done on its efficacy.

In 1999,  Gambaasi et al concluded a study entitled Predictors of mortality in patients with Alzheimer's disease living in nursing homes who aim was to analyze the concept of caregiving in nursing homes. Caregiving involves modifying the lifestyle and living conditions of the patient in order to ensure patient safety. Feeding tubes should be used in patients who cannot swallow food. Physical restraints may be used in uncooperative patients who could harm themselves. Studies have shown that the efficacy of caregiving is determined by the expectations of the caregiver (Gambaasi, 1999).

Conclusion.

AD causes dementia in the geriatric age group. It can also occur at any age in adulthood. The symptoms of AD do cause impairment in social and occupational functioning thus leading the patient to suffer social exclusion which precipitates depression. Imaging studies have shown that AD is characterized by cerebral atrophy whose distribution pattern is multifocal. Research has shown that there is a regional distribution of both neurofibrillary tangles and senile neuritic plaques in both normal individual and AD patients. Point mutations in genes located on chromosome 21 causes autosomal dominant early-onset AD. Also, mutations in the coding region for presenilin 1 and presenilin 2 proteins do predispose an individual to a familial variant of early-onset AD. Moreover, age does predispose an individual to AD, and the severity of AD lesions does determine the severity of the dementia. Chronic inflammation of the cerebral cortices does contribute to AD, and it can be mitigated by anti-inflammatory drugs. Hormonal replacement therapy reduces the incidence of AD. Also, a combination therapy containing tacrine and estrogen does reduce the severity of AD symptoms.

AD can be considered as both a proteopathy and taupathy. APP is vital for the survival, growth and repair of neurons. However, in AD there is excess APP proteolysis thus impairing neuronal functions. Tau proteins stabilize the microtubule framework of the neuron, and its dysfunction results in disintegration of the neuronal transport system. The most useful imaging modalities in the diagnosis of AD are CT, MRI, PET and SPECT scans.

Management of AD is palliative in nature and the current management modalities can be categorized as pharmacological therapy, psychotherapy and caregiving. The drugs used to manage AD do belong to either drug group; acetylcholinesterase inhibitors or NMDA receptor antagonists.

References.

Munoz, D & Feldman, H. (2000). Causes of Alzheimer’s disease. Canadian Medical Association Journal, 162(1), 65–72.

Wenk,D.(2003).Neuropathologic changes in Alzheimer's disease. Journal of Clinical Psychiatry, 64(supplement 9), 7- 10.

Wyss-Coray, T., & Rogers, J. (2012). Inflammation in Alzheimer disease—a brief review of the basic science and clinical literature. Cold Spring Harbor Perspectives in Medicine, 2(1), 1-7.

Gheorghita, M; Gabos-Grecu, I; Buicu, G; Gabos-Grecu, M; Salcudean, A;  Todoran, A. (2010). Pathophysiology of Alzheimer’s Disease. Romanian Journal of Psychopharmacology, 10, 1-8.

Klafki, H; Staufenbiel, M; Kornhuber, J; Wiltfang,J. (2006). Therapeutic approaches to Alzheimer’s disease. Brain, 129, 2840–2855.

Mayeux, R & Stern, Y. (2012). Epidemiology of Alzheimer Disease. Cold Spring Harbor Perspectives in Medicine, 2, 1-19.

Dubois, B; Feldman, H; Jacova, C; DeKosky, S; Barberger-Gateau, P; Cummings, J. (2007). Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS—ADRDA criteria. The Lancet Neurology, 6 (8), 734 – 746.

Gambassi, G; Landi, F; Lapane, K; Sgadari, A; Mor, V& Bernabei, R (1999). Predictors of mortality in patients with Alzheimer's disease living in nursing homes. Journal of Neurology, Neurosurgery and Psychiatry, 67(1), 59–65.