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Bio-Genetics Journal
Vol. 1, No. 1 (2013): 18-31 Review Article Open Access ISSN: 2347-7407

A Literature Review on: Pathogenesis and
Management of Dementia due to Alzheimer Disease

Getu Melesie and Hunduma Dinsa*
Department of pharmacy, College of medicine and health sciences, Ambo University, Ethiopia

* Corresponding author: Hunduma Dinsa; e-mail: [email protected]
Received: 10 November 2013 Accepted: 20 November 2013 Online: 20 November 2013
INTRODUCTION
peptide synthesis and contribution to ischemic brain Dementia is an age-related progressive impairment of degeneration and finally to dementia [8]. memory, language, visual processing, problem solving skills, and eventually ability to function independently Epidemiological studies have identified many risk [1]. It was ascribed its present meaning in 19th century factors for dementia, including age, medical factors based up on pathology and clinical futures [2].
(cardiovascular disease, history of depression, head injury), demographic factors (low levels of education), fronttemporal dementia (FTD), and dementia with as well as family history and genotype. Therefore, it is Lewy bodies are the most common diseases that cause important to identify protective and risk factors for dementia both in the elderly and in younger patients, dementia to prevent this disease at an early stage [9]. although not in those who are younger than 35 years. However, the clinical features of these diseases in Signs and symptoms of dementia includes, gradually younger patients can differ from those seen at a later increasing memory loss, confusion, unclear thinking including losing, problem-solving skills, agitated behavior or delusions, becoming lost in formerly, Dementia mostly affects elderly population over age 65 familiar circumstances, loss of interest in daily or usual years and has predominance in women [4, 5]. It is activities[10]. The diagnostic approach to dementia estimated that 24.3 million people have dementia includes clinical examination of associated neurological today, with 4.6 million new cases annually. Moreover, or systemic symptoms, neuropsychological testing as a result of our aging population, the number of (differentiating frontal, cortical or sub cortical profile) people affected with dementia is expected to double and a detailed medical history about the onset and every 20 years [6]. The incidence of dementia among course of symptoms. Cerebral magnetic resonance the elderly population is rising rapidly worldwide. In imaging (MRI) can detect specific focal atrophy, white- the United States, AD is the leading type of dementia matter changes or other clues as to underlying disease. and was the fifth and eighth leading cause of death in Lumbar puncture should be performed to detect women and men aged ≥ 65 years, respectively, in 2003. inflammatory signs (infectious or autoimmune In Taiwan and many other counties, dementia is a disorders), and dementia markers, especially Aβ and hidden health issue because of its underestimation in tau protein, should be measured. In young-onset the elderly population and the prevalence of the dementia in particular, genetic testing should be part of disease in the country for people aged ≥ 65 years was the diagnostic approach [11]. 2–4% by 2000. In Western countries, the prevalence of AD increases from 1–3% among people aged 60–64 With the rapidly growing numbers of elderly people, years to 35% among those aged > 85 years [7]. the numbers of dementia patients are also increasing at a very high speed in most countries. As a result, the Molecules like β-amyloid (Aβ) peptide, apolipoproteins, management of dementia patients is now becoming one presenilins, and tau protein, α-synuclein and of the most important public health problems [12]. The inflammation factors causes' neuronal death in brain main goals of treatment for dementia are symptomatic following ischemic episode and results in dementia. improvement, disease modification with slowing or The interactions of these molecules has influence on Aβ arrest of symptom progression of the dementing Getu Melesie and Hunduma Dinsa / Bio-Genetics J. 2013, 1(1): 18-31 process and primary prevention of disease by individuals rising from 7% to 12%.1,2 Developing intervention in key pathogenic mechanisms at a pre- countries will see the greatest rise in absolute numbers symptomatic stage [13]. Generally, this review is of older individuals, and will contribute to worldwide concerned on the definition, epidemiology, risk factor, population aging with an increase from 59% to 71%.3 pathophysiology, differential diagnosis and treatment Dementia is strongly associated with increasing age, and consequently neurodegenerative disorders are anticipated to pose significant 2. Dementia
challenges to public healthcare systems worldwide in 2.1. Definition
the coming decades [16]. Dementia as a clinical syndrome is characterized by global cognitive impairment, which represents a By 2005, 24.2 million people worldwide had dementia decline from previous level of functioning, and is and 4.6 million new cases of this condition were arising associated with impairment in functional abilities and, every year, 70% of these cases were attributed to AD. Among regional populations of individuals aged ≥60 disturbances. The current definition of dementia by the years, those from North America and Western Europe World Health Organization (1993), in the 10th edition of exhibited the highest prevalence of dementia (6.4% and International Classification of Diseases (ICD_10) is: ‘a 5.4%, respectively), followed by those from Latin syndrome due to disease of the brain, usually of a America (4.9%) and China and its western-Pacific chronic or progressive nature, in which there is neighbours (4.0%). Meanwhile, the annual regional disturbance of multiple higher cortical functions, dementia incidence rates were estimated to be 10.5 for North America, 8.8 for Western Europe, 9.2 for Latin America, and 8.0 for China. For all these populations, language, and judgments. Consciousness is not the incidence rate for dementia increased exponentially impaired. Impairments of cognitive function are with age, with the most notable rise occurring through commonly accompanied, occasionally preceded, by the seventh and eighth decades of life. The prevalence deterioration in emotional control, social behaviour, or and incidence rates for AD also increase exponentially motivation [14]. To characterize dementia, in addition to forgetfulness The incidence rates of AD and dementia in people aged patient should have a symptom of memory loss, <75 years seem to be relatively similar across several language difficulty, difficulty with spatial awareness studies, but in the oldest age groups these rates vary and skilled movement, a loss of knowledge and (Supplementary Figure 1 online). Methodological issues understanding of world, problem with reasoning, partly account for the observed divergence; however, planning and judgments, Changes in personality, the estimates might also reflect geographical behaviors and emotional control are at least exist differences in age-dependent incidence owing to together [14, 15]. variation in survival and the prevalence of risk and protective factors [17]. These key symptoms and various neurological features (sometimes referred to as primary symptoms) are 2.3. Etiology
often more directly determined by the location and Neurodegenerative diseases are the most frequently severity of the brain damage. Other psychiatric causes of dementia. Of which AD is the commonest features, such as anxiety, depression, suspiciousness, cause. Other neurodegenerative diseases which have delusions, and, obstinacy seem to be more related to contribution in the occurance of dementia next to AD the patient's awareness of, and reactions and responses include FTD, Huntington's disease, and Creutzfeldt - to, cerebral dysfunction and its consequences. These Jakob disease and Familial prion disease [18]. secondary or accessory symptoms are also influenced by the patient's premorbid personality and previous Stroke or cerebrovascular accidents can cause experience, as well as related to better preserved brain dementia and are associated with sudden onset of focal functions. However, dementia may evolve according to neurologic deficits. Cerebrovascular accidents are extraordinary, miscellaneous and variable scenarios, so caused by thrombus formation at a site of arterial that a symptom should be interpreted cautiously. What blockage or atherosclerotic debris that are dislodged is regarded as a primary symptom in one type or stage and ultimately cause arterial blockage in the brain [19]. of dementia may be a secondary symptom in another Vascular dementia is another cause of dementia and it can present as an abrupt deterioration in cognitive function or in a fluctuating, stepwise manner. It may be 2.2. Epidemiology
dominated by subcortical features, such as early gait Population aging and increased life expectancy has disturbances with falls, early urinary difficulties, become a worldwide epidemiological phenomenon. pseudo-bulbar palsy and other frontal subcortical Global projections for the number of older individuals deficits, such as mood changes and emotional liability (>65 years) are expected to increase from 420 million in 2000, to nearly 1 billion by 2030, with a corresponding increase in the proportion of older Getu Melesie and Hunduma Dinsa / Bio-Genetics J. 2013, 1(1): 18-31 In addition to the preceding categories, a number of developing vascular dementia, which may lessen the general medical conditions can cause dementia. These likelihood of developing pure AD. Gender-related conditions include structural lesions (e.g., primary or differences in risk could be at least partly ascribed to secondary brain tumors, subdural hematoma, slowly hormonal factors, as several studies suggest that progressive or normal-pressure hydrocephalus), head estrogen replacement can prevent or delay the onset of trauma, endocrine conditions (e.g., hypothyroidism, AD. Estrogen may be implicated in AD in several ways, hypercalcemia, hypoglycemia), Psychiatric diseases via reduction in β-amyloid deposition, improvement in such as; dementia of depression, schizophrenia, among cerebral blood flow, neuroprotection or suppression of others nutritional conditions (e.g., deficiency of vitamin apolipoprotein E (ApoE) [12, 26]. Higher survival rate B12, thiamine, or niacin [21], other infectious in women than male is another reason for AD more conditions (e.g., HIV, neurosyphilis, Cryptococcus), prevalent in female than male [12].
derangements of renal and hepatic function, neurological conditions (e.g., multiple sclerosis), effects 2.4.2. Stroke and Vascular Risk Factors
of medications (e.g., benzodiazepines, beta-blockers, Dementia develops in approximately a third of people anticholinergics), autoimmune diseases (e.g., lupus who survive to three months after a stroke. The erythematosus, vasculitis, Hashimoto's encephalopathy, distinction between AD and vascular dementia is neurosarcoidosis), environmental toxins (e.g., heavy becoming less clear since many people who develop metals, organic hydrocarbons), and the toxic effect of dementia after a stroke appear to develop AD rather long-standing substance[22]. than a dementia which is explained by further strokes. It is possible that the presence of small strokes may 2.4. Risk Factors
bring forward the age at which the symptoms of AD are Many different factors have been suggested to have an noticed. People who have diseases which affect the effect on the occurrence of dementia [23]. These risk circulation (such as high blood pressure, diabetes, and factors are common to most types of dementia and heart disease) have a higher than average risk of others are specific to particular types. Risk factors can developing dementia again apparently both vascular be considered as genetic, environmental and genotypic. dementia and AD. It is likely that treatment of Genetic and genotypic risk factors will modify an conditions which affect the circulation will reduce this individual's reaction to those environmental risk risk, although this is still being actively researched [23]. factors to which he or she is exposed [24]. The identification of these factors must be a priority in Vascular factors and conditions, including history of order to define the best approach for early prevention stroke or transient ischemic attack, diabetes mellitus, hypertension, congestive heart failure and obesity are major risks for cognitive decline and dementia by 2.4.1. Sociodemographic Factors
accelerating Alzheimer-type changes in the brain. Age and education
Indeed, vascular disease is thought to reduce blood Dementia may occur at any age but is very rare below flow to the brain and hypoperfusion (decreased blood the age of 60 years. Dementia becomes more common flow through an organ) has been found to cause with increasing age, occurring in around 1% of people oxidative stress, neurodegeneration and cognitive aged 65-69 but in around 24% of those aged 85 or decline. Stroke and hypertension accelerate atrophy older. It is still not known, however, whether increased and degenerative changes resulting from neuronal rates of dementia with age are simply caused by the shrinkage or loss. The aggregation of risk factors is brain becoming older or whether they are because of suggested to have a greater impact on the development other diseases or events which become more common of dementia than each factor independently [27]. in later life [23]. Furthermore, the relationship between vascular factors Several studies showed that aging is the main risk of and dementia has been found to be moderated by dementia and AD. A meta-analysis that included 17 various genetic and non-genetic factors including ApoE Chinese studies has also shown that the prevalence of and age [27]. ApoE is a plasma cholesterol transport AD and VaD increases with age. As a whole, the effect of molecule found on chromosome and it occurs in 3 aging is a relatively consistent risk factor for dementia common alleles (є2, є3, and є4). It is a key constituent across various ethnic groups [7]. The relationship in very low density lipoproteins and is vital in the between education and dementia is one of the most transport of cholesterol and other lipids throughout the controversial issues in the epidemiology of dementia. brain. ApoE in the central nervous system is expressed Many studies show that dementia, and AD in particular, primarily in astrocytes but can also be found in is less common in people with higher levels of microglia and neurons. The mechanisms by which ApoE contributes to AD and dementia are not completely understood. Many studies have demonstrated that Gender and hormonal effects
isoform-specific capabilities (є2, є3, and є4) for acting Even when controlling for differences in longevity, in as a chaperone molecule for Aβ and influences Aβ most studies AD is more prevalent in female than in metabolism, deposition, toxicity, fibril formation, and male although not in all studies. This is complicated by clearance from the brain. In addition, ApoE could also the observation that men have a greater risk of mediate tau hyperphosphorylation and modulate the Getu Melesie and Hunduma Dinsa / Bio-Genetics J. 2013, 1(1): 18-31 distribution and metabolism of cholesterol in neuronal and it accounts major causes of dementia. It is membranes in an isoform-dependent manner [28]. characterized by gradually progressive decline in cognitive function, with deficits especially in memory
retrieval [33]. Family history is the second-greatest risk
factor for the disease after age [30]. Additional
environmental risk factors of AD are history of head
trauma associated with loss of consciousness, reduced
educational attainment, and diet related cardiovascular
risk factors [33].

Pathological mechanisms of AD
The exact mechanism underlying the etiology of the
disease
hypotheses have been raised to explain the pathological alterations observed. Loss of neurons and brain-impaired function occur in the early phase of the disease and cause synaptic dysfunction, leading to Figure 1. Hypothetical scheme showing the consequences of
memory loss and cognitive impairment, two main vascular disease risk clustering factors leading to brain features of AD presentation [34]. degeneration and dementias. Different vascular risk factor such as stroke, hypertension, diabetes, dyselipedimia, obesity Its neuropathological hallmarks are intraneuronal and atherosclerosis cause vessel wall damage resulting in hypoperfusion and white matter lesion end up with protein clusters of hyperphosphorylated tau protein accumulation of amyloid precursor protein(APP)/Aβ. This (neurofibrillary tangles) and extracellular Aβ protein accumulation of these substances may result either vascular aggregation. This aggregation is the result of an dementia (VaD) as result of stroke or AD [29]. abnormal APP cleavage by β- and γ-secretases and initiates a pathogenic, self-perpetuating cascade 2.5. Pathophysiology of dementia
ultimately leading to neuronal loss and dementia [35]. Cerebral nerve cells have the following three basic functions: storing information, processing information, Amyloid cascade hypothesis
and transmitting information. When these nerve cells The amyloid cascade hypothesis postulates that the are damaged, stored information is inaccessible, the build up of Aβ in the brain causes damage to neurons, processing of sensory input ceases, and commands to leading to dysfunction and loss of neurons, and the other areas of the body cannot be transmitted. The clinical phenotype of the amnestic dementia symptoms of dementia are the result of progressive characteristic of AD. All known mutations that result in nerve cell deterioration altering the three basic autosomal dominant forms of early-onset familial AD cerebral functions [5]. cause increased production of Aβ 42; a form of the Aβ at is particularly relevant in AD. Other proteins that are The abnormal microscopic change of dementia includes crucial to the pathogenesis of AD are the presenilins 1 plaques, are extracellular deposits of normal and and 2, which are intimately involved with Aβ mutated protein of Aβ precursor protein, causing AD; production and when mutated in familial forms of AD intercellular mutated protein of α-synuclein, causing cause increases in Aβ [36]. PD; APP or in microtubule-associated protein tau, causing FTD with parkinsonism [5, 30]. It is not
Mutations in three genes have been found to cause known if these plaques are the cause or the effect dementia of AD (figure 2). The first gene identified was of the underlying disease process that is the APP on chromosome 21. APP is a membrane bound characteristic of dementia. The plaques may cause protein that can undergo a series of endoproteolytic neuron degeneration and death or merely stimulate an cleavages by enzymes known as secretases. When inflammatory process around the nerve cell. The nerve cleaved by α- secretase in the middle of the Aβ domain cell damage results in decreased amounts of within APP, a soluble fragment of the protein is neurotransmitter released, and there is no accumulation of the peptide; presynaptic cholinergic neurons in the cerebral cortex. whereas when it is cleaved at the β and γ sites, the Aβ Lack of cholinergic activity is indirectly related to peptide is released, which can undergo further cognitive ability [31]. conformational change into an insoluble form that aggregates in senile plaques. APP mutations that are 2.5.1. Types of Dementia
causal for early-onset familial AD all promote cleavage Different forms of dementia are now distinguished:-AD, at the β or γ sites, leading to an overproduction of the dementia with Lewy bodies, FTD, VaD, mixed types of Aβ peptide [37]. dementia and dementia secondary to disease [4]. Two other genes with mutations that cause early-onset 2.5.1.1. Alzheimer Disease
familial AD are presenilin 1 (PS1) and Presenilin 2 AD is a progressive neurodegenerative disorder (PS2), which are located on chromosomes 14 and 1, characterized by the gradual onset of dementia [32] respectively. Both PS1 and PS2 play an important role Getu Melesie and Hunduma Dinsa / Bio-Genetics J. 2013, 1(1): 18-31 in the γ- secretase complex, and mutations in these (lacunes, infarcts, white matter lesions) with genes lead to an excessive cleavage at the γ site leading compromised neuronal metabolism, mitochondrial to excessive production and accumulation of Aβ. Taken deficiency, oxidative stress and protein degradation together, the three causal genes identified to date for failure promoting cytoskeletal lesions with deposition AD provide strong support for the amyloid cascade of Aβ and formation of neuritic lesions (fibrillary hypothesis, in which the accumulation of Aβ peptide tangles etc). Both factor groups finally induce brain into senile neuritic plaques is central to the atrophy with cognitive and memory impairment (Fig. pathogenesis of AD [37] Figure 3. Pathogenic factors in the development of mixed
dementia. AD pathology (plaques, tangles, synapse loss, neuronal loss, and amyliod angiopathy) and vascular Figure 2. Hypothetical model of the pathological processes in
pathology (atherosclerosis, decreased perfusion, and cerebral AD, focusing on the amyloid Aβ cascade. Three clinical phases embolism) are some of the responsible causes of mixed of the disease are defined: preclinical which may last for dementia through consequential damage in different part of several years until the overproduction and accumulation of Aβ in the brain reaches critical level that triggers the cascade; in the predementia phase, early stage pathology is present in 2.5.1.4. Frontotemporal Dementia
varying degrees according to individual resilience and brain FTD is characterized by a progressive deterioration of reserve. Finally, in the dementia phase there is progressive behavior, personality or language abilities in accumulation of neuritic plaques and neurofibrillary tangles association with prominent frontal and temporal lobar those results in cognitive deficits and functional impairment atrophy. Clinical subgroups of FTD includes progressive non-fluent aphasia, speech is laboured, with frequent 2.5.1.2. Vascular Dementia
VaD is a dementia syndrome resulting from comprehension, at least at the single word level, is cerebrovascular damage [39] and it is the second most generally intact until late in the disease course and common cause of dementia [40]. It is a heterogeneous semantic aphasia and associative agnosia, speech is disease that has been classified based on clinical and fluent and grammatically correct; but probing reveals imaging features as cortical VaD, subcortical VaD, and profound difficulties with naming and comprehension strategic infarct dementia. These subtypes are likely to of less common word meanings owing to a progressive be determined by the pattern of underlying vascular loss of the knowledge base underlying language usage disease (such as, large artery, small artery, cardioembolic), which are known to have different risk factors and varying racial– genetic predisposition [41]. 2.5.1.5. Lewy Body Dementia
As its name implies, Lewy body dementia (LBD) is 2.5.1.3. Mixed Dementia
characterized by the presence of Lewy bodies, proteins Mixed dementia (MD) refers to a combination of in the cerebral cortex (which governs thought processing) and brain stem (which coordinates Microvascular changes in the aged brain and in AD movement). Lewy bodies are also common among include impairment of cerebral perfusion, in particular individuals with PD. Although prevalence estimates decrease of regional blood flow, a reduction of glucose vary, some researchers have estimated that LBD transport and utilization, the loss of vascular accounts for 15% to 20% of all cases of dementia. As innervations with special impact on the cholinergic and might be expected, people with LBD have been found to other transmitter deficits in AD, impairment of manifest signs of parkinsonism such as difficulties in neurogenic cerebrovascular regulation, ultrastructural initiating movements, slowness of movement, muscular changes in capillaries and basement membranes, and rigidity, and tremor [44].
frequent deposition of Aβ with breakdown of the blood–brain barrier and impairment of amyloid Clinically, LBD is characterized by progressive cognitive clearance. The pathogenic chain of these factors finally impairment with fluctuating course, recurrent visual produces either structural cerebral disintegration hallucinations, and Parkinsonism. Although formal Getu Melesie and Hunduma Dinsa / Bio-Genetics J. 2013, 1(1): 18-31 clinical criteria have been proposed, there is a in cases of classic AD, including in patients with pronounced clinical and neuropathological overlap mutations in APP, PS1, and PS2 [30]. However, with AD as well as PD with dementia (PDD). The distinguishing these two forms of dementia is crucial, predominant histological feature of LBD is the presence because individuals with LBD are highly sensitive to the of cortical and subcortical Lewy bodies, but many adverse effects of antipsychotic drugs, which may be patients with LBD also have AD pathology, i.e., cortical administered with the intent of providing relief from Conversely, Lewy bodies are also frequently observed
Table1. Summary of main type dementia with there causes and Primary impairments symptoms [27]
Primary impairments/disability/ symptoms
Prominent and progressive memory impairment, language Neuritic plaques and deficits, spatial and visuoperceptual difficulties, practical Neurofibrillary tangles inability, and global cognitive impairment. Abrupt onset, stepwise deterioration, vascular risk factors, Problems of circulation of blood to the brain patchy cognitive impairment, focal neurological signs and related to stroke, high blood pressure and nocturnal confusion Either prominent personality changes or problems with Frontal lobe degeneration language, memory and, and onset more common under age 65 progressive cognitive decline, simultaneous or later development Presence of Lewy bodies which refer to of parkinsonian features abnormal structures within nerve ,well-formed visual hallucinations ,fluctuating attention and cells of the brain alertness and sleep disorder parkinsonian features (such as rigidity tremor) before onset of Degeneration of dopamine in the brain dementia, cognitive slowing, executive dysfunction and poor memory retrieval
2.6. Symptoms of Dementia
progress to be implemented, and allows individuals and Dementia of every type is marked by loss of intellectual their families to plan for the future [48]; Optimizing function. The major symptom is a loss of memory. The physical health, cognition, activity and well-being; person is unable to either learn new information or to Detecting and treating behavioural and psychological recall recently acquired information. Usually long-term symptoms; and Providing information and long-term memory is well preserved until late in the disease support to carers [49]. process. Short-term memory loss is accompanied by difficulties that include: 3.2. Diagnosis of Dementia
Language disturbances (aphasia), e.g. being The diagnostic process in dementia has three major unable to understand spoken or written conceptual components: the clinical diagnosis, a logical instructions, or to make oneself understood search for the cause, and the identification of treatable Impaired ability to perform practical co- comorbid conditions and other contributing factors, ordinated tasks (apraxia) e.g. dressing such as the degree of cerebrovascular disease. The Inability to remember the date, day, year or diagnostic process should involve 6 main steps: taking time of day (disorientation) the patient's history, interviewing a caregiver or family Having trouble recognising objects or people member, physical examination, brief cognitive tests, including oneself in the mirror (agnosia) basic laboratory tests, and structural imaging for Difficulty organising, planning and ordering patients meeting certain criteria. The conclusion involves meeting with the patient and his or her family Change in personality and inability to to discuss the results and diagnosis, and their recognise that anything is wrong (lack of implications [50]. A gradual withdrawal from social and personal Early identification of dementia can facilitate detailed assessment, control of risk factors and initiation of Extreme emotional outbursts or reactions to minor treatment [51]. Cognitive impairment resulting from conditions like dementia, delirium, or depression represents critically serious pathology and requires 3. Diagnosis and Management of Dementia
urgent assessment and tailored interventions. Yet, 3.1. General Management Principles
diminished or altered cognitive functioning is often Distinguishing and accurately diagnosing the various perceived by health care professionals as a normal types of dementia is essential for understanding their consequence of aging and opportunities for timely mechanism and for developing efficient therapeutic intervention are too often missed. Although distinctions strategies, preventive and curative [47]. The principal have been made comparing the clinical features of the goals of dementia management and care are early common cognitive impairments associated with diagnosis dementia which allows: treatable conditions delirium, dementia, and depression (table 2), it is such as depression to be managed, offer the difficult to do clinically as these conditions often coexist opportunity for a number of interventions to slow and older adults can demonstrate atypical features in any of these conditions [45, 52]. Getu Melesie and Hunduma Dinsa / Bio-Genetics J. 2013, 1(1): 18-31 Table 2. Comparison of the clinical features of delirium, dementia, and depression [45, 53]
Depression
Delirium
Dementia
Chronic; responds to Acute; responds to treatment Chronic, deterioration over concerned about memory May be aware of changes in Likely to be unaware of cognitive deficits Activities of Daily
May neglect basic self- May be intact or impaired May be intact early, impaired Living (ADLs)
as disease progresses Figure 4. A hierarchical approach to diagnosing dementia and the major subtypes of dementia. The sequence of decisions
reflects a hierarchy of importance of diagnostic information: features appearing earlier in the decision tree suggests diagnoses
regardless of features assessed later. ADL = activities of daily living necessary for independent life, MS = mental status, assessed
through bedside mental status testing or formal neuropsychological evaluations [57]
The first step in evaluating patients with cognitive
present operational criteria for diagnosing types of complaints is defining whether dementia is present. dementia, such as AD, VaD and so on. Although they This requires the identification of the cognitive contain criteria for dementia due to PD, they do not problem, time of onset, progression (if any) and what include criteria for some important forms of dementia, functional impairment(s) have resulted. This often such as DLB or FTD [55]. The diagnosis of dementia requires more than one visit before dementia can be includes detecting for the ability to loss cognitive, disability as a result of cognitive loss, and evidence of disease progression [56]. simultaneously [54]. 3.2.1. Detailed History
The two standard systems in use for the diagnosis of The importance of a detailed history in determining dementia are DSM-IV and ICD-10, which are basically similar. Both define the dementia syndrome and then overemphasized. Depending on the degree of cognitive Getu Melesie and Hunduma Dinsa / Bio-Genetics J. 2013, 1(1): 18-31 impairment, the amount and accuracy of the folate levels, rapid plasma reagin for syphilis screening, information given by the patient will vary. Even if the and HIV antibodies were recommended [50, 62]. patient appears to have reasonable insight into their difficulties, it is vital to obtain a collateral history from 3.2.5. Neuropsychological testing
a source that has regular contact with the patient (e.g. a Neuropsychology contributes greatly to the diagnosis healthcare professional, carer or family member). The
of dementia: it documents significant cognitive decline history taking should focus on the cadence of the illness and reveals patterns of cognitive dysfunction that (gradual and insidious in AD, stepwise in VaD) and the suggest the cause of the dementia. Therefore carrying relation to any vascular events such as stroke. Causes of out the neuropsychological assessment at an early dementia such as alcohol abuse and renal failure should stage of dementia has two goals: revealing memory be assessed [50] disorders, which are not always associated with memory complaints and characterizing the memory 3.2.2. Mini mental state evaluation (MMSE)
disorder in the context of cognitive neuropsychology, The MMSE is a tool for cognitive screening used thus allowing other cognitive and noncognitive worldwide for global evaluation. It was developed by functions to be integrated with the memory disorder Folstein et al. in 1975 and has versions in different into a broader syndrome [63]. languages and countries. This instrument was developed as a brief cognitive evaluation (5-10 min) in 3.2.6. Radiology/neuroimaging
psychiatric patients. The test was named "mini" Computed tomography (CT) and MRI can exclude because it focuses only on the cognitive aspects of structural brain lesions responsible for cognitive mental functions and excludes questions about mood, symptoms, such as tumours, cerebral infarctions, abnormal mental phenomena and thought patterns subdural or extradural hematomas, cerebral abscess and hydrocephalus. CT is the most commonly used scanning technique in the assessment of dementia and It is one of the most widely used cognitive tests and it can provide valuable information on the cause of a assesses cognitive function in the domains of short- diagnosed dementia syndrome. Indications for CT
term memory, concentration, and spatial orientation, scanning includes short duration of cognitive and scoring ranges from 0 to 30 points. It is important impairment, sudden onset of symptoms or rapid, recent to keep in mind that lower levels of education and the head trauma, suspicion of a space-occupying lesion, presence of language barriers or speech impairment suspicion of normal-pressure hydrocephalus, (such as. reduce the validity of the MMSE. Likewise, a higher urinary incontinence, ataxia), localized neurological level of education has been associated with higher signs and age less than 60 years [53]. scores despite obvious decline. The MMSE should be administered on initial evaluation, before and after 3.3. Management of Dementia
beginning therapy, and then at 3-month intervals to After treatment the expected outcomes from the assess deterioration or response to medication [59]. patient with dementia includes; Improvements in end of life care, quality of life, and quality of dying, security 3.2.3. Physical examination
and peace of mind for clients through having a service that can meet nursing and social needs responsively, practitioner should pay particular attention to the decrease in burden and stress for carer, family, potential signs of stroke. The presence of small-vessel reduction in hospital admissions and nursing home ischemic cerebrovascular disease with concurrent admissions and reduction in break down of care senile neuritic plaques and neurofibrillary tangles packages and break down of family carer [64]. increases the risk of dementia [50]. This examination should include assessment of cognitive domains, Based on the distinct aetiologies and clinical features including speech (aphasia), motor memory (apraxia), there will be probably be no single "anti-dementia" sensory recognition (agnosia) and complex behavior drug, but different drugs should be developed directed sequencing (executive functioning) [60]. towards either symptomatic change or to modification of aetiological and pathophysiological processes. The 3.2.4. Laboratory investigations
main goals of treatment for dementia are symptomatic The primary role of laboratory investigations is rarely improvement, which may consist in enhanced to identify the cause of dementia, but rather to identify cognition, more autonomy and/or improvement in comorbidity and/or complication; to reveal potential neuropsychiatric and behavioral dysfunction, disease risk factors; and to explore the background of modification with slowing or arrest of symptom progression of the dementing process and primary recommended basic investigations for all patients, prevention of disease by intervention in key pathogenic including complete blood count, thyroid stimulating mechanisms at a pre-symptomatic stage [13]. hormone, and serum calcium, electrolytes and fasting glucose [61]. Other laboratory tests were to be applied 3.3.1. Non-pharmacological
selectively based on an individual's presenting medical Non-pharmacological treatment or psychological history, and cognitive and physical examination intervention should be considered in treatment of findings. Selective testing of serum vitamin B12 and cognitive, as well as emotional and behavioral, Getu Melesie and Hunduma Dinsa / Bio-Genetics J. 2013, 1(1): 18-31 disturbances and other functional manifestation of the increase physical activity, exercise, cognitive leisure disease. It often used to comprise a number of specific activities and social interaction [70]. therapeutic intervention principles for patients, as well as caregiver intervention programs [61]. 3.3.2. Pharmacological therapy
Several classes of drugs have been studied for the The consensus statement of the American Association prevention of progression to dementia. These include for Geriatric Psychiatry, the Alzheimer's Association cholinesterase inhibitors and estrogen replacement and the American Geriatrics Society states that non- therapy [44]. Other approaches include the use of anti- pharmacological treatment is the most appropriate first oxidants, which work by minimizing the effects of free step to treating behavioural disturbances in patients radicals that are released through normal oxidative with dementia [65]. metabolism. These free radicals may cause neuronal damage and play a role in the development of Brain activating rehabilitation is a new non- dementia. Similarly, it is believed that inflammation pharmacological therapy and its aim is to enhance contributes to nerve cell damage and dementia; hence patients' motivation and maximize the use of their anti-inflammatory drugs may act by decreasing remaining function, recruiting a compensatory inflammation, potentially reducing nerve degeneration, network, and preventing the disuse of brain function. It which may in turn slow or even prevent dementia consists of five principles: enjoyable and comfortable activities in an accepting atmosphere; two-way communication between the therapist and patient, as Additional pharmacological interventions that have well as between patients; therapists should praise been studied include cholesterol-lowering agents, anti- patients to enhance motivation; therapists should try to hypertensive, folic acid, behavior and mood altering offer each patient some social role that takes advantage drugs, anti-amyloid strategies (e.g. immunization, of his/her remaining abilities; and the activities should aggregation inhibitors, and secretase inhibitors), nerve be based on errorless learning to ensure a pleasant atmosphere and to maintain a patient's dignity [66]. neurotransmitters other than acetylcholine and its receptors [71].
Psychosocial interventions for carers, such as teaching them specific problem-solving skills, are more effective Antipsychotic medication is most effective in the if the patient is also involved. Other factors that appear to be important include structured individual counseling, involvement of the extended family and consistent professional long-term support. These Benzodiazepines with lower toxicity and shorter half- interventions can help to reduce the psychological life (such as, temazepam, and/or oxazepam) are burden and can reduce the need for institutional care of preferred to longer-acting agents (like, diazepam, the patient [67]. and/or nitrazepam). Antidepressant medications are underused in people with dementia, despite the Behavior management
common occurrence of depression in dementia and the Behavioral and psychological symptoms of dementia documented therapeutic value of these drugs. Some (BPSD) are common, occurring in 90% of those with people may present as agitated when suffering a dementia at some point in their course. These include: depressive disorder [72]. hallucinations, delusions, misidentifications, agitation, depression, anxiety, aberrant motor behaviour and 3.3.2.1. Acetylcholinesterase (AChE) Inhibitor
aggression [68, 69]. These symptoms may lead to
Dementia is associated with reduced levels of the increased psychological morbidity in the carer and neurotransmitter acetylcholine. Acetylcholine is a often to a need for residential care. Management of chemical messenger important for learning and BPSD involves a combination of support and memory and its levels are low in the brains of people information for the carer, assessment of environmental with AD. AChEIs inhibit acetylcholinesterase, an triggers, exclusion of underlying medical causes (i.e. enzyme responsible for the destruction of acetylcholine pain, infection) and, finally, the judicious use of leading to increased concentrations of acetylcholine in medications in some cases. Medications such as central synapses, and the increased concentrations are antipsychotics (including atypical ones) and mood believed to be responsible for the improvement seen stabilizers are used, although the evidence for their use during treatment [73]. Three AChEIs, donepezil, is not broad [69]. rivastigmine, and galantamine, are licensed to treat mild to moderately severe AD, in turn dementia [53]. Lifestyle and activity
Early intolerance is characterized by the typical Higher levels of physical and mental activity as well as gastrointestinal cholinergic adverse events (anorexia, social interaction help maintain cognitive function nausea, vomiting, and diarrhoea), and occurs at during aging. Given the current data and biologic initiation of therapy and at dose escalation. Late plausibility regarding the relationship between lifestyle and dementia risk (as well as other health benefits), it bradycardia), insomnia, muscle cramps, weight loss, etc seems reasonable to encourage patients to maintain or Getu Melesie and Hunduma Dinsa / Bio-Genetics J. 2013, 1(1): 18-31 Galantamine is a selective, competitive and reversible vomiting and diarrhoea. These side effects, together AChEIs. It works by inhibiting AChE and by with occasional bradycardia, syncope and changes in allosterically modulating nicotinic receptors. It has the sleep architecture, are directly associated with a recently been studied and shown to be effective for use central and peripheral enhancement of cholinergic in the treatment of AD, VaD and AD with function. At the present time, Donepezil is the most widely prescribed anticholinesterase in the United galantamine showed significant improvement in the States and Europe [76]. Because rivastigmine is areas of cognition global function and activities of daily metabolized primarily through hydrolysis by esterases, minimal interaction with drugs metabolized by CYP450 Donepezil is primarily a reversible inhibitor of AChE interactions have been demonstrated [77, 78]. with a long elimination half-life. It causes nausea,
Table 3. Pharmacological properties of most common three cholinesterase inhibitors [74, 79]
Donepezil
Galantamine
Mechanism
Dose range (mg/kg)
Target dose (mg/kg)
Dose frequency
Dose titration
Metabolism
Protein binding (%)
Most common side effect
Nausea, Vomiting and Dizziness Nausea, Vomiting and Anorexia bid = two times a day qid = four times a day
3.3.2.2. Memantine
to its feminizing effects. Estrogen protects neurons and may interact with nerve growth factor to help neuronal glutamate excitotoxicity is a major factor responsible development and survival [81]. for Aβ induced neuronal death. NMDA receptors therefore appear promising target for preventing MAO-B inhibitors: - The monoamine oxidase-B (MAO-
progression of neurodegeneration. Theoretically, any B) inhibitor L-deprenyl (Selegiline) is effective in disorder of central nervous system characterized by treating PD and possibly AD, with a concomitant excitotoxicity-induced extension of life span. It has been suggested that the should be cured with treatment of NMDA-receptor therapeutic efficacy of L-deprenyl may involve actions other than the inhibition of the enzyme MAO-B. L- antagonist of the NMDA receptor. It inhibits the release deprenyl stimulates nitric oxide (NO). L-Deprenyl of glutamate (a neurotransmitter), is indicated for more induced rapid increases in NO production in brain advanced disease and may be used in conjunction with tissue and cerebral blood vessels. The drug also a cholinesterase inhibitor. Memantine requires dose protected the vascular endothelium from the toxic titration over a month to minimize the adverse effects effects of Aβ peptide. Because NO modulates activities of agitation, hallucination and headache. Memantine is including cerebral blood flow and memory, and excreted in the urine [80]. reduced NO production has been observed in AD brain, stimulation of NO production by L-deprenyl could 3.3.2.3. Other Drugs
contribute to the enhancement of cognitive function in Anti-inflammatory drugs
AD. MAO-B inhibitors are unique in that they exert It is thought that the anti-inflammatory drugs change protective effects on both vascular and neuronal tissue the cerebral inflammatory response to amyloid protein and thus warrant further consideration in the deposits, thereby reducing the risk of developing AD or treatment of vascular and neurodegenerative diseases slowing the progression of symptoms [81].Treating associated with aging [83]. mice with the NSAID ibuprofen reduce brain inflammatory activity and also reduce plaque Statins: - Statins are a class of drugs that inhibit 3-
deposition [82]. hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. HMG-CoA reductase is the rate-limiting Estrogen: - The hormone estrogen shows promise as a
enzyme in the cascade of cellular cholesterol treatment for cognition, mood, behavior, and motor biosynthesis. Statins thereby reduce the formation and disturbances associated with dementia. It is thought entry of LDL cholesterol into the circulation and that estrogen either aids the metabolism of APP, upregulate LDL receptor activity, lowering LDL preventing it from forming Aβ fibers, or has antioxidant cholesterol and triglycerides and increasing HDL effects that are protective to nerve cells in the limbic cholesterol. Several studies in cell culture and animals system, cerebral cortex, and hippocampus regions of have demonstrated that treatment with cholesterol the brain. It is interesting to note that the lowering drugs reduces the production of Aβ. It was neuroprotective properties of estrogen are not related therefore hypothesized that reduction of Aβ levels by Getu Melesie and Hunduma Dinsa / Bio-Genetics J. 2013, 1(1): 18-31 statins may have neuroprotective effects in patients treatment of neuropsychiatric symptoms of dementia antidepressants like trazodone and citalopram [87]. Antidepressants: - Depression is common in patients
with dementia. As many as 40% of patients with Ginkgo biloba: - Ginkgo biloba is an herbal supplement
dementia have significant depressive symptoms at that has been widely marketed as a memory and some stage. Selective serotonin reuptake inhibitors concentration enhancer. Its antioxidant properties, its (SSRI's) may have "neuroleptic" effects by reducing ability to promote blood flow to the brain and/or its affect on Aβ metabolism suggest that it may potentially serotonergic neurotransmission may play an important benefit cognitive function. Now it is prescribed as a role in the psychotic symptoms of dementia patients [85]. SSRIs have well-established efficacy, safety, and particularly cerebral insufficiency, including general tolerability in older patients with depression, including dementia and AD. The most important components of depression secondary to stroke or dementia or other ginkgo biloba are flavonoids and terpenoids, and these comorbid physical disorders. Citalopram (10 to 40 mg components are responsible for the mechanism of at bedtime) or sertraline (25 to100 mg every morning) action of the drugs [88, 89]. are generally preferred agents [86]. Other drugs for the
Table 4. Proposed mechanisms of action for agents in treating dementia [copied from 84]
proposed mechanisms
Oxidative stress (a harmful condition that occurs when there is an excess of free radicals and a decrease in antioxidant levels) may play a role in the pathogenesis of dementia; antioxidants (e.g., vitamins A, C, and E) may protect cells from oxidative damage High homocysteine levels have been linked with an increased risk for AD; possible explanatory Vitamins B6, B12 and Folate
mechanisms are diverse and include microvascular damage, endothelial dysfunction, excitotoxicity, induction of apoptosis and/ or oxidative stress; deficiencies of folate and/ or B12 are common causes of hyperhomocysteinemia and supplementation with these vitamins (and B6) can lower homocysteine level Inflammation is felt to be part of the pathological cascade that leads to AD; dampening down the inflammatory response might be beneficial; certain nonsteroidal anti-inflammatory have also been found to affect Aβ deposition and metabolism. Beta secretase seems to be more efficient in producing Aβ in cholesterol-rich environments; studies have demonstrated that treatment with statins reduces the production of Aβ .These agents might also be beneficial by decreasing the likelihood of vascular events. Estrogens have a variety of potential benefits that include protection from ischemic injury, facilitation of a number of neurotransmitter systems, and neuroprotective/neurotrophic effects; testosterone, Sex Steroids
either directly through androgen receptors or indirectly through estradiol (testosterone is converted to estradiol by aromatase), is also felt to have neuroprotective/ neurotrophic effects

4. Future Perspectives
and physical activity improve cognitive performance Dementia is a multifactorial, progressive illness that and slow cognitive decline. Future studies should has both presymptomatic and symptomatic phases. continue to examine the implication of risk factor Over the next 10–20 years, it is likely that new modification in controlled trials, with particular focus strategies for the prevention and treatment of dementia on whether several simultaneous interventions may will be developed. Simultaneously, biomarkers and have additive or multiplicative effects [92]. imaging techniques will make it possible to more accurately diagnose dementia earlier in the course of The newer therapies for the treatment of dementia the disease, possibly even in the presymptomatic include strategies targeting the underlying cellular and phase. Dementia Risk Indices will play an important molecular pathology in AD. These include two clinical and research role by helping to identify high- fundamental approaches: attempts to prevent the risk individuals who should be referred for more deposition of amyloid and/or tau proteins; and frequent monitoring or targeted for new behavioral attempts to remove the deposited amyloid using either and pharmacologic interventions as they are [91]. active or passive immunization approaches. An early study using active immunization unfortunately had to Some of the most promising strategies for the be terminated due to development of a fatal prevention of dementia include vascular risk factor meningoencephalitis in some of the participants. control, cognitive activity, physical activity, social However, of great interest, subsequent autopsy studies engagement, diet, and recognition of depression. In suggested that amyloid had indeed been cleared from observational studies, vascular risk factors - including the brains of those immunized, though cognitive benefit diabetes, hypertension, dyselipedimia, and obesity - are was not always apparent and in future these strategies fairly consistently associated with increased risk of benefit patient of dementia [93]. dementia. Most promisingly, interventions of cognitive Getu Melesie and Hunduma Dinsa / Bio-Genetics J. 2013, 1(1): 18-31 Figure 5. Algorithm for management of symptoms of dementia [90]

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