Assessing and Treating Clients With Dementia

chapter13_introduction.pdf

Home >Nursing homework help >Assessing and Treating Clients With Dementia

Dementia and its treatment

This chapter will provide a brief overview of the various causes of dementias and their pathologies, including the most recent diagnostic criteria and the emerging integration of biomarkers into clinical practice for Alzheimer’s disease. Full clinical descriptions and formal criteria for how to diagnose the numerous known dementias should be obtained by consulting standard reference sources. The discussion here will emphasize the links between various pathological mechanisms, brain circuits, and neurotransmitters and the various symptoms of dementia, with an emphasis on Alzheimer’s disease. The goal of this chapter is to acquaint the reader with ideas about the clinical and biological aspects of dementia and its currently approved treatments as well as new treatments that are on the horizon. The emphasis here is on the biological basis of symptoms of dementia and of their relief by psychopharmacologic agents, as well as on the mechanism of action of drugs that treat these symptoms. For details of doses, side effects, drug interactions, and other issues relevant to the prescribing of these drugs in clinical practice, the reader should consult standard drug handbooks (such as ).Stahl’s Essential Psychopharmacology: the Prescriber’s Guide

Causes, pathology, and clinical features of dementia

Dementia consists of memory impairment (amnesia) plus deficits in either language (aphasia), motor function (apraxia), recognition (agnosia), or executive function such as working memory and problem solving. Personality changes can also be present,

Table 13-1 Pathological features of selected degenerative dementias

Downloaded from http://stahlonline.cambridge.org by IP 100.101.44.120 on Tue Apr 28 19:41:06 UTC 2020 Stahl Online © 2020 Cambridge University Press. All rights reserved. Not for commercial use or unauthorized distribution.

Table 13-2 Not all memory disturbance is Alzheimer’s disease: clinical features of selected degenerative dementias

sometimes even before memory impairment begins. There are many causes of dementia (Tables through ), and the unique pathologies associated with some of the major dementias are13-1 13-3

listed in . Knowing the pathology does not mean that a treatment is available, as it is oftenTable 13-1 not evident how to translate information about brain pathology into pharmacological treatments. The best hope currently is in the area of amyloid pathology, where new treatments under investigation are attempting to interfere with amyloid processing in Alzheimer’s disease, as will be discussed later in this chapter.

Just because a patient develops memory disturbance does not mean it is Alzheimer’s disease (Table ). Alzheimer’s dementia is perhaps the best-known and commonest dementia, but it is often the13-2

other symptoms associated with memory loss that help make the diagnosis clinically ( ).Table 13-2 Just to complicate things, many patients have mixed types of dementia, particularly Alzheimer’s dementia plus dementia with Lewy bodies, or Alzheimer’s dementia plus vascular dementia (Figure

). Such cases13-1

Figure 13-1. . There are several types of dementia, of which Alzheimer’s disease is the mostMixed dementia common. They are distinguished by their underlying pathologies. It is possible to have more than one dementia, and in fact many patients have both Alzheimer’s disease and either dementia with Lewy bodies or vascular dementia.

are complicated to diagnose clinically, and definitive diagnosis sometimes must await autopsy. Most dementias are really pathological diagnoses, not clinical diagnoses.

Table 13-3 Nondegenerative dementias

A wide variety of dementias are considered nondegenerative, and these are listed in .Table 13-3 Many of these are treatable upon discovering the underlying cause, but others are not. Extensive clinical evaluation and laboratory testing must rule out these causes prior to concluding that a case of dementia is due to Alzheimer’s disease.

Alzheimer’s disease: -amyloid plaques and neurofibrillary tangles

Without the introduction of disease-modifying treatments, Alzheimer’s disease is poised for an exponential increase throughout the world, with projections that it will quadruple over the next 40 years to affect 1 in every 85 people on earth: over 100 million people by 2050. Fortunately, new treatments are being designed to interfere with various known pathological processes, particularly the formation of amyloid plaques, in an attempt to halt or slow disease progression in Alzheimer’s disease before neurons are irretrievably lost. To understand the current diagnostic criteria for Alzheimer’s disease, how and why biomarkers are being integrated into the diagnosis of this disorder, and the rationale behind the hot pursuit of new therapeutics, it is necessary to understand how the two hallmarks of this disorder, amyloid plaques and neurofibrillary tangles, are thought to be formed in the brain in Alzheimer’s disease.

The amyloid cascade hypothesis

The leading contemporary theory for the biological basis of Alzheimer’s disease centers around the formation of toxic amyloid plaques from peptides due to the abnormal processing of amyloid precursor protein (APP) into toxic forms of Abeta (A) peptides ( through ). Why doFigures 13-2 13-9 we make A in the first place? Although this is not fully understood, nontoxic A peptides have antioxidant properties, can chelate metal ions, regulate cholesterol transport, and may be involved in blood vessel repair, as a sealant at sites of injury or leakage, possibly protecting from acute brain

injury. Hypothetically, Alzheimer’s disease is a disorder in which toxic A peptides are formed, leading to deposition of amyloid plaque in the brain, with the ultimate destruction of neurons diffusely throughout the brain, somewhat analogous to how the abnormal deposition of cholesterol in blood vessels causes atherosclerosis.

Thus, Alzheimer’s disease may be essentially a problem of too much formation of A amyloid-forming peptides, or too little removal of them. One idea is that neurons in some patients destined to have Alzheimer’s disease have abnormalities either in genes that code for a protein called amyloid precursor protein (APP), or in the enzymes that cut this precursor into smaller peptides, or in the mechanisms of removal of these peptides from the brain and from the body. APP is a

Figure 13-2. . The way in which amyloidProcessing of amyloid precursor protein into soluble peptides precursor protein (APP) is processed may help determine whether an individual develops Alzheimer’s disease or not. A nontoxic pathway for APP processing is shown here. APP is a transmembrane protein with the C-terminal inside the neuron and the N-terminal outside the neuron. The enzyme -secretase cuts APP close to where it comes out of the membrane to form two peptides: -APP, which is soluble, and an 83-amino-acid peptide that remains in the membrane. A second enzyme, -secretase, cuts the embedded peptide into two smaller peptides, p7 and p3, which are not "amyloidogenic" and thus are not toxic.

transmembrane protein with the C-terminal inside the neuron and the N-terminal outside the neuron. One pathway for APP processing does not produce toxic peptides and involves the enzyme -secretase ( ). Alpha-secretase cuts APP close to the area where the protein comes out ofFigure 13-2 the membrane, forming two peptides: a soluble fragment known as -APP and a smaller 83-amino-acid peptide that remains embedded in the membrane until it is further cleaved by a second enzyme acting within the neuronal membrane, called -secretase ( ). That enzymeFigure 13-2 produces two smaller peptides, p7 and p3, which are apparently not "amyloidogenic" and therefore not toxic ( ).Figure 13-2

Another pathway for APP processing can produce toxic peptides that form amyloid plaques (i.e., "amyloidogenic" peptides). In this case a different enzyme, -secretase, cuts APP a little bit further away from the area where APP comes out of the membrane, forming two peptides: a soluble fragment known as -APP and a smaller 91-amino-acid peptide that remains embedded in the membrane until it is further cleaved by -secretase within the membrane ( ). This releasesFigure 13-3 A peptides of 40, 42 or 43 amino acids that are "amyloidogenic," especially A42 ( ).Figure 13-3

In Alzheimer’s disease, genetic abnormalities may produce an altered APP that, when processed by this second pathway involving -secretase, produces smaller peptides that are especially toxic. Individuals who do not get Alzheimer’s disease may produce peptides that are not very toxic, or may have highly efficient removal mechanisms that prevent neuronal toxicity from developing. The amyloid cascade hypothesis of Alzheimer’s disease therefore begins with an APP that is hypothetically genetically abnormal, or genetically or environmentally abnormal in the way it is processed, so that when it is cut into smaller peptide fragments too many toxic peptides are made, accumulate, and form neuron-destroying amyloid plaques, i.e., amyloidosis, and neurofibrillary tangles. Hypothetically, this process triggers a lethal chemical cascade that ultimately results in Alzheimer’s disease ( through ).Figures 13-3 13-8

Figure 13-3. . The way in which amyloid precursorProcessing of amyloid precursor protein into A peptides protein (APP) is processed may help determine whether an individual develops Alzheimer’s disease or not. A toxic pathway for APP processing is shown here. APP is a transmembrane protein with the C-terminal inside the neuron and the N-terminal outside the neuron. The enzyme -secretase cuts APP at a spot outside the membrane to form two peptides: -APP, which is soluble, and a 91-amino-acid peptide that remains in the membrane. Gamma-secretase then cuts the embedded peptide; this releases A peptides of 40, 42, or 43 amino acids. These toxic (amyloidogenic) peptides form amyloid plaques.

Specifically, abnormal genes or other influences cause the formation of an altered APP, or altered

processing into too many toxic A42 peptides ( ). Next, the A42 peptides form oligomers (aFigure 13-4 collection of a few copies of A42 assembled together: ). These oligomers can interfereFigure 13-5 with synaptic functioning and neurotransmitter actions such as those of acetylcholine, but they are not necessarily lethal to the neurons at first. Eventually, A42 oligomers form amyloid plaques, which are even larger clumps of A42 peptides stuck together with a number of other molecules (Figure 13-6 ). A number of nasty biochemical events then occur, including inflammatory responses, activation of microglia and astrocytes, and release of toxic chemicals including cytokines and free radicals (Figure

). These chemical events then hypothetically trigger the formation of neurofibrillary tangles within13-6 neurons by altering the activities of various kinases and phosphatases, causing hyperphosphorylation of tau proteins, and converting neuronal

Figure 13-4. . One theory for theAmyloid cascade hypothesis, part 1: increased production of A42 pathophysiology of Alzheimer’s disease is that there are genetic abnormalities in amyloid precursor protein (APP), so that when it is processed by the pathway involving -secretase, it produces smaller, toxic peptides (especially A42, as shown here).

Figure 13-5. Amyloid cascade hypothesis, part 2: A42 oligomers form and interfere with synaptic . A42 peptides assemble together to form oligomers, which interfere with synaptic functioning andfunction

neurotransmitter actions but are not necessarily lethal to neurons.

Figure 13-6. .Amyloid cascade hypothesis, part 3: formation of amyloid plaques causing inflammation A42 oligomers clump together along with other molecules to form amyloid plaques. These plaques can cause inflammatory responses, activation of microglia and astrocytes, and release of toxic chemicals such as cytokines and free radicals.

microtubules into tangles ( ). Finally, widespread synaptic dysfunction from A42 oligomers,Figure 13-7 neuronal dysfunction and death from formation of amyloid plaques outside of neurons and neurofibrillary tangles within neurons leads to diffuse neuronal death ( ) and regionalFigure 13-8 expansion of neuronal destruction in the cortex, causing the relentless progression of Alzheimer’s symptoms of amnesia, aphasia, agnosia, apraxia, and executive dysfunction. Some investigators believe that Alzheimer’s disease may spread from neuron to neuron, with pathological phosphorylated tau transported down axons, released at synapses and then taken up by neighboring cells. Pathological tau possibly then latches onto normal tau in the connected neurons, triggering the formation of new pathological mis-folded tau, from one affected neuron to the next.

Figure 13-7. . AmyloidAmyloid cascade hypothesis, part 4: amyloid plaque induces formation of tangles plaques and the chemical events they cause activate kinases, cause phosphorylation of tau proteins, and convert microtubules into tangles within neurons.

Support for the amyloid cascade hypothesis comes from genetic studies of those relatively rare inherited autosomal dominant forms of Alzheimer’s disease. Sporadic (i.e., noninherited) cases account for the vast majority of Alzheimer’s disease cases, but inherited cases can provide clues for what is wrong in the usual sporadic cases of Alzheimer’s disease. Rare familial cases of Alzheimer’s disease have an early onset (i.e., before age 65) and have been linked to mutations in at least three different chromosomes: 21, 14, and 1. The mutation on chromosome 21 codes for a defect in APP, leading to increased deposition of -amyloid. Recall that Down’s syndrome is also a disorder of this same chromosome (i.e., trisomy 21), and virtually all such persons develop Alzheimer’s disease if they live past age 50. A different mutation on chromosome 14 codes for an altered form of a protein called presenilin 1, a component of the -secretase enzyme complex. A third mutation, on chromosome 1, codes for an altered form of presenilin 2, a component of a different form of -secretase. It is not yet clear what if anything these three mutations in the rare familial cases tell us about the pathophysiology of the usual sporadic, nonfamilial, and late-onset cases of Alzheimer’s disease. However, they all point to abnormal processing of APP into amyloidogenic -amyloid peptides as a cause for the dementia, consistent with the amyloid cascade hypothesis. Theoretically, different abnormalities in amyloid processing may occur in sporadic Alzheimer’s disease from those identified in inherited cases, and there may even be multiple abnormalities that could be responsible for sporadic Alzheimer’s disease as a final common pathway, but the evidence nevertheless implicates something in the amyloid cascade that goes wrong in Alzheimer’s disease. If so, this implies that preventing the formation of amyloidogenic peptides could prevent Alzheimer’s disease.

ApoE and risk of Alzheimer’s disease

A corollary to the amyloid cascade hypothesis is the possibility that something may be wrong with a protein that binds to amyloid peptides in order to remove them ( ). This protein is calledFigure 13-9

apolipoprotein E (ApoE). In the case of "good" ApoE, it binds to -amyloid peptides and removes them, hypothetically preventing the formation of Alzheimer’s disease and dementia ( ). InFigure 13-9A the case of "bad" ApoE, a genetic abnormality in the formation of ApoE causes it to be ineffective in how it binds to -amyloid peptides. This causes amyloid plaques to be formed and deposited around neurons, which goes on to damage neurons and cause Alzheimer’s disease ( ).Figure 13-9B

Genes coding for ApoE are associated with different risks for Alzheimer’s disease. There are three alleles (or variants) of this gene coding for this apolipoprotein called E2, E3, and E4, and everyone has two alleles. The E4 variant on chromosome 19 ("bad" ApoE) is linked to many cases of late-onset Alzheimer’s disease, the usual form of this

Figure 13-8. . The effects of amyloidAmyloid cascade hypothesis, part 5: neuronal dysfunction and loss plaques and the build-up of neurofibrillary tangles can ultimately lead to neuronal dysfunction and death.

illness. ApoE is associated with cholesterol transport and involved with other neuronal functions including repair, growth, and maintenance of myelin sheaths and cell membranes. Having one or two copies of E4 increases the risk of getting Alzheimer’s disease. In fact, some studies show that you have a 50-90% chance of developing Alzheimer’s disease by age 85 if you are an E4 homozygote (i.e., you have two copies of E4); a 45% chance if you are a heterozygote for E4, versus the risk in the general population at 20%. Alzheimer’s patients with the E4 gene also have more amyloid deposits and progress more rapidly to dementia than those without the E4 gene. The E2 variant may actually be somewhat protective.