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dementia. (n.d.) Mosby's Medical Dictionary, 8th edition. (2009). Retrieved March 20 2012 from http://medical-dictionary.thefreedictionary.com/dementia Ref I 1, 2. Ref C 3-4.
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Ref AThis is a startling statistic emphatically declaring the need for intensive AD research and development.
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Imagine being able to see deep inside the brain tissue of a living person. If you could do that, you could find out whether the AD process was happening many years before symptoms were evident. This knowledge could have a profound impact on improving early diagnosis, monitoring disease progression, and tracking response to treatment.Then read through bullets and then caption.Ref, text and image, E
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Ref BThis image tells the story of the destruction that is occuring within the heads of AD patients and underscores the need for further study.
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Ref IRead textAs a result of this last finding, further study may reveal the more severe atrophy will correlate with more severe clinical symptoms.
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Ref JRead textNote the Misidentifying people, Paranoia, and believing the dead are still alive were the most common psychotic symptoms. Hallucinations, auditory and visual, along with believing their house was not their home were the next most significant group. Only 7.7% thought the television was real and 5.2 could not recognize themselves.
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Ref D This slide shows the trade names for the 3 approved cholinesterase inhibitors trade names Donepezil, Rivastigmine, and Galantamine; that is, Aricept, Exelon and Razadyne respectively. Note Exelon is also indicated for treatment of Parkinson’s type dementia. Exelon has a patch form and Razadyne has an extended release version. Also note in the footnote that Tacrine (Cognex) is rarely used due to liver enzyme elevations.
Ref D Note the trade name, Namenda. This slide indicates Memantine is approved only for moderate to severe AD. Renal failure is a contraindication and dosage should be reduced by 50%.
Ref D 1-2 . Ref K 3-4. Read text. Only donepezil in approved in the US for use in severe AD. At some point, patients taking any of the other drugs would have to stop if their symptoms worsened causing further deterioration even if the treatment was helping.
Ref HImmunotherapeutic agents capable of reversing or preventing AD appear to offer the greatest promise for future treatment of AD.Read Text.While studies with AN1792 were discontinued due to the occurrence of meningoencephalitis, the trials paved the way for the many active immunotherapeutic clinical trials currently in progress
Ref H This just to show the other active immunotherapy AD trials that have begun out of the lessons learned from the AN1792 trial. Note there are three compounds in phase 2 status.
Ref HRead text Note in each of the top slides, the amount of red decreased from screening to week 78. However, in the bottom slides, the amount of red increases from screening to week 78 for each patient. These findings demonstrate the effectiveness of bapineuzumab in reducing the amount of cortical beta amyloid. The placebo subjects saw and increase in cortical beta amyloid. Unfortunately, these findings have not been correlated to a reduction in clinical symptoms or a slowing or reversing of AD progression.
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Ref JRead textAn important question then is in what way genetic factors might lead to psychosis in Alzheimer’s disease
Ref H Rosiglitazone, Statins, Estrogen, NSAIDs, B-vitamins, HGH/IGF-1, Lithium, Valproic Acid, while they may have certain benefits to AD structural or behavioral signs and symptoms, are not actively being pursued as a viable treatment for AD. Interestingly, Dimebon, a mitochondrial neuroprotectant, has a Phase III add-on trial in progress. Similarly, Insulin, to improve AD pathology and improve synaptic dysfunction has Phase II trials planned. Rosiglitazone made it to Phase III but is currently not being actively pursued.
Ref HNote that Resveratrol and NGF gene delivery are the only of these substances being pursued further according to this report as a treatment option for AD. A considerable drawback of NGF gene delivery is that is requires a neurosurgical procedure to administer. Axona and Souvenaid suffered negative trial results yet are marketed as medical food. Xaliproden and Idebenone are not actively sought for AD treatment. Vitamin E use is limited by Toxicity concerns. And, acetyl-L-carnitine as well as leuprolide received negative outcomes on clinical trials.
http://www.alz.org/documents_custom/2012_Facts_Figures_Fact_Sheet.pdfhttp://www.alzinfo.org/07/about-alzheimers/non-genetic-risk-factorshttp://www.nlm.nih.gov/medlineplus/ency/article/000760.htmPaul S. Aisen, et. al.: “Symptomatic and Nonamyloid/Tau Based Pharmacologic Treatment for Alzheimer Disease.” Cold Spring Harb Perspect Med, 2012; 2:a006395“Alzheimer’s Disease: Unraveling the Mystery.” U.S. Department of Health and Human Services, NIH Publication Number: 08-3782 September 2008.Wierenga, C et. al.: “Use of Functional Magnetic Resonance Imaging in the Early Identification of Alzheimer’s Disease.” Neuropsychol Rev. 2007 June ; 17(2): 127–143. doi:10.1007/s11065-007-9025-y.“Genetics of Late-Onset Alzheimer’s Disease: Update from the Alzgene Database and Analysis of Shared Pathways.” International Journal of Alzheimer’s Disease Volume 2011, Article ID 832379, 14 pages, doi:10.4061/2011/832379.Lobello K et. al.: “Targeting Beta Amyloid: A Clinical Review of Immunotherapeutic Approaches in Alzheimer’s Disease.” International Journal of Alzheimer’s Disease Volume 2012, Article ID 628070, 14 pages, doi:10.1155/2012/628070.Bateman RJ, et al.: “Autosomal-dominant Alzheimer’sdisease: a review and proposal for the prevention of Alzheimer’s disease.” Alzheimer’s Research & Therapy 2011, 3:1.Sweet R et. al.: “Assessment and familial aggregation of psychosis in Alzheimer’s disease from the National Institute on Aging Late Onset Alzheimer’s Disease Family Study.” Brain 2010: 133; 1155–1162.http://www.health.gov.bc.ca/pharmacare/adti/clinician/cholinesterase.htmlhttp://youtu.be/VlD2xIuiMEUhttp://www.med.harvard.edu/aanlib/home.html
Scott Zatzkis recently relocated to France with his family, where he continues to pursue his freelance career. Mr. Zatzkis enjoys delivering high-quality research, presentations, and reports, including creative and cutting-edge solutions, for his individual and corporate clientele.Mr. Zatzkis obtained his Bachelor of Arts degree in English from Vanderbilt University in Nashville, Tennessee. He also received his Juris Doctorate from Quinnipiac University Law School in Hamden, Connecticut. He practiced law for 12 years in Louisiana. During his professional career, Mr. Zatzkis drafted numerous legal documents and reports for presentation to clients, attorneys, judges and other groups. He strives to bring a creative edge to his freelance work that often was not appreciated in his legal work. Please feel free to contact him at firstname.lastname@example.org or visit his freelance work site on Elance.com at http://scott_zatzkis.elance.com
Alzheimers Causes and Treatments
As the title suggests, this presentation is a survey of current structural and behavioralAlzmeimer’s Disease (AD) signs, causes and treatments. Structural issues concerneffects of the disease on brain structures such as nerve cells and brain tissue. Behavioralissues include effects on memory and personality.First, it describes AD itself in general terms and the scope of the impact the disease hason global society. These impacts are financially, emotionally, and biologically substantial.Next, I show the genetic and non-genetic risk factors for developingAD.Then, it examines AD pathophysiology, including the mechanisms by which AD inflicts itsterrible toll. After delineating the stages of AD, it presents two case studies of afflictedindivuduals. Are you able to note the behavioral issues?Finally, it surveys and analyzes the currently approved drug therapies, includingpsychotropic drugs for psychotic symptoms. In addition, it examines and looks forwardto potential immunotherapies. And, lastly, it critiques some of the non-approved drugtreatments and trials.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized bythe accrual of neuritic plaques and neurofibrillary tangles that result in a disruption ofneuronal function and which causes cognitive and behavioral dysfunction (Braak &Braak, 1991).AD causes an insidious and progressive loss of cognitive function and independence,taking a heavy personal and financial toll on the patient and the family. Alzheimersdisease, Picks disease, and other organic forms of dementia are generally consideredirreversible, progressive, and incurable.AD is the most common cause of dementia among older people. Dementia is a loss ofmental ability severe enough to interfere with normal activities of daily living, lastingmore than six months, not present since birth, and not associated with a loss oralteration of consciousness.Dementia is a group of symptoms caused by gradual death of brain cells. The loss of cognitiveabilities that occurs with dementia leads to impairments in memory, reasoning, planning, andbehavior. While the overwhelming number of people with dementia are elderly, dementia isnot an inevitable part of aging; instead, dementia is caused by specific brain diseases.
In 2010, an estimated 36 million people worldwide were living with dementia—anumber that is projected to increase to 66 million in 2030, and 115 million in 2050. 1 to3 percent of people older than 65 who have normal cognition will develop AD in any oneyear.According to the World Alzheimer Report, the worldwide cost of dementia is estimatedat USD $604 billion for 2010, and according to one model, this cost has increased by34% between 2005 and 2009.Alzheimer’s disease is the 6th leading cause of death in the United States and the 5thleading cause of death for those aged 65 and older. And, Alzheimer’s is the only causeof death among the top 10 in America without a way to prevent, cure or even slow itsprogression.Approximately 5% of all persons over age 70 have AD; this proportion raises to 25%–45%in “oldest old” (>85 years) individuals. About 10% of AD patients develop symptomsbefore age 65, more often in their 40 s or 50 s.
Deaths from Alzheimer’s increased 66 percent between 2000 and 2008, while deathsfrom other major diseases, including the number one cause of death (heart disease),decreased.Due to the physical and emotional toll of caregiving on their own health, Alzheimer’sand dementia caregivers had $8.7 billion in additional health care costs in 2011.An estimated 800,000 individuals with Alzheimer’s (more than one in seven) live alone.Of those who live alone, up to half of them do not have an identifiable caregiver.People with Alzheimer’s and other dementias who live alone are exposed to higher risks– including inadequate self-care, malnutrition, untreated medical conditions, falls,wandering from home unattended, and accidental deaths – compared to those who donot live alone.
Age: Mitochondria become more susceptible to damage; Inflammation (swelling)increases, which can injure nerve cells, such as after a head injury;Oxidative stress, which is caused by the release of molecules called free radicals fromnormal cellular processes, increases.Education level: Research suggests the more years of formal education one has, the lesslikely one is to develop Alzheimers. Some experts theorize that longer education mayproduce a denser network of synapses. This may create a kind of "neural reserve" thatenables people to compensate longer for the early brain changes.Race and Ethnicity: African-Americans and Hispanics are about twice as likely todevelop Alzheimer’s as white Americans of the same age. While the reasons for this areunclear, there is some speculation that it may have to do with the fact that these groupshave a higher incidence of high blood pressure and diabetes.High blood pressure and high cholesterol: There is growing evidence that many of thewell-established risk factors for cardiovascular disease, including high cholesterol andhigh blood pressure, may also be risk factors for Alzheimers disease.
Diabetes: Diabetes has been implicated as a risk factor for eventually developingAlzheimers disease. There are many ongoing studies attempting to understand theconnection, and some diabetes drugs appear to slow the cognitive decline associatedwith Alzheimers disease.Head trauma: Some studies have found that Alzheimers occurs more often in peoplewho have suffered traumatic brain injury earlier in life. A history of head injury is clearlya risk factor for Alzheimers in people who carry the APOE-4 Alzheimers gene.Diet: Obesisty doubled the risk of developing AD; Foods high in fat and sugar, as well aslarger amounts of red and processed meats increased risk versus lean meats (fish andpoultry) and more fruits and vegetables.The cause of AD is not clear. Your genes and environmental factors seem to play a role.Aluminum, lead, and mercury in the brain is no longer believed to be a cause of AD.
The only identified deterministic factors for the development of AD are the presence ofmutations in one of three genes – amyloid precursor protein (APP), presenilin 1 (PSEN1)or presenilin 2 (PSEN2) – or duplication of APP.Even if only one of these genes that are inherited from a parent contains a mutation, theperson will almost inevitably develop early-onset AD. (≈100%)You are more likely to get Alzheimers disease (AD) if you:• Have a close blood relative, such as a brother, sister, or parent with AD.• Have certain genes linked to AD, such as APOE epsilon4 alleleThis gene, called APOE, produces a protein called apolipoprotein E. APOE comes inseveral forms, or alleles—ε2, ε3, and ε4. APOE ε4 occurs in about 40 percent of allpeople who develop late-onset AD and is present in about 25 to 30 percent of thepopulation.
Notably, the cognitive declines and functional changes in APOE ε4 carriers tend tobecome most evident after age 65 (Jorm et al., 2007; Mondadori et al., 2006b),suggesting that the negative effects of the APOE ε4 allele accelerate with age.The genetics of late-onset Alzheimer’s disease (LOAD) has taken impressive stepsforwards in the last few years. To date, more than six-hundred genes have been linkedto the disorder. However, only a minority of them are supported by a sufficient level ofevidence.The quality of studies was assessed using criteria such as size of research samples,heterogeneity across studies, and protection from publication bias. This produced a listof 15 top-rated genes: APOE, CLU, PICALM, EXOC3L2, BIN1, CR1, SORL1, TNK1, IL8, LDLR,CST3, CHRNB2, SORCS1, TNF, and CCR2.A systematic analysis of gene ontology terms associated with each marker showed thatmost genes were implicated in cholesterol metabolism, intracellular transport of beta-amyloid precursor, and autophagy of damaged organelles. Further analysis highlightsthe role of inflammatory response in AD pathogenesis.
The brains of people with AD have an abundance of two abnormal structures—amyloidplaques and neurofibrillary tangles—that are made of misfolded proteins . The third mainfeature of AD is the loss of connections between cells. This leads to diminished cell functionand cell death.Accumulation of toxic beta amyloid with the formation of extracellular betaamyloid-containing plaques: We still do not know whether amyloid plaques themselves causeAD or whether they are a by-product of the AD process. However, genetic mutations canincrease production of beta-amyloid and can cause rare, inherited forms of AD.Development of intracellular neurofibrillary tangles: Tangles are abnormal collectionsof twisted protein threads found inside nerve cells. The chief component of tangles is aprotein called tau.Neuronal degeneration: The AD process not only inhibits communication betweenneurons but can also damage neurons to the point that they cannot function properlyand eventually die. As neurons die throughout the brain, affected regions begin to shrinkin a process called brain atrophy.
Amyloid precursor protein (APP) becomesembedded in cell surfaceSpecific enzymes snip, or cleave, APP intodiscrete fragments, some are Beta-amyloid(Aβ) peptidesAggregates of two, three, four, or even up to adozen beta-amyloid peptides are calledoligomers.As the process continues, oligomers growlarger, becoming entities called protofibrils andfibrils. Eventually, other proteins and cellularmaterial are added, and these increasinglyinsoluble entities combine to become the well-known plaques that are characteristic of AD.
Multiple lines of evidence now suggest that it is not just the presence of Aβ but theproduction and/or deposition of toxic forms of beta amyloid, along with the slowing of Aβclearance, that act as the central and primary events in AD pathogenesis, while neurofibrillarytangle formation and neuronal cell death occur downstream in this amyloid cascade.Elevated levels of tau protein in the cerebrospinal fluid (CSF) are markers of activeneuronal degeneration, while levels of abnormally phosphorylated tau (P-tau) appear tocorrelate with the quantity of neurofibrillary tangles in the brain, suggesting that CSF P-tau may serve as an in vivo biomarker of the neurofibrillary pathology of AD.Cells and compounds known to be involved in inflammation are found in AD plaques.Some researchers think that components of the inflammatory process may play a role inAD. Other players in the aging process that may be important in AD are free radicals,oxygen or nitrogen molecules that combine easily with other molecules.Betaamyloid deposition within the CNS would bring about the activation of microgliaand thus initiate a proinflammatory cascade leading to release potentially neurotoxicsubstances (cytokines; chemokines; reactive oxygen andnitrogen species; proteolyticenzymes) and to amplify neural damage.
Healthy neurons are internally supported in part bystructures called microtubules, which help transportnutrients and other cellular components, from the cell bodydown the axon.As a result of “hyperphosphorylation,” tau disengages fromthe microtubules and begins to come together with othertau threads.These tau threads form structures called paired helicalfilaments, which can become enmeshed with one another,forming tangles within the cell.The microtubules can disintegrate in the process, collapsingthe neuron’s internal transport network. This collapsedamages the ability of neurons to communicate with eachother.
On this slice, the atrophic hippocampus and amygdala can be seen. Thesestructures subserve memory function, and are the sites of major damage inAlzheimers disease.
Here is a mid-ventricular slice which demonstrates the commonest finding infunctional imaging of Alzheimers disease. The dark blue regions in theparietal lobes represent areas of decreased blood flow or perfusion. Thisreduction in blood flow is due in part to the underlying atrophy, in part to thepresence of diseased brain, and in part to the functional "disconnection" ofthis from other brain regions affected by the disease.
The association cortex of the parietal lobes is often severely affected, asillustrated in this case.
MRI and PET scan image overlay for corresponding slice showing perfusionand atrophy in the associated areas of reduced blood flow.
Scientists developed a radiolabeled compound called Pittsburgh Compound B (PiB). PiB binds to beta-amyloid plaques in the brain and can be imaged using PET scans. Initial studies showed that people with AD take up more PiB in their brains than do cognitively healthy older people. Since then, scientists have found high levels of PiB in some cognitively healthy people, suggesting that the damage from beta amyloid may already be underway. In this PET scan, the red and yellow colors indicate that PiB uptake is higher in the brain of the person with AD than in the cognitively healthy person.
The compensatory hypothesis is an explanation of differential regional (brain regions)activity seen in at-risk groups.The compensatory hypothesis holds that as AD-related degenerative processes progressthe brain employs various compensatory measures to overcome these pathologicencroachments until the decline in cognitive abilities becomes apparent and, ultimately,daily functioning is disrupted.Accordingly, increased functional activity has been interpreted as a compensatoryprocess whereby greater cognitive effort—usually reflected by increases in BOLD (bloodoxygen level)activity—is required to perform at an equivalent level compared to healthycontrol groups.Similarly, decreased activity in healthy functioning has been interpreted as evidence ofefficient processing (Mondadori et al., 2006b), whereas decreased activity inneurodegenerative diseases appears to reflect cortical compromise or disconnection.
AD begins deep in the brain, in the entorhinal cortex, a brain region that is near thehippocampus and has direct connections to it. Healthy neurons in this region begin towork less efficiently, lose their ability to communicate, and ultimately die.This process gradually spreads to the hippocampus, the brain region that plays a majorrole in learning and is involved in converting short-term memories to long-termmemories. Affected regions begin to atrophy.Ventricles, the fluid filled spaces inside the brain, begin to enlarge as the processcontinues.Scientists believe that these brain changes begin 10 to 20 years before any clinicallydetectable signs or symptoms of forgetfulness appear. That’s why they are increasinglyinterested in the very early stages of the disease process.
As some people grow older, they develop memory problems greater than thoseexpected for their age. But they do not experience the personality changes or otherproblems that are characteristic of AD. These people may have a condition called mildcognitive impairment (MCI).People with MCI are a critically important group for research because a much higherpercentage of them go on to develop AD than do people without these memoryproblems. About 8 of every 10 people who fit the definition of amnestic MCI go on todevelop AD within 7 years.Those with MCI who had lots of trouble moving their legs and feet were more thantwice as likely to develop AD as those with good lower body function.However, researchers are not yet able to say definitively why some people withamnestic MCI do not progress to AD, nor can they say who will or will not go on todevelop AD.
As AD spreads through the brain, the number of plaques and tangles grows, shrinkageprogresses, and more and more of the cerebral cortex is affected. Memory losscontinues and changes in other cognitive abilities begin to emerge. The clinical diagnosisof AD is usually made during this stage.In mild AD, a person may seem to be healthy but is actually having more and moretrouble making sense of the world around him or her. The realization that something iswrong often comes gradually to the person and his or her family.Signs of mild AD can include: Memory loss Confusion about the location of familiarplaces (getting lost begins to occur); Taking longer than before to accomplish normaldaily tasks; Trouble handling money and paying bills; Loss of spontaneity and sense ofinitiative; Mood and personality changes, increased anxiety and/or aggressionAccepting these signs as something other than normal and deciding to go for diagnostictests can be a big hurdle for people and families.
By this stage, AD damage has spread to the areas of the cerebral cortex that controllanguage, reasoning, sensory processing, and conscious thought. Affected regionscontinue to shrink, ventricles enlarge, and signs and symptoms of the disease becomemore pronounced and widespread.Behavioral problems, such as wandering and agitation, can occur. More intensivesupervision and care become necessary, which can be difficult for many spouses andfamilies. Some of these symptoms may become worse in the evening (a phenomenoncalled “sundowning”) or during daily routines, especially bathing.The symptoms of this stage can include: Increasing memory loss and confusion;Inappropriate outbursts of anger; Problems recognizing friends and family members;Difficulty with language; Restlessness, agitation, anxiety, tearfulness, wandering—especially in the late afternoon or night. And,Hallucinations, delusions, suspiciousness or paranoia, irritability; Loss of impulse control(shown through undressing at inappropriate times or places or vulgar language); Aninability to carry out activities that involve multiple steps in sequence, such as dressing,making a pot of coffee, or setting the table.
People with severe AD cannot recognize family and loved ones or communicate in anyway. They are completely dependent on others for care.Symptoms can include: Weight loss; Seizures; Skin infections; Difficulty swallowing;Groaning, moaning or grunting; Increased sleeping; Loss of bladder or bowel control.Near the end, the person may be in bed much or all of the time. The most frequentcause of death for people with AD is aspiration pneumonia. This type of pneumoniadevelops when a person is not able to swallow properly and takes food or liquids intothe lungs instead of air.To qualify for hospice benefits under Medicare, a physician must diagnosis the personwith Alzheimer’s disease as having less than six months to live.
This diagram reveals the neuropathological hallmarks of ADthat include neuritic (also ‘senile’) plaques, neurofibrillarytangles (NFTs), and amyloid angiopathy.Neuritic plaques are extracellular aggregates of beta(β)-amyloid protein in a milieu of reactive astrocytes andactivated microglia.NFTs are intraneuronal cytoplasmatic filaments composedof hyperphosphorylated tau, frequently conjugated withubiquitin.
One type is the rare, early-onset Alzheimer’s disease. It usually affects people aged 30to 60. Some cases of early-onset disease are inherited and are called familial AD (FAD).It is acknowledged that 75% of people with AD have sporadic AD (SAD) a form of late-onset AD (LOAD). This is most likely a multifactorial condition, which involves acombination of genetic, lifestyle, and environmental factors. 25% is familial AD (FAD).Early-onset AD encompasses 5% of FAD cases.Early-onset FAD is inherited in an autosomal dominant manner and is caused bymutations in one of these three genes: APP, PSEN1, and PSEN2.The principal neuropathological changes in ADAD, a form of early-onset AD, – neuronalloss, neurofibrillary tangles, senile plaques, and cerebral amyloid angiopathy (CAA) –mirror those seen in SAD (LOAD) providing strong support for ADAD as a model forstudying AD.
The other is late-onset Alzheimer’s disease (LOAD). It is by far the more common formand occurs in those 60 and older.As for LOAD, the only established genetic factor is apolipoprotein E (APOE). APOEassociated Alzheimer’s disease is due to a specific variation in the APOE gene called e4allele. It is estimated that 40–65% of AD patients have at least one copy of the e4 allele.Individuals with two e4 alleles have up to 20 times the risk of developing AD.Nonetheless, a third of patients with AD are ApoE4 negative, and some ApoE4homozygotes never develop the disease.More severe medial-temporal lobe atrophy may be present in symptomatic ADAD (earlyonset) carriers compared with SAD (late onset).
Memory loss that disrupts daily life: forgetting recently learned information, important datesor events; asking repetitively for things; using memory aides (e.g., reminder notes or electronicdevices) or family members for things they used to handle on their own. What’s Typical: Sometimes forgetting names or appointments, but remembering them later.Challenges in planning or solving problems: Some people may experience changes in theirability to develop and follow a plan or work with numbers. They may have trouble following afamiliar recipe or keeping track of monthly bills. They may have difficulty concentrating andtake much longer to do things than they did before. What’s Typical: Making occasional errors when balancing a checkbook.
Difficulty completing familiar tasks at home, at work or at leisure: People with Alzheimer’soften find it hard to complete daily tasks. Sometimes, people may have trouble driving to afamiliar location, managing a budget at work or remembering the rules of a favorite game. What’s Typical: Occasionally needing help to use the settings on a microwave or to record a television show.Confusion with time or place: People with Alzheimers can lose track of dates, seasons and thepassage of time. They may have trouble understanding something if it is not happeningimmediately. Sometimes they may forget where they are or how they got there. What’s Typical: Getting confused about the day of the week but figuring it out later.
Trouble understanding visual images and spatial relationships: For some people, havingvision problems is a sign of Alzheimers. They may have difficulty reading, judging distance anddetermining color or contrast. In terms of perception, they may pass a mirror and thinksomeone else is in the room. They may not recognize their own reflection. What’s Typical: Vision changes related to cataracts.New problems with words in speaking or writing: People with Alzheimers may have troublefollowing or joining a conversation. They may stop in the middle of a conversation and have noidea how to continue or they may repeat themselves. They may struggle with vocabulary, haveproblems finding the right word or call things by the wrong name (e.g., calling a watch a "handclock"). What’s Typical: Sometimes having trouble finding the right word.
Misplacing things and losing the ability to retrace steps: A person with Alzheimer’s diseasemay put things in unusual places. They may lose things and be unable to go back over theirsteps to find them again. Sometimes, they may accuse others of stealing. This may occur morefrequently over time. What’s Typical: Misplacing things from time to time, such as a pair of glasses or the remote control.Decreased or poor judgment: People with Alzheimers may experience changes in judgment ordecision making. For example, they may use poor judgment when dealing with money, givinglarge amounts to telemarketers. They may pay less attention to grooming or keepingthemselves clean. What’s Typical: Making a bad decision once in a while.
Withdrawal from work or social activities: A person with Alzheimers may start to removethemselves from hobbies, social activities, work projects or sports. They may have troublekeeping up with a favorite sports team or remembering how to complete a favorite hobby.They may also avoid being social because of the changes they have experienced. What’s Typical: Sometimes feeling weary of work, family and social obligations.Changes in mood and personality: The mood and personalities of people with Alzheimers canchange. They can become confused, suspicious, depressed, fearful or anxious. They may beeasily upset at home, at work, with friends or in places where they are out of their comfortzone. What’s Typical: Developing very specific ways of doing things and becoming irritable when a routine is disrupted
Psychosis is frequent in late onsetAlzheimer’s disease, with a medianprevalence across studies of 41%.Psychosis significantly aggregated withinlate onset Alzheimer’s disease familiessuggesting that it may identify agenetically determined subgroup.Evidence indicates that psychosis is amarker for more severe cognitiveimpairments and a more rapidlyprogressive phenotype of late onsetAlzheimer’s disease.
A 73 year old woman, was brought to neurological evaluation by her brother because of a 3 year history of memory impairment. She had completed high school and worked in a clerical position until her retirement in 1985. She had lived alone and maintained her own home and financial affairs since the death of her husband in 1980. The brother had begun to notice gradually worsening memory impairment and difficulty finding words, but the patient became angry at the suggestion that she may have a progressive impairment. Others had noted decline in housekeeping and financial affairs, but she had no complaints. Elevated arterial blood pressure was documented on several occasions, but she never took medication. She had no children and had a hysterectomy. She was a well-groomed woman who was alert and friendly. General and elemental neurological exams were normal.
Her speech was highly anomic and paraphasic, with a tendency to use vague referents such as "things" and "stuff". She was able to provide her name, but when asked about her current age, she said: "I dont know . . ., about 8 I think." She incorrectly stated her birth month, but then became aware of this. Given three choices, she was able to give the correct month. She was unable to give the year of her birth, the current year, or the name of the current U.S. President. On formal testing, she scored well below average in all cognitive domains. These tests included the Wechsler Memory scale, the Wechsler Adult Intelligence Scale, digit span and similarities subtests, the Boston Naming Test, the CERAD Word List Memory Test, the CERAD Visuo-spatial Construction, the Cross Circle Tests, the California Proverb Test, and the Graphomotor Alternation Test. She tended to perseverate both verbal and motor responses. The conclusion of the evaluation was that she met research criteria for "probable" Alzheimers disease, that she required complete supervision around the clock to insure her safety, and that she would probably benefit from social stimulation provided by a group living situation.
North American(FDA) and European Union(EMA) regulatory criteria for marketing approval of putative symptomatic and disease-modifying therapeutic agents for AD based on: a demonstration of efficacy supported by improvements compared to placebo treatment on cognitive function, activities of daily living (ADL)and often evidence of overall clinical improvement or less overall decline accompaniedby adequate evidence of safety.
standardized protocols: mild to moderate AD is indexed by a Mini- Mental State Examination (MMSE) score of 10–26 and the Alzheimer’s Disease Assessment Scale— Cognitive Portion (ADAS-cog), theAlzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scale, or the Disability Assessment for Dementia (DAD). A clinician’s global assessment (known as a Clinician InterviewBased Impression of Change with caregiver input [CIBICþ] or ADCS Clinical Global Impression of Change [CGIC]) or the Clinical Dementia Rating (CDR), an interview-based overall dementia severity assessment, are the conventional outcomes measures.
Acetylcholinesterase inhibitors (AChE-Is) are the first class of agents specifically approved by the US Food and Drug Administration (FDA)or the treatment of mild to moderate AD. The responses to treatment with different AChE-Is have overlapping confidence intervals (CI), and no individual cholinesterase inhibitor has been shown to be superior to others in terms of efficacy Continuing benefit from use of AChE-Is has been shown in trials lasting up to 2 years, among patients followed over that length of time (AD2000 Collaborative Group 2004). In addition, patients with severe AD—not previously treated with AChE-Is—respond to treatment with AChE-Is, and donepezil is approved for treatment in this advanced phase of the disease.
Memantine was used in Germany for the treatment of Parkinson’s disease prior to its approval in the USA and globally for treatment of AD. Memantine is an NMDA receptor antagonist that replaces potassium in the NMDA receptor channel to reduce entry of calcium into neurons and avoid calcium-stimulated apoptotic cell death cascades. Clinical trials of memantine have been very similar in design to those conducted with AChE-Is, but have involved patients with moderate to severe AD, rather than mild to moderate AD. Memantine is not approved by the FDA for patients with mild AD. European regulatory authorities extended the range of approval for use of memantine to patients with MMSE scores of 19 and below.
Cholinesterase inhibitors and memantine are potential therapies for the management ofmany cognitive symptoms of AD, but these neurotransmitter-based approaches do notaddress the underlying pathology of the illness, and ultimately fail to prevent itsprogression.Gastrointestinal side effects : Anorexia, nausea, vomiting, diarrhea, and weight lossmay occur and should be monitored in patients treated with these agents. In addition,cholinergic influences may slow heart rate and bradycardia is a contraindication to useof AChE-Is.In cases where these drugs appear to be effective, patients and caregivers reported aslowing in symptoms such as memory loss, reduced anxiety, improved mood andrestored confidence levels. Some patients will respond and others not to AChE-Is.Once a patient stops taking a drug, their condition will deteriorate over a period of 4 to6 weeks until they are at the same point as an individual who has not taken the drug.
Passive immunotherapy refers to the direct administration of anti-beta-amyloidantibodies, obviating the need for patients to mount an antibody response. Passiveimmunotherapy in the form of specifically designed monoclonal antibodies allows forthe precise targeting of beta-amyloid epitopes.In contrast, active immunotherapy involves the administration of either full-lengthbetaamyloid peptides or peptide fragments to activate the patient’s immune system inorder to produce anti-betaamyloid antibodies.AN1792, a synthetic beta-amyloid peptide, was the first active amyloid immunotherapytested in clinical trials. As compared with placebo treated patients, antibody respondershad a 25% lower decline in activities of daily living as assessed by the DAD. The trial wasstopped due to cases of meningoencephalitis.Bapineuzumab is a humanized monoclonal antibody (passive) that targets the N-terminal region of beta amyloid. Bapineuzumab/placebo differences in 11C-PiBretention were statistically significant in all prespecified cortical regions (anterior andposterior cingulate, frontal, temporal, parietal, and occipital cortex).
Positron emission tomography (PET) carbon-11-labelled Pittsburgh compound B (11C-PiB) images from patients treated with bapineuzumab and those given placebo. Thisfinding correlates to an approximately 25% reduction in cortical beta amyloid inbapineuzumab-treated patients.
There is an urgent need for effective, safe, psychotropic agents for treatment of behavioral disturbances in AD and other dementing disorders.Behavioral disturbances are common in AD, including depression, agitation, irritability,aberrant motor behaviors, and psychosis. There are no agents approved by the FDAspecifically for treatment of behavioral disturbances in AD.Antipsychotics— both conventional and atypical—are associated with increasedmortality and some antipsychotics are associated with increased risk for cerebrovascularaccidents or stroke when administered to elderly patients with AD. The risk of death isincreased from 2.6% to 4.5% during an average of 10 weeks of therapy.Several 1–12 week long clinical trials suggest that risperidone and possibly other atypicalantipsychotic agents in low doses are efficacious in reducing psychosis and agitation inmainly nursing home patients with AD.
Strategies for use of antipsychotics in patients with AD involve avoiding their use inpatients with cardiovascular or pulmonary disease (the two most common causes ofdeath in mortality studies), using these agents only in patients for whomnonpharmacologic interventions have failed and the behaviors are extreme.Clinical trials have been largely negative in showing benefit for treatment of depressionin AD with antidepressant medications. Individual practitioners may use practice-basedevidence to guide their therapeutic decisions.Anxiolytics and hypnotics are generally to be avoided in patients with AD as they mayincrease confusion. Short term use of benzodiazepines such as lorazepam orclonazepam may be useful in patients with episodes of agitation.Greater cognitive impairment is by far the most consistent correlate of psychosis in lateonset Alzheimer’s disease. Also, Evidence of familial aggregation of psychosis inAlzheimer’s disease suggests that this phenotype is under genetic control.
A. http://www.alz.org/documents_custom/2012_Facts_Figures_Fact_Sheet.pdfB. http://www.alzinfo.org/07/about-alzheimers/non-genetic-risk-factorsC. http://www.nlm.nih.gov/medlineplus/ency/article/000760.htmD. Paul S. Aisen, et. al.: “Symptomatic and Nonamyloid/Tau Based Pharmacologic Treatment for Alzheimer Disease.” Cold Spring Harb Perspect Med, 2012; 2:a006395E. “Alzheimer’s Disease: Unraveling the Mystery.” U.S. Department of Health and Human Services, NIH Publication Number: 08-3782 September 2008.F. Wierenga, C et. al.: “Use of Functional Magnetic Resonance Imaging in the Early Identification of Alzheimer’s Disease.” Neuropsychol Rev. 2007 June ; 17(2): 127–143. doi:10.1007/s11065-007-9025-y.G. “Genetics of Late-Onset Alzheimer’s Disease: Update from the Alzgene Database and Analysis of Shared Pathways.” International Journal of Alzheimer’s Disease Volume 2011, Article ID 832379, 14 pages, doi:10.4061/2011/832379.H. Lobello K et. al.: “Targeting Beta Amyloid: A Clinical Review of Immunotherapeutic Approaches in Alzheimer’s Disease.” International Journal of Alzheimer’s Disease Volume 2012, Article ID 628070, 14 pages, doi:10.1155/2012/628070.I. Bateman RJ, et al.: “Autosomal-dominant Alzheimer’sdisease: a review and proposal for the prevention of Alzheimer’s disease.” Alzheimer’s Research & Therapy 2011, 3:1.J. Sweet R et. al.: “Assessment and familial aggregation of psychosis in Alzheimer’s disease from the National Institute on Aging Late Onset Alzheimer’s Disease Family Study.” Brain 2010: 133; 1155–1162.K. http://www.health.gov.bc.ca/pharmacare/adti/clinician/cholinesterase.htmlL. http://youtu.be/VlD2xIuiMEUM. http://www.med.harvard.edu/aanlib/home.html
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