Contact:
sales@biotechnologyforums.com to feature here

Thread Rating:
  • 0 Vote(s) - 0 Average
  • 1
  • 2
  • 3
  • 4
  • 5
Cure and Causes of Alzheimer's Disease: A Must Read!
#1
Exclamation 
What is Alzheimer's Disease? And why is it called so?
Alzheimer's causes memory loss and is more prevalent among older people. Cure and causes of Alzheimer's disease are discussed in this article.

Before we dwell into the details about the disease, let us go back into the history first, and find out about the nomenclature (story of it's name). In 1901, a German Psychiatrist, Alois Alzheimer, confronted a patient with severe memory loss (or dementia). 

The patient was a fifty-year-old woman, Auguste Deter. Dr. Alzheimer thoroughly studied her case till her death in 1906, and then reported (published) his observations.

Born in 1850, Auguste Deter had a very normal life. But after 1890, she started suffering from dementia, characterized by loss of memory, delusions, and even temporary vegetative states. The effects of this unknown disease started reflecting in term of sleeplessness, screaming in the middle of the night, dragging sheets across house etc. With no hope of cessation of her disease, her husband decided to admit her in mental institution in 1901. And, that's when Dr. Alois Alzheimer confronted this unique case.


Auguste Deter died in April 1906 (cause of her death was infection due to a bedsore). Dr. Alzheimer named the disease as Alzheimer's Disease (a case that was too close to him). And, to let you people understand, what a typical Alzheimer's disease can be like, let me brief you about the description of the symptoms of the first ever 'reported' patient of Alzheimer's Disease:
[Image: 159px-Auguste_D_aus_Marktbreit.jpg]
Auguste Deter: The First Reported Patient of Alzheimer's Disease
Source: Wikimedia


Symptoms and Severity of Alzheimer's Disease:

Dr. Alzheimer observed that Auguste had no sense of time or place. There was nearly total loss of memory about the details of her own life. The answers given by her to the questions asked were senseless and incoherent. There were frequent mood swings between anxiety, mistrust, withdrawal and 'whininess'! A part of pity as well as curiousness was that "she was aware of her helplessness, and would utter "Oh, God!", and, "I have lost myself, so to say".

Causes of Alzheimer's Disease

What leads to memory loss, fits, mood swings, screaming (or total dementia) in Alzheimer's disease has been very well researched. But what exactly leads to that particular state has been eluding the scientific community till date. Speculations though have always been pointed towards: Environmental factors, genetic pre-disposition (less than 5% cases owed to genetic causes), lifestyle etc.
Anatomical causes of Alzheimer's disease (that have been very well researched and established) include the following:
  • Damage and death of brain cells
  • Very few brain cells (neurons) and very few inter-neuronal connections among surviving cells
  • Significant brain shrinkage

Autopsy of brain tissue of Alzheimer affected patients has revealed two types of abnormalities under microscope, which have become the index (hallmark) of the disease:


Plaques: There is protein on the surface of almost all cells through-out the body called APP (Amyloid-beta precursor protein).  The intact form of APP is a receptor protein that sends signals through the G-protein system and binds to many structural molecules outside cells, such as heparin and laminin, playing a role in cellular communication as well as cell adhesion. In neurons the intact APP plays an essential role in neural growth and repair.

There's a little peptide portion of APP which when broken off the intact protein, causes severe damage to the brain cells. The free peptide of APP can aggregate into long fibrils through shape changes. These aggregates of tough fibrils end up forming dense plaques on nerve cells.

These plaques gradually lead to brain damage and interference with cell-to-cell communication. Scientists are yet to figure out the precise event leading to the death of nerve cells (note: nerve cells lack the ability to divide, thus any death/loss of nerve cells is a "permanent damage"), but the plaque development is indeed the prime suspect that leads to death of brain cells.


Tangles: 
A protien named "Tau" is very crucial for the smooth operation of "nutrient and other essential materials transport" throughout the long-extensions of brain cells.
It has been observed in the autopsy of Alzheimser's patients' brains that Tau protein tends to form abnormal tangles in the brain cells through twisting of its threads. The abnormal transformation of Tau into Tangles leads to the failure of the nutrient/essential material transport system. This makes the presence of Tangles as another strong contender for the ultimate brain cell death.

Following videos should give you an idea about Alzheimer progression due to plaques and tangles:

One of the best videos!

Another precise and to the point video:


Diagnosis and Treatment of Alzheimer's Disease

Alzheimer’s disease can be diagnosed using couple of techniques:
A. Brain imaging (computed tomography or magnetic imaging)
B. Neuropsychological tests
C. Blood analysis (couple of known markers exist)


Although there is no drug available to reverse the brain-damage due to Alzheimer's diasease, there are indeed some medications avilable to improve/control congnitive/behavioral problems. The focus of current treatments is thus focused on the main attributes of Alzheimer’s disease: dementia (memory loss), depression and cognitive impairments. Most drugs aim at slowing down the progression of neurodegeneration but they can’t prevent/reverse the disease.

Typical Mechanism of Action of Drugs used for treatment of Alzheimer's patients:
  • Typical mechanism of action is focused on proteolysis of amyloid precursor protein; latest drugs could prevent proteolysis or bind to already formed beta amyloid prior its aggregation and eliminate it.
  • Other drugs affect distribution of beta amiloid through the brain or decrease the rate of neuroinflammation.  Alzheimer’s disease is one of the most common neurodegenerative disorders associated with old age and one of the most expensive to be treated because patients demand special care due to physically, physiologically and socially altered behavior.

Some Drugs for Alzheimer's Patients (US FDA Approved)
The U.S. Food and Drug Administration (FDA) has approved two types of drugs/medications aimed at treating the cognitive symptoms (memory loss, confusions, behavioral swings, reasoning and thinking disability) of Alzheimer's disease:
a) Cholinesterase inhibitors (Poular brands: Aricept, Exelon, Razadyne)
b) Memantine (Popular brand: Namenda)

Three cholinesterase inhibitors are commonly prescribed:
  • Donepezil (Aricept) is approved to treat all stages of Alzheimer's.
  • Rivastigmine (Exelon) is approved to treat mild to moderate Alzheimer's.
  • Galantamine (Razadyne) is approved to treat mild to moderate Alzheimer's.


Keep Watching This Space for Some of the Most Interesting Facts about
The CURE and CAUSES of Alzheimer's Disease

REFERENCES (for the content till now):
Like Post Reply
#2
Doctors who study or treat Alzheimer's disease and its early clinical stages (mild cognitive impairment, MCI) are focused on the obvious problems with short-term memory. However, a new study suggests that people with later development of Alzheimer's disease can have problems much earlier, in the processing of semantic information or data based on previous knowledge, which could have great significance in the manner in which these patients are functioning in everyday life.

First Indications of Cognitive Problems

Terry Goldberg, PhD, a professor of psychiatry and behaviorism in the Hofstra North Shore-LIJ School of Medicine at Hofstra University and director of department for neurocognition in the Alzheimer's Disease and Memory Disorders Center at the Feinstein Institute for Medical Research in in Manhasset, New York, said that doctors have noticed a variety of cognitive disorders in patients with Mild Cognitive Impairment, but they were not systematically studied. A large number of experts noted that some of the patients find even the simplest tasks extremely confusing. In this latest study, which was published in monthly American Journal of Psychiatry, cleverly designed tests are used to analyze the ability of individuals for the processing of semantic information.

Do people with Mild Cognitive Impairment have problems in accessing certain types of prior acquired knowledge? Are there any obvious semantic problems which have not been observed? The answer is yes.

The Experiment

To test the system is semantic processing, dr Goldberg and his colleagues needed a task that does not include a verbal response. That would be confusing, and the results would be more difficult to interpret. They decided to use size to test a person's ability to use semantic information to make a conclusion on two opposed definitions. Doctor Goldberg explained: "If someone is asked what is more, the key or ant, he will respond more slowly than if you ask him what is larger, a house or a key." The greater the difference in size between the two things, the more quickly will the person, being healthy or not , recognize the difference and respond.

The study included 25 patients with mild cognitive impairment (MCI), 27 with Alzheimer's disease and 70 people with no cognitive problems. They found that there are significant differences between healthy controls and patients with Mild Cognitive Impairment and Alzheimer's disease. Doctor Goldberg concluded that the results indicate problems in the processing of semantic information. It is mostly seen when the patients with mild cognitive disorder and Alzheimer's disease cope with the task with small differences in size.

Then they made the task more complicated by showing patients the images of little ants and big houses or big ants and small houses. This time the patients with mild cognitive disorder and with Alzheimer's disease solved the first part of the test without any problems - when they were asked what is bigger, they chose a house, not an ant. But if the pictures did not reflect reality - a big ant looked like a little house - they were confused, answered incorrectly, or they took longer to respond.

Patients with mild cognitive impairment were somewhere between those of healthy and those with Alzheimer's disease. "When the decision was difficult, the reaction time was slower."

Would Damage to The Semantic System Influence The Everyday Functions?

To answer this question, researchers have turned to UCSD scale to evaluate the use of skills, the tool which is used in patients with mild cognitive disorder and Alzheimer's disease and in patients with schizophrenia, to determine the functional deficiencies. The test examines the ability of a person to perform complex checks or to organize a trip to the zoo for a cold day.

It's a good way to check whether someone has a problem with the semantic knowledge. Semantic processing takes place in the left temporal lobe. "The semantic system is organized as a network that reflects the various types of relationships and associations," said the researchers in the study. "Semantic data and knowledge are acquired in the larger intervals, often through a large number of repetitions, and do not reflect what has been recently adopted."

Doctor Goldberg says that this discovery is very important because it might be possible to strengthen by training the connections that arise in semantic processing. "This suggests that patients are getting slow due to semantic and not episodic memory," said Goldberg. Patients will be observed further in order to determine whether the deteriorating semantic problems worsen as the disease progresses.

Within additional article, David P. Salmon, Ph.D., from Department of Neuroscience at the University of California, said that "deficiencies in semantic memory, that this study demonstrated, confirm the suspicion that in patients with mild cognitive impairment of an anamnestic type, happens a slight cognitive impairment. Since the task did not require problematic remembering and reproduction of certain words or linguistic structures, it can be concluded that these shortcomings reflect the early and gradual loss of the integrity of semantic knowledge. "

He added that "This study proves that the deterioration of semantic memory in patients with mild cognitive impairment can contribute to the reduced ability to perform everyday activities."

Institute for Medical Research Feinstein

The Institute for Medical Research Feinstein, based in Manhasset, New York, many leading international scientists are engaged in areas such as Parkinson's disease, Alzheimer's disease, psychiatric disorders, rheumatoid arthritis, lupus, sepsis, genetics, pulmonary hypertension, leukemia, neuroimmunology, and medical chemistry. The institute, which is part of the North Shore Health System , belongs to the top 5% of all state institutes according to scholarships awarded to research centers for health care.

A Major Step Toward Developing The Vaccine For Alzheimer's Disease


A team of researchers from the Center for Research CHU (France, Centre Hospitalier Universitaire) at the University of Laval in Quebec and pharmacological company GlaxoSmithKline (GSK) has found a way to stimulate the natural defense mechanisms of the brain in people who suffer from Alzheimer's disease. This is an important achievement, and its details have been published in the online edition of the journal Proceedings of the National Academy of Sciences. This research opened the door to the development of effective treatment for Alzheimer's disease and toward finding an efficient vaccine.

____________________________________________________________
 ----  Article by BojanaL----
____________________________________________________________
Treatment for Alzheimer disease: 


Modern medicine and well established healthcare system prolonged the average length of the human life. Old age is associated with numerous neurodegenerative disorders; most typical is Alzheimer’s disease. Risk for developing Alzheimer’s disease is increasing with the age. It is estimated that 10% of people over the age of 65, and 50% of those over 85 suffers from Alzheimer’s disease. Most cases develop sporadically and just 1-5 % of Alzheimer’s cases are genetically inherited.

Alzheimer’s disorder is first described in 1906. Post mortem brain analysis and blood markers provided more information on this pathological brain disorder over the past 100 years, but exact trigger for the disease and successful treatment method are still lacking. Alzheimer’s disorder is characterized by brain shrinkage, loss of neuronal connections and disrupted blood brain barrier. Several theories about disorder genesis exist: cholinergic theory, where lack of acetylcholine triggers disorder, herpes simplex virus induced disorder, age related impaired myeline breakage or oxidative stress as a cause of neurodegeneration…Most probable are ones associated with altered metabolism of amyloid precursor protein and tau protein. Amyloid precursor protein is building part of neuronal synapses and essential ingredient of various cell membranes in the body. Proteolitic degradation of amyloid precursor protein results in formation of the fibrial protein - beta amiloid that is found in brain plaques, typical for Alzheimer’s disorder. Beta amiloid alters calcium ion homeostasis (resulting in apoptosis), inhibits enzymatic activity and prevents glucose utilization. Tau protein is essential for development of neuronal polarity; it promotes neuronal microtubule assembly and enhances axonal dynamics. When tau protein is hyperphosphorilated, it becomes insoluble and forms inclusions known as neurofibrillary tangles. Those tangles are associated with neuronal degeneration. Alzheimer’s disease can be diagnosed using couple of techniques: brain imaging (computed tomography or magnetic imaging), through neuropsychological tests or by blood analysis (couple known markers exist). Current treatments are focused on the main attributes of Alzheimer’s disease: dementia (memory loss), depression and cognitive impairments. Medication used is just slowing down the progression of neurodegeneration but it can’t prevent disease. Typical mechanism of action is focused on proteolysis of amyloid precursor protein; latest drugs could prevent proteolysis or bind to already formed beta amyloid prior its aggregation and eliminate it. Other drugs affect distribution of beta amiloid through the brain or decrease the rate of neuroinflammation.  Alzheimer’s disease is one of the most common neurodegenerative disorders associated with old age and one of the most expensive to be treated because patients demand special care due to physically, physiologically and socially altered behavior.

Latest discoveries in the stem cells field could move Alzheimer’s treatment in completely new direction. Scientists from the University Of California, Irvine developed new line of stem cells - choroid plexus epithelial cells (CPECs) using human and mouse embryonic cells.  Choroid plexus is part of the brain ventricles where cerebrospinal fluid is produced. This liquid is important for cleaning the waste products and metabolites that could damage the brain function. 500 milliliters of cerebrospinal fluid is produced each day, and it is renewed 4 times a day to ensure efficient detoxification of the neuronal tissue. CPECs are forming important blood - cerebrospinal fluid barrier. Neurodegenerative disorders are associated with dysfunctional CPECs and inefficient removal of the waste material (like beta amiloid) from the cerebrospinal fluid. Scientists were familiar with the role and importance of CPECs cells, but until now they couldn’t find the way to produce those cells in vitro. Embryonic cells are pluripotent and different transcription factors determine their cellular faith (direction of their differentiation). After discovering that brain morphogenic factor 4 (BMF4) is responsible for differentiation of the neuronal progenitor cells into CPECs, researchers applied BMF4 to produce sufficient amount of CPECs. Both human and mouse neuronal progenitor cells used in the experiment matured successfully into CPECs after BMF4 was applied. Developed CPECs act just like naturally produced cells; they could integrate in choroid plexus epithelium and form secretory vesicles. Neurological disorders associated with the accumulation of the peptides, proteins and other metabolites that alter normal function of the brain could be treated using CPECs. Scientists are hoping that this approach will be especially helpful in Alzheimer’s and Huntington’s disease as well in treatment of pediatric neurodegenerative disorders.
Like Post Reply
#3
According to the Alzheimer’s Association, there are 10 early signs and symptoms of Alzheimer’s disease. These are the following:

If you’re starting to have memory loss that disrupts your daily activities, you might want to consider a doctor’s appointment. The kind of memory loss associated with Alzheimer’s are the short term ones or the forgetting of recently learned info. These would include forgetting essential events or dates, repeated asking of information, increasing need of memory aids, among others.

Now if you notice yourself finding planning and solving problems more difficult, then you might need related help. Developing or following a plan or working with numbers tend to be more challenging for people who will later develop the disease. Concentration may be more difficult at this time which may affect in a way such as having trouble tracking monthly bills or following a memorized recipe.

Another symptom would be having difficulty completing familiar tasks at home, work, or leisure. This could include getting lost traveling in a familiar location, having trouble managing funds at work, or forgetting the rules of a favorite game.

When you find yourself more in confusion with place and time, like losing track of dates and seasons, or not remembering why you came to a certain place or room, this could also be another sign.

People who later develop Alzheimer’s discover that they have early trouble understanding spatial relationships and visual images. Driving at this condition is risky since judging distance and determining contrast or color can be a problem.

Expressive and receptive aphasia, or the difficulty in communication are also part of the list. The person will have problems understanding words or language, such as in a conversation or when reading and writing.

Things are misplaced and there is also difficulty in retracing steps. Belongings may be placed on unusual areas and some persons may even resort to accusing others for stealing.

Since judgment at this time may be poor or decreased, money handling can be a dilemma. Self-care such as grooming and hygiene is also less attended to.

Anhedonia or the loss of interest in once fond activities can also be a manifestation. Such individuals may withdraw from work projects, sports, social activities, or even hobbies. They tend to be withdrawn due to the changes they experience.

Mood and personality can also change for people with Alzheimer’s. Aside from depression, there can also be bouts of suspicion, anxiety, confusion, and fearfulness. Once out of their comfort zone, they may easily experience this change of mood.
Lyka Candelario, RN
Like Post Reply
#4
Alzheimer's disease is a disorder caused by neurological problems in which the death of brain cells causes memory loss and cognitive decline. A neurodegenerative type of dementia, the disease starts mild and gets progressively worse.

Alzheimer’s disease where there is a family link, called familial Alzheimer’s disease (FAD), is more common amongst younger people.

All the Familial Alzheimer’s disease known so far has an early commencement, and as many as 50 percent of the cases are now known to be caused by defects in three different genes located at three different chromosomes of human, the structures inside cells that house the genetic code. Some families have mutations in a gene called amyloid precursor protein (APP), which causes an abnormal form of the amyloid protein to be produced. The other families have mutations in a gene called presenilin-1, which causes an abnormal Presenilin-1 protein to be produced. Still others have mutations in a very similar gene called presenilin-2, which causes an abnormal Presenilin 2 protein to be produced.

Even if one of these mutations is present in only one of the two copies of a gene inherited from a person's parents, the person will inevitably develop that form of early-onset Alzheimer's (this is called autosomal dominant inheritance). However, the total known number of these cases is small (between 100 and 200 worldwide), and there is as yet no evidence that any of these mutations play a major role in the more common, sporadic or non-familial form of late-onset Alzheimer's. Scientists are working to reveal the normal function of APP and presenilins and to determine how mutations of these genes cause the onset of familial Alzheimer’s disease.

Treatment:

Till date there is no preventative or curative treatment for this disease. Many of drugs exist, which can help to ease certain symptoms such as depression, anxiety, confusion, agitation, hallucinations, and insomnia. Regrettably, these drugs have a propensity to be effective for a limited number of patients, only for a small period of time and may cause adverse side effects.
Like Post Reply
#5
A new study from the Scripps Institute in Florida has identified regulator of BACE1, a protein that has been implicated in progression of Alzheimer’s disease (AD). The study, published in an advance online edition of the Journal of Biological Chemistry showed that a protein called Rheb (ras homolog enriched in brain) can reduce levels of BACE1 and may hold the key to future drug targets for Alzheimer’s disease.

BACE1 (β-site amyloid precursor protein (APP)-cleaving enzyme 1) is an enzyme that has been shown to kick off amyloid β (Aβ) production via amyloidogenic processing of amyloid precursor protein (APP). Aβ generation from neurons and deposition is widely accepted to be pivotal to development of Alzheimer’s disease. BACE1 protein levels are raised in AD brain; however this does not appear to be regulated via up-regulation of transcription of the gene that encodes BACE1 to messenger RNA (mRNA), the intermediary between gene and protein, but to be a direct effect on protein production. Rheb is a protein belonging to a family called GTPases and has recently been shown to protect neurons in Parkinson’s disease and may be important in neural plasticity. It is known to be important in regulating turnover of proteins via pathway known as mTOR, which is involved in many human diseases including neurodegenerative disorders. However, Rheb also has some mTOR-independent effects.

Given the known effects of Rheb on protein turnover and its potential role in neural plasticity, it seemed reasonable to enquire whether Rheb could influence expression of BACE1 protein. In a combination of in vitro cell line studies and in vivo mouse studies, the researchers showed that Rheb could down-regulate expression of BACE1. This down-regulation was not mediated via any change in mRNA levels but instead was due to a direct physical interaction between Rheb and BACE1 proteins which resulted in a reduction of BACE1 half-life and accelerated degradation of BACE1 protein. This Rheb-mediated degradation of BACE1 was independent of mTOR but dependent on GTP. It was mediated via both lysosomal and proteosomal pathways. Intriguingly, protein expression studies on AD post-mortem brains revealed significant loss of Rheb levels compared to non-AD brains. This reduction in Rheb correlated with increased BACE1.

Thus this study identifies Rheb as an inhibitor of BACE1 via a number of mechanisms in a pathway that may have profound implications for ageing brain biology and disease. A lot more research lies ahead to clarify the mechanisms at work, but this research holds promise for effective drug therapies in the future for AD.

Sources
Shahani N, Pryor W, Swarnkar S, Kholodilov N, Thinakaran G, Burke RE, et al. Rheb GTPase Regulates β-Secretase Levels and Amyloid β Generation. Journal of Biological Chemistry. 2013 Dec; Available from: http://dx.doi.org/10.1074/jbc.m113.532713.

Press release: http://www.scripps.edu/news/press/2014/2...aniam.html
Like Post Reply
#6
A new study suggests that novel protein fragments (peptides) can protect against Alzheimer’s disease pathology, including the Alzheimer's disease (AD) toxin (amyloid-β 1–42 peptide) and also against tau-like protein tangle formation and cognitive decline in a mouse model of AD. The study, published in the Journal of Alzheimer's Disease, comes from researchers in Tel Aviv University in Israel.

Alzheimer’s disease is a devastating neurodegenerative condition characterised by amyloid-β 1–42 peptide accumulation and tangles formed from abnormal tau proteins, a marker of cognitive decline. Research is focused on trying to elucidate the pathology as well as harness potential protective or regenerative brain cell properties that could contribute to therapy. AD and other neurodegenerative diseases feature breakdown of the microtubule network. This forms part of all cells in our bodies. In nerve cells it is particularly important for transport of essential proteins and communication between cells. The research in the current study focused on the microtubules, in particular on the microtubule subunit tubulin and in the microtubule associated protein, tau.

Previously, the researchers in this project had identified a peptide called NAP, which acts to stabilise microtubules and is a drug candidate showing promise in treatment of mild cognitive impairment. In the current study, the research team scanned the protein sequences of tubulin and tau and identified NAP-like homologies. They derived NAP-like peptides called NAT and STPTAIPQ from tubulin, and TAP from tau. These peptides were shown to provide neuroprotection against the Alzheimer's disease (AD) toxin, the amyloid-β 1–42 peptide, in a tissue culture in vitro model. TAP and NAT were more potent than STPTAIPQ . Lead author Prof Ilana Gozes explains: “The newly discovered protein fragments, just like NAP before them, work to protect microtubules, thereby protecting the cell."

In an in vivo mouse model of AD at 10 months old, both NAT and TAP were able to inhibit the tau-like aggregation that characterises cognitive decline in AD. Further testing of NAT showed that in the AD mouse model, in which there was significantly decreased levels of NAP parent protein, NAT was able to restore NAP levels. Brain-to-body mass ratio, which is an indicator of brain degeneration, was also significantly decreased in the AD mouse model compared to normal mice, but was also restored to normal by NAT treatment. Dr Gozes explains: "We clearly see here the protective effect of the treatment…We witnessed the restorative and protective effects of totally new protein fragments, derived from proteins critical to cell function, in tissue cultures and on animal models."

Sources

Gozes, I., Iram, T., Maryanovsky, E., Arviv, C., Rozenberg, L., Schirer, Y., Giladi, E. and Furman-Assaf, S. (2014). Novel Tubulin and Tau Neuroprotective Fragments Sharing Structural Similarities with the Drug Candidate NAP (Davuentide). Journal of Alzheimer's Disease, DOI 10.3233/JAD-131664

Press release: Tel Aviv University, available at http://www.aftau.org/newsroom?7d56804a-2...cacd9b1135
Like Post Reply
#7
8-May-2015 - New research using a mouse model has discovered evidence that suggests Alzheimer's disease may be affected by elevated blood sugar (it speeds up the production of beta-amyloid protein linked to Alzheimer's).

This research was done by the School of Medicine at Washington University (St. Louis), and has been published in The Journal of Clinical Investigation.

Diabetic patients beware !!
Like Post Reply
#8
Information 
INTRODUCTION

Alzheimer’s Disease accounts for about 70 per cent of cases of dementia, and is presently the most prevalent and best-studied neurodegenerative disorder. It is associated with significant morbidity and mortality, and imposes high personal and financial costs on society and on its sufferers and their caregivers. Its pathophysiology is coming to be understood, and some therapeutic options are now available for the disorder[1].

History and Time-line
The Ebers Papyrus, the earliest extant Egyptian medical text, described many medical conditions, including childishness, language difficulties, memory impairment and nocturnal confusion now recognized as dementia and “sundowning”. Pythagoras, Hippocrates and other ancient Greeks ascribed dementia along with other neurobehavioral disturbances to brain disorders rather than to supernatural agencies, and were the first to invoke a chemical or humoral cause. Roman medicine was also cognizant of dementia, and after the observations of Galen on the cerebral arteries tended to invoke circulatory causes; Roman literature such as the Satires of Juvenal featured elderly characters with probable senile dementia, and republican Roman law provided for the guardianship and care of demented adults[2].

There was little attention to dementia during the medieval period, probably because most people did not live long enough for it to be an issue. Survival to the senium was often a rarity, and presenile dementia tended to be classified with the mental disorders, and often treated in a custodial fashion. There are literary examples of possible dementia in Hamlet, Lear and other Renaissance writings, and Francis Bacon around 1600 suggested that the posterior part of the brain was the “home of forgetfulness”. It has also been proposed that symptoms of dementia caused some women in Europe and America to be designated as witches[3].

The term démence or dementia, literally meaning loss of the mind, was first proposed by Phillipe Pinel as part of the revolution in psychiatric treatment he initiated in Paris at the end of the 18th century. Benjamin Rush, the founder of American neurology and psychiatry, introduced the term in the United States soon after, and in both cases it was applied to what are now considered primary psychiatric disorders as well as neurodegenerative diseases. In particular, 19th century clinicians differentiated between senile dementia and cognitive and behavioral symptoms that developed in younger patients (dementia praecox). The German school of neuropsychiatry, most notably Emil Kraepelin and Eugen Bleuler, codified the manifestations of presenile dementia into several psychiatric entities, chiefly schizophrenia[4].

In 1901 one of Kraepelin’s chief lieutenants, Alois Alzheimer, undertook the care of Auguste Deters, a 51-year-old woman hospitalized for cognitive decline, language difficulties, paranoia, hallucinations and delusions and aggressive behavior, considered the symptoms of senile dementia but beginning atypically early. Alzheimer, who was gifted with tenacity and single-mindedness as well as skill in neuropathology, and was independently wealthy and did not need to earn his living by clinical practice, followed her case attentively for 5 years and examined her brain thoroughly after her death. Although other clinicians had observed early occurrence of senile dementia and there had been other reports of the plaques and neurofibrillary tangles that are now recognized as the cardinal pathological changes in the disorder, this comprehensive case report led Kraepelin and others to apply Alzheimer’s name to the disorder[5].

In subsequent years, a variety of variants of the disorder were described. Dementia with predominantly behavioral and language changes had been described by Arnold Pick a decade earlier, and Alzheimer in 1911 identified a variant of  neurofibrillary tangles that he named Pick bodies in what was later to be called frontotemporal dementia. Alzheimer’s student Friedrich Lewy described the following year a dementing disorder associated with inclusion bodies in neurons that now bears his name. Dementia associated with Parkinson’s disease, amyotrophic lateral sclerosis and multiple cerebral infarctions was subsequently described, as well as a dementing disorder characterized by slowly progressive aphasia[6].

During the remainder of the 20th century the incidence of Alzheimer’s disease has increased with more precise diagnosis, longer life-span and progress against other diseases of aging. There has also been an enormous advance in understanding of the cause or causes of the disorder, and considerable progress in its treatment and management. Alzheimer’s disease remains a widespread and costly medical and social problem, however[7].

CLINICAL FEATURES
  • Alzheimer disease is characterized pathologically by progressive loss of synapses and neurons, the accumulation of amyloid plaques and neurofibrillary tangles and clinically by a spectrum of disease ranging from an asymptomatic state to dementia.
  • Clinical definitions require only the documentation of cognitive deficits not due to some other cause; if these interfere with daily functioning, the diagnosis is Dementia due to Alzheimer’s disease is given. Evident cognitive decline that does not interfere with with daily functioning is termed Mild Cognitive Impairment due to Alzheimer’s disease.
  • Two classification systems for the disease are currently in use, and terminology for the phase of the disease depends upon which system is used. A clinical-pathological classification, which is presumptive unless the signature changes of the disease are found by biopsy, is the most useful and commonly used in clinical practice[8]. 
  • Mild Cognitive Impairment from Alzheimer’s  disease is diagnosed by the presence of mild deficits not attributable to another cause after evaluation. Independent functional ability is preserved, and there is no significant impairment of social or occupational functioning. Cognitive impairment is most commonly in episodic memory. Dementia due to Alzheimer’s disease is diagnosed by the presence of cognitive deficits plus functional decline  not attributable to other cause after evaluation[9].
  • A clinical-biological diagnostic classification makes the diagnosis of Alzheimer’s disease definitive, but requires some kind of biomarker for confirmation. This is more useful in research settings but may become clinically applicable when validated biomarker testing becomes more available. The diagnosis of  asymptomatic preclinical Alzheimer’s disease is possible if a biomarker is present. Prodromal Alzheimer’s disease (mild cognitive impairment) would be identified by the presence of a biomarker plus episodic memory loss without impairment in activities of daily living.  Alzheimer’s disease dementia would be diagnosed by the presence of a biomarker plus episodic memory impairment plus impairment in activities of daily living[10].
  • Possible Alzheimer’s disease biomarkers include atrophy of the medial temporal lobe on MRI scan and diminished function of the frontal and temporal lobes or decreased tracer uptake on PET or SPECT scans. Alzheimer’s disease is also apparently associated with altered levels in the cerebrospinal fluid of several forms of amyloid and tau protein, the two proteins that make up the plaques and neurofibrillary tangles characteristic of the disease. Reduced levels in the cerebrospinal fluid of amyloid-ß peptide, elevated levels of tau protein and tau protein that is excessively phosphorylated may be present in early or asymptomatic Alzheimer’s disease[11].

DIAGNOSIS

CLINICAL PRESENTATION

  • The history of suspected dementia should be obtained from the patient and from an informant such as a family member, friend, or caregiver[13].
  • Learning and memory symptoms include early onset of memory impairment, especially episodic memory such as autobiographical recollections of events, times, places, and who was present then.
Quote:Semantic memory, the recall of facts and concepts, is usually preserved until later in the disease, while the ability to activate semantic memory for purposes of problem solving (working memory) is affected early on[14].
  • Executive functioning is very often compromised.
  • Characteristic symptoms reported by the patient, but often more evident to an observer, include loss of the ability to multitask and confusion when trying to follow simple instructions.
  • Conversations are often difficult to follow when the subject is changed, even if no conversational difficulty had been evident previously.
  • Complex attention is also impaired, and it takes longer to complete tasks, the patient is more easily distracted while doing them and mental calculations, solving problems and sequential actions such as dialing a telephone number become increasingly difficult.

Language impairment is manifested early, with difficulty in word-finding and use of the wrong word as well as grammatical errors. Reading and language comprehension are also compromised early on. Symptoms of perceptual motor-visual function difficulty include becoming lost in hitherto familiar places, greater reliance than before on maps and written notes and new difficulty using appliances and tools.


The involvement of social cognition may be indicated by behavioral disinhibition and actions that were never done before and are noticeably different from past behavior, although this is usually more characteristic of frontotemporal dementia (Pick’s disease).
Quote:Social interactions are more often preserved in the early stages of Alzheimer’s disease, although there may be occasional reports of inappropriate behavior or poor judgement that was not evident in the past. Other psychiatric symptoms usually develop later but may be occasionally evident early on . These include depression, anxiety, apathy and irascibility.

The physical and neurological examination and standard cognitive testing may well be normal in the prodromal stages of Alzheimer’s disease. When mild cognitive impairment has begun the examination is usually normal, but cognitive testing may show difficulties with memory, particularly episodic memory. Physical examination findings after dementia has become established vary with its severity: there may be evidence of poor nutrition and hygiene, infections at skin creases and in irritated places, perineal skin irritation or breakdown if incontinent and decubitus ulcers if confined to bed. The neurologic examination may be normal except for increasingly abnormal cognition.

When  present, neurologic signs can include slowed gait, impaired coordination and abnormal reflexes, particularly the “frontal release signs” associated with frontal lobe injury or deterioration, such as the snout or palmomental reflex. Brief cognitive testing such as the Mini-mental state examination, Mini Cognitive Assessment instrument or Montreal Cognitive Assessment test will show abnormality, or if done before will demonstrate a decline from previous performance.

CAUSES OF ALZHEIMER'S DISEASE AND RISK FACTORS

Quote:About 10 per cent of Alzheimer’s diseases cases are familial, but 50 per cent of early-onset dementia is inherited. 
  • Sporadic disease, which is usually late in onset but can begin in early adulthood, comprises the other 90 per cent, and remains of unknown cause.
Quote:Early-onset disease is defined as onset before age 40, while late-onset dementia begins after age 65 and most typically between 75 and 85.
  • Increasing age is the strongest risk factor, with prevalence doubling every 5 years after age 65; prevalence in patience older than 85 years ranges from 25 to 47 per cent in different studies. The incidence of Alzheimer’s disease is similar in women and men, but prevalence is higher in women because they are longer-lived[15]
  • One of the strongest risk factors is family history, particularly of early-onset Alzheimer’s disease. 
  • Early-onset familial cases generally show a mutation in a gene on chromosome 2q that codes for amyloid precursor protein; less frequent mutations include one on chromosome 14 that encodes the protein presenelin 1 and another involving a gene on chromosome 1 responsible for presenelin 2
  • Alzheimer’s disease of late onset has been associated with polymorphism of apolipoprotein E, encoded by chromosome 19. This is apparently a “housekeeper” protein involved in the clearance of proteins such as amyloid and tau, and individuals with the E4 allele may be more likely to develop the disease. The relationship is not absolute, however, as the presence of the allele does not always result in Alzheimer’s disease and its absence does not always protect against the disease.




Quote:Black and Hispanic populations have a higher incidence of Alzheimer’s disease, and other potential risk factors include low educational level, past history of head injury and the presence of chronic inflammation, which may also be associated with the apolipoprotein E gene[16].



DIAGNOSTIC PROCEDURES

The disease is identified primarily by history, a screening assessment of cognition and the assessment of daily functioning to distinguish between dementia and mild cognitive impairment. Several quick tests may detect dementia but not necessarily milder degrees of cognitive impairment, such as the Mini Cognitive Assessment instrument, the Mini Mental State Examination or the Montreal Cognitive Assessment. The widely-used first version of the Mini Mental State Examination (MMSE-1) may be sensitive to education, race and socioeconomic status, and a more generally applicable version (MMSE-2) is now available. These results can be clarified if necessary through neuropsychological tests like the Wechsler Adult Intelligence Scale or Halsted-Reitan Battery.

The patient’s ability to carry out the activities of daily living may be assessed through a nonstructured interview with the patient and an informant. There are also more structured methods of inquiry, such as the Assessment of Instrumental Activities of Daily Living and the Functional Assessment Questionnaire.

The cognitive screening and functional assessment together may indicate either dementia, not necessarily of the Alzheimer type, or mild cognitive impairment. The criteria for identifying dementia of all causes are significant decline in one or more cognitive domains that is not due to delirium or some other psychiatric disorder; this can include impaired ability to acquire and recall new information; impaired reasoning, ability to handle complex tasks or judgement; impaired visuospatial abilities; impaired language functions, whether spoken, read or written; or changes in personality and behavior. These problems must interfere with the performance of everyday activities, including occupational and social function15.

The diagnostic requirements for mild cognitive impairment from any cause are concern about mental decline and modest impairment in one or more cognitive domains that do not interfere with independence. The concern may be voiced by the patient, expressed by the informant or noticed by the clinician, and the cognitive impairment should be demonstrated by appropriate testing and will usually involve memory. Although the symptoms must not interfere with the activities of daily living, the patient may require more time and effort, need accommodation or use compensatory strategies. Social and occupational function are not affected in mild cognitive impairment15.

The American Academy of Neurology has recommended that medical causes of dementia or mild cognitive impairment be sought with complete blood count, electrolyte determinations and measurement of thyroid stimulating hormone (TSH) and vitamin B12 level along with brain CT scan or MRI. Lumbar puncture is appropriate when infection or inflammation of the central nervous system are suspected? Perform routine investigations to assess for medical causes of dementia/mild cognitive impairment: the American Academy of Neurology recommends CBC, electrolytes, TSH, vitamin B12, and brain CT or MRI; lumbar puncture is indicated when central nervous system infection or inflammation is reasonably probable.

With respect to diagnostic biomarkers, the level of amyloid-ß-protein in the cerebrospinal fluid is useful measure in demented individuals but has a low yield in patients with mild cognitive impairment; it may nevertheless be appropriate when there is a family history of Alzheimer’s disease and the patient desires an early diagnosis and wishes to be considered for clinical trials and early interventions. The level of tau protein is usually elevated in Alzheimer’s disease, and is again appropriate when family history is positive and the earliest possible diagnosis is desired17. Genetic counseling is appropriate for any patient who has or may have familial Alzheimer’s disease, but recent reviews do not recommend routine PET scanning because it is costly and the threshold for determination of test positivity has not yet been agreed on18

With respect to imaging, structural brain MRI is preferred over CT scan, because it will exclude other brain lesions and disorders even if it cannot conclusively identify Alzheimer’s disease. The presence of atrophy of the medial temporal lobe may predict progression from mild cognitive impairment to demential. Volumetric MRI measurements may be more sensitive in identifying atrophy, but this is not yet generally available or recommended in terms of cost effectiveness19. PET scanning accurately discriminates between Alzheimer’s disease patients and normal subjects, and a negative PET scan indicates a low probability of the disease while a positive scan with a positive cerebrospinal fluid biomarker make the diagnosis of Alzheimer’s disease very likely. A positive PET scan by itself is not specific for the disease, however, and the test is not yet clinically recommended20

DIFFERENTIAL DIAGNOSIS

The most common alternative diagnosis is cerebrovascular or muli-infarct dementia, which is the second most common dementing disorder. The presentation depends on the location of the strokes and can be gradual or rapid in onset or incremental in progression. There is a history of strokes or transient ischemic attacks, and the cognitive impairment usually involves complex attention or executive function. CT or MRI imaging will show white matter lesions, small lacunar strokes or large infarcts in the distributions of one or more cerebral arteries15.

The other major differential possibility is frontotemporal dementia or neurocognitive disorder, previously called frontotemporal lobar degeneration and before that Pick’s disease. The onset is between age 50 and 60 in 75 per cent of patients, and memory and other cognitive symptoms are often subordinate to disinhibited behavior and social withdrawal. Neuroimaging shows diferent degrees of atrophy of frontal or temporal lobe structures. A language variant of the disorder has been described with 3 subtypes: a fluent aphasia with blunting of emotions and perseverative behavior, a slowly progressive nonfluent aphasia with halting speech and word-finding difficulty and a progressive logopenic aphasia, with marked reduction of speech and difficulty comprehending language and naming objects15.

Dementia or neurocognitive disorder with Lewy bodies sometimes resembles Parkinson’s disease but begins around the age range for Alzheimer’s disease (70 to 85 years) and is often characterized by severe cognitive impairment and visual hallucinations. The protein-filled Lewy bodies are seen pathologically, but the disease can be recognized radiologically by MRI atrophy or deficient dopamine transporter uptake in  the basal ganglia on SPECT or PET scans; while the electroencephalogram (EEG) is sometimes normal and often nonspecifically abnormal in most dementing disorders, Lewy body disease is accompanied by temporal lobe sharp transients resembling those in epilepsy on the EEG15.

TREATMENT

Until the 1980s there were essentially no effective therapies for dementia in general and Alzheimer’s disease in particular. The demonstration of degeneration and loss of acetylcholine-containing neurons and cholinergic synapses in several brain regions has led to the development of  somewhat effective drugs that enhance the amount or prolong the effectiveness of the available acetylcholine at the surviving synapses/ The goals of treatment are to improve the memory and other cognitive symptoms of the disease , and to ameliorate behavioral symptoms such as anxiety, depression, apathy and aggression.

For mild-to-moderate dementia, acetylcholinesterase inhibitors produce moderate improvement in the primary symptom of memory loss and modest improvement in cognition and behavioral functioning. The first centrally-acting cholinesterase inhibitor and cholinergic agonist, tacrine, was approved in 1993 but had to be withdrawn due to a possible association with hepatotoxicity and bone marrow suppression, and its manufacture was discontinued in 2013. Subsequent drugs with better adverse event profiles were donepezil, rivgastigmine and galantamine; numerous studies have shown little difference in efficacy between them but there are fewer adverse effects with donepezil.

Donepezil is the only cholinesterase inhibitor presently approved for moderate-to-severe dementia, in  which language and executive function are affected as well as memory. Memantine, which affects several different receptor types, has been shown to have some cognitive benefit in more advanced Alzheimer’s disease. Memantine is primarily an antagonist of the excitatory neurotransmitter glutamate that blocks the N-methyl-D-aspartate (NMDA) receptor that is apparently involved in neuronal cell death; it also affects the nicotinic acetylcholinergic receptors and antagonizes one of the serotonin receptor types (5-HT3) and the D2 dopamine receptor, both of which may be involved in the behavioral manifestations of dementia. Its effects are more marked on the more severe and widespread symptoms of advanced Alzheimer’s disease than on mild-to-moderate memory symptoms.

An alternative to pharmacologic treatment is cognitive stimulation therapy, which involves activities which involve thinking and memory, such as discussion groups, puzzles, word games, listening to music and the pursuit, assisted if necessary, of hobbies such as cooking or gardening. This is usually done at centers or facilities for outpatient treatment of Alzheimer’s disease, but can be carried out at home. Several studies have shown beneficial effect on cognition in mild-to-moderate dementia.

PROGNOSIS AND OUTLOOK

More than 50 per cent of patients with mild cognitive impairment will progress to dementia within 5 years after diagnosis. The mean survival thereafter is around 10 years. There are no known protective factors, although eating a Mediterranean diet has been suggested to be beneficial. Higher levels of physical activity may be associated with a better prognosis, and people in highly cognitive occupations and professions may have a lower incidence of the disorder. Recent studies have suggested that the statins, which lower cholesterol levels by inhibiting the enzyme HMG-coA reductase which is crucial to cholesterol production in the liver, may have a protective effect against dementia in general. These and other observations suggest that Alzheimer’s disease is more manageable than it was a generation ago. The growing concensus about the cause of many neurodegenerative disorders, the improving understanding of the role of genetics in susceptibility to the disease and the significant increase in therapeutic options are grounds for cautious optimism about its future management.

REFERENCES

1. Burns A, Iliffe S (2009). Alzheimer's disease. Brit Med J (Clinical research ed.) 338: b158.

2. Boller F, Forbes MM (1998). History of dementia and dementia in history: an overview. J Neurol Sci, 158(2): 125-133.

3. Berchtold NC, Cotman GW (1998). Evolution in the conceptualization of dementia and Alzheimer’s disease: Greco-Roman period to the 1960s. Neurobiol Aging, 19(3): 173-189.

4. Berrios GE (1990): Alzheimer’s disease: A conceptual history. Int J Ger Psychiat, 5(6): 355-365.

5. Hippius H, Neuendörfer G (2003). The discovery of Alzheimer’s disease. Dialogue Clin Neurosci, 5(1): 101-108.

6. Berrios GE, Freeman H (1991). Alzheimer and the Dementias. London, Royal Society of Medicine.

7. Querfurth HW, LaFerla FM (2010). Alzheimer's disease. New Engl J Med, 362 (4): 329–44.

8. Molinuevo JL, Rami L (2013).  Applying the IWG research criteria in clinical practice: feasibility and ethical issues. Med Clin North Am, 97(3):477-484.

9. Albert MS, DeKosky ST, Dickson D (2011). The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer'sAssociation workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement, 7(3):270-279.

10. McKhann GM, Knopman DS, Chertkow H (2011).  The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement, 7(3):263-269.

11. Cummings JL, Dubois B, Molinuevo JL, Scheltens P. (2013). International Work Group criteria for the diagnosis of Alzheimer disease. Med Clin North Am, 97(3):363-368.

12. Galvin JE, Sadowsky CH (2012).  Practical guidelines for the recognition and diagnosis of dementia. J Am Board Fam Med, 25(3): 367-382.

13. Harrison J (2013).  Cognitive approaches to early Alzheimer’s disease diagnosis. Med Clin North Am, 97(3):425-438.

14. Hugo J, Ganguli M (2014).  Dementia and cognitive impairment: epidemiology, diagnosis, and treatment. Clin Geriatr Med, 30(3):421-442.

15. Schott JM, Revesz T (2013).  Inflammation in Alzheimer’s disease: insights from immunotherapy. Brain,136(Pt 9):2654-2656.

16. Lourida I, Soni M, Thompson-Coon J, Purandere N, Lang IA, Oukromunne OC, Llewellyn DJ (2013). Mediterranean diet, cognitive function and dementia: a systematic review. Epidemiology, 24(4): 479-489.

17. Ritchie C, Smailagic N, Noel-Storr AH (2014). Plasma and cerebrospinal fluid amyloid beta for the diagnosis of Alzheimer’s disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev, 6:CD008782.

18. Goldman JS, Hahn SE, Catania JW (2011).  Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genet Med, 13(6):597-605.

19. Woods B, Aguirre E, Spector AE, Orrell M (2012).  Cognitive stimulation to improve cognitive functioning in people with dementia. Cochrane Database Syst Rev. 2012;2:CD005562

20. Birks J (2006).  Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev, 1::CD005593.

21. Lin JS, O’Connor E, Rossom RC (2014). Screening for Cognitive Impairment in Older Adults: An Evidence Update for the U.S. Preventive Services Task Force. http://www.ncbi.nlm.nih.gov/books/PMH0063382/.

22. Hamer M, Chida Y (2009). Physical activity and risk of neurodegenerative disease: a systematic review of prospective evidence. Psychol Med, 39(1):3-11.
About Author:

Miles E. Drake
Ph.D., M.D


A.B.- Harvard University
M.D.- Duke University School of Medicine

Professor emeritus (1982 to 2007) -Ohio State University College of Medicine and Public Health
Lecturer (2007-2013) - AGU School of Medicine
Like Post Reply
#9
Need answers please..

1) Is there really any role of placebos in treating Alzheimer's?

2) Is Alzheimer life threatening, how long do patients live?

3) Are their any preventive therapies for this Alzheimer?
Like Post Reply
  

Possibly Related Threads...
Thread
Author
  /  
Last Post



Users browsing this thread:
1 Guest(s)

Cure and Causes of Alzheimer's Disease: A Must Read!00