1
AUTISM:
1.1.
Introduction:
Autism is a developmental disorder characterized by
difficulties with social interaction and communication, and by restricted and
repetitive behavior. Parents often notice signs during the first three years of
their child's life. These signs often develop gradually, though some children
with autism experience worsening in
their communication and social skills after reaching developmental milestones at a normal pace.
Autism is associated with a combination of genetic and environmental factors. Risk factors during
pregnancy include certain infections, such as rubella,
toxins including valproic acid, alcohol, cocaine, pesticides, lead, and air pollution, fetal growth restriction, and autoimmune diseases. Controversies surround other proposed
environmental causes; for example, the vaccine hypothesis, which has been
disproven. Autism affects information processing in the brain and
how nerve cells and
their synapses connect
and organize; how this occurs is not well understood. The Diagnostic and
Statistical Manual of Mental Disorders (DSM-5), combines autism
and less severe forms of the condition, including Asperger syndrome and pervasive
developmental disorder not otherwise specified (PDD-NOS) into
the diagnosis of autism spectrum disorder (ASD).
1.2. CAUSE:
It has
long been presumed that there is a common cause at the genetic, cognitive, and
neural levels for autism's characteristic triad of symptoms. However, there is
increasing suspicion that autism is instead a complex disorder whose core
aspects have distinct causes that often co-occur. 
Deletion
(1)
duplication
(2)
and inversion
(3)
are all chromosome abnormalities that have
been implicated in autism.
Autism has a strong genetic basis, although the genetics of autism are complex and it is
unclear whether ASD is explained more by rare mutations with
major effects, or by rare multigene interactions of common genetic
variants. Complexity arises due to interactions among multiple genes, the
environment, and epigenetic factors which do not
change DNA sequencing
but are heritable and influence gene expression.
Many genes have been associated with autism through sequencing the genomes of
affected individuals and their parents. Studies of twins suggest that heritability is
0.7 for autism and as high as 0.9 for ASD, and siblings of those with autism
are about 25 times more likely to be autistic than the general
population. However, most of the mutations that increase autism risk have
not been identified.
Typically, autism cannot be traced to a Mendelian (single-gene)
mutation or to a single chromosome abnormality, and none of the genetic
syndromes associated with ASDs have been shown to selectively cause
ASD. Numerous candidate genes have been located, with only small effects
attributable to any particular gene. Most loci individually explain less than
1% of cases of autism. The large number of autistic individuals with unaffected
family members may result from spontaneous structural variation — such as deletions, duplications or inversions in genetic material
during meiosis. Hence,
a substantial fraction of autism cases may be traceable to genetic causes that
are highly heritable but not inherited: that is, the mutation that causes the
autism is not present in the parental genome. Autism may be underdiagnosed in
women and girls due to an assumption that it is primarily a male condition, but
genetic phenomena such as imprinting and X linkage have
the ability to raise the frequency and severity of conditions in males, and
theories have been put forward for a genetic reason why males are diagnosed
more often, such as the imprinted brain theory and the extreme male brain theory.
Maternal nutrition and inflammation during
preconception and pregnancy influences fetal neurodevelopment. Intrauterine growth restriction is
associated with ASD, in both term and preterm infants. Maternal inflammatory and autoimmune diseases may damage fetal
tissues, aggravating a genetic problem or damaging the nervous system.
Exposure to air pollution during
pregnancy, especially heavy metals and particulates, may
increase the risk of autism. Environmental factors that have been
claimed without evidence to contribute to or exacerbate autism include certainfoods, infectious diseases, solvents, PCBs, phthalates and phenols used
in plastic products, pesticides, brominated flame retardants, alcohol,
smoking, illicit drugs, vaccines,
and prenatal stress. Some, such as the MMR vaccine,
have been completely disproven.
Parents may first become aware of autistic symptoms in
their child around the time of a routine vaccination. This has led to
unsupported theories blaming vaccine "overload", a vaccine preservative, or the MMR vaccine for causing autism. The latter
theory was supported by a litigation-funded study that has since been shown to
have been "an elaborate fraud". Although these theories lack
convincing scientific evidence and are biologically implausible, parental
concern about a potential vaccine link with autism has led to lower rates
of childhood immunizations, outbreaks of previously controlled childhood diseases in
some countries, and the preventable deaths of several children.
1.3.
Classification:
Autism is one of the five pervasive developmental disorders (PDD),
which are characterized by widespread abnormalities of social interactions and
communication, and severely restricted interests and highly repetitive behavior.
These symptoms do not imply sickness, fragility, or emotional disturbance.
Of the five PDD forms, Asperger syndrome is
closest to autism in signs and likely causes; Rett syndrome and childhood disintegrative disorder share
several signs with autism, but may have unrelated causes; PDD not otherwise specified (PDD-NOS; also
called atypical autism) is diagnosed when the criteria are not met
for a more specific disorder. Unlike with autism, people with
Asperger syndrome have no substantial delay in language development. The terminology of autism
can be bewildering, with autism, Asperger syndrome and PDD-NOS often called
the autism spectrum disorders (ASD) or sometimes
the autistic disorders, whereas autism itself is often
called autistic disorder, childhood autism, or infantile
autism. In this article, autism refers to the classic
autistic disorder; in clinical practice, though, autism, ASD,
and PDD are often used interchangeably. ASD, in
turn, is a subset of the broader autism phenotype,
which describes individuals who may not have ASD but do have
autistic-like traits, such as avoiding eye contact.
Autism can also be divided into syndromal and
non-syndromal autism; the syndromal autism is associated with severe or
profound intellectual disability or a congenital
syndrome with physical symptoms, such as tuberous sclerosis. Although individuals with
Asperger syndrome tend to perform better cognitively than those with autism,
the extent of the overlap between Asperger syndrome,
HFA, and non-syndromal autism is unclear.
Some
studies have reported diagnoses of autism in children due to a loss of language
or social skills, as opposed to a failure to make progress, typically from 15
to 30 months of age. The validity of this distinction remains controversial; it
is possible that regressive autism is a specific
subtype, or that there is a continuum of behaviors between autism with and
without regression.
Research into causes has been hampered by the
inability to identify biologically meaningful subgroups within the autistic
population and by the traditional boundaries between the disciplines
of psychiatry, psychology, neurology and pediatrics.
Newer technologies such as fMRI and diffusion tensor imaging can help identify
biologically relevant phenotypes (observable traits) that can be
viewed on brain scans, to help further neurogenetic studies
of autism; one example is lowered activity in the fusiform face area of the brain, which is
associated with impaired perception of people versus objects. It has been
proposed to classify autism using genetics as well as behavior.
Spectrum
Autism
has long been thought to cover a wide spectrum,
ranging from individuals with severe impairments—who may be silent, developmentally disabled, and prone to frequent
repetitive behavior such as hand flapping and rocking—to high functioning
individuals who may have active but distinctly odd social approaches, narrowly
focused interests, and verbose, pedantic communication.
Because the behavior spectrum is continuous, boundaries between
diagnostic categories are necessarily somewhat arbitrary.[52] Sometimes
the syndrome is divided into low-, medium- or high-functioning autism (LFA, MFA, and
HFA), based on IQ thresholds.
Some people have called for an end to the terms
"high-functioning" and "low-functioning" due to lack of
nuance and the potential for a person's needs or abilities to be overlooked.
2. Alzheimer's disease:
2.1.
Introduction :
Alzheimer's disease (AD),
also referred to simply as Alzheimer's,
is a chronic neurodegenerative disease that usually
starts slowly and gradually worsens over time. It is the cause of 60–70% of
cases of dementia The
most common early symptom is difficulty in
remembering recent events. As the disease advances, symptoms can
include problems with language, disorientation (including easily getting
lost), mood swings, loss of motivation,
not managing self-care, and behavioural issues. As a person's condition
declines, they often withdraw from family and society. Gradually, bodily
functions are lost, ultimately leading to death. Although the speed of
progression can vary, the typical life expectancy following diagnosis is three
to nine years.
The cause of Alzheimer's disease is poorly understood.
About 70% of the risk is believed to be inherited from a
person's parents with many genes usually
involved. Other risk factors include a history of head injuries, depression, and hypertension. The
disease process is associated with plaques and neurofibrillary tangles in the brain. A
probable diagnosis is based on the history of the illness and cognitive testing with medical imaging and blood tests to
rule out other possible causes. Initial symptoms are often mistaken for normal
ageing. Examination of brain tissue is needed for a definite diagnosis. Mental and physical exercise,
and avoiding obesity may decrease the risk of AD;
however, evidence to support these recommendations is weak. There are no
medications or supplements that have been shown to decrease risk.
2.2.
Causes:
The cause for most Alzheimer's cases is still mostly unknown
except for 1% to 5% of cases where genetic differences have been identified. Several
competing hypotheses exist trying to explain the cause of the
disease.
2.2.1. Genetic :
The
genetic heritability of Alzheimer's disease (and memory components thereof),
based on reviews of twin and family studies, ranges from 49% to 79%. Around
0.1% of the cases are familial forms of autosomal (not sex-linked) dominant inheritance, which have an onset
before age 65. This form of the disease is known as early onset familial Alzheimer's disease. Most
of autosomal dominant familial AD can be attributed to mutations in one of
three genes: those encoding amyloid precursor protein (APP) and presenilins 1
and 2. Most mutations in the APP and presenilin genes increase the production
of a small protein called Aβ42,
which is the main component of senile plaques.
Some of the mutations merely alter the ratio between Aβ42 and the other major
forms—particularly Aβ40—without increasing Aβ42 levels. Two other genes
associated with autosomal dominant Alzheimer's disease are ABCA7 and SORL1.
Most
cases of Alzheimer's disease do not exhibit autosomal-dominant inheritance and
are termed sporadic AD, in which environmental and genetic differences may act
as risk factors.
The best known genetic risk factor is the inheritance of the ε4 allele of
the apolipoprotein E (APOE). Between 40 and
80% of people with AD possess at least one APOEε4 allele. The APOEε4 allele
increases the risk of the disease by three times in heterozygotes and by 15
times in homozygotes. Like many human diseases, environmental effects and
genetic modifiers result in incomplete penetrance.
For example, certain Nigerian populations do not show the relationship between
dose of APOEε4 and incidence or age-of-onset for Alzheimer's disease seen in
other human populations. Early attempts to screen up to 400 candidate genes for
association with late-onset sporadic AD (LOAD) resulted in a low yield. More
recent genome-wide association studies (GWAS)
have found 19 areas in genes that appear to affect the risk.
These
genes include:
CASS4, CELF1, FERMT2, HLA-DRB5, INPP5D, MEF2C, NME8, PTK2B, SORL1, ZCWPW1, SlC24A4, CLU, PICALM, CR1, BIN1, MS4A, ABCA7, EPHA1, and CD2AP.[48]
Alleles in
the TREM2 gene
have been associated with a 3 to 5 times higher risk of developing Alzheimer's
disease. A suggested mechanism of action is that in some variants in TREM2
white blood cells in the brain are no longer able to control the amount of beta
amyloid present. Many SNPs are associated
with Alzheimer's with a 2018 study adding 30 SNPs by differentiating AD into 6
categories, including memory, language, visuospatial, and executive
functioning.
2.2.2. Cholinergic hypothesis:
The
oldest hypothesis, on which most currently available drug therapies are based,
is the cholinergic hypothesis, which proposes
that AD is caused by reduced synthesis of the neurotransmitter acetylcholine.
The cholinergic hypothesis has not maintained widespread support, largely
because medications intended to treat acetylcholine deficiency have not been
very effective.
2.2.3. Amyloid hypothesis:
In 1991, the amyloid hypothesis postulated
that extracellular amyloid beta (Aβ) deposits are the fundamental
cause of the disease. Support for this postulate comes from the location of the
gene for the amyloid precursor protein (APP) on chromosome 21,
together with the fact that people with trisomy 21 (Down Syndrome)
who have an extra gene copy almost universally exhibit at
least the earliest symptoms of AD by 40 years of age. Also, a
specific isoform of apolipoprotein, APOE4, is a major genetic
risk factor for AD. While apolipoproteins enhance the breakdown of beta
amyloid, some isoforms are not very effective at this task (such as APOE4),
leading to excess amyloid buildup in the brain. Further evidence comes from the
finding that transgenic mice that
express a mutant form of the human APP gene develop fibrillar amyloid plaques
and Alzheimer's-like brain pathology with spatial learning deficits.
An experimental vaccine was found to clear the amyloid
plaques in early human trials, but it did not have any significant effect on
dementia. Researchers have been led to suspect non-plaque Aβ oligomers (aggregates
of many monomers) as the primary pathogenic form of Aβ. These toxic
oligomers, also referred to as amyloid-derived diffusible ligands (ADDLs), bind
to a surface receptor on neurons and change the structure of the synapse,
thereby disrupting neuronal communication. One receptor for Aβ oligomers
may be the prion protein,
the same protein that has been linked to mad cow disease and
the related human condition, Creutzfeldt–Jakob disease, thus potentially
linking the underlying mechanism of these neurodegenerative disorders
with that of Alzheimer's disease.
In 2009, this hypothesis was updated, suggesting that
a close relative of the beta-amyloid protein, and not necessarily the
beta-amyloid itself, may be a major culprit in the disease. The hypothesis
holds that an amyloid-related mechanism that prunes neuronal connections in the
brain in the fast-growth phase of early life may be triggered by ageing-related
processes in later life to cause the neuronal withering of Alzheimer's disease.
N-APP, a fragment of APP from the peptide's N-terminus,
is adjacent to beta-amyloid and is cleaved from APP by one of the same enzymes.
N-APP triggers the self-destruct pathway by binding to a neuronal receptor
called death receptor 6 (DR6, also known as TNFRSF21). DR6
is highly expressed in the human brain regions most affected by Alzheimer's, so
it is possible that the N-APP/DR6 pathway might be hijacked in the ageing brain to
cause damage. In this model, beta-amyloid plays a complementary role, by
depressing synaptic function.
2.2.4. Osaka mutation:
A
Japanese pedigree of familial Alzheimer's disease was found to be associated
with a deletion mutation of codon 693 of APP. This mutation and its association
with Alzheimer's disease was first reported in 2008. This mutation is
known as the Osaka mutation. Only homozygotes with this mutation develop
Alzheimer's disease. This mutation accelerates Aβ oligomerization but the
proteins do not form amyloid fibrils suggesting that it is the Aβ
oligomerization rather than the fibrils that may be the cause of this disease.
Mice expressing this mutation have all usual pathologies of Alzheimer's
disease.
2.2.5.
Tau hypothesis:
In
Alzheimer's disease, changes in tau protein lead to the disintegration of
microtubules in brain cells.
The tau hypothesis proposes
that tau protein abnormalities initiate the
disease cascade. In this model, hyperphosphorylated tau begins to pair
with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell
bodies. When this occurs, the microtubules disintegrate,
destroying the structure of the cell's cytoskeleton which
collapses the neuron's transport system. This may result first in malfunctions
in biochemical communication between neurons and later in the death of the
cells.
2.3.
Types:
Nearly everyone with Alzheimer’s disease will
eventually have the same symptoms -- memory loss, confusion,
trouble with once-familiar tasks, and making decisions. Though the effects of
the disease are similar, there are two main types.
2.3.1.
Early-onset Alzheimer's:
This type happens to people who are younger than age 65. Often, they’re
in their 40s or 50s when they’re diagnosed with the disease. It’s rare -- up to
5% of all people with Alzheimer's have early-onset. People with Down syndrome have
a higher risk for it.
Scientists have found a few ways in which early-onset Alzheimer’s is different
from other types of the disease. People who have it tend to have more of
the brain changes
that are linked with Alzheimer’s. The early-onset form also appears to be
linked with a defect in a specific part of a person’s DNA: chromosome 14. A
form of muscle twitching and
spasm, called myoclonus, is also more common in early-onset Alzheimer's.
2.3.2.
Late-onset Alzheimer's:
This is the most common form of the disease, which happens to people age
65 and older. It may or may not run in families. So far, researchers haven’t
found a particular gene that causes it. No one knows for sure why some people
get it and others don’t.
3.
Relation between autism and alzheimer’s disease:
Autism spectrum disorder (ASD) and Alzheimer's disease (AD)
are neurodevelopmental and neurodegenerative disorders respectively, with
devastating effects not only on the individual but also the society.
Collectively, a number of factors contribute to the expression of ASD and AD.
It is of utmost curiosity that these disorders express at different stages of
life and there is an involvement of certain susceptible genes. This genetic
basis makes the background of common associations like memory deficits,
cognition changes, demyelination, oxidative stress and inflammation, an
integral part of both disorders. Modern technology resulting in genetically
modified crops and increase in gadgets emitting electromagnetic frequencies
have resulted in enhanced risks for neurological dysfunctions and disorders
like ASD and AD. Subsequent advances in the psychological, pharmacological,
biochemical and nutritional aspects of the disorders have resulted in the
development of newer therapeutic approaches. The common clinical features like
language impairment, executive functions, and motor problems have been
discussed along with the patho-physiological changes, role of DNA methylation,
myelin development, and heavy metals in the expression of these disorders.
Psychopharmacological and nutritional approaches towards the reduction and
management of risk factors have gained attention from the researchers in recent
years. Current major therapies either target the inflammatory pathways or
reduce cellular oxidative stress. This contribution focuses on the
commonalities of the two disorders.
4.
Genetic link between Autism and Alzheimer’s Disease:
A
gene called ADNP could be responsible for causing higher levels of autism in
boys — who suffer from the condition far more than girls do — as well as the
increased levels of Alzheimer’s disease in elderly women.
If
we understand how ADNP, an activity-related neuroprotective protein, which is a
major regulatory gene, acts differently in males and females, we can try to
optimize drugs for potential future therapeutics to treat both autism and
Alzheimer’s disease.
ADNP,
or activity-dependent neuroprotective protein, is actually used as the name for
the gene that encodes a protein called activity-dependent neuroprotector
homeobox (the term “gene” and “protein” are generally applied interchangeably
to ADNP in scientific literature). In studies over the past 15 years,
scientists, have found that ADNP mutations can cause not only autism, but also
Alzheimer’s.
The
team of scientists discovered how loss of NAP, a snippet of ADNP essential for
brain formation, exposes cells to physical damage that eventually destroys
them, triggering dementia-related diseases like Alzheimer’s. However, applying
proteins with NAP-like properties to cells makes them healthy again — opening
the door to possible treatments for Alzheimer’s and other degenerative
diseases.
The study,
published in the Journal of Translational Psychiatry, sheds even more light on
how ADNP affects Alzheimer’s patients — and provides insights into how the gene
could affect males and females differently. In the study, scientists examined
the behavioral response of male and female mice — both ADNP-altered and normal
— to different cognitive challenges and social situations. To do so, they
removed one copy of the ADNP gene from some mice, and then examined their
respective responses to unfamiliar objects, odors, and other mice.
Their results revealed
sex-specific learning and memory differences in the mice. In the younger male
mice, the lack of ADNP caused deficiencies in object recognition and social
memory, typical of autistic behavior. However, for older females, the removal
of the gene caused them to withdraw and become more socially deficient, a
hallmark of dementia-related diseases, especially Alzheimer’s. According to the
study, “given the sex and genotype differences in ADNP positive or negative
mice, we were interested to see if ADNP expression is sex-dependent in the
hippocampus, a brain area directly associated with learning and memory.”
The results showed, for
the first time, that there was a gender-related — and age-related — difference
in the effect of ADNP on mouse behavior. The next step, of course, is to expand
the study and extend it to human clinical trials.
“This study emphasizes
the need to analyze men and women separately in clinical trials to find cures
for diseases, because they may respond differently,” scientists explained.
ADNP is gender-dependent
expression changes male and female chemical tendencies toward different
neurological disorders. Male and female mice may look the same and their brains
may look the same, but they are not. When the expression of ADNP is different,
it may cause different behaviors and different cognitive abilities.”
Further work is needed,
added the professor, but the team’s research could one day turn into a
treatment to alleviate, or even reverse, Alzheimer’s disease, as well as
autism.
References :
https://books.google.co.in/books?id=3QSNBAAAQBAJ&pg=PT154&lpg=PT154&dq=difference+of+autism+and+alzheimer%27s+wikipedia&source=bl&ots=AjWVGaTexq&sig=ACfU3U0y2ccBZ0WHSWdVg87mtq6zzjZfFw&hl=en&sa=X&ved=2ahUKEwj-kv3VlZzoAhWy8HMBHQauD6cQ6AEwFHoECBQQAQ#v=onepage&q=difference%20of%20autism%20and%20alzheimer's%20wikipedia&f=false
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