DEGENERATIVE and Inflammatory DISORDERS

Degenerative disease is the result of a continuous process based ondegenerative cell changes, affecting tissues or organs, which will increasingly deteriorate over time, whether due to normal bodily wear or lifestyle choices such as exercise or eating habits.

Degenerative disease

Alzheimer’s Disease
Amyotrophic Lateral Sclerosis (ALS)
Huntington’s Disease
Parkinson’s Disease

Inflammatory

Multiple Sclerosis
Spinocerebellar Ataxia
Myasthenia Gravis
Congenital Myasthenic Syndrome

Alzheimer’s Disease

a form of dementia
most common form of Dementia is Alzheimer’s disease.
Rare before age 60 but increasingly prevalent in each decade thereafter
affects 5 percent of Americans age 65 to 74 and nearly half of those age 85 and older.
As many as 5.3 million Americans have Alzheimer’s.
The disease is predicted to affect approximately 14 million individuals in the United States by the year 2050.

The earliest symptoms of Alzheimer’s:

forgetfulness
disorientation as to time or place
difficulty with
- concentration
- calculation
- language
- judgment

As it Progresses:

some have severe behavioral disturbances and may even become psychotic.

Final stages:

incapable of self-care and becomes bedridden.

usually die from

pneumonia or
other complication of immobility

Alzheimer’s disease is the seventh leading cause of death in the United States and the fifth leading cause of death for Americans aged 65 and older.

In the earliest stages,

the clinical diagnosis of possible or probable Alzheimer’s can be made with greater than 80 percent accuracy.
disease progresses, the accuracy of diagnosis at Alzheimer’s research centers exceeds 90 percent.

The diagnosis depends on

medical history
laboratory tests
psychological testing
brain imaging studies
physical and neurological examinations

The causes and mechanisms of Alzh's

not yet fully understood
progress via study of
- genetics
- biochemistry
- cell biology
- experimental treatments

What we Know From Recent Findings:

brain imaging
reductions
neuritic plaques
Early-onset Alzh’s disease
Alzh’s disease-associated mutations

Brain Imaging

enable visualize Alzheimer’s neuropathology during life.
final confirmation of the diagnosis requires examination of brain tissue, usually obtained at autopsy.
can only be confirmed definitively at a post-mortem when microscopic examination of the brain reveals the cell loss
- also see
  - Neuritic Plaques
    - widespread abnormal deposition of an amyloid protein in scattered small degenerating amyloid plaques
  - Neurofibrillary tangles
    - a tangled mess of rod-like proteins that are normal constituents of brain cells
Goal: diagnosis w/ a mildly radioactive chemical marker that shows amyloid plaques and tau tangles in living people.

Reductions

Damage to these neural systems
- ACh, somatostatin, monoamines, and Gm.
- critical for attention, memory, learning, and higher cognitive abilities
believed to cause the clinical symptoms.

Neuritic Plaques

Microscopic examination of brain tissue from people who died from Alzheimer’s shows abnormal accumulations of a small fibrillar peptide, termed beta amyloid, in the spaces around synapses.
- referred to as neuritic plaques.
Another: neurofibrillary tangles
- Identified as a modified form of the protein tau, which is found in the cell bodies of neurons.
all forms of Alzheimer’s develop plaques and tangles in brain regions important for memory and intellectual functions.

Early-onset Alzheimer’s disease

rare, dominantly inherited form of the disease.

Genetic Mutations.

mutations in genes that encode amyloid precursor protein
- gene encoding the amyloid precursor protein (APP) = chromosome 21. (from which amyloid is made)
In some families with early-onset Alzheimer’s, mutations have been identified in the presenilin 1 and 2 genes.
- presenilins encode enzymes that break the precursor protein down
Genes that cause dominant Alzheimer’s appear to do so by causing beta amyloid plaques to accumulate.
Apolipoprotein E (apoE), which influences susceptibility for Alzheimer’s later in life, exists in three forms.
The variant known as APOE epsilon 4 is clearly associated with enhanced risk.
- Inheritance of the variation apoE-4 is also a major risk factor in the disease
genetic factors do not tell the whole story: environmental factors, such as toxins and other insults such as traumatic brain injury, may also play an important role.
nevertheless, they are still improtant :laboratory animals have been bred that show features of the disease

Latest Research and Treatments

Currently approved treatments for Alzheimer’s disease do not modify the course of the disease and offer only temporary mitigation of some symptoms, such as agitation, anxiety, unpredictable behavior, sleep disturbances, and depression.

Five drugs have been approved by the FDA to treat Alzheimer’s.

Four prevent the breakdown of acetylcholine, a brain chemical important for memory and thinking.
- nerves cells using ACH are vulnerable to attack in the condition.
- Inhib of ACHase drugs have a modest treatment effect in both animal models and some clinical cases
The fifth regulates glutamate, a brain chemical that may cause brain cell death when produced in large amounts.

These agents temporarily improve memory deficits and provide some symptomatic relief but do not prevent progression of the disease. Several other approaches, such as antioxidants, are being tested.

Mice

Research: Alzh’s disease-causing genes in mice.

carry mutant genes linked to inherited Alzh’s

develop behavioral abnormalities and

some of the microscopic changes in tissue structure that occur in humans.

Goal: mouse models will prove useful for studying the mechanisms of the disease and testing novel therapies, although appropriate caution must be taken.

Experimental therapies in models of other neurodegenerative diseases — amyotrophic lateral sclerosis, for example — have been effective in mice with the disease but not in humans.

can modulate the actions of genes that play critical roles in the production of amyloid in animal models.

These genes encode beta and gamma secretases, which cut amyloid peptide from a larger protein.

How it Works

As Alzheimer’s disease develops, brain cells die: the cortex thins and the ventricles (the fluid filled spaces in the brain) enlarge.
The amyloid peptide is released from the neuron into the space around synapses, where it can accumulate and form plaques.
Amyloid-destroying enzymes, known as alpha secretases, break up the amyloid peptide, preventing amyloid accumulation.
Anti-amyloid therapies for Alzheimer’s aim either to remove existing amyloid or decrease production of new amyloid. Within the past three to five years, greater appreciation has developed for the surprisingly important roles that diet and lifestyle play in determining risk for Alzheimer’s disease.

Cognitive activity, physical activity, and heart-healthy diets lower the risk for Alzheimer’s, while obesity, high blood pressure, high cholesterol, metabolic syndrome, and diabetes raise the risk.

Some evidence indicates that successful management of these cardiovascular risks can delay the onset or slow the progression of dementia.

deposition- The accumulation or laying down of matter by a natural process, as the laying down of sediments in a river or the accumulation of mineral deposits in a bodily organ.

Amyotrophic Lateral Sclerosis (ALS)

progressive disorder
most common motor neuron disorder
strikes approximately 5,600 Americans annually,
average survival time is just 2-5 years from symptom onset.
typically 30,000 Americans have the disease at any given time.
costs of both care and treatment for ALS are expensive, and they continue to rise as the disease progresses.

In the final stages, ALS can cost as much as $200,000 a year per family, and costs Americans some $300 million annually.

Commonly known as Lou Gehrig’s disease, ALS affects neurons that control voluntary muscle movements such as walking.

reasons not completely understood, motor neurons in the brain and SC begin to disintegrate.

signals from the brain are not carried by these damaged nerves to the body, the muscles begin to weaken and deteriorate from the lack of stimulation and resulting disuse.

The first signs of progressive paralysis are usually seen in the hands and feet or in the muscles of speech and swallowing.

Early symptoms include

weakness in the legs
difficulty walking
slurred speech
clumsiness of the hands when washing and dressing.

Eventually, almost all muscles under voluntary control, including those of the respiratory system, are affected.

mind and the senses remain intact.

Death by respiratory failure or pneumonia.

Daignoses

No specific test identifies ALS, but

electrical tests of muscle activity
muscle biopsies
blood studies
computed tomography (CT), and
magnetic resonance imaging (MRI) scans

help diagnose the disease and rule out other disorders.

In more than 90 percent of cases, ALS is sporadic, arising in individuals with no known family history of the disorder.

Potential causes or contributors to the disease include

an excess amount of the neurotransmitter glutamate, which becomes toxic;
oxygen in a dangerous form in the body, resulting in what is called oxidative distress;
environmental factors; and
an autoimmune response in which the body’s defenses turn against body tissue.

other 5 to 10 percent of cases, ALS is familial — transmitted to family members because of a gene defect.

most common and well-studied mutation is

gene that codes for superoxide dismutase, a defense against oxidative distress.

Scientists believe that whatever they learn from studying this and other genes will have relevance for understanding the more common, sporadic form of this motor neuron disease.

Prognosis

no cure
slow its progression
can ease muscle cramping and neurological stiffness
An anti-glutamate drug slows the disease’s progression modestly.
Additional drugs are now under study.
Protecting or regenerating motor neurons using nerve growth factors, other more potent drugs, and stem cells may someday provide additional benefits for patients.

Experimental therapies in models of other neurodegenerative diseases (Ex. amyotrophic lateral sclerosis) have been effective in mice with the disease but not in humans.

Huntington’s Disease

30,000 Americans
200,000 more Americans at risk for inheriting from parent
considered one of the most common hereditary brain disorders.
named after the doctor who first described the condition.

due to a repeat mutation in one of the largest genes in the human genome called huntingtin.
progresses slowly over a 10- to 20-year period
eventually robs the affected individual of the ability to walk, talk, think, and reason.
appears between the ages of 30 and 50.
affects both the basal ganglia, which controls coordination, and the brain cortex, which serves as the center for thought, perception, and memory.

Symptoms

involuntary jerking movements of the limbs, torso, and facial muscles.
mood swings
depression
irritability
slurred speech
clumsiness.
reductions of eye movements
can't stick tongue out
difficulty with sustained movement
quasi-purposeful movements
swallowing is affected

progresses, symptoms include

difficulty swallowing
unsteady gait
loss of balance
impaired reasoning
memory problems.

Eventually becomes dependent on others

death often due to
- pneumonia
- heart failure, or
- another complication.

Diagnosis

detailed clinical examination & family history.
Brain scans
1993 indentify gene that causes Hunt’s; simplified genetic testing,
used to help confirm a diagnosis.

Researchers and genetic counselors-> specific protocols for predictive genetic testing to ensure that the psychological and social consequences of a positive or negative result are understood.

available only for adults
children under 18 may be tested to confirm a diagnosis of juvenile-onset Huntington’s disease.
Prenatal testing.
ethical issues must be considered
individual must be adequately informed
(there is no effective treatment or cure)

medications help control some of the symptoms.

no effective treatments for slowing disease progression exist

Causes

affects basal ganglia,
- controls coordination, and
brain cortex,
- serves as the center for thought, perception, and memory.
disease mutation for huntingtin protein
- an expanded triplet repeat — a kind of molecular stutter in the DNA.
- codes for an abnormal version of the protein called huntingtin.
- normal function is still unknown,
- widely distributed in the brain
- appears to be associated with proteins involved in transcription (turning genes on), protein turnover, and energy production.
- suspected to be caused by the gain of a new and toxic function among these proteins.

Cell and animal models test for therapies;

meds being researched to slow the progression or delay onset of the disease while continue working to a cure.

https://www.youtube.com/watch?v=KleHA0fv0Eg

Parkinson’s Disease

~1.5 million individuals in the US

start showing symptoms over the age of 50.

aging is the only known risk factor for the development of this disorder.

characterized by

slowness of movement
muscular rigidity
slowness
stiffness
tremor & unsteadiness
walking and balance impairment
mirographia
tend to be stiff
Overactive bladdder (blader spasms)
may develop a resting tremor as well.

Besides impairment in motor movement, Parkinson’s may also cause changes in non-motor brain function.

early onset forms due to problems in genes coding for Parkin.

What Happens

loss of dopamine-producing cells in substantia nigra pars compacta (midbrain).
40 percent of cells must be lost before symptoms occur, suggesting that perhaps the brain has a way of warding off symptoms.
Eventually these mechanisms begin to fail, or the continued loss of cells leads to a threshold from which the brain can no longer recover.

Cause

unknown
both genetic and environmental factors that contribute to the injury and eventual loss of these dopamine-producing cells.
most cases do not not appear to be inherited, there are certain situations in which genetic factors may be involved.
early onset forms due to problems in genes coding for Parkin.
Research on various forms help provide clues about it and new treatments.

Treatment

1950's: levels of dopamine are decreased
1960's: successul LEVODOPA treatment
- converted to dopamine in the brain.
- one of the greatest medical breakthroughs in the field of neurology.

other drugs either

boost the effect of dopamine
- inhibiting breakdown, or
extend the length of dopamine-like effects
- through their ability to bind and act on similar brain regions for longer periods of time.

Dopamine Replacement Therapy

carbidopa is often combined with levodopa;
- combined effect reduces the breakdown of levodopa in the bloodstream
  - greater levels of dopamine to reach the brain.
  - reduces side effects, such as nausea.
effective in alleviating many of the motor symptoms of Parkinson’s, still critical need to find better treatments.
DRT neither cures the disease nor slows its progression.
DRT doesn't treat non-motor aspects
- anxiety and sleep issues.
less effective over time in helping with gait and balance problems

Neurotoxin MPTP

1-methyl-4-phenyl-1, 2, 3, 6 tetrahydropyridine
Rodent and nonhuman primate
late 1970s: accidentally synthesized by designers of illicit drugs looking for ways to produce a heroin-like compound.
self-injected the MPTP
developed a neurological condition that was indistinguishable from PD
converted in the brain to a substance that destroys dopamine neurons.
This finding led to using MPTP as a tool for medical studies.

Alpha-Synuclein

In rare cases of familial forms of Parkinson's disease, there is a mutation in the gene coding for alpha-synuclein.
- certain mutations of alpha-synuclein may cause it to form amyloid-like fibrils that contribute to PD
alpha-synuclein aggregates to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such :
- Parkinson's disease,
- dementia with Lewy bodies and
- multiple system atrophy.
- These disorders are known as synucleinopathies.
Alpha-synuclein is the primary structural component of Lewy body fibrils.
- Occasionally, Lewy bodies contain tau protein;
- Alpha-synuclein pathology is also found in both sporadic and familial cases with Alzheimer's disease.[49]

Protein aggregation is a biological phenomenon in which mis-folded proteins aggregate (i.e., accumulate and clump together) either intra- or extracellularly. These protein aggregates are often toxic; protein aggregates have been implicated in a wide variety of disease known as amyloidoses, including ALS, Alzheimer's, Parkinson's and prion disease.

Research on Treatments

Primate models
- pallidum and subthalamic nucleus are abnormally overactive
- surgical deactivation or destruction of these overactive structures greatly reduces symptoms of Parkinson’s disease.
- The past decade has witnessed a resurgence in this surgical procedure, called pallidotomy.
recently, chronic deep-brain stimulation has been used.
- highly successful for treating patients who have experienced significant worsening of symptoms and are troubled by the development of drug-related involuntary movements.
for rapid progression
- surgical implantation of cells (Ex. fetal cells, stem cells) capable of producing dopamine.
gene transfer of trophic factors
- animal models and is being tested in clinical trials.
gene therapy
- clinical trials
- testing wether it can provide symptomatic or neuroprotective benefit to patients

genetic testing

diagnosis
advise other family members about their risks of
- developing diseases, or
- passing it on to their children.

The same gene defect can cause different diseases in different people, and different gene defects can cause very similar diseases. Understanding what it is that defines these differences, and how your genetic makeup interacts with the world in which you live and which you build around you, is one of the next great challenges for the genomic era in which we live.

Neuroinflammatory- Remitting

Multiple Sclerosis
Guillain Barre Syndrome
Myasthenia Syndrome
congenital myasthenic Syndrome

Multiple sclerosis

autoimmune disease
attack the myelin sheath in CNS neurons
disease of young adults.
lifelong ailment of unknown origin
400,000 Americans and 2.5 million people worldwide
diagnose ages of 20 and 40
earnings losses of about $10.6 billion annually for individuals with MS and their families.
Caucasians are more susceptible than other races (genes)
why=???????

Symptoms

repeated episodes of weakness
numbness
double vision or poor balance
last for a few weeks before recovery - apparently back to normal.

Symptoms depend on the site of the damage.

Commonly affected:

spinal cord
cerebellum
optic nerve

Symptoms such as

numbness,

clumsiness, and

blurred vision often occur.

Could also affect many other areas; WM and GM

Symptoms may also include

slurred speech,
weakness,
loss of coordination,
pain,
uncontrollable tremors,
loss of bladder control,
memory loss and
other cognitive problems,
depression, and
fatigue.

The cycle between periods of illness and remission is a feature of the disease.

Relapsing/Remitting Vs. Progressive

relapsing/remitting
- acute attack symptoms may last from several weeks to months and then spontaneously improve.
progressive MS
- ongoing nerve fiber degeneration, symptoms become permanent and gradually worsen
- progressive accumulation of disability usually affecting mobility, strength, balance, and coordination
- this cannot be cured
- several medications help control R/R forms of MS by limiting the immune attack and reducing associated inflammation

Causes

inflammation in the nervous system that flares up and then settles down again.
immune system -> fight-> bacteria or viruses.
- autoimmune assault on myelin around CNS neurons
- local area of inflammation that causes demyelination
- inflammation usually settles down, the myelin is repaired, and things return to normal.
- dont know why inflammation starts
- ppl w/ demyelination only have one brief episode.
- some have recurrent bouts affecting different parts of the brain.
- don't know what triggers inflammation in MS, we cannot completely stop it.
- attacks can be made shorter using drugs such as steroids that dampen down IS.
For patients with severe MS, some doctors believe that permanently dampening down certain parts of the immune system with drugs like azathioprine or ß-interferon can be beneficial.
There is still considerable uncertainty about their use.

* loss of myelin results in damage to the nerve fibers.

* damage may be so severe that the nerve fiber deteriorates.

* after loss of myelin, axon’s sheath is either repaired or replaced by scars, or scleroses, of hardened patches of tissue.

* Scarring is usually associated with further degeneration of the nerve fibers.

* Areas of disease activity, called lesions or plaques, appear in multiple places within CNS.

* Siblings of people with MS are at a 2-3% risk of developing MS (10-15x higher than the general population)

* risk identical twin is much higher (~30%)

* 5x more prevalent in temperate than tropics

developed MS before the age of 15 were affected by environmental factors, but more recent, larger studies suggest that there is no exact age cutoff.

Treatments

Steroids
30 years
effective in shortening attacks
speed recovery from MS-related acute attacks
control symptoms such as muscle stiffness (spasticity), pain, fatigue, and mood swings, as well as bladder, bowel, or sexual dysfunction, no treatments are available for the nerve degeneration that causes the progression of the disease.

Guillain Barré Syndrome

immune system can also attack the junctions connect with nerves as they emerge from the spinal cord

The immune system can also attack the junctions where nerves connect with muscles or the nerves as they emerge from the spinal cord, resulting in a condition called Guillain Barré syndrome.

Myasthenia Gravis

autoimmune channelopathy disorder
muscle weakness
fatigue
weak muscles can be caused by circulating in the blood
- even cause destruction of AChR @ NMJ
- causing ACh to not be able to bind to AChR
- no excitement or stimulation of muscle contraction
features antibodies directed against IC proteins

Treatments

AChase inhibitors and immunosuppressants

allow patients to have normal life expectancy

Congenital Myasthenic Syndrome

inherited neuromuscular disorder
abnormal NAChR, makes up the NMJ
similar effects to MG, but not autoimmune, genetic
more than 50% mutations foun d on 4 AChR genes

Treatments

AChase inhibitors

quinidine, fluoxetine

depends on subtype of CMS

Spinocerebellar Ataxia

Inheritable
increasingly unsteady w/ age
know the precise gene defects that cause it
diagnostic genetic testing
- this and other conditions identified by cause
- routine for suspected patients of
  - spinocerebellar ataxia or
  - other genetic conditions.
made more quickly and with much greater certainty than before.

PSYCHIATRIC DISORDERS

Anxiety Disorders
Tourette Syndrome
Major Depression
Bipolar Disease
Schizophrenia
Dissociative

Anxiety Disorders

most common mental illnesses,

anxiety disorders affect an estimated 18 percent of the adult population in a given year, or 40 million Americans.

Anxiety disorders

OCD
panic disorder
phobias such as
- acrophobia, or fear of heights and
- agoraphobia, or fear of open spaces
SAD
GAD
PTSD

OCD

can be crippling, to the point of keeping people completely housebound.
often occur with depression, and individuals doubly afflicted are at a high risk of suicide.
OCD People with OCD become trapped, often for many years, in repetitive thoughts and behaviors, which they recognize as groundless but cannot stop.

Such behavior includes

repeatedly washing hands
checking that doors are locked
stoves turned off

The illness is estimated to affect 2.2 million American adults annually.

One-third of adults develop their symptoms as children.

environmental factors and genetics probably play a role in the development of the disorder.

PET scans reveal abnormalities in both cortical and deep areas of the brain, implicating CNS changes in individuals with OCD.

OCD not limited to people either.

Treatments of OCD

certain breeds of large dogs develop acral lick syndrome; severely sore paws from compulsive licking.
they respond to the serotonergic antidepressant clomipramine,
- which was the first effective treatment developed for people w/ ocd
- This + other serotonergic antidepressants, as well as SSRIs such as sertraline and paroxetine, are effective in treating it
behavioral intervention, called exposure and response prevention, also is effective in many patients.

Panic Disorder

a lifetime prevalence rate of 4.7 percent in the US,

usually start unexpectedly.

Patients experience

an overwhelming sense of impending doom
accompanied by sweating
weakness
dizziness
shortness of breath

With repeated attacks, patients may develop anxiety in anticipation of another attack.

As a result, people may avoid public settings where attacks might occur.

If these individuals are untreated, they may develop agoraphobia and become virtually housebound.

Antidepressants, including SSRIs, are effective, as is CBT.

Phobia

an intense, irrational fear of a particular object or situation.

Individuals can develop phobias of almost anything, including dogs, dating, blood, snakes, spiders, or driving over bridges. Exposure to the feared object or situation can trigger an extreme fear reaction that may include

a pounding heart

shortness of breath

sweating

CBT is an effective treatment.

It is likely that panic disorders and phobias have similar neurochemical underpinnings that emerge as the result of a particular “stressor.”

PTSD

Extreme stressors such as trauma in

combat
being a victim of assault or sexual abuse
experiencing or witnessing a crime
can lead to a form of stress that can last a lifetime.

In the United States, this condition has a lifetime prevalence rate of 6.8 percent (9.7 percent in women and 1.8 percent in men).

It is characterized by

intense fear
helplessness or horror
intrusive recollections of the traumatic event
avoidance and numbing
hyperarousal

associated with

dysregulation of stress hormones
disordered sleep
major depressive disorder

Military personnel are at elevated risk for exposure to trauma, so they have higher prevalence rates compared to the general population.

studied PTSD in depth: very high levels of Npe released in the brain during stress remain at heightened levels.

Medications that work well for patients with PTSD have emerged from basic research into Npe’s actions in different brain regions.

The alpha-1 blocker prazosin, a drug used to lower blood pressure for more than 20 years, is now used to treat nightmares experienced with PTSD.
- People treated with prazosin include those with a very long-standing illness, such as Holocaust survivors.
Beta-blockers such as propranolol also are being tested in individuals exposed to trauma, but these agents must be administered shortly after the trauma, before PTSD has been established, which brings up complex ethical issues.
PTSD also is treated with
- antidepressant medications
- atypical antipsychotic medications
- psychotherapies such as
  - CBT
  - eye movement desensitization
  - reprocessing therapy

The discovery of brain receptors for the benzodiazepine anti-anxiety drugs has sparked research to identify the brain’s own anti-anxiety chemical messengers.

Benzodiazepines bind to GABA receptors and enhance responsiveness to endogenous GABA, the major inhibitory NT in the brain.

Indeed, recent studies have revealed alterations in certain GABA receptors in the CNS of patients with PTSD, effectively providing an additional neurochemical link between different anxiety disorders.

This finding may lead to new ways to modulate anxiety disorders.

Tourette Syndrome

One of the most common and least understood neurobiological disorders
inherited disorder that affects about 200,000 Americans.
Males are affected three to four times as often as females.

Symptoms 4-8 YO, but in rare cases may emerge in the late teenage years.

motor and vocal tics
repetitive
involuntary movements
utterances that are rapid, sudden and
persist for more than one year.

The types of tics may change frequently and increase or decrease in severity over time.

In ~ 1/2 of individuals, this disorder lasts a lifetime, but the remaining patients may experience a remission or decrease in symptoms as they get older.

A high percentage of people with TS also have associated conditions

problems with learning
difficulties with attention
obsessive thoughts and compulsive rituals.

Often these manifestations are more troublesome to individuals than the tics themselves, so physicians must consider them when choosing a treatment regimen.

Tourette syndrome is inherited and seems to result from abnormal activity in a brain system called the basal ganglia.

Research suggests that genes associated with TS, perhaps together with in utero or early environmental conditions, cause abnormalities in basal ganglia development or excesses in certain chemicals, including the NT Dp.

The majority of people with Tourette syndrome are not significantly disabled by symptoms, so they do not require medication.

However, antipsychotics and SSRIs, as well as drugs to control tics, nausea, high blood pressure, seizures, or anxiety, are available to help control symptoms when they interfere with functioning.

genes+utero or early environ= developmental or chemical abnormalities in BG (Dp excess)

tics+nausea+HBD+seizures+anxiety = antipsychotics and SSRIs

Stimulant medications such as methylphenidate and dextroamphetamine, which are prescribed for ADHD, have been reported to improve attention and decrease tics in Tourette syndrome. For obsessive-compulsive symptoms that interfere significantly with daily functioning, SSRIs, antidepressants, and related medications may be prescribed. Medication dosages that achieve maximum control of symptoms vary for each person and must be gauged carefully by a doctor.

The medicine is administered in small doses, with gradual increases to the point where there is maximum alleviation of symptoms with minimal side effects.

Side effects of medications are :

weight gain
muscular rigidity
fatigue
motor restlessness
social withdrawal

Most of these side effects can be reduced with specific medications. Other side effects, such as depression and cognitive impairment, can be alleviated with dosage reduction or a change of medication. Other types of therapy also are helpful.

Behavioral therapies, such as those used to treat similar disorders that emerge in childhood, have been receiving more attention. Aimed at training circuits to control the specific behavior related to the tic, these therapies have proven to be highly effective in reducing the severity of tics in some subtypes of TS. Psychotherapy and counseling can assist people with this disorder, as well as providing coping mechanisms for family members.

Major Depression

Clinical or major depression
harrowing feelings of sadness
hopelessness
pessimism
loss of interest in life
reduced emotional well-being
one of the most common and debilitating mental disorders.
disturbances of sleep and appetite,
decreased energy, and often
cognitive disturbances such as
difficulty concentrating and
remembering.
failing concentration and memory
loss of interest in life.
depression and neurodegeneration can be bedfellows
severely depressed patients can lose brain cells
1 in 5 may suffer at some time in their lives from some degree of depressive disorder

Depression is as disabling as heart disease or arthritis. depressed individuals are at a significantly elevated risk of suicide.

genes + environment =a role in risk for depression

stress also can trigger a depressive episode.

Causes

physical symptoms may reflect disturbances in the Hus, resulting in an excessive production of stress hormones.
lab: depressed patients fail to shut off secretion of cortisol in response to potent synthetic analogs that normally feedback to shut off secretion.
Experiments with positron emission tomography (PET) imaging have also implicated a region of the anterior cingulate gyrus within the prefrontal cerebral cortex in depression.
This region, which normally integrates aspects of cognition and emotion, is the chief experimental target for deep brain stimulation in severely depressed patients who have not responded to other treatments.

anterior cingulate gyrus within the prefrontal cerebral cortex integrates aspects of cognition and emotion

Deep Brain Stimulate it!

80 percent of these individuals respond to drugs, psychotherapy, or a combination of the two.

Some severely depressed patients can be helped with electroconvulsive therapy. As mentioned above, those patients who do not respond to the standard antidepressant drugs may be helped by deep brain stimulation approaches, which were originally developed for patients with neurodegenerative disease.

Treatment Options

Antidepressant drugs
- increase levels of Npe or 5HT in synapses.
- A few medications also target dopamine.
- The well-known SSRIs act on serotonin alone.
  - The increased levels of neurotransmitters then initiate plastic changes in cells and circuits, leading to an improvement in symptoms over several weeks.
CBT=effective
ketamine (blocks NMDA glutamate receptors) alleviate depressed symptoms rapidly.
- has many side effects, not likely to be used clinically, but these findings have set off an exciting search for new pharmacologic approaches.
Electroconvulsive Therapy
DBS
- orginally created for patients with neurodegenerative disease.

How Major Depressions Effects The Body

unbalancing effect on the control of stress hormones, such as (Ex. cortisol)
- stress hormones are beneficially released acutely during stressful situations.
when chronically activated
- stress hormones may actually damage brain cells
- particularly in the frontal and temporal lobes of the brain.

It has recently been found that antidepressant drugs promote the integrity of brain cells and increase the rate at which new neurons are produced in the hippocampus. Thus may protect against and even reverse the toxic effects of stress on the brain.

Bipolar Disorder

BD (past: manic-depressive illness)
usually experience episodes of deep depression and manic highs.
Many patients return to normal moods in between acute episodes, but a large number continue to have troubling symptoms, usually of depression.
increased risk of suicide.

depressive episodes are virtually indistinguishable from major depression

characterized by

sad mood
loss of interest
lack of energy
disturbances of sleep and appetite
difficulty concentrating
feelings of hopelessness and worthlessness
suicidal thoughts
sometimes suicidal acts

Symptoms of mania include

increased energy
decreased need for sleep
marked interest in goal-directed activities
poor judgment

Ex. manic episodes->spend excessively or engage in uncharacteristic drug abuse or sexual behaviors.

Individuals with mania may be euphoric, but some are predominantly irritable.

Typically, manic individuals are grandiose, and when the mania is particularly severe, they may have delusions or hallucinations.

In such instances, patients may believe that they are prophets, deities, or on a special mission. Sometimes, too, mania can be mild. Then it is called hypomania.

Bipolar disorder that is characterized by full manic episodes and depressions affects about 1% of the population worldwide.

men affected=women affected

BD is highly influenced by many different genes.

identify a small number of these genes.

typically have recurrences of acute mania or depression throughout their lives.

hypomania+depression= prevalence goes up to 2.6% (based on study of Americans 18+YO)

Treatment

all medications have side effects
lithium
late 1940s: guinea pigs injected with lithium, became placid, thus lithium had a mood-stabilizing effect.
given to manic patients, Li improved all manic symptoms and stabilized their moods.
enabled people to return to work and live relatively normal lives.
In conjunction with Li, may require additional treatments, esp for depression.
Other medications with mood-stabilizing effects used to treat bipolar disorder include some drugs, such as valproate, that were first developed as anticonvulsants.

Schizophrenia

disturbances in
- attention
- memory
- thinking
- emotional reactions
- social behavior
- delusions
- hallucinations
- ability to work.
usually results in chronic illness and personality change.
Affecting about 1.1% of the population, or 2.4 million Americans, Schiz is disabling and costly.
Annually costs total about $62.7 billion.
Despite psychological symptoms, it is considered a brain disease
progressive and potentially very disabling condition that affects 1 in 100.
starts in early adulthood and is said to blight more lives than cancer.

2 SPOTLIGHT SYMPTOMS

Delusions
- abnormal beliefs; commonly bizarre ideas which are often persecutory in nature
Hallucinations
- disordered perception
- abnormal sensory impressions, such as hearing voices when there is no one there

Causes; Schiz and the Brain

1. may be caused by the disruption of neurodevelopment through a genetic predisposition, which may be exacerbated by environmental factors such as maternal infections or direct brain trauma.

2. mutations in several genes involved in controlling nerve cell communication have been identified that appear to increase the risk of developing schizophrenia.

3. Brain scans and postmortem studies show abnormalities in some people with schizophrenia, such as

enlarged ventricles (fluid-filled spaces) and
reduced size of certain brain regions.

4. Functional neuroimaging scans such as PET and fMRI taken while individuals perform cognitive tasks, particularly those involving memory and attention, show abnormal functioning in specific brain areas of people with this illness.

5. Brain systems using the chemicals particularly involved in the development of the disorder:

dopamine
glutamate
GABA

6. Ventricles of the brain enlarge in the condition, and that the activity of the frontal lobes becomes impaired.

7. post-mortem studies suggest that the way that neurons have connected up during development may be abnormal, and that other neurotransmitter systems, such as glutamate, may be malfunctioning.

Diagnosis

ages of 15 and 25.
Few patients recover fully following treatment,
most continue to have moderate or severe symptoms that may be aggravated by life stressors.
About 15% of individuals return to a productive life after a single episode,
60% will have intermittent episodes throughout their lives,
and an additional 25% will not recover their ability to live as independent adults.

Treatment Options

1950s: accidentaly discovery of first antipsychotic drug, chlorpromazine
shown to reduce symptoms of schizophrenia
Clinical trials demonstrated that chlorpromazine was more effective than a placebo or a sedative.
Subsequently, more than 20 effective antipsychotic drugs were developed.

First generational Anti-Leptics (typical)

acts by inhibiting certain dopamine receptors.
reducing the frequency and impact of symptoms
mechanism accounts for the high prevalence of side effects, similar to those seen with PD
mechanism also explains the risk of developing an irreversible movement disorder, tardive dyskinesia, which results in aimless, uncontrollable movements, such as grimacing or rapid eye blinking.

Second Generational Anti-Psychotics (atypical)

more effective in treating the positive symptoms of schizophrenia.
They do not have the same likelihood of causing Parkinsonian effects but can lead to other debilitating side effects, such as very large weight gain, blood disorders, and muscle pain and dysfunction.

Deficits in cognition are frequent, lifelong manifestations in most patients, even those who show good recovery from more acute “positive” symptoms, such as hallucinations, delusions, and confused thinking.

“Negative” symptoms, such as inability to experience pleasure and lack of motivation, may be the most debilitating part of the disorder.

These symptoms make it difficult for many people to lead productive lives. Unfortunately, many of these symptoms are generally resistant to drug treatment.

not realated to “split personality” with which it is often confused, nor as a rule are sufferers in any way violent.

Extrapyramidal symptoms

also known as extrapyramidal side effects (EPSE), are drug-induced movement disorders that include acute and tardive symptoms. These symptoms include dystonia (continuous spasms and muscle contractions), akathisia (motor restlessness), parkinsonism (characteristic symptoms such as rigidity, bradykinesia, and tremor), and tardive dyskinesia (irregular, jerky movements). Antipsychotics are often discontinued due to inefficacy and intolerable side effects such as extrapyramidal symptoms.

But What if a Patient Had Parkinsons and Schizophrenia

Interestingly, there are a number of case reports in the literature that indicate that the atypical antipsychotic medication clozapine can be an effective treatment for the psychosis associated with schizophrenia, while at the same time helping to improve the physical symptoms associated with Parkinson's, such as the tremor and dyskinesia. Unlike typical antipsychotics, such as haloperidol, and some atypical antipsychotics, such as risperidone, clozapine is relatively unique in its lack of producing Parkinsonian-like symptoms, even at high doses. This is in part because clozapine binds relatively weakly to the D2 dopamine receptor compared to most other antipsychotics.

Dissociative Disorders

Dissociation is a mental process where a person disconnects from their thoughts, feelings, memories or sense of identity. Dissociative disorders include dissociative amnesia, dissociative fugue, depersonalisation disorder and dissociative identity disorder.

The Neuroscience Center

DEGENERATIVE and Inflammatory DISORDERS

PSYCHIATRIC DISORDERS

Extrapyramidal symptoms

Topics