neurodegenerative disorders

Diseases & Treatment of Neurodegenerative Disorders

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Diseases & Treatment of

Neurodegenerative Disorders by

Md. Monirul Islam

Pharmacy Discipline

Khulna University

Bangladesh


1. Introduction

Neurodegenerative disease is an umbrella term for a range of conditions which primarily affect

the neurons in the human brain.

Neurons are the building blocks of the nervous system which includes the brain and spinal cord.

Neurons normally don’t reproduce or replace themselves, so when they become damaged or die

they cannot be replaced by the body. Examples of neurodegenerative diseases include

Alzheimer's disease and other dementias, brain cancer, degenerative nerve diseases, encephalitis,

epilepsy, genetic brain disorders, head and brain malformations, hydrocephalus, stroke,

Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS or Lou Gehrig's

Disease), Huntington's disease, prion disease, and others.

Neurodegenerative diseases are incurable and debilitating conditions that result in progressive

degeneration and / or death of nerve cells. This causes problems with movement (called ataxias),

or mental functioning (called dementias).

2. Causes of neurodegeneration

Only an extremely small proportion (less than 5%) of neurodegenerative diseases is caused by

genetic mutations. The remainders are thought to be caused by the following:

A build up of toxic proteins in the brain

A loss of mitochondrial function that leads to the creation of neurotoxic molecules

Although the cause may vary, experts generally agree that the result is promotion of apoptosis or

programmed cell death, which is deliberate suicide of the cell for the purpose of protecting other

nearby neurons from toxic substances.

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3. Mechanism of neuronal death

3.1. Caspase-dependent neuronal apoptosis

Apoptosis is an active and highly orderly process displaying characteristic morphologic changes

including nuclear condensation and fragmentation, cytoplasmic shrinkage, plasma membrane

blebbing, and exposure of phosphatidylserine. The Bcl-2 (a family of mitochondria-associated

proteins), caspase (cysteine proteases), and Apaf-1/ced-4 (adaptor proteins required for the

activation of caspases) families constitute the core apoptotic machinery in neurons as well as in

many other cell types.

In living cells, mitochondrially localized Ced-9 binds to Ced-4, which prevents Ced-4 from

activating Ced-3. In dying cells, the expression of egl-1 is induced. Egl-1 binds to Ced-9 to

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Figure 1: Apoptosis pathways of C. elegans and mammalian cells

alleviate its inhibition of Ced-4. Ced-4 then translocates to the area around nucleus and activates

Ced-3. The activation of Ced-3 is at least partially responsible for the mitochondrial release of

Cps-6 and Wah-1, which may cooperate to induce DNA fragmentation. In mammalian cells,

anti-apoptotic Bcl-2 family proteins and anti-apoptotic kinase Akt and ERK protect the

mitochondrial integrity by inhibiting pro-apoptotic Bcl-2 family members. In dying cells, several

pro-apoptotic members of Bcl-2 family (tBid, Dp-5, Bim, Bax, Bak, and BAD) may antagonize

the anti-apoptotic Bcl-2 family proteins to induce mitochondrial damage. The subsequent release

of cytochrome c from damaged mitochondria induces the formation of apoptosome by recruiting

caspase-9 and Apaf-1. Active caspase-9 cleaves and activates caspase-3, which in turn cleaves a

variety of cellular substrates including ICAD (inhibitor of caspase-activated DNAase) and allows

CAD (caspase-activated DNAase) to induce DNA laddering. Apoptotically damaged

mitochondria also release other factors, such as AIF and EndoG, to facilitate DNA fragmentation

and Smac/Diablo to facilitate caspase activation.

3.2. AIF—a double agent of life and death

AIF (apoptosis-inducing factor), a mitochondrial flavoprotein with an oxidoreductase domain,

was identified in a screen for mitochondria-released pro-apoptotic factors. AIF is localized to the

mitochondrial intermembrane space in living cells and translocates to the cytoplasm and nucleus

under certain apoptotic conditions. In mammalian cells, AIF was shown to induce nuclear

condensation and large-scale DNA fragmentation to ∼50 kb fragments in a caspase-independent

fashion. A possible role of AIF in mediating neuronal cell death was highlighted by a report from

the laboratory of Valina Dawson, demonstrating that AIF is a downstream mediator of

poly(ADP-ribose) polymerase-1 (PARP-1)-induced neuronal cell death. PARP-1 mediates

protein ADP ribosylation in response to DNA damage, and its activation has been found to

contribute to a variety of cell death paradigms. PARP has been shown to play a role in neuronal

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cell death induced by ischemia-reperfusion injury and in NMDA-induced excitatory neuronal

cell death.

3.3. The role of autophagy in neuronal cell death

Autophagy is an intracellular lysosome-mediated catabolic mechanism that is responsible for the

bulk degradation and recycling of damaged or dysfunctional cytoplasmic components and

intracellular organelles. At the ultrastructural level, the main criterion for recognizing autophagy

is the appearance of intracellular double membrane vacuoles containing cytoplasmic components

such as fragments of endoplasmic reticulum or mitochondria and lysosomal hydrolases.

Autophagy is an evolutionarily ancient cellular response to both extracellular stress conditions

(nutrient deprivation, hypoxia) and intracellular stress conditions (accumulation of damaged

organelles and cytoplasmic components) that allows lower eukaryotic organisms such as yeast to

survive nutrient starvation conditions by recycling. The evidence of activation of autophagy has

been found in neurodegenerative diseases. Increased levels of autophagy are observed in

neuronal cell lines expressing mutant proteins associated with Parkinson's disease (PD).

3.4. Regulated cellular necrotic program

Members of the degenerin gene family of C. elegans encode the subunits of the amiloride-

sensitive epithelial membrane sodium channel, in which some mutations can cause necrotic

neuronal degeneration including intracellular vacuolation and swelling. Most degenerating

mutations in this family are dominant gain-of-function mutations that result in altered and/or

increased channel activity.

In C. elegans, specific dominant gain-of-function mutations in the cytoplasmic membrane Na+

channel protein MEC-4 or Ca2+ channel protein DEG-3 result in the abnormal rises in [Ca2+]i

through either release of ER Ca2+ storage or increased entry of extracellular Ca2+. Elevated [Ca2+]i

results in the activation of calpains, CLP-1 and TRA-3, which in turn activate the cytosolic

cathepsins, ASP-3 and ASP-4 (aspartyl proteases), and necrosis. In mammalian cells, low levels

of [Ca2+]i rises from releases of ER Ca2+ storage may induce apoptosis through localized calpain

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activation, which in turn activates caspase-12. High levels of [Ca2+]i may induce necrosis by

extensive activation of calpains, which subsequently activate cathepsins.

Fig: The mechanism of necrosis in C. elegans and in mammalian cells

4. Stroke

Stroke is a disease that affects the arteries

leading to and within the brain. A stroke

occurs when a blood vessel that carries

oxygen and nutrients to the brain is either

blocked by a clot or bursts (or ruptures).

When that happens, part of the brain cannot

get the blood (and oxygen) it needs, so it and brain cells die.

Fig: Condition of stroke

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4.1. Types of stroke

The most common ischemic strokes include:

Thrombotic stroke: A thrombotic stroke occurs when a blood clot (thrombus) forms in

one of the arteries that supply blood to the brain. A clot may be caused by fatty deposits

(plaque) that build up in arteries and cause reduced blood flow (atherosclerosis) or other

artery conditions.

Embolic stroke: An embolic stroke occurs when a blood clot or other debris forms away

from the brain — commonly in the heart — and is swept through bloodstream to lodge in

narrower brain arteries. This type of blood clot is called an embolus.

Fig: Types of stroke

Hemorrhagic stroke: Hemorrhagic stroke occurs when a blood vessel in brain leaks or

ruptures. Brain hemorrhages can result from many conditions that affect blood vessels,

including uncontrolled high blood pressure (hypertension), overtreatment with

anticoagulants and weak spots in blood vessel walls (aneurysms).

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4.2. Signs and Symptoms of stroke

Strokes occur quickly and as such their symptoms often appear suddenly without warning.

The main symptoms of stroke are as follows:

Confusion, including trouble with speaking and understanding

Headache, possibly with altered consciousness or vomiting

Numbness of the face, arm or leg, particularly on one side of the body

Trouble with seeing, in one or both eyes

Trouble with walking, including dizziness and lack of co-ordination.

Strokes can lead to long-term problems. Depending on how quickly it is diagnosed and treated,

the patient can experience temporary or permanent disabilities in the aftermath of a stroke. In

addition to the problems listed above continuing, patients may also experience the following:

Bladder or bowel control problems

Depression

Pain in the hands and feet that gets worse with movement and temperature changes

Paralysis or weakness on one or both sides of the body

Trouble controlling or expressing emotions.

4.3. Causes of stroke

Many factors can increase risk of a stroke. They are:

4.3.1. Lifestyle risk factors

Being overweight or obese

Physical inactivity

Heavy or binge drinking

Use of illicit drugs such as cocaine and methamphetamines

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4.3.2. Medical risk factors

High blood pressure — the risk of stroke begins to increase at blood pressure readings

higher than 120/80 millimeters of mercury (mm Hg).

Cigarette smoking or exposure to second hand smoke.

High cholesterol.

Diabetes.

Cardiovascular disease, including heart failure, heart defects, heart infection or abnormal

heart rhythm.

4.3.3. Other factors associated with a higher risk of stroke include:

Personal or family history of stroke, heart attack or transient ischemic attack.

Being age 55 or older.

Race — African-Americans have a higher risk of stroke than do people of other races.

Gender — Men have a higher risk of stroke than women.

4.4. Treatment and support for stroke

Seek immediate medical attention if any signs or symptoms of a stroke are noticed, even if they

seem to fluctuate or disappear.

Think "FAST" and do the following:

Face. Ask the person to smile. Does one side of the face droop?

Arms. Ask the person to raise both arms. Does one arm drift downward? Or is one arm

unable to raise up?

Speech. Ask the person to repeat a simple phrase. Is his or her speech slurred or strange?

Time: If any of these signs are observed, contact the emergency services.

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The medicines used for the early treatment of ischemic stroke are aspirin and anticoagulants.

Aspirin — Antiplatelet therapy helps prevent new clots from developing. Unlike

thrombolytic drugs, these agents do not dissolve clots that are already present. They are

often used acutely if thrombolytic drugs cannot be given or after thrombolytics have been

given.

Anticoagulants — Anticoagulants are often, but incorrectly, referred to as blood

thinners. They work by decreasing the formation of additional blood clots. Heparin and

low molecular weight heparin are anticoagulants.

Long term prevention of ischemic stroke

For people who have already had an ischemic stroke, doctors often prescribe medicines that can

prevent another stroke from happening. This is called secondary prevention. The treatments for

secondary prevention of ischemic stroke include antiplatelet medications, anticoagulants, and

surgical procedures to reopen blockages in blood vessels (revascularization).

Antiplatelet therapy: The antiplatelet medicines aspirin, clopidogrel, and the

combination of aspirin plus extended-release dipyridamole are all acceptable options for

preventing recurrent ischemic stroke for patients other than those who have a stroke

caused by embolism from the heart.

Anticoagulant therapy: Anticoagulant therapy is used to prevent stroke for selected

patients. As an example, for long-term stroke prevention, virtually all patients with atrial

fibrillation who have a history of embolic stroke or transient ischemic attack should be

treated with anticoagulation (warfarin or one of the newer oral anticoagulant drugs) in the

absence of contraindications.

Revascularization: Revascularization is the medical term for reestablishing blood flow

to an area. In people who have had a stroke, revascularization usually refers to a surgical

procedure (carotid endarterectomy) that opens a blocked artery in the neck (the carotid

artery), which improves blood flow to the brain and reduces the risk of stroke. The

amount of blockage in the carotid artery can be measured with an ultrasound imaging

test, CT angiogram, MR angiogram, or conventional arteriogram.

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Carotid endarterectomy: It is most successful when it is performed by a vascular

surgeon who has specialized training and experience with the procedure.

5. Alzheimer's disease (AD)

Alzheimer's disease is the most common cause of dementia. The word dementia describes a set

of symptoms that can include memory loss and difficulties with thinking, problem-solving or

language. Symptoms usually develop slowly and get worse over time, becoming severe enough

to interfere with daily tasks.

Fig: Alzheimer's disease

5.1. Symptoms of Alzheimer's disease

In the early stages the symptoms of Alzheimer's disease can be very subtle. However, it often

begins with lapses in memory and difficulty in finding the right words for everyday objects.

Other symptoms may include:

Persistent and frequent memory difficulties, especially of recent events

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Vagueness in everyday conversation

Apparent loss of enthusiasm for previously enjoyed activities

Taking longer to do routine tasks

Forgetting well-known people or places

Inability to process questions and instructions

Deterioration of social skills

Emotional unpredictability

Symptoms vary and the disease progresses at a different pace according to the individual and the

areas of the brain affected. A person's abilities may fluctuate from day to day, or even within the

one day, becoming worse in times of stress, fatigue or ill-health.

5.2. Diagnosis of Alzheimer's disease

Alzheimer's disease is usually diagnosed based on the person's medical history, history from

relatives, and behavioural observations. The presence of characteristic neurological and

neuropsychological features and the absence of alternative conditions is supportive. Advanced

medical imaging with computed tomography (CT) or magnetic resonance imaging (MRI), and

with single-photon emission computed tomography (SPECT) or positron emission tomography

(PET) can be used to help exclude other cerebral pathology or subtypes of dementia. Moreover,

it may predict conversion from prodromal stages (mild cognitive impairment) to Alzheimer's

disease.

Assessment of intellectual functioning including memory testing can further characterise the

state of the disease. Medical organisations have created diagnostic criteria to ease and

standardise the diagnostic process for practising physicians. The diagnosis can be confirmed with

very high accuracy post-mortem when brain material is available and can be examined

histologically.

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5.3. Treatment and support for Alzheimer's disease

There is currently no cure for Alzheimer's disease, but there is a lot that can be done to enable

someone to live well with the condition. This will involve drug and non-drug care, support and

activities.

There are drug treatments for Alzheimer's disease that can temporarily alleviate some symptoms

or slow down their progression in some people

A person in the mild or moderate stages of Alzheimer's disease or mixed dementia will often be

prescribed a drug such as donepezil, rivastigmine or galantamine. The drug may help with

memory problems, improve concentration and motivation, and help with aspects of daily living

such as cooking, shopping or hobbies.

A person in the moderate or severe stages of Alzheimer's disease or mixed dementia may be

offered a different kind of drug such as memantine. This may help with mental abilities and daily

living, and ease distressing or challenging behaviours such as agitation and delusions.

If someone is depressed or anxious, talking therapies (such as cognitive behavioural therapy) or

drug treatments (such as antidepressants) may also be tried. Counseling may help the person

adjust to the diagnosis.

There are many ways to help someone remain independent and cope with memory loss. These

include practical things like developing a routine or using a weekly pill box. There are other

assistive technology products available such as electronic reminders and calendar clocks.

It is beneficial for a person with Alzheimer's to keep up with activities that they enjoy. Many

people benefit from exercising their mind with reading or puzzles. There is evidence that

attending sessions to keep mentally active helps (cognitive stimulation). Life story work, in

which someone shares their life experiences and makes a personal record, may help with

memory, mood and wellbeing. As the dementia worsens, many people enjoy more general

reminiscence activities.

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https://www.alzheimers.org.uk/site/scripts/documents_info.php?documentID=147


Over time, changes in the person's behaviour such as agitation or aggression become more likely.

This could be from a medical condition such as pain; because they misunderstood something or

someone; or perhaps because they are frustrated or under-stimulated. Individualised approaches

should look for, and try to address, the underlying cause. General non-drug approaches often also

help. These include social interaction, music, reminiscence, exercise or other activities that are

meaningful for the person. They are generally tried before additional drugs are considered,

particularly antipsychotics.

6. Parkinson's disease (PD)

Parkinson's disease (PD) is a chronic and progressive movement disorder, meaning that

symptoms continue and worsen over time.

Parkinson’s involves the malfunction and death of vital nerve cells in the brain, called neurons.

Parkinson's primarily affects neurons in an area of the brain called the substantia nigra. Some of

these dying neurons produce dopamine, a chemical that sends messages to the part of the brain

that controls movement and coordination. As PD progresses, the amount of dopamine produced

in the brain decreases, leaving a person unable to control movement normally.

Fig: Parkinson's disease

6.1.

Signs and symptoms of Parkinson’s disease

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Parkinson's signs and symptoms may include:

Tremor. A tremor, or shaking, usually begins in a limb, often in hand or fingers. Patient

may notice a back-and-forth rubbing of your thumb and forefinger, known as a pill-

rolling tremor.

Slowed movement (bradykinesia). Over time, Parkinson's disease may reduce ability to

move and slow movement, making simple tasks difficult and time-consuming. Steps may

become shorter when patient walk, or patient may find it difficult to get out of a chair.

Also, patient may drag feet as he tries to walk, making it difficult to move.

Rigid muscles. Muscle stiffness may occur in any part of the body. The stiff muscles can

limit range of motion and cause pain.

Impaired posture and balance. Posture may become stooped, or patient may have

balance problems as a result of Parkinson's disease.

Loss of automatic movements. In Parkinson's disease, patient may have a decreased

ability to perform unconscious movements, including blinking, smiling or swinging arms

while walking.

Speech changes. Patient may have speech problems as a result of Parkinson's disease.

Patient may speak softly, quickly, slur or hesitate before talking.

Writing changes. It may become hard to write, and writing may appear small.

6.2. Causes of Parkinson’s disease

Pesticide exposure,

Head injuries

Living in the country or farming.

Rural environments and the drinking of well water may be risks as they are indirect

measures of exposure to pesticides.

Heavy metals exposure has been proposed to be a risk factor, through possible

accumulation in the substantia nigra

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At least 5% of people are now known to have forms of the disease that occur because of a

mutation of one of several specific genes.

6.3. Treatment and support for Parkinson's disease

6.3.1. Pharmacological treatment

There is no cure for Parkinson's disease, but medications, surgery and multidisciplinary

management can provide relief from the symptoms. The main families of drugs useful for

treating motor symptoms are:

levodopa (usually combined with a dopa decarboxylase inhibitor or COMT inhibitor

which does not cross the blood–brain barrier),

dopamine agonists and

MAO-B inhibitors.

Other drugs such as amantadine and anticholinergics may be useful as treatment of motor

symptoms.

6.3.2. Surgery

Treating motor symptoms with surgery was once a common practice, but since the discovery of

levodopa, the number of operations declined. Surgery for PD can be divided in two main groups:

lesional and deep brain stimulation (DBS). Deep brain stimulation (DBS) is the most commonly

used surgical treatment. Target areas for DBS or lesions include the thalamus, the globus pallidus

or the subthalamic nucleus. Other, less common, surgical therapies involve intentional formation

of lesions to suppress overactivity of specific subcortical areas. For example, pallidotomy

involves surgical destruction of the globus pallidus to control dyskinesia.

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6.3.3. Gene therapy

Gene therapy typically involves the use of a non-infectious virus (i.e., a viral vector such as the

adeno-associated virus) to shuttle genetic material into a part of the brain. The gene used leads to

the production of an enzyme that helps to manage PD symptoms or protects the brain from

further damage.

6.3.4. Palliative care

Palliative care is specialized medical care for people with serious illnesses, including

Parkinson’s. The goal of this speciality is to improve quality of life for both the person suffering

from Parkinson’s and the family by providing relief from the symptoms, pain, and stress of

illnesses. As Parkinson’s is not a curable disease, all treatments are focused on slowing decline

and improving quality of life, and are therefore palliative in nature.

6.3.5. Prevention

Exercise in middle age reduces the risk of Parkinson's disease later in life.

Caffeine also appears protective with a greater decrease in risk occurring with a larger

intake of caffeinated beverages such as coffee. Although tobacco smoke causes adverse

health effects, decreases life expectancy and quality of life, it may reduce the risk of PD

by a third when compared to non-smokers. Tobacco smoke contains compounds that act

as MAO inhibitors that also might contribute to this effect.

Antioxidants, such as vitamins C and D, have been proposed to protect against the

disease

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7. Huntington's disease (HD)

Huntington's disease is an inherited condition that damages certain nerve cells in the brain. This

brain damage gets progressively worse over time and can affect movement, cognition

(perception, awareness, thinking, judgement) and behavior.

Huntington's disease was originally called Huntington's chorea ("chorea" is the Greek word for

dancing). This is because the involuntary movements associated with the condition can look like

jerky dancing. However, "disease" is now the preferred term, because the condition involves a lot

more than just abnormal movements.

7.1. Signs and symptoms of Huntington's disease

7.1.1. Movement disorders

The movement disorders associated with Huntington's disease can include both involuntary

movements and impairments in voluntary movements:

Involuntary jerking or writhing movements (chorea)

Muscle problems, such as rigidity or muscle contracture (dystonia)

Slow or abnormal eye movements

Impaired gait, posture and balance

Difficulty with the physical production of speech or swallowing

Impairments in voluntary movements — rather than the involuntary movements — may have a

greater impact on a person's ability to work, perform daily activities, communicate and remain

independent.

7.1.2. Cognitive disorders

Cognitive impairments often associated with Huntington's disease include:

Difficulty in organizing, prioritizing or focusing on tasks

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Lack of flexibility or the tendency to get stuck on a thought, behavior or action

(perseveration)

Lack of impulse control that can result in outbursts, acting without thinking and sexual

promiscuity

Lack of awareness of one's own behaviors and abilities

Slowness in processing thoughts or ''finding'' words

Difficulty in learning new information

7.1.3. Psychiatric disorders

The most common psychiatric disorder associated with Huntington's disease is depression. This

isn't simply a reaction to receiving a diagnosis of Huntington's disease. Instead, depression

appears to occur because of injury to the brain and subsequent changes in brain function. Signs

and symptoms may include:

Feelings of irritability, sadness or apathy

Social withdrawal

Insomnia

Fatigue and loss of energy

Frequent thoughts of death, dying or suicide

Other common psychiatric disorders include:

Obsessive-compulsive disorder, a condition marked by recurrent, intrusive thoughts and

repetitive behaviors

Mania, which can cause elevated mood, overactivity, impulsive behavior and inflated

self-esteem

Bipolar disorder, or alternating episodes of depression and mania

In addition to the above symptoms, weight loss is common in people with Huntington's disease,

especially as the disease progresses.

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7.1.4. Behavioral changes

Loss of previously learned academic or physical skills

Rapid, significant drop in overall school performance

Behavioral problems

7.1.5. Physical changes

Contracted and rigid muscles that affect gait (especially in young children)

Changes in fine motor skills that might be noticeable in skills such as handwriting

Tremors or slight involuntary movements

Seizures

7.2. Cause of Huntington's disease

Huntington's disease is caused by a faulty gene that runs in families. Humans have 46

chromosomes (23 pairs). The faulty gene that causes Huntington's disease is found on

chromosome number four.

The normal copy of the gene produces a protein called huntingtin, but the faulty gene contains an

abnormal region of what are called CAG repeats. This area is larger than normal and produces a

mutant form of huntingtin. Cells in parts of the brain – specifically, the basal ganglia and parts of

the cortex – are very sensitive to the effects of the abnormal huntingtin. This makes

them function poorly and eventually die.

The brain normally sends messages through the basal ganglia and cortex to control movement

and thinking, as well as motivation. If this part of the brain is damaged, it causes problems

with control of movement, behaviour and thinking. It's still unclear exactly how abnormal

huntingtin affects the brain cells and why some are more sensitive than others.

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7.3. Treatment and support for Huntington's disease

7.3.1. Medications

There's no cure for Huntington's disease and its progress can't be reversed or slowed down.

As the condition progresses, it may put a strain on family and relationships. Treatments for

Huntington's disease aim to improve any mood disturbance; this is done to maintain skills used

in daily living that can deteriorate over time.

Antidepressants to treat depression

Antidepressants can help improve mood swings and treat depression. They include:

SSRI antidepressants – such as fluoxetine, citalopram and paroxetine

tricyclic antidepressants – such as amitriptyline

other types of antidepressants – including mirtazapine, duloxetine and venlafaxine

Mood stabilisers to treat irritability or mood swings

Mood stabilisers, particularly carbamazepine, may be considered as a treatment for

irritability. Olanzapine can also help, along with sodium valproate and lamotrigine.

The dose of carbamazepine needs to be slowly increased and any side effects monitored.

Carbamazepine can't be used during pregnancy.

Medication to suppress involuntary movements

The medications listed below suppress the involuntary movements – or chorea – seen in

Huntington's disease. In the UK, antipsychotic medicines are usually preferred.

Antipsychotic medication – such as olanzapine, sulpiride, risperidone and quetiapine

Tetrabenazine – reduces the amount of dopamine reaching some of the nerve cells in the

brain

Benzodiazepines – such as clonazepam and diazepam .

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7.3.3. Improving cell survival

Among the approaches aimed at improving cell survival in the presence of mutant huntingtin are

correction of transcriptional regulation using histone deacetylase inhibitors, modulating

aggregation of huntingtin, improving metabolism and mitochondrial function and restoring

function of synapses.

7.3.3. Physical therapy

People with Huntington's disease may see a physical therapist for non-invasive and non-

medication-based ways of managing the physical symptoms. Physical therapists may implement

fall risk assessment and prevention, as well as strengthening, stretching, and cardiovascular

exercises. Walking aids may be prescribed as appropriate. Physical therapists also prescribe

breathing exercises and airway clearance techniques with the development of respiratory

problems.For long-term independent management, the therapist may develop home exercise

programs for appropriate people.

8. Prion diseases

Prion diseases comprise several conditions. A

prion is a type of protein that can trigger normal

proteins in the brain to fold abnormally. Prion

diseases can affect both humans and animals and

are sometimes transmitted to humans by infected

meat products. The most common form of prion

disease that affects humans is Creutzfeldt-Jakob

disease (CJD). Prion diseases are rare.

Fig: Prion protein

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8.1. Types of prion diseases

Types of prion diseases include:

Creutzfeldt-Jakob Disease (CJD): A person can inherit this condition, in which case it's

called familial CJD. Sporadic CJD, on the other hand, develops suddenly without any

known risk factors. Most cases of CJD are sporadic and tend to strike people around age

60. Symptoms of CJD quickly lead to severe disability and death. In most cases, death

occurs within a year.

Variant Creutzfeldt-Jakob Disease (vCJD): This is an infectious type of the disease that

is related to “mad cow disease.” Eating diseased meat may cause the disease in humans.

The meat may cause normal human prion protein to develop abnormally. The disease is

also thought to spread to people receiving cornea transplants from infected donors and

from contaminated medical equipment. This type of the disease usually affects younger

people.

Variably protease- sensitive prionopathy (VPSPr). This is also extremely rare, it is

similar to CJD but the protein is less sensitive to digestion. It is more likely to strike

people around age 70 who have a family history of dementia.

Gerstmann- Straussler-Scheinker disease (GSS). Extremely rare, but occurs at an earlier

age, typically around age 40.

Kuru. This disease is seen in New Guinea. It's caused by eating human brain tissue

contaminated with infectious prions. Because of increased awareness about the disease

and how it is transmitted, kuru is now rare.

Fatal insomnia (FI). Rare hereditary disorder causing difficulty sleeping.

8.2. Causes of prion disease

Prion diseases occur when normal prion protein, found on the surface of many cells, becomes

abnormal and clump in the brain, causing brain damage. This abnormal accumulation of protein

in the brain can cause memory impairment, personality changes, and difficulties with movement.

Experts still don't know a lot about prion diseases, but unfortunately, these disorders are

generally fatal.

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Family history of prion disease

Eating meat infected by “mad cow disease”

Infection from receiving contaminated corneas or from contaminated medical equipment

8.3. Signs and symptoms of prion disease

8.3.1. Behavioural Symptoms

Mood disturbance e.g. aggression or loss of interest and personality changes

Anxiety and

Depression

Lack of social judgement and disinhibition.

8.3.2. Communication Problems

Slurred speech (dysarthria)

Communication difficulties

Reduction in the content of language

Repetition of words or sentences

The ability to read and write are gradually lost

8.3.3. Memory/Cognitive Deficits

Forgetfulness of day to day events

Disorientation

Poor concentration or attention.

8.3.4. Movement Problems

Ataxia

Jerky movements (myoclonus)

Clumsiness

Tremor

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8.3.5. Swallowing Problems

With the progression of the disease there may also be difficulty in swallowing.

As swallowing becomes increasingly difficult in the later stages of the disease, it may be

suggested that nutrition be supplemented with tube feeding.

8.3.6. Visual/Perceptual Problems

Double vision

Difficulty in moving eyes to follow objects

Hallucinations are fairly common

cortical blindness

8.3.7. Seizures

Very occasionally a person may suffer from seizures in the later stages of the disease.

Medication is available to help control seizures should they occur.

8.4. Treatment and support for prion diseases

Prion diseases can't be cured, but certain medications may help slow their progress. Medical

management focuses on keeping people with these diseases as safe and comfortable as possible,

despite progressive and debilitating symptoms.

Properly sterilizing medical equipment may prevent the spread of the disease. If you have or may

have CJD, you should not donate organs or tissue, including corneal tissue. Newer regulations

that govern the handling and feeding of cows may help prevent the spread of prion diseases.

As prion diseases progress, people with these diseases generally need help taking care of

themselves. In some cases they may be able to stay in their homes, but they eventually may need

to move to a care facility.

9. References:

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1. Junying Yuan, Marta Lipinski,and Alexei Degterev. “Diversity in the Mechanisms

Review of Neuronal Cell Death”. Neuron, Vol. 40, 401–413, October 9, 2003.

2. Sullivan, Jonathon. "What is Brain Ischemia?" WSU Emergency Medicine Cerebral

Resuscitation Laboratory. Retrieved 2008-11-11.

3. Burns A, Iliffe S (5 February 2009). "Alzheimer's disease". BMJ 338: b158.

4. Querfurth HW, LaFerla FM (28 January 2010). "Alzheimer's disease". The New England

Journal of Medicine 362 (4): 329–44.

5. Shulman JM, De Jager PL, Feany MB (February 2011) [25 October 2010]. "Parkinson's

disease: genetics and pathogenesis." Annual Review of Pathology 6: 193–222.

6. Samii A, Nutt JG, Ransom BR (29 May 2004). "Parkinson's disease". Lancet 363 (9423):

1783–1193.

7. Hammond K, Tatum B (26 June 2010). "The Behavioral Symptoms of Huntington's

Disease".

8. Dobson CM (Feb 2001). "The structural basis of protein folding and its links with human

disease" (PDF). Philosophical Transactions of the Royal Society of London. Series B,

Biological Sciences 356 (1406): 133–45.

9. Dovey, Dana (2 September 2015). “Prion Diseases". United States Centers for Disease

Control and Prevention.

26 | P a g e

http://www.cdc.gov/prions/index.html

http://rstb.royalsocietypublishing.org/content/356/1406/133.full.pdf+html?sid=b4dec236-78b0-44b9-8d64-3b37b1ddc0c9

http://rstb.royalsocietypublishing.org/content/356/1406/133.full.pdf+html?sid=b4dec236-78b0-44b9-8d64-3b37b1ddc0c9

http://web.stanford.edu/group/hopes/cgi-bin/wordpress/2010/06/the-behavioral-symptoms-of-huntingtons-disease/

http://web.stanford.edu/group/hopes/cgi-bin/wordpress/2010/06/the-behavioral-symptoms-of-huntingtons-disease/

https://en.wikipedia.org/wiki/Lancet_(journal)

http://sullydog.com/sullysites/qm/brainischemia101syllabus/syllabus/presentation1_9_1.html

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