KURSK STATE MEDICAL UNIVERSITY

FACULTY OF FOREIGN MEDICINE

Department of Pathological Anatomy

Course research work of pathological anatomy

Theme: Degenerative brain disorder in aging people

Student: Gustavo Duarte Viana

3rd year 2nd semester

Group:17

Supervisor: associated professor Goryainova, G. A.

KURSK

20130

Contents

• General Considerations 2

• Classification 2

• Basic concept of dementia 3

• Most common degenerative disease list 3

• Alzhimer’s disease 4

• Pick’s disease 12

• Parkinson’s disease 14

• Huntington’s disease 21

• Amyotrophic lateral sclerosis 24

• Conclusion 26

• References 27

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General considerationDegenerative disorders occurs during aging and may worse with time, in contrast the youth brain disorders is infectious more than degenerative one.

DEGENERATIVE DISEASES are Gray matter disease with progressive loss of neurons and secondary changes in white matter tracts.

Degenerative manifests as disturbed organism with inclusions according the inside of the cells contents and atrophy of the cells and loss of cells.

it mainly occur in patients without clear inciting event of previous neurologic deficits, it has Intracellular abnormalities and only loss of affected neurons

Classifications• DEGENERATIVE DISEASES are Grouped according to anatomic regions affected:

CEREBRAL CORTEX – Alzheimer disease, Pick’s disease

SUBCORTICAL AREAS – movement disorders (tremors and dyskinesia): Parkinsonism, Huntington’s chorea, etc.

Motor neurons of spinal cord: Amyotrophic lateral sclerosis

• The etiology is classified as primary or secondary according to neurological or systemic causes

Primary Degenerations:

Global – Alzheimer & Lewibody

Selective/System – Parkinsons , Huntingtons , MND.

Secondary Degenerations: Toxic, metabolic(storage), infections, nutritional. Alcohol & B12 deficiency, Cerebrovascular disease – stroke. Infections (e.g. Creutzfeldt-Jakob, syphilis, HIV.), neoplasma, heamatoma, hydrocephalus and etc.

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Basic concept of DementiaDementia: Acquired global impairment of intellect-intact consciousness > 15% of adults over 80 are demented. Primary & secondary degenerative disorders cause dementias.

Dementia (taken from Latin, originally meaning "madness", from de- "without" + ment, the root of mens "mind“) is a chronic or persistent disorder of the mental processes caused by brain disease or injury and marked by memory disorders, personality changes, and impaired reasoning more than expected in normal aging.

Most common degenerative disease list• There are many degenerative diseases recognized, we are going to

speculate the five most common types:

Alzheimer disease

Pick’s disease

Parkinson Disease

Huntington’s disease

Amyotrophic lateral sclerosis (ALS)

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Alzheimer’s disease• ALZHEIMER DISEASE DEMENTIA is acquired or inherited disorder of

progressive loss of cognitive function independent of the state of attention.

• Insidious impairment of higher intellectual function, mood and behavioral alterations.

• progressive disorientation, memory loss, aphasia

• 5 to 10 yrs – disabled, mute, immobile

• Mostly sporadic, elderly – major medical, social and economic problems

History of Alzheimer’s disease

• It was first described by German psychiatrist and neuropathologist Alois Alzheimer in 1906 and was named after him. Alois Alzheimer was a talented Doctor which with the difficulties at that time he developed and used new technologies and new staining to investigate the slices of normal and demented patients and he observed many characteristics which is even today the defining key of Alzheimer

Figura 1

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Statistic for Alzheimer’s disease rate according aging

By this graphic we may conclude that aging and women are really a risk factor for Alzheimer’s development.

Figura 2

• Alzheimer’s disease rate according to race In this graphic we see that Hispanic and Africans are essentially predisposed to Alzheimer disease. (Theory of gene for APOE4 )

Figura 3

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Risk factors for Alzheimer Majors

• Aging: (in contrast to what Alois Alzheimer said, the AD is more susceptible in aging)

• Family History: Genetic play a important role, Apolipoprotein E is a normal protein produced in the body, by the genetic difference there are 3 types E2, E3 and E4, E4 is highly related to alzheimer, 60% are carrier of APO E4.

• Down syndrome people are more susceptible to Alzheimer and it is in early age.

Minor

• Head Injury

• Low education

• Mental inactivity

• Smoking

• Sedentary lifestyle

• Cerebrovascular disease

• Diet in low fat

Three metals which can be the cause of Alzheimer

The scientists now are thiking about the theory that 3 main metals are strongly linked with Alzheimer’s disease, it is already know that they are neurotoxic and we should keep the balance required daily of those.

IronIt's the fuel that allows red blood cells to transport oxygen throughout the body. But when it comes to brain health, a 2011 study in the journal Neurology showed that people with high hemoglobin (an indicator of iron levels) were more than three times as likely to develop Alzheimer's as

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those with levels in a healthy range.

Get smart: Go easy on meat -- it's loaded with easily absorbable heme iron, which your body can't regulate well. Dark leafy greens can help you meet the recommended daily allowance (RDA) for iron (18 mg for women ages 19 to 50; 8 mg for women 50+). They're also rich in antioxidants that "bind to iron so it can't cause as much damage," says UCLA psychiatry professor George Bartzokis, MD.

Quick fix: Swap out your cast-iron pans for stainless steel. One study found that the iron content of spaghetti sauce increased more than nine times after being cooked in a cast-iron skillet.

AluminumThe aluminum-Alzheimer's link remains hotly contested, but most experts agree that the metal can be a neurotoxin. Although our bodies don't need aluminum to function, it seeps in through antacids ("they can deliver a hundred times more aluminum than you'd get from a day's worth of food," Barnard says); soda cans, which can leach aluminum; and tap water (aluminum can be introduced during purification). In one British study, people with high levels of aluminum in their tap water had a 50 percent increased risk for Alzheimer's compared to those with the least exposure.

Get smart: Call your local water supplier and ask for the aluminum level. "If your city's range is anything higher than undetectable, install an under-sink filter," Barnard says.

Quick fix: Store your leftovers in glass; acidic foods like pizza or pasta sauce can absorb aluminum from foil.

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CopperDietary copper (in foods like shellfish, nuts, and beans) is generally safe. But inorganic copper -- the type in multivitamins and tap water -- largely bypasses the liver's filtration system and heads directly to the blood and brain. It's especially dangerous when combined with saturated and trans fats: Research has found that individuals whose high-fat diets included 1.6 or more mg of copper a day experienced a loss of mental function equivalent to an extra 19 years of aging, compared with those who took in an average of 0.9 mg a day.

Get smart: Check your pipes. If you have copper plumbing, let the water run for a minute in the morning before drinking from the tap, to flush out any copper that may have built up overnight.

Morphological features

Macromorphology: Cortical atrophy: wide sulci (frontal, temporal, parietal lobes), narrowed gyri.

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Figura 4

Cortical atrophy: wide sulci (frontal, temporal, parietal lobes), narrowed gyri, compensatory ventricular enlargement (hydrocephalus ex vacuo)

Figura 5

Microscopic Morphology of Alzheimer’s disease

• Neuritic (senile) plaques: dystrophic neurites, amyloid core of Aβ from APP (amyloid precursor protein), it forms grey-pink formations in the

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cortex and more rare in the subcortical region, their sizes are about 20mm-2cm in diameter and hard, it is stained by congo red because of amyloid.

• Neurofibrillary tangles: disorder of the normal skeleton of the neurons in Alzheimer's neurofibers, it contain hyperphosphorylated form of protein tau, it forms big bands instead of thin, this protein is need in norm to make the roles for passage of nutrients to the cells.

• Amyloid angiopathy: narrowed lumens with thikened walls and it depends according of the amyloid concentration.

Pattern:

1. Earliest in the entorhinal cortex

2. Spread to hippocampal formation and isocortex

3. Extend to the neocortex

Microscopically

Senile plaques accumulation of beta amyloid and Tangles which are Nuerofibrillary tau protein.

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Figura 6

Microscopically showing Plaques and tangles

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Figura 7

Amyloid angiopathy by congo red

Figura 8

Clinical features

• Progression is slow (> 10 yrs) but relentless

• Initial symptoms – forgetfulness

• Language deficits, loss of mathematical skills, loss of learned motor skills

• Final stage: incontinent, mute, unable to walk with intercurrent disease, ex. Pneumonia

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Pick’s diseasePicks is a disease of the brain, it is a rare form of dementia and is very serious and my be fatal.

It makes a lot of damage to the brain specially in the frontal and parietal lobes, it is a slow process and takes a while to damage the brain enough that the patient

cant remember basically anything. People with pick’s disease have pick bodies inside their brain, pick’s bodies have certain type off cell in them that needs a great amount of protein (tau), the brain cells shrink and patient lose the memory. Doctors haven't yet discovered clearly what cause the pick’s diesase, there is a theory that is genetically transferred.

The patient with Pick’s disease and details:

• Age in between 45-65. • repeated speech because don’t remember if they said or not• limited and problems during speech• sometimes they are unable to talk at all, because lost all speech area in

the frontal lobe, thus they describe what they want instead.• The patient usually die due to infections such as pneumonia.

Figura 9

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Micro: Hippocampus stained with anti-tau antibody. Many neuronal cell bodies contain sharply circumscribed, spherical cytoplasmic inclusion bodies (Pick bodies)

Figura 10

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Parkinson’s diseaseGeneral considerations

• Establish diagnosis: there are a lot of parkinsonism and not all are Parkinson's disease.

• Age: there are differently treated and thus age has a lot to imply.

• Disability (symptoms and severity) e.g Artist and pensionist.

Features

• Tremor (rest)

• Rigidity

• Bradykinesia/Akinesia

• Decrease facial expression (Mask or parkinsonian face)

• Stooped posture

• Micrographia/ hypophonia

• Postural instability

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Some feature of a parkinsonian patients below

Figura 11 Figura 12

Test of cogweel and patient with rolling pill hand movement

Figura 13 Figura 14

Not all Parkinsonians are Parkinson’s disease:

• Neurodegenerative disorders

Parkinson’s disease

Multiple system atrophy (MSA)

Frontotemporal degeneration

Diffuse lewi bodies disease

• Secondaty parkinsonims

vascular

Medications (neuroleptics

Normal pressure hydrocephalus

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Specific features of Parkinson's disease to distinguish between others parkinsonism

• With

Asymmetric onset

L-dopa responsive

Rest tremor

• Without

Early falls

Cerebellar signs

Pyramidal tract signs

Early dysautonomia

Causes for Parkinson’s disease

• Idiopathic (free radical-induced oxidative damage?)

• Immunological theory (antibodies against the dopaminargic neurons.

• Post-encephalitic

• Post-traumatic

• Ischaemia

• Drug-induced (heroin)

• Toxic damage (CO, manganese poisoning)

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Statistics on Parkinson’s disease

Parkinson rate according to age

We conclude that the Parkinson increase with aging process and the pick is about 60-64 years old

Figura 15

Parkinson rate according to countries

By this map we can conclude that the incidence for Parkinson is higher in most of the cases in high developed countries which people live a longer life

Figura 16

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Path. Physiology

No specific, standard criteria exist for the neuropathologic diagnosis of

Parkinson disease, as the specificity and sensitivity of its characteristic findings

have not been clearly established. However, the following are the 2 major

neuropathologic findings in Parkinson disease:

• Loss of pigmented dopaminergic neurons of the substantia nigra pars

compacta:

The loss of dopamine neurons occurs most prominently in the ventral lateral

substantia nigra. Approximately 60-80% of dopaminergic neurons are lost before

the motor signs of Parkinson disease emerge.

• The presence of Lewy bodies and Lewy neurites

Some individuals who were thought to be normal neurologically at the time of

their deaths are found to have Lewy bodies on autopsy examination. These

incidental Lewy bodies have been hypothesized to represent the

presymptomatic phase of Parkinson disease. The prevalence of incidental Lewy

bodies increases with age. Note that Lewy bodies are not specific to Parkinson

disease, as they are found in some cases of atypical parkinsonism, Hallervorden-

Spatz disease, and other disorders. Nonetheless, they are a characteristic

pathology finding of Parkinson disease.

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Pathological anatomy

• Pathology Pallor of the substantia nigra; decrease in number of pigmented neurons and other neurons in the same region show shrinkage and vacuolation.

• Loss of neurons replaced by macrophage

• Marked degree of astrocyte gliosis.

• Lewy bodies (hyaline bodies)

Macro Specimen in Parkinson’s disease

Macro specimen in cross section of the mesencephalon showing the disappearance of substantia nigra containing dopaminergic neurons.

Figura 17

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Macro specimen showing the disappearance of substantia nigra and in micro the the intracytoplasmic lewy body.

Figura 18

Prognosis of Parkinson’s disease

The severity of Parkinson's disease symptoms vary greatly from individual to individual and it is not possible to predict how quickly the disorder will progress. Parkinson's disease itself is not a fatal disease, and the average life expectancy is similar to that of people without the disease. Secondary complications, such as pneumonia, falling-related injuries, and choking can lead to death. There are many treatment options that can reduce some of the symptoms and can prolong the quality of life of an individual with Parkinson's diseas

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Huntington’s disease• HD runs in family and affects about 110,000 people in western countries,

and those people have 50% chance to pass it on each time they have a child.

• It cause the brain to malfunction, which cause the people with HD to have problems in movement, thinking and mood.

• The symptoms starts aroud 30-50 for most of HD patients, but 6% may develop it in childhood and most patients die after 20-30 years after the symptoms appear.

Path. Physiology

In the DNA there is a sequence of CAG in the DNA structure, this is a abnormal sequence and it starts to produce a 36 aminopeptide of glutamete which is toxic to the glutaminergic neurons in the basal ganglia, specially the striatal.

This protein accumulates in the neurons and interfere with the functional system of the cells and leading to its death.

Pathological anatomy

• It is a neurodegenerative disorder specifically in the basal ganglia.

• Basal ganglia helps us to control the movement that we want to start or stop and organize thoughts and regulate emotion, thus the disease cause the neurons in the basal ganglia to degenerate and thus arising the symptoms.

• Small brain, atrophy of caudate nucleus and putamen, Secondarily atrophic globus, pallidus and dilated ventricles, Frontal and less often parietal, severe loss of striatal neurons with fibrillary gliosis

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The difference between a normal brain and a HD brain

Figura 19

Figura 20

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Symptoms of Huntington’s disease

1) Movements are the most significant, they feels restlessness and jerking movements (chorea).

2) Loss of control of emotion: said, anxiety, aggressive and social innapropriate.

3) Depression

4) it begins to be difficult to talk, walk, writting and solving tasks

5) Loss of attention and cant organize the thoughts

6) Difficult to thinking.

Prognosis

• There is no cure for the disease, there are only palliative treatment to relieve the symptoms like Chorea, instability of emotions, depression and so on.

• The lifetime of the disease is around the age of 40 or 50.

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Amyotrophic sclerosis, Motor neurone disease or Lou Gehrig’s disease

Degenerative disorder of the peripheral nervous system

• Degeneration and death of motor nerves

– Upper Motor Neuron

• within brain/spinal cord

– Lower Motor Neurons

• leaves brain (stem)/spinal cord

• Relatively spared

– Eye movements and bowel/bladder function

Epidemiology

• Etiology – unknown

• Average age of onset mid-50’s

• Mode of transmission

– Sporadic – 90-95%

– Familial – 5-10% (autosomal dominant)

• Male : Female – 3:2

Clinical features

• Lower motor neuron signs

– Weakness, muscle wasting, hyporeflexia, muscle cramps, fasciculations

• Upper motor neuron signs

– Spasticity, hyperreflexia, weakness, faciculations

• Asymmetric Weakness – most common

• Onset single limb or bulbar

• Local spread then regional spread

– Bulbar, cervical, thoracic, lumbosacral

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Pathological Anatomy

The dying neurons are replaced with proliferating astrocytes (a type of glial cell) in a process known as gliosis. This proliferation of glial cells leads to "glial scarring".

In addition, amyotrophic lateral sclerosis neurons also have intracellular inclusions when viewed under the microscope. These inclusions are composed of different abnormal protein molecules that can be phosphorylated or ubiquinated. A specific type of inclusion known as a Bunina body is also commonly seen.

Figura 21

Prognosis for amyotrophic lateral sclerosis

• ALS is a fatal disease. Median survival is 3 years from clinical onset of weakness. However, longer survival is not rare. About 15% of patients with ALS live 5 years after diagnosis, and about 5% survive for more than 10 years. Long-term survival is associated with a younger age at onset, being male, and limb (rather than bulbar) symptom onset. Rare reports of spontaneous remission exist

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Conclusion

In general overview degenerative disease are more prevalent in aging people than in young people, in young people it’s more prevalent infectious disease, it affects people nearby to the age of 60 years old and it is a disease more distributed in well developed countries because of the long life time of the citizens, but it not only aging is a major factor for degenerative disorders, the sex is a factor also which differ from each disease, for example men are more predisposed to Parkinson and women are predisposed to Alzheimer’s disease.

Also genetic plays a very important role in all degenerative disease, like in Alzheimer by finding the high level of APOE4 (Apo lipoprotein E4) in people from Nepal and other countries which the life time is shorter than in well developed countries, there are many factors like low educations (may be people which are high educated have a high financial status), stress, professional occupation, sleep disorders, head injury which caused changes in brain architecture, estrogen replacement therapy, pharmacological therapy (often may lead to parkinsonism), and so on, these factors can lead to degenerative disorders or can progress them to a grave stage.

Unfortunately science didn’t find the radical cure for these diseases, but they are trying and there are many palliative pharmacological therapies to minimize their suffering and give them a better life, we should always have patience with such patients, because they are aware that they are not as they were before as person and because of this may lead to a very profound depression and may worse the stage of the disease, we should motivate them to go on and make them hope for a better time to come.

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References

• Harrison’s principles of Internal Medicine, 16th edition, chapter 350, pag 2393, Alzheimer’s Disease and other Dementias, by thomas D. bird/ Bruce L. Miller.

• Harrison’s principles of Internal Medicine, 16th edition, chapter 351, Pag 2406, Parkinson’s Disease and other Movement disorders, by Mahlon R. Delong/ Jorge L.Juncos

• Harrison’s principles of Internal Medicine, 16th edition, chapter 353, Pag 2424, Amyotrophic lateral Sclerosis and others motor neuron disease,

• http://en.wikipedia.org/wiki/Alois_Alzheimer

• http://www.epgonline.org/login. cfm ?path=www.epgonline.org ~parkinsons - disease~about~making - a-diagnosis-of-parkinsons-disease . cfm~pageid ~2308

• http://www.holistic-doc-pain-support.com/parkinsons-disease.html

• http://www.parkinsons.ie/Professionals_What_Is_Parkinsons

• http://www.epgonline.org/login. cfm ?path=www.epgonline.org ~parkinsons - disease~about~making - a-diagnosis-of-parkinsons-disease . cfm~pageid ~2308

• http://www.medicinenet.com/parkinsons_disease_pictures_slideshow/ article.htm

• http://alexanderthomson.wordpress.com/2011/03/17/parkinsons-disease-and- gene-therapy/

• http://www.medicinenet.com/parkinsons_disease/ page6.htm# what_is_the_prognosis_of_parkinsons_disease

• http://www.alzheimer-adna.com/Gb/Diseases/Pick_disease.html

• http://emedicine.medscape.com/article/1170097-overview

• http://www.nlm.nih.gov/medlineplus/amyotrophiclateralsclerosis.html

• http://emedicine.medscape.com/article/1150165-overview

• http://forum.facmedicine.com/threads/study-3-metals-that-cause-memory- problems.17117/

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References of Photos

http://en.wikipedia.org/wiki/Alois_Alzheimer (Figure 1) http://www.alzheimersreadingroom.com/2010/11/race-gender-and-alzheimers-

disease.html (Figure 2) http://seniorjournal.com/NEWS/Alzheimers/2012/20120308-

New_Alzheimers_Report.htm (Figure3) http://guardianlv.com/2013/10/alzheimers-diabetes-with-a-peanut-allergy/

(Figure 4) http://www.forbes.com/sites/stevensalzberg/2012/02/10/a-possible-

breakthrough-in-alzheimers-treatment/ (Figure 5) http://journals.prous.com/journals/servlet/xmlxsl/

pk_journals. xml_summary_pr ? p_JournalId =2& p_RefId =1192677& p_IsPs =N (Figure 6)

http://ksj.mit.edu/tracker/2010/08/nytimes-default-hypothesis-alzheimers-ma (Figure 7)

http://en.wikipedia.org/wiki/Cerebral_amyloid_angiopathy (Figure 8) http://www.alzheimer-adna.com/Gb/Diseases/Pick_disease.html (Figure 9) http://www.alzheimer-adna.com/Gb/Diseases/Pick_disease.html (Figure 10) http://www.parkinsons.ie/Professionals_What_Is_Parkinsons (Figure 11) http://www.medicinenet.com/parkinsons_disease_pictures_slideshow/

article.htm (Figure 12) http://www.holistic-doc-pain-support.com/parkinsons-disease.html (Figure13) http://www.youtube.com/watch?v=0-t4RTQ0EsM (Figure 14) http://www.medicine.ox.ac.uk/bandolier/booth/neurol/incpd.html (Figure 15) http://www.targetmap.com/ThumbnailsReports/15367_THUMB_IPAD.jpg

(Figure 16) http://alexanderthomson.wordpress.com/2011/03/17/parkinsons-disease-and-

gene-therapy/ (Figure 17)

http://www.neuroanatomy.wisc.edu/virtualbrain/BrainStem/20Substantia.html (Figure 18)

https://www.stanford.edu/group/hopes/cgi-bin/wordpress/2010/06/the-basic- neurobiology-of-huntingtons-disease-text-and-audio/ (figure 19)

https://www.stanford.edu/group/hopes/cgi-bin/wordpress/2010/06/the-basic- neurobiology-of-huntingtons-disease-text-and-audio/ (Figure 20)

http://www.virtualmedstudent.com/links/neurological/ amyotrophic_lateral_sclerosis.html (Figure 21)

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