1. Introduction to degenerative brain disease
Dr. Mamlook Elmagraby

2. Objectives of the lecture:
Upon completion of this lecture, students should be able to:
Know the definition of “dementia” syndrome
List the possible causes of dementia
Explain the basic pathological concepts of neurodegenerative disease, using Alzheimer‟s and Parkinson disease as a classical example
Understand the major clinic-pathological features of Alzheimer disease

3. Objectives of the lecture:
Hypothesize the possible etiologies of Alzheimer‟s disease
List the causes of Parkinsonism
Understand the major clinical and pathological feature of Parkinson disease
Hypothesize the possible etiologies of Parkinson disease

4. Overview
Neurodegenerative diseases are disorders characterized by the progressive loss of neurons
Typically affecting groups of neurons with functional relationships even if they are not immediately adjacent
There are protein aggregates that are resistant to degradation
Protein aggregates may arise because of:
Mutations that alter the protein's forms or disrupt the pathways involved in clearance of the proteins
Imbalance between protein synthesis and clearance
Inclusions nuclear or cytoplasmic aggregates of stainable substances, usually proteins

5. Overview These aggregates are recognized histologically as inclusions
The basis for aggregation:
An intrinsic feature of mutated protein
An intrinsic feature of a peptide derived from a larger precursor protein
an unexplained alteration of a normal cellular protein
Degenerative diseases can be grouped using two approaches:
Symptomatic/anatomic
Pathologic
An intrinsic feature natural or inherent part or quality

6. Degenerative diseases affecting the cerebral cortex
Alzheimer disease (AD) The major cortical degenerative disease
Its principal clinical manifestation is dementia
The most common cause of dementia in the elderly
The disease becomes clinically apparent as:
Impairment of higher intellectual function
Changes in mood and behavior

7. Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging
Causes of Dementia
Major Causes of Dementia
The most common causes of dementia:
Alzheimer’s disease (AD; 60%)
Atherosclerosis and multiinfarct dementia (15%–20%)
Multifactorial dementia or a combination of Alzheimer and multiinfarct dementia (15%)
Various other less common forms of dementia
Some less common forms of dementia.
Parkinsonism (2%)
Chronic alcoholism (2%)
Pick disease (1%)
Huntington disease (1%)
AIDS (1%)
Syphilis (1%)
Creutzfeldt–Jakob disease (very rare, <1%)

8. Alzheimer disease (AD)
Later, progressive disorientation, memory loss, and aphasia Eventually, the affected individual becomes disabled, mute, and immobile Patients rarely become symptomatic before 50 years of age Most cases are sporadic The combination of clinical assessment and modern radiologic methods allows accurate diagnosis

9. Alzheimer disease (AD)
Pathogenesis
The fundamental abnormality in AD is the accumulation of two proteins (Aβ and tau) in specific brain regions
Accumulation of these proteins result in secondary effects including:
Neuronal dysfunction
Neuronal death
Inflammatory reactions
Role of inflammation
Deposits of Aβ stimulate an inflammatory response
Inflammatory response may stimulate the secretion of mediators that cause neuronal injury

10. Alzheimer disease (AD)
Role of Aβ
Aβ is created when the transmembrane protein amyloid precursor protein (APP) is cleaved by the enzymes γ-secretase
Mutations in APP or in γ-secretase (encoded by the presenilin-1 or presenilin-2 gene) lead to familial AD by increasing Aβ generation
The risk for AD is higher in those with an extra copy of the APP gene because this leads to greater Aβ generation
There is evidence that these Aβ generation
Decrease the number of synapses present
Alter the function of synapses that remain

11. Alzheimer disease (AD)
Role of tau
Tau is a microtubule-associated protein present in axons in association with the microtubular network
With the development of tangles in AD, tau
Becomes hyperphosphorylated
Loses the ability to bind to microtubules
Two pathways have been suggested:
Aggregates of tau protein can leads to cell death
Loss of microtubule stabilizing function of tau protein leads to neuronal toxicity and death

12. Alzheimer disease (AD)
Morphology
The brain shows cortical atrophy marked by:
widening of the cerebral sulci
compensatory ventricular enlargement
The major microscopic abnormalities of AD are:
Neuritic plaques
Neurofibrillary tangles
There is progressive and severe neuronal loss and reactive gliosis in the same regions that show plaques and tangles

13. Brains, cerebral atrophy (left) and normal (right) – Gross, dorsal surfaces
Compare the brain of AD patient (left) with that of a cognitively normal person (right).
Note the extensive widening of the sulci and narrowing of gyri in the patient's brain, indicative of substantial loss of brain parenchyma

14. Alzheimer disease (AD)
Neuritic plaques:
Focal, spherical collections of dilated, tortuous, neuritic processes often around a central amyloid core
They are found in the hippocampus, neocortex
There is usually relative sparing of primary motor and sensory cortices
The neocortex is part of the cerebral cortex (cortical parts of the limbic system)
It is involved in higher functions such as sensory perception, generation of motor commands, spatial reasoning, conscious thought, and in humans, language

15. Alzheimer disease (AD)
Neurofibrillary tangles:
Bundles of filaments in the cytoplasm of the neurons that displace or encircle the nucleus
They are commonly found in cortical neurons, hippocampus
A major component of filaments is hyperphosphorylated forms of the protein tau.
Other components include ubiquitin

16. Brain, cerebral cortex, Alzheimer disease, silver stain
The neurofibrillary tangles are densely staining deposits within neuronal cell bodies;
The neuritic plaques, also highlighted in this image, are composed of dystrophic neurites, surrounding a core containing ß-amyloid

17. Alzheimer disease (AD)
Other pathologic findings seen in the setting of AD:
Cerebral amyloid angiopathy
Granulovacuolar degeneration
Hirano bodies
Amyloid angiopathy presents as deposits of amyloid in the small cerebral arteries and arterioles.
These deposits, however, are not specific for AD.
Granulovacuolar degeneration is primarily found in the hippocampus.
Neurons of this area show an increased number of lysosomes in their cytoplasm.
By light microscopy, these lysosomes appear as clear cytoplasmic vesicles with a central basophilic dot.
Hirano bodies appear as elongated bodies composed of actin filaments are also found in the
hippocampus.
They lie adjacent to neurons or, less often, within their cytoplasm.

18. Alzheimer’s disease. Histopathologic findings include the following:
A, Neurofibrillary tangles.
B, Neuritic plaques.
C, Amyloid deposits in the wall of blood vessels.
D, Hirano bodies.
E, Granulovacuolar degeneration of neurons

19. Alzheimer disease (AD)
Clinical Features
The progression of AD is slow but continous
A symptomatic course often running more than 10 years
Initial symptoms are forgetfulness
With progression of the disease other symptoms appear:
language deficits
loss of mathematical skills
loss of learned motor skills

20. Alzheimer disease (AD)
In the final stages of AD, affected individuals may become incontinent, mute, and unable to walk
Intercurrent disease, often pneumonia, is usually the terminal event in these individuals

21. Degenerative diseases of basal ganglia and brainstem
These diseases are frequently associated with movement disorders, including:
Rigidity
Abnormal posturing
Chorea
The most important disorders in this group are those associated with:
parkinsonism
Huntington disease
Chorea Irregular, involuntary movements of the limbs or facial muscles, often accompanied by hypotonia

22. Parkinsonism Parkinsonism is a clinical syndrome characterized by:
Diminished facial expression
Stooped posture
Slowness of voluntary movement
Festinating gait
Rigidity
“pill-rolling” tremor

23. Parkinsonism
This motor disturbance occurs in conditions that have damage to the nigrostriatal dopaminergic system:
Parkinson disease (PD)
Postencephalitic parkinsonism (rare today)
Ischemia of basal ganglia (relatively common)
Drugs (phenothiazine and haloperidol)
Toxins (carbon monoxide poisoning and methanol)
Head trauma, repetitive (boxers)
idiopathic parkinsonism associated with hypotension and other autonomic symptoms
Parkinsonism may also be induced by drugs that affect this system (dopamine antagonists and other toxins)
phenothiazine and haloperidol: antipsychotics

24. Parkinson Disease (PD)
Idiopathic Parkinson disease damages neuronal pathways from the substantia nigra to the corpus striatum
This damage results in dopamine depletion of the corpus striatum
Therapy with L-dopa, a dopamine precursor, is often effective
Familial forms of PD with autosomal dominant or autosomal recessive inheritance exist
Idiopathic PD is the most common cause of parkinsonism
PD disease appears clinically most often after 50 years of age
The corpus striatum is a collective name given to the caudate nucleus and lentiform nucleus within the basal ganglia.
substantia nigra a basal ganglia structure

25. Parkinson Disease (PD)
Pathogenesis.
Abnormal protein and organelle clearance due to defects in autophagy and lysosomal degradation have a pathogenic role in the disease
Mutations and duplications of the gene encoding α-synuclein cause autosomal dominant PD
Several mutations associated with PD are in genes whose products (e.g. Parkin) all appear to have roles in autophagy
Autophagy lysosomal digestion of a cell's own cytoplasmic material
Turnover degradation

26. Parkinson Disease (PD)
Morphology
Histologic manifestations include depigmentation of the substantia nigra and locus ceruleus
The loss of the pigmented neurons is associated with gliosis
Damaged cells contain intracytoplasmic inclusions (Lewy bodies)
Lewy bodies :
cytoplasmic, eosinophilic inclusions
single or multiple
round to elongated
They often have a dense core surrounded by a pale halo
These bodies are filaments composed of α-synuclein
Filaments & Microtubules
The cytoskeleton of a cell is made up of microtubules, actin filaments, and intermediate filaments. These structures give the cell its shape and help organize the cell's parts. In addition, they provide a basis for movement and cell division
substantia nigra a basal ganglia structure
locus ceruleus a nucleus in the pons of the brainstem involved with physiological responses to stress and panic. It is a part of the reticular activating system

27. Midbrains, normal (left) and Parkinson disease (right) – Gross, horizontal sections
A transverse section of the midbrain from an elderly patient with a history of abnormally slow voluntary movement, festinating gait, pill-rolling tremor, and rigidity is shown on the right.
Compare with a section of normal midbrain taken at the same level on the left

28. Brain, substantia nigra, Lewy bodies
This image illustrates Lewy bodies in the cytoplasm of pigmented neurons of the substantia nigra.

29. Parkinson Disease (PD)
Clinical Features.
The movement disorder associated with loss of the nigrostriatal dopaminergic pathway is an important feature of PD
PD commonly manifests as a movement disorder in the absence of a toxic exposure or other known underlying etiology
The disease usually progresses over 10 to 15 years, eventually producing severe motor slowing to the point of near immobility
Movement symptoms of PD initially respond to L-DOPA, but this treatment does NOT slow disease progression
Aspiration: the act of inhaling fluid or a foreign body into the bronchi and lungs

30. Parkinson Disease (PD)
Over time, L-DOPA becomes less effective
Lesions in the brain stem can give rise to sleep disorder often before the motor problems
Dementia emerges in many individuals with PD and is attributable to involvement of the cerebral cortex
Death usually is the result of:
Aspiration pneumonia
Trauma from falls caused by postural instability
sleep disorder insomnia (the inability to obtain an adequate amount or quality of sleep) and excessive daytime sleepiness