Introduction to degenerative brain disease Dr. Mamlook Elmagraby

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

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

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

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

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

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%)

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

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

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

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

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

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

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

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

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

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.

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

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

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

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

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

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

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

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

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

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

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

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

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