Pathogenesis of Degenerative Diseases and Dementias D r. Ali Eltayb ( U. of Omdurman. I ). M. Path (U. of Alexandria)
Dementias Defined: as the development of memory impairment and other cognitive deficits with preservation of a normal level of consciousness. Is NOT part of normal aging. Always represents a PATHOLOGIC process. 3
Degenerative Diseases It is a group of a diseases affecting gray matter characterized by: progressive selective loss of neurons with associated secondary changes in white matter tracts. presence of protein aggregates that are resistant to degradation is an important feature in microscopic diagnosis.
Characteristics of neurodegenerative disease Insidious in onset Progressive course Selective death/dysfunction of neurons Etiology unclear
Examples of neurodegenerative disease Alzheimer s disease Parkinson s disease Huntington s disease Frontotemporal dementia Amyotrophic lateral sclerosis (Lou Gehrig s disease) Spinocerebellar ataxia
Neurodegenerative diseases Diseases that affect cerebral cortex primarily (e.g., Alzheimer disease) are more likely to cause cognitive change, alterations in personality, and memory disturbance..diseases that affect basal ganglia (e.g., Huntington or Parkinson disease) have motor symptoms as prominent clinical features.
the Diseases that affect cerebral cortex primarily Epidemiology Most common cause of dementia in the elderly. Prevalence increases with age. the incidence of Alzheimer disease is : 3% for individuals 65 to 74 years old, 19% for 75 to 84 years 47% for 85 years or more. cdown syndrome has a strong association with AD. 9
Pathogenesis 1. Accumulation β-amyloid (Aβ) protein (Neuritic plaques) in following sites:medial temporal lobe,frontal cortex. Aβ is a metabolic product of amyloid precursor protein (APP) 2. Formation of neurofibrillary tangles that contain the tau protein. Action of Aβ: (1)Neuronal and synaptic dysfunction ( 2)Signaling for neuronal apoptosis. ( 3)A local inflammatory response result in further cell injury. ( 4)the protein tau aggregates into tangles causing neuronal dysfunction and cell death. ( 5)deposits in the wall of cerebral vessels producing amyloid angiopaihy. 10
Continued Alzheimer Disease Mechanism of formation Aβamyloid protein 11
Morphology Gross: 1. cortical atrophy with widening of the cerebral sulci that is most pronounced in the frontal, temporal, and parietal lobes. Occipital lobe is usually spared. 2. compensatory ventricular dilatation (hydrocephalus ex vacuo). 12
Morphology 13
14
Morphology Microscopic: Extracellular Neuritic plaques. Neurofibrillary tangles(not specific). Amyloid angiopathy: (1) Aβ is present in cerebral vessels. (2) Causes weakening of vessels with increased risk for hemorrhage Neuritic plaques IHC for Aβ 15
Clinical findings insidious impairment of higher intellectual function, with alterations in mood and behavior. progressive disorientation, memory loss, and aphasia indicate severe cortical dysfunction. loss of ADLs, over the next 5 to 10 years, the patient becomes profoundly disabled, mute, and immobile. Death usually occurs from intercurrent pneumonia or other infections. 16
Parkinsonism is a clinical syndrome characterized by: diminished facial expression (masked faces), stooped posture slowness of voluntary movement festinating gait (progressively shortened, accelerated steps) Rigidity "pill-rolling" tremor. In parkinsonism there is alteration in Dopaminergic pathways involved in voluntary muscle movement damage to dopaminergic neurons of the substantia nigra or to their projection to the striatum. 19
Parkinsonism Causes Parkinsonism: Drugs: dopamine antagonists that affect dopaminergic neurons of the substantia nigra, antipsychotic drugs (e.g.. phenothiazines). Toxins: e.g. Addiction to MPTP. a derivative of meperidine l-methyl-4-phenyl-1.2.3.fttetrahydropyridine. Chronic carbon monoxide poisoning. 20
Parkinsonism Causes Parkinsonism: continued Diseases: Idiopathic Parkinson disease. post-encephalitic parkinsonism (associated with the influenza pandemic) multiple system atrophy. progressive supranuclear palsy corticobasal degeneration some cases of Huntington disease. Encephalitis, ischemia. 21
Idiopathic Parkinson disease (PD) Is the most common parkinsonism. Diagnosis is made if their is: 1. No other etiologic causes (e.g. toxins). 2. Clinical response to (l-dopa). 22
PD: Fpidemiology (1) Occurs between 45 and 65 years of age (2) Distribution is equal in men and women. (3) Most cases are sporadic. (4) Familial forms with autosomal dominant and recessive inheritance exist. 23
PD: Pathogenesis No unifying pathogenic mechanism in PD. SO suggested possible mechanism include: Neuronal accumulation of misfolded protein α-synuclein cause neuronal death (gliosis) Defective proteosomal function Altered mitochondrial function 24
PD: Pathogenesis All the above mentionmed mechanism Contribute to: Degeneration /depigmentation of neuron in substantia nigra causes : 1. Deficiency of dopamine 2. Presence of intracytoplasmic eosinophilic inclusion (Lewy bodies -ubiquitinated damaged neurofilaments. 25
PD: Morphology Macroscopic: Pallor of the substantia nigra. Microscopic: Loss of the pigmented, catecholaminergic neurons, gliosis. Lewy bodies: It is a cytoplasmic eosinophilic inclusions often have a dense core surrounded by a pale halo composed of α-synuclein. 26
PD: Clinical pictures and Treatment Tremor, Rigidity, Bradykinesia, and Masked faces, dementia 10-15% dementia Symptomatic ttt: L-DOPA effective in early neural transplantation (HOPE IN FEUTURE) gene therapy and stem cell injection 27
Huntington`s disease is an inherited autosomal dominant disease characterized progressive movement disorders(chorea) and dementia with degeneration of the striatum (caudate and putamen). Middle age
Huntington`s disease pathogenesis: Huntington disease is caused by trinucleotide repeat expansionscag in the gene encoding huntingtin, resulting in disease-causing gain of function. Morphology On gross the brain is small and shows striking atrophy of the caudate nucleus and, sometimes less dramatically, the putamen. On microscopic examination there is severe loss of neurons from these regions of the striatum.
Huntington disease. clinical course: jerky, hyperkinetic, sometimes dystonic movements (chorea) affecting all parts of the body The disease is relentlessly progressive, resulting in death after an average course of about 15 years.
Huntington disease.
THANK YOU 32