Neurodegenerative

disorders
Dr. Hafiz Muhammad Irfan
Introduction
• Neurodegenerative disorders are characterized by progressive and
irreversible loss of neurons from specific regions of the brain.
• Prototypical neurodegenerative disorders include:
Parkinsonism________ Loss of neurons from basal ganglia- result in
abnormalities in the control of movements
Huntington disease___
Loss of hippocampal and cortical neurons-leads
Alzheimer s disease to impairment of memory and cognitive function

Degeneration of spinal, bulbar and cortical

motor neurons- leads to muscular weakness
Amyotrophic lateral sclerosis
Prevalence

• Parkinsonism disease (PD) is observed in more than 1% of individuals

over the age of 65.
• Alzheimer disease (AD) affects more than 10% of same population
• Huntington disease (AD) and Amyotrophic lateral sclerosis (ALS) are
relatively rare.
• Currently available therapies alleviate the disease symptoms but do
not alter the underlying neurodegenerative process.
Causes of neurodegeneration
• The process of neural injury results from the interaction of genetic
and environmental influences.
• E.g apolipoprotein E genotype constitutes an important risk factor for
AD. This alter beta-amyloid aggregation.
• Environmental factors may include infectious agents or environmental
toxin. E.g epidemic of encephalitis lethargica may develop PD.
• Similarly, N-methyl-4-phenyl -1…tetrahydrpyridine can induce a
condition related to PD.
Causes of neurodegeneration
• Aging is also associated with a progressive impairment in the capacity
of neurons for oxidative metabolism.
• Production of reactive compounds such as hydrogenperoxide and
oxygen radicals.
• These reactive species can lead to
DNA damage,
Peroxidation of membrane lipids and
Neuronal death.
Cellular mechanism of
neurodegeneration
• HD is transmitted by autosomal dominant inheritance.
• PD, AD and ALS are mostly sporadic without clear pattern of inheritance.
But gene mutation may give rise to disease. e.g;
Gene mutation in α- synuclein, Parkin, DJ-1, PINK1 give rise to PD.
Mutation in the genes coding for the amyloid precursor protein (presenilin).
Mutation in the gene coding for copper-zinc superoxide dismutase (SOD1)
account for ALS.
• Age related decline in the ability to clear misfolded proteins (alpha-
synuclein in PD, amyloid and tau in AD, huntingtin in HD and SOD, TDP-43 in
ALS are the main features of neurodegenerative disorders.
Cellular mechanism of
neurodegeneration
• The presence of excess glutamate in the brain can lead to excitotoxic
cell death.
• These effects are mediated by glutamate receptors particularly N-
methyl-D-aspartate (NMDA).
• Excitotoxic injury contributes to the neuronal cell death that occurs in
acute processes such as stroke and head trauma.
Parkinsonism
• Clinical features include:
Bradykinesia –slowness of movement
Resting tremor-during voluntary movement
An impairment of postural balance- lead to disturbance of gait and
falling
Muscular rigidity
The non-motor features of PD are sleep disorders, depression, and
memory impairment.
Introduction
• Parkinsonism was first described by James Parkinson in 1817.
• The main cause is the loss of dopaminergic neurons of the substantia
nigra pars compacta with the appearance of intracellular inclusions
known as Lewy bodies.
• The loss of dopaminergic neurons is also the feature of normal aging.
• Death usually results from complications of immobility, including
aspiration pneumonia or pulmonary embolism.
• The disorder also affects other brain structures including brain stem,
hippocampus, and cerebral cortex.
Causes of parkinsonism
• Other factors that may produce parkinsonism include
stroke, and
intoxication with DA-receptor antagonists.
• Drugs that may cause parkinsonism include:
Antipsychotics such as haloperidol and thorazine
Anti-emetics such as prochlorperazine and metoclopramide
Pathophysiology
• Dopamine (DA), a catecholamine is synthesized in the terminals of
dopaminergic neurons from tyrosine and stored, released from neurons.
• The action of DA in the brain are mediated by a family of DA-receptor
proteins (D1-D5). All the DA-receptors are G-protein coupled receptors.
• D1 and D5 stimulate the synthesis of intracellular second messenger
cyclic AMP, while D2, D3 and D4 inhibit cyclic AMP.
• D1 and D2 are abundant in the striatum, D4 and D5 present in extra
striatal whereas D3 expression is in nucleus accumbens and olfactory
tubercle.
Pathophysiology
• The basal ganglia can be viewed as a modulatory side loop that
regulates the flow of information from the cerebral cortex to the
motor neurons of the spinal cord.
• The neostriatum is the principal input structure of the basal ganglia
and receives excitatory glutamatergic input from many areas of the
cortex.
• Most neurons within the striatum are projection neurons that
innervate other basal ganglia structures.
• Acetylcholine (ACh) and neuropeptides are used as transmitters by
these striatal interneurons.
Pathophysiology

• The outflow of the striatum proceeds along two distinct

routes, termed the direct and indirect pathways.
• The direct pathway is formed by neurons in the striatum
that project directly to the output stages of the basal
ganglia, the substantia nigra pars reticulata (SNpr) and
the globus pallidus interna (GPi); these, in turn, relay to
the ventroanterior and ventrolateral thalamus, which
provides excitatory input to the cortex.
Pathophysiology
• The neurotransmitter of both links of the direct pathway is γ-
aminobutyric acid (GABA), which is inhibitory, so that the net effect of
stimulation of the direct pathway at the level of the striatum is to
increase the excitatory outflow from the thalamus to the cortex.
pathophysiology
• The indirect pathway is composed of striatal neurons that project to the
globus pallidus externa (GPe).
• This structure, in turn, innervates the subthalamic nucleus (STN), which
provides outflow to the SNpr and GPi output stage.
• As in the direct pathway, the first two links—the projections from
striatum to GPe and GPe to STN—use the inhibitory transmitter GABA;
however, the final link—the projection from STN to SNpr and GPi—is an
excitatory glutamatergic pathway.
• Thus, the net effect of stimulating the indirect pathway at the level of
the striatum is to reduce the excitatory outflow from the thalamus to the
cerebral cortex.
Pathophysiology