(NHN) pathology 4- degenerative disorders of the nervous system

multiple sclerosis

it is a demyleination disorder, it is an autoimmune disease (affects females more) in origin which has defective mylein sheath production leaving the axons exposed.

recurrent episodes (remissions and exacerbations) of demyleination in the brain (including the optic nerves) and spinal cord. it results in progressive neurological deficits (motor or sensory depending on the location of the lesion)

what are the causes of multiple sclerosis?

• genetic → HLA DR 15 mutation

• enviornmental → viral infection, vitamin D deficiency, smoking

pathogenesis of multiple sclerosis?

predisposing factors whether genetic or enviornmental activate the T helper lymphocytes in the blood and cause deficits in the BBB causing these activated T helper cells to pass the BBB going into the brain proper. inside the brain proper the T helper will:

• activate macrophages which phagocytose the mylein sheath on neurones

• activate B lymphocytes causing them to release anti mylein antibodies

• activate T cytotoxic cells which directly attack the oligodendrocytes in the brain

all of these cause formation of mylein fragments which are picked up by APC causing reactivation of more T helper lymphocytes which release cytokines that activate astrocytes leading to reactive gliosis.

how does acute MS progress?

increased macrophages increasing demyleinated plaques

pathologic features of acute MS?

gross → well cricumscribed gray lesions or plaques (gray due to the demyleinated plaques) with bilateral distribution that is not particularly symmetrical and frequently is periventricular.

mic → chronic inflammation around blood vessels in the brain with phagocytosis of mylein by macrophages. axons are initially preserved

how can chronic MS progress?

• inflammation subsides and remyleination plus gliosis occur leading to functional recovery (although the reformed mylein is not as thick and with the same quality as the normal mylein)

or

• complete destruction of nerve due to failure of functional recovery

pathologic features of chronic MS?

no inflammation with axons showing remyleination although the remyleination (functional recovery) is defective (mylein is thinner and is not as good as the normal mylein)

clinical features of MS? (general)

• affects women more than men

• affects people of the 3rd to 4th decade (mid age - 30s, 40s)

• remissions and exacerbations

clinical features of acute MS?

nerve conduction is entirely blocked causing acute neurologic deficit depending on the location of lesion

example:

• if it affects optic nerve → blindness

• if it affects motor nerves → paralyis

• if it affects sensory nerves → sensory loss

• etc…

clinical feature of chronic MS?

slower nerve conduction allowing partial recovery with recurrent acute attack it is reversible but on the long run can cause progressive neurologic deterioration based on the location of lesion.

symptoms of MS?

• early symptoms → sensory problems, paresis (muscle weakness/partial paralysis) and visual dysfunction

• as the disease progresses → fatigue, bladder dysfunction, spasticity and ataxia

diagnosis and treatment of MS?

diagnosed most importantly by clinical history and MRI but also CSF studies and electrophysiological studies can help.

treatment is by immunosuppressive drugs

pathogenesis of parkinsonism?

normally in the brain, there is a protein called alpha synuclein present in either monomer or tetramer form. in parkinsonism, this protein goes through misfolding into oligomers then into fibrils then into lewy bodies (all of these forms of protein are pathogenic)

the lewy bodies start to aggregate in the substantia nigra (whic is responsible for dopamine production) causing destruction and ruining the nerve especially dopaminergic nerves showing parkinsonism symptoms

→ loss of dopaminergic neurones in the substantia nigra leading to tremors, rigidity. akinesia

dopamine normally?

secreted by neurones of the substantia nigra which sends signals to basal ganglia

functions:

• initiate and control patterns of movement by suppressing/inhibiting unintended involuntary movements

• inhibitor neurotransmittor

causes of parkinsonism?

there is no particular or specific cause discovered yet but it is thought to either be

• genetic → SNCA gene mutation (alpha synuclein)

• enviornmental → infection, vascular, toxic, pesticides

symptoms of parkinsonism?

non motor symptoms in the prodromal phase

• hyposmia (decreased or loss of sense of smell)

• sleep disorder

• constipation

• depression

as the disease progresses, motor symptoms start to show:

• tremors

• rigidity

• imbalance

morphology of parkinsonism?

gross → pallor of substantia nigra

mic:

• loss of pigmented (dopaminergic) neurones in the substantia nigra

• residual neurons show lewy bodies which are intracytoplasmic eosinophilic inclusions containing misfolded alpha synuclein

clinical picture of parkinsonism?

it depends on the location of the lesion

• in substantia nigra / nigrostriatal pathaway → movement disorders (akinaesia, rigidity, mask face (lack of facial expressions), tremors, shuffling gait)

• in higher cortex (amygdala, cingulate gyrus) → dementia, psychosis

Huntingtion disease

autosomal dominant disorder which causes degeneration of GABAergic neurones of the caudate nucleus. it is clinical presented with involuntary movements, cognitive decline and behavioural changes.

pathogenesis of huntington disease

normally in the body, there is gene HTT present on chromosome 4 this gene encodes for a protein called huntingtin protein. this protein normally has maximum 26 repeats of the cytosine-adenine-guanine segments (CAG) or in other words glutamine.

in this disease, a mutation occurs on the HTT gene causing there to be an expansion in the number of CAG repeats which can be up to 100-200 repeats. the protein produced will be unstable and can not be removed from the cell so it will aggregate in the GABAergic neurons of the caudate nucleus, this will cause loss of inhibitory influence of extrapyramidal circuits thus leading to chorea

clinical manifestations of huntington’s disease

• clinical onset is typically in decades 3-5 (middle age)

• 3 main symptoms → chorea, cognitive decline and psychiatric symptoms

• chorea is characterised by sudden, unexpected and purposless jerky contractions of proximal muscles while awake

• cognitive decline → dementia

• psychiatric symptoms may predate motor symptoms

• disease progression leads to dependancy and death.

gross features of huntington’s disease

atrophy of the cerebral nerve tissue and basal ganglia with marked enlargement of lateral ventricles

or

atrophy of the caudate nucleus with secondary ventricular dilation

CT scan features of Huntington’s disease

atrophy of cerebral nerve tissue and basal ganglia with marked enlargement of the ventricles

microscopic features of huntington’s disease

loss of small neurones and large neurons later on in the caudate nucleus

diagnosis of huntington’s disease

a definitive diagnosis is made based on the clinical symptoms with an affected parent (autosomal dominant disease).

DNA determination

Prenatal diagnosis

Alzheimer disease (AD)

causes 60% of all cases of dementia. it is the most common cause of dementia in people of age >65

genetic predisposing factors of AD

about 5-10% of AD cases are hereditary with early onset and is transmited as autosomal dominant. there are 3 genes that when mutated cause autosomal dominant AD:

• APP (amyloid precursor protein)

• Presenilin 1 and 2 (PSEN1 and PSEN2)

these 2 mutations cause development of early onset AD (symptoms appear before age 65)

• APOE gene → late onset AD

enviornmental predisposing factors of AD

• aging

• head trauma

high level of education (high mental functionality) is protective against AD

pathogenesis of AD

• Aβ amyloid protein

• tau protein hyperphosphorylation

• cerebral amyloid angiopathy

Aβ amyloid protein pathogenesis pathway

normally, in the cell membrain of nerve cells there is a transmembrane protein named amyloid precursor protein (APP) this protein, like any other protein, goes through enzymatic degradation. normally it is broken down by α-secretase and then followed by γ-secretase producing P3 protein which is easily gotten rid of by the body

in AD, APP instead of being broken down by α-secretase, it is broken down by β-secretase which causes the release of amyloidβ protein (Aβ) which can not be gotten rid of by the body so instead it aggreagates in the form of fibril plaques causing amyloidosis and AD

pathogenesis of tau protein hyperphosphorylation in AD

normally in the neurone, there is a protein called tau. this protein is responsible for stabilising the microtubule, and regulating cellular signaling, neuronal development and cognitive function and therefore leading to good cellular function and memory

in AD, hyperphosphorylation of tau protein occurs, the tau protein becomes unable to perform its function, and its structure becomes very hard to get rid of by the body due to the hyperphosphorylation so it aggregates in the cell body, dendrites and axon of the neurone as neurofibrillary tangles and neuric plaques causing disintegration and loss of mictotubule integrity therefore disrupting cellular signaling and cognitive function leading to dementia.

the body releases metabolites as a way of trying to get rid of the neurofibrillary tau tangles but these metabolites are toxic to the neurones

pathogenesis of cerebral amyloid angiopathy in AD

accumulation of Aβ amyloid within the tunica media of small and medium sized intracerebral and leptomeningeal arteries causing a decrease in the elasticity and viability of the blood vessel which can lead to rupture of the blood vessel thus causing intracerebral haemorrhage.

gross feature of AD

atrophy of affected regions (usually hippocampus and temporal lobes) of the brain with thinner gyri and wider sulci

microscopic features of AD

• neurofibrillary tangles

• amyloid plaques (seen by congo red stain)

clinical presentation of AD

related to site

affected areas are involved in learning and memory.

it has insiduous onset and typically affect people of 7-8 decades (but if there is genetic predisposition it affects earlier ages)

symptoms include:

• progressive memory impairment (early onset short term memory loss and progressively becomes worse)

• alterations in mood and behaviour

• progressive disorientation

• aphasia (loss of language skills)

• apraxia (loss of learned motor skills)

within 5-10 years patient becomes mute and be