Neurodegenerative Diseases

• SNc → Substantia Nigra

• Norepinephrine locked in ICU → Locus ceruleus

• ↑↑ Dopamine activity → Madly (Schizophrenia) hunting ()

• ↓↓ GABA → ↓↓ inhibitions → during anxiety () and hunting ()

• Norad → patients becomes anxious ()

• ↓↓ AcH → Alzheimer's, Huntintons (↑↑ in Park)

Condition	NT	Location
Alzheimer's disease	↓↓ Acetyl choline	Nucleus basalis of Meynert
Parkinson's disease	Dopamine ↓↓ ↳ bradykinesia ↑↑ Acetyl choline	Nigrostriatal Mnemonic: Mayil (Meynert) Basil (Basalis) nu Achingum (Acetylcholine) Alzheimersum vannu
Addiction	Dopamine	Nucleus accumbens Mesolimbic Location ↳ Medial Frontal area ↳ Ventral tegmental area
ALS	Glutamate Amy → Glue	Hippocampus, Subthalamic nucleus → Memory A-delta fibres → Fast pain
Huntington's chorea	Dopamine ↑↑ GABA ↓↓ AcH ↓↓	Loss of GABA in striatum
Tetanospasmin ↳ spastic paralysis ↳ Presynaptic	GABA	Inhibits release of GABA
Strychnine ↳ spastic paralysis ↳ Postsynaptic	Glycine Stry → Gly	Inhibits release of glycine.
Mesocortical	ㅤ	Prefrontal cortex ↳ Motivation ↳ Emotional regulation ↳ Decision making ↳ Memory
Tuberoinfundibular	Dopamine	• Hypothalamus • Physiologic inhibition of prolactin

Parkinson's Disease

• Reason: Decrease in dopaminergic neurons.

Gross Finding: 

• Substantia nigra appears pale 
  (normally brown due to melanin, which decreases with dopamine).

Microscopic Finding: 

• Presence of Lewy bodies.
• Description: Round bodies, darker in center, whiter at periphery.
• Composition: Made of alpha-synuclein.
• Park (Parkinson's) is synonymous (Synuclein) with lawn (Lewy bodies

Lewy Body Disease (Dementia due to Lewy bodies)

• Second most common overall cause of dementia.

• Subcortex > cortex

Three core features:

1. Fluctuating cognitive impairment (variations in attention/alertness)

2. Visual hallucinations.

3. Motor features of parkinsonism (tremors, rigidity, bradykinesia)

Suggestive features:

• REM sleep behavior disorder.

• Severe neuroleptic sensitivity.

Supportive features:

• Repetitive falls, syncope, transient loss of consciousness.

• Severe autonomic dysfunction.

• Systematized delusions
• e.g., delusion of persecution
• Capgras syndrome.

• Other delusions or hallucinations (auditory, tactile).

Microscopic findings:

• Lewy bodies
• eosinophilic inclusions of alpha-synuclein
• Also found in Parkinsons and MSA
• Lewy Parkin Shy

Differential diagnosis with Parkinson's disease dementia:

• Parkinson's disease dementia:
• Motor symptoms develop first.
• Cognitive symptoms follow (at least 1 year later).
• It is a subcortical dementia.

• Lewy body disease:
• Cognitive symptoms present from the beginning.
• Motor symptoms may be present initially or occur later.

Assessment of Dementia

• Tool: Mini Mental State Examination (MMSE).

• A screening tool for cognitive symptoms.

• Score < 24 out of 30 is suggestive of dementia.

• Developed by Folstein et al.

Progressive Supranuclear Gaze Palsy

 

• Mnemonic: Square frame wave cheythu → Humming bird ullil kude mukalilot parannu poi

• Seen in Atypical Parkinsonism.
• unresponsive to levodopa

• Tauopathy

• a type of Parkinson's plus syndrome.

Multisystem Atrophy (MSA) / shy dragger

• Parkinson's plus syndromes
• α synuclein accumulate in Oligodendrocyte

• Autonomic symptoms (Erectile dysfunction) ++
• recurrent urinary infections

• cerebellar signs

• "bent-over" posture
• (stooped posture observed in idiopathic PD)

• Types
• MSA P → Parkinsonian → Putaminal ring
• MSA C → Cerebellar → Hot cross bun sign

• Lewy Parkin Shy

• Cross cut Bun with a dagger

Corticobasal degeneration

• Alien limb phenomenen

• Parkinson's plus syndromes

Alzheimer's Disease (AD)

• Most common type of dementia.

• Cortical dementia.

• Seen in senile old age (after 70 years).

• Gradual and insidious onset.

• Temporal → Parietal → Frontal

• Slightly more common in females.

• Most common presentation:
• memory deficit.
• Language disturbance and other domains (agnosia, apraxia) affected gradually.

• Genetic Factors:

Genetic Factor	Chr.	Associated Effect
Amyloid Precursor Protein (APP)	21	• Premature Alzheimer's by 30 years in Down Syndrome • due to increased APP • APP → Premature
Presenilin 1 (PS1)	14	ㅤ
Presenilin 2 (PS2)	1	ㅤ
APOE E4 mutations	19	• Results in late onset Alzheimer's • Bad Prognosis • APO E → Early • 4 bad people
Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)	6	• late onset Alzheimer's
APO E2	ㅤ	• Good Prognosis • too (2) good

• Mnemonic (PS): 
• PlayStationil (PS → Presenilin) Game (gamma secretase activity) → from 14 years old (chromosome 14)
• At 21 → Alzheimers () vannu → aappilaayi (APP)

• Diagnosis: 4A
• Amnesia
• Apraxia
• Agnosia
• Aphasia
• → Apraxia/Aphasia:
• Parietal and temporal lobe involvement

Clock face test:

• Hemineglect

• Finds cognition defect > Apraxia

Microscopic Findings:

Neurotransmitters implicated:

• Acetylcholine is reduced.

• Glutamate is increased (can cause excitatory damage).

Screening test:

• MMSE (mini-mental state examination)
• MMSE <24/30 suggestive of Dementia
• MMSE may be false positive in depression

Investigation of choice:

• Functional MRI
• Detects hypometabolism in parietal & temporal lobe

Treatment:

• Cholinesterase Inhibitors:
• Mechanism: Increase acetylcholine levels.
• Drugs: Donepezil, Rivastigmine, Galantamine.
• Rivastigmine and Donepezil
• transdermal patch
• Tacrine not used much (hepatotoxicity).
• Can cause severe GI side effects.

• Memantine:
• Mechanism:
• Non-competitive NMDA antagonist
• decreases glutamate levels
• Used in moderate to severe Alzheimer's disease.
• Can be used as monotherapy or with Donepezil.

• Monoclonal Antibodies for Alzheimer's Disease
• Mechanism:
• Human IgG1 monoclonal antibodies that clear A beta deposits.
• Given as IV infusion.
• Approved for mild cognitive impairment or mild dementia stage of AD.
• Mnemonic (AL D):
• Alzheimer patient says
  “Le i can (Lecanemab) still Adukaam (Aducanumab) → Do None (Donenumab) ”
• Aducanumab.
• Lecanemab (Approved 2023).
• Side effects:
• headache,
• infusion reactions,
• ARIA (Amyloid Related Imaging Abnormalities).
• Donanemab (Approved July 2024).

Normal Pressure Hydrocephalus (NPH):

• Wet-Wacky-Wobbly Grandpa

• Presents with Hakim's triad (Adam's triad):
1. Cognitive impairment.
2. Gait abnormality (magnetic gait).
• Shuffling gait with preserved arm swing
3. Urinary incontinence.

• Treated by shunting.

HIV associated Neurocognitive disorder (HAND)

• HIV + Subcortical dysfunction

• Microglial nodule + Giant cell

Huntington's Chorea

• Autosomal Dominant

• 50-60 years of age.

• Genetics: 
• Involves CAG repeats on the exon of chromosome number 4.

• Increased Proteins: 
• Huntington protein and ubiquitin ↑↑ in caudate nucleus

• U quit (ubiquitin) hunting (huntington protein) in kaadu (caudate)

• Atrophy of caudate nucleus.
• Frontal horn of lateral ventricles dilates.
• MRI head: Boxcar ventricle.

Note

• Corpus Callosum Lipoma
• Shows bracket calcification.
• Mnemonic:
1. C C → Brackets
2. Lip → Put brackets

Important Information

• Neurotransmitters affected:
• Dopamine: ↑↑.
• NOTE: In parkinsonism (Typical or atypical variety):
• Dopamine values are less.
• GABA: ↓↓↓
• ↓ inhibitions
• Low inhibitions and high dopamine when hunting

Callosal dysgenesis/agenesis

• Square root wave sign in cardiac catheterization finding with constrictive pericarditis

Motor Neurone Disease

• Disorder of Hexanucleotide repeats

Three main types:

1. Lower motor neuron type

• Flaccid weakness

• Absent reflex

• Site: Anterior horn cells of spinal cord
• Lesion → current will not flow → LMN lesion

• Progressive muscular atrophy
• Limb weakness
• Areflexia

• Progressive bulbar palsy

---

• Ipsilateral Bulbar Palsy
• Injury to Nucleus Ambiguus (LMN Lesion)
• Features
• (tongue spared)
• Dysphagia
• Dysarthria
• Nasal speech
• Loss of GAG reflex
• High risk of aspiration
• Wasting & fasciculations of palate/pharynx

Region	Location	Structures	Nucleus
Vision	Midbrain	Oculomotor Nerve, Superior Colliculus	Edinger–Westphal (EW) nucleus
Pharynx & Larynx	Medulla	Cranial nerves 9, 10, 11	Nucleus Ambiguus

---

2. Upper motor neuron type

• Spasticity

• Brisk reflex

• Primary lateral sclerosis
• Involves corticospinal pathway

• Pseudobulbar palsy is a sign B/L UMN lesion

• Hoffman’s sign
• Can be present in normal individuals
• UMN lesion above C5–C6 level
• Patient relaxes hand.
• Examiner holds middle finger and flicks the distal phalanx downward.
• Observe thumb and/or index finger:
• Flexion or adduction of the thumb → Positive

3. Both LMN + UMN involvement

Amyotrophic lateral sclerosis

• UMN + LMN.

• M/c: Autosomal Dominant

• Lou Gehrig's disease.

• Mnemonic: Stephan hawking was in love (lou Gehrig. like to eat Banana (Bonina) and drink SODA (SOD1), edavazhiyil (Edavarone) Mulli (Riluzole)

• Gradual onset weakness over years

• Asymmetrical pattern
• Example
• Knee/ankle jerk (left):
• Brisk
• Biceps jerk (right):
• Absent

• Onset Types:
• Limb-onset ALS → Starts in the hands or feet.
• Bulbar-onset ALS → Initial symptoms are difficulty speaking and swallowing.

• Sensory, sexual, and cognitive functions remain intact.

• Clinical Sign: 
• Hoffman's sign positive → Indicates Upper Motor Neuron Lesion (UMNL).

Microscopic Finding: 

• Shows Bonina bodies.

Death due to

• Respiratory failure (Pneumonia)

Management of ALS:

• Increase longevity
• Riluzole
• Edaravone

• New drugs
• Tofersen
• Turursodiol

• Mnemonic:
• ALS padikkan poyapo edavazhiyil (edavarone) Banana (Bonina) and toffee (toferson) turi (riluzole, turursodiol)

UMN + LMN
(absent ankle jerk, extensor plantars):

• B12 deficiency
• posterior columns Sensory loss present → think B12 deficiency

• Friedreich ataxia
• Most common inherited ataxia
• Onset in childhood/adolescence (<15 years)
• Autosomal recessive
• Genetic testing: GAA repeat expansion in FXN gene
• Combination of: ataxia + absent reflexes + cardiomyopathy + scoliosis
• Friedreich = “feet first” mnemonic: gait ataxia, pes cavus

• Amyotrophic lateral sclerosis
• Fasciculations + mixed UMN & LMN signs → think ALS

• GBS is an 
• acute onset (≤4 weeks)
• bilateral symmetrical
• inflammatory
• autoimmune polyradiculoneuropathy.

• Autoimmune Demyelination of peripheral nervous system.

• Ascending, symmetrical, flaccid paralysis.

• 7th cranial nerve is most commonly involved

• Bladder and bowel spared (if involved → transverse myelitis)

• GBS is usually post-infectious (2-3 weeks).
• A/w Campylobacter

• AIDP is most common GBS.

• Antibody: Anti GM1 Antibody.
• NOTE:
• Miller Fisher: Anti GQ1 Antibody.
• Mnemonic: Fish vangan Que nikkanam

• Brighton criteria for diagnosis.
• NOTE: Revised McDonald criteria for Multiple sclerosis.

Pathophysiology

• IgG Antibodies → Bind to Myelin/Axons → Activates complement → Macrophage invasion → Vesicular degeneration

Inciting Factors/Triggers

• Gastroenteritis/URTI (Past 4 weeks):
• Present in 60-70% of GBS cases.

• Campylobacter jejuni (Most common trigger)
• Molecular mimicry implicated.

• CMV (Cytomegalovirus)

• EBV (Epstein-Barr Virus)

• Mycoplasma

• Hep A/B

• HIV

• Zika virus

• Vaccination associated.

• C. jejuni also A/w
• IPSID- Immunoproliferative Small Intestinal Disease/Lymphoma

Features:

• Earliest sign: Distal areflexia.

• Bilateral ascending symmetrical flaccid paralysis.
• Maximum severity of 2 weeks after initial onset

• B/L atonic areflexic paraparesis (Proximal > distal) of lower limbs.

• Equal paralysis of both legs
• quadriplegia

• Neuropathic pain, particularly in the legs
• Large fibre (Aα) sensory loss.

• Truncal paralysis
• Cant sit up in the bed

• Cervical demyelination
• respiratory paralysis

• Neck floppiness.

• 7th nerve palsy (facial diplegia) → M/c CN involved

• In severe cases ➔ Respiratory failure ➔ FVC should be done to assess ventilation

Brighton Criteria for GBS

• Bilateral and flaccid limb weakness.

• Decreased/absent deep tendon reflexes in weak limbs.

• Monophasic course;
• onset 12 hours to 28 days.

• No alternative diagnosis for weakness.

• Albumino-cytological dissociation

• Nerve conduction:
• consistent with GBS (latency increased).

Prognosis

• 80% recover.
• Begins 2-4 weeks after progression ceases.

• 4-15% mortality.

Bad Prognostic Factors

• Autonomic Nervous System
• Labile hypertension (Extreme BP fluctuations).
• Postural hypotension (Orthostatic hypotension).
• Arrhythmias.
• Anhidrosis.
• Tachycardia.

Typical Electrodiagnostic Features (NCS)

• Prolonged latency.

• Decreased conduction velocity.

• Conduction block.

• Absent/prolonged F-wave & H-reflex.

• Temporal dispersion.

LP: Albumino-cytological dissociation.

• CSF cells < 50/ml

• CSF protein concentration > 60 mg/dL.

• CSF opening pressure: normal.

• Sugar: normal.

• Color: normal.

Treatment

• DOC: IV Immunoglobulins.

• Plasmapheresis → PLEX (Plasma Exchange) Therapy

• Both therapies equally effective.

• No role for steroids.

DD

• Transverse myelitis vs GBS
• Bladder/bowel involvement.
• Root pain.
• Urinary incontinence.

Comparison Table

• CIDP (Chronic Inflammatory Demyelinating Polyneuropathy):
• Chronic, >8 weeks.

Classification

• All antibodies associated are IgGs.