Neurodegnerative diseases

Alzheimer's Disease (AD)

• Definition & Epidemiology: Most common cause of dementia in older adults

• Pathogenesis: Accumulation of pathogenic A\beta peptides (specifically A\beta 42 plaques🛑intraneuronal) produced via sequential cleavage of APP by \beta-secretase and \gamma-secretase) and hyperphosphorylated tau protein(Neurofibrillary tangles)

+oxdative stress,Neuroinflammation,mitochondrial dysfunction and synaptic dysfunction

• Genetic Factors:

• APP gene located on Chromosome 21 (higher risk in Down syndrome).

• Mutations in APP, Presenilin-1, or Presenilin-2 lead to familial AD.

• Apolipoprotein E (ApoE) on Chromosome 19 strongly influences sporadic risk.

• Gross Morphology: Cortical atrophy with widened sulci (pronounced in frontal, temporal, and parietal lobes) and compensatory hydrocephalus (ventricular enlargement).

• Microscopic Morphology:

• Extracellular neuritic plaques (amyloid core surrounded by microglial cells and astrocytes).

• Intracellular ★ Neurofibrillary tangles (composed of hyperphosphorylated tau).

• Cerebral amyloid angiopathy (CAA).

• Clinical Presentation: ★ Progressive dementia, initial insidious impairment of higher cognitive functions (memory, language, judgment, visuospatial orientation), progressing over 5–10 years to severe disability, mutism, and immobility

Inheritance of Dementia

5 forms of diseases

• 1. Alzheimer’s Disease (AD):rare form is Familial AD (FAD): autosomal dominant pattern with a 50% transmission risk per child

Rare!

   • ⭐️Presenilin-1(PSEN1):Chromosome 14; involved in APP processing.

   •Presenilin-2(PSEN2): Chromosome 1:involved in APP processing and signaling.

   • Amyloid precursor protein(APP):Chromosome 21;directs neuronal migration.

• 2. Frontotemporal Dementia(FTD):heterogenous progressive atrophy of the frontal and temporal lobes.

  1-frontal lobe Behavioural-variant FTD (bvFTD)most familial

2-Temporal lobe Primary Progressive Aphasia (PPA)language loss

  • autosomal dominant ⭐️C9orf72 (most common genetic cause) 9 رقم الكروموسوم

GRN (granulin/progranulin)

MAPT (tau protein)

• 3. Vascular Dementia (VaD):Results from cerebrovascular disease.

  • Heritable Forms:

   • CADASILcerebral autosomal dominant arteriopathy +subcortical infract+leukoencephalopathy:Most frequent heritable form; caused by NOTCH3 mutations (19p13.12) leading to vascular smooth muscle cell degeneration and ischemic stroke leading to migrain w aura

   • CARASIL: Caused by ⭐️HTRA1 mutations (recessive).

   • CAA Cerebral amyloid angiopathy;caused by amyloid-beta deposits from APP mutations (plus PSEN1, PSEN2, TTR, CST3).

   • RVCL retinal vasculopathy with serebral leukodystrophy: Caused by TREX1 mutations which impair DNA repair.

• 4. Lewy Body Dementia (LBD):

  • Characteristics: Marked by microscopic protein deposits (Lewy bodies), cognitive decline, parkinsonism, visual hallucinations, and sleep behavior disorder (survival 5–7 years).

 🛑Autosomal dominant ⭐️when caused by ⭐️SNCA (alpha-synuclein) or rarely SNCB (beta-synuclein); GBA1 gene variants increase risk.

• Early-Onset Dementia (EOD):

  • Etiology Distribution: Led by Alzheimer’s disease (~35%), Vascular dementia (~15-20%), and Frontotemporal lobar degenerations (~10-15%).

Parkinson's Disease (PD)

• Definition: A neurodegenerative disease marked by a hypokinetic movement disorder.

• Pathogenesis: Loss of dopaminergic neurons from the substantia nigra. Associated with protein aggregation, mitochondrial dysfunction, and mutations (e.g., \alpha-synuclein, LRRK2 gain-of-function).

*PD neurotrnasmitter:

⬆ACh and Glutmatae

⬇Dopamine and GABA

(DA⬇→⬇Direct→⬆indirect→⬆GPi inhibition→⬇Thalamus→⬇Cortex→

⬇movement)

*Oxidative stress (ROS) causes Nucleic acid and protein damage + altered DP release+⬆a-synuclein

What protect from OS?DO transporter!

• Gross Morphology: Pallor (depigmentation) of the substantia nigra and locus coeruleus.

• Microscopic Morphology:

• Loss of pigmented, catecholaminergic neurons with gliosis.

Types of PD:

1. Late-onset PD - begins after age 50 • The most common type & the risk of developing this condition increases with age.

2. Early-onset PD -  begins before age 50

3. Juvenile-onset PD -  begins before age 20

Genetics/Inheritance of PD (very variants)

- LRRK2 or SNCA cause Parkinson's disease with autosomal dominant inheritance

LRRK2 - Makes a protein kinas while SNCA - Makes the protein alpha-synuclein. Mutations in SNCA occur in early-onset PD

-PRKN, PINK1 or PARK7 can cause it with autosomal recessive

PINK1 - Makes a protein kinase that protects mitochondria from stress. PINK1 mutations occur in early-onset Parkinson’s disease. • PARK7 - Makes the protein DJ-1, which protects cells against oxidative stress. Mutations in PARK7 cause a rare form of early-onset PD. • PRKN (formerly PARK2) - Makes the protein parkin, which helps cells break down and recycle proteins

• 🛑★ Lewy bodies: Eosinophilic round/elongated cytoplasmic inclusions containing 🛑★ \alpha-synuclein.

• Lewy neurites: Dystrophic processes containing aggregated \alpha-synuclein.

• Clinical Presentation:TRAP

• Clinical triad/quadrad: ★ Resting "pill-rolling" 🛑tremor,🛑Akinesia/bradykinesia, 🛑rigidity, and 🛑Postural instability.

• Additional signs: Diminished facial expression (masked facies), stooped posture, festinating gait (short, accelerated steps).

• Non-motor symptoms: Sleep disorders, dementia with hallucinations (termed Lewy body dementia if dementia occurs within 1 year of motor onset).

• Complications: Death often results from aspiration pneumonia or traumatic falls.

Huntington's Disease (HD)

• Definition: An autosomal dominant ★ hyperkinetic movement disorder.

• Pathogenesis: CAG trinucleotide repeat expansion in the huntingtin (htt) gene on Chromosome 4. Misfolded huntingtin protein accumulates and forms toxic nuclear inclusions.

Normally, the CAG segment is repeated 10 to 35 times within the gene

. ▪ 27 to 35 repeats: do not cause the disease, but can lengthen when passed on.

▪ 36 to 39 repeats: may or may not develop the disease.

▪ 40 or more repeats: almost always develop the disease.

• Target Brain Region: Neurodegeneration and loss of inhibitory neurons in the ★ striatum (caudate nucleus and putamen). Loss of inhibitory control over cortical motor areas causes hyperkinesia.

• Gross Morphology: Small brain with severe atrophy of the caudate nucleus and putamen, dilated lateral and 3rd ventricles, and cortical atrophy (frontal/parietal).

• Microscopic Morphology: Severe neuronal loss and gliosis in the striatum; intranuclear inclusions containing ubiquitinated huntingtin.

• Clinical Presentation:

• Typical age of onset: 35–45 years.

• Motor: Involuntary jerky movements of all body parts (chorea), writhing extremities, unsteady gait, slurred speech.

• Cognitive & Psychiatric: Early forgetfulness, mood swings, thought/affective disorders progressing to severe dementia.

• Course: Persistently progressive over an average course of ~15 years.

Tagem3at

تجميعات محاضرة Degenerative brain diseases:

-444-

-Huntington disease is a CNS disease caused hypokinetic disorder due to

neurodegeneration in caudate and putamen nuclei.

A. True.

B. False.

Answer: False

- 443 -

1. A patient presented with signs of Parkinson’s disease. Which one of the following intraneuronal inclusion will be found?

A. Beta amyloid

B. Alpha synuclein

C. Huntington

D. Tau

Answer: B

- 439 -

2. A patient dies of pneumonia. Biopsy of the brain showed neurofibrillary tangles. Which other symptoms will be present in this case?

A. Progressive dementia

B. Mask face

C. Tremors

D. Chorea

Answer: A

3. A patient presented with signs of Parkinson’s disease. Which one of the following intraneuronal inclusion will be found?

A. Beta amyloid

B. Alpha synuclein

C. Huntingtin

D. Tau

Answer: B

4. Pill-rolling tremor is one of the clinical features of Alzheimer’s disease.

A. True

B. False

Answer: False, Parkinson’s disease

5. Which one of the following CNS diseases cause hyperkinetic disorder due to neurodegeneration in caudate nucleus and putamen?

A. Huntington disease

B. Parkinsonism

C. Alzheimer disease

D. MS

Answer: A

#Pathology

#تجميعات