NeuroDegen Diseases

Describe ALZHEIMER DISEASE (AD)

• Stats

• Genetic Stats

• Clinical Presentation

• Patho

• STATS

  • MCC of dementia

  • onset > 50 yrs.

  • Prevalence increases with increasing age

• Genetics Stats :

  • Majority = sporadic

  • 5 - 10% = familial

  • Trisomy 21 -> develop manifestations of AD

• Clinical Presentation:

  • impairment of higher intellectual function, 

  • memory loss,

  • isorientation, 

  • poor judgement, 

  • Aphasia,

  • alterations in mood & behavior  

• Pathogenesis:

  • formation of amyloid beta peptide (AB)

    • an amyloidogenic peptide

NOTE:

• Clinical assessment and imaging studies allow accurate Dx in 80% to 90% of cases

Describe the generation of Amyloid-Beta Peptide (Aβ)

1. List the Evidence implicating AB in the pathogenesis of AD

2. Which gene is largely responsible for AD

   • Alleles?

   • Fxn

   • How it increases risk

3. Describe the gross and Histological associations w/ AD

Evidence implicating AB in the pathogenesis of AD

• found in brains of patients with AD

• relatively specific for AD

• AB = neurotoxic ( in vitro evidence)

• some forms of familial AD have mutations in APP gene -> produces AB

• APP gene= on chromosome 21 -> trisomy 21  -> gene dosage -> increases production of APP -> AB

• mutations in genes encoding presenilin-1 & presenilin-2 -> familial AD -> increases y-secretase activity -> production of AB

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ApoE Gene

• Alleles:

  • E2, E3, E4 -> Isoforms ApoE2, ApoE3, & ApoE4

• Fxn:

  • facilitate clearance of Aβ from the brain

• ApoE4 = increases risk of AD 

  • not as efficient as other isoforms in clearance of Aβ

  • increases production of Aβ42

  • exacerbates tau hyperphosphorylation

NOTE:

Mutations in tau gene -> Frontotemporal Lobar Degenerations, but not AD

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• Gross:

  • Cortical atrophy w/ secondary ventricular enlargement

    • Esp in frontal, temporal & parietal lobes,

  • medial temporal lobe are involved early -> atrophic in later stages

• Histology:

  • Neuritic Plaques: 

    • spherical collections of neuritic processes surrounding a central core of amyloid (AB)

  • Neurofibrillary Tangles

    • cytoplasmic bundles of paired helical filaments composed of hyperphosphorylated tau

  • Cerebral Amyloid Angiopathy: 

    • vascular deposits of amyloid (AB40)
      
      

What does a normal brain look like vs one w/ AD

Describe CTE

• Pt Profile

• Pathogenesis

• Clinical Manifestations

• Pathologic findings

Chronic Traumatic Encephalopathy (CTE)

• Pts Profile:

  • individuals w/ history of mild repetitive TBI

  • Clinical onset of CTE can range from the 2nd to the 7th decades of life

• Pathogenesis:

  • DAI

    • Diffuse Axonal Injury

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Clinical manifestations

• Behavioral & mood disturbances

  • Impulsive behavior

  • Mood swings with outbursts of rage

  • Substance abuse

  • Depression with suicidal behavior

• Dysarthria

• Dementia

• Ataxia

• Parkinsonism

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Pathologic Findings 

• Cerebral atrophy w/ enlargement of ventricles

• Fenestrated cavum septum pellucidum

• NFTs around small blood vessels in cerebral cortex, particularly @ depths of the sulci

  • Severe: NFTs are present throughout the brain

• TDP-43 inclusions

Describe Frontotemporal Lobar Degenerations (FTLDs)

• What is it?

• Clinical Manifestations

• STATs

• Pathos

  • Two types?

• What is it?

  • Heterogeneous group of disorders associated w/  focal degeneration of frontal and/or temporal lobes

• Clinical Manifestations:

  • Alterations in personality, behavior, and language

  • Precedes memory loss

  • Dementia (as it progresses)

• STATs

  • same frequency as AD in those < 65

• Patho:

• Caused by aggregation of specific proteins

  • Two Types

    • FTLD-tau

    • FTLD-TDP

Describe Pick Disease

• What is it?

• Clinical Manifestations

• Genetics

• Patho

• Morphology

• What is it?

  • FTLD-tau

• Clinical Manifestations:

  • Behavioral and personality changes

  • Language disturbances

• Genetics:

  • Most cases are sporadic

  • Familial forms due to mutations in the MAPT gene

• Patho:

  • Aggregation of tau w/in neurons

• Morphology

  • Atrophy of frontal & temporal lobes

  • “Knife-edge” atrophy

  • Marked neuronal loss with reactive gliosis

  • Many residual neurons exhibit “Pick bodies”

Describe PARKINSON DISEASE (PD)

• Genetics

• Clinical manifestations

• Patho. (theories)

• Histo

• Neurochem

• Rx

PARKINSON DISEASE (PD)

• Genetics:

  •  appears in the 6th - 8th decades

  • Most = sporadic, some autosomal dom./recessive

• Clinical Manifestations:

  • Decreased Face. expression

  • Stooped posture, 

  • festinating gait, 

  • bradykinesia, 

  • rigidity & pill rolling tremor, 

  • ± dementia

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Pathogenesis (theories):

• Aggregation of alpha-synuclein w/in neurons

  • major component of Lewy Bodies

  • autosomal dominant forms: mutations in the alpha-synuclein gene (SNCA)

• mitochondrial dysfunction

  • Decreases ATP, Increases ROS + release of Cyt. C

  • PINK1 & parkin are involved in mitophagy

    • Mutation in genes = AR forms of PD

•  mutations in glucocerebrosidase gene

  • impairment of autophagy -> accumulation + aggregation a-synuclein

• exposure to toxins

  • pesticides

---

• Histology: 

  • loss of pig. Dopa neurons in substantia nigra w/ gliosis,

  • intracytoplasmic Lewy bodies

• Neurochemistry: 

  • marked depletion of dopamine in the striatum

• Rx: 

  • L-DOPA

Describe the relationship between Parkinson Disease & Dementia

• Relationship

• Pt. Presentation

• Characteristic Clinical features

• Mech

• Terminology

Parkinson Disease & Dementia

• Relationship:

  • 50 – 80% of patients with Parkinson disease will eventually develop dementia

• Pt. Presentation:

  • Some have pathologic evidence of AD

  • Some have Lewy bodies in cortex + brainstem

• Characteristic clinical features

  • fluctuating course

  • hallucinations

• Mechanism:

  • neurons take up aggregates of α- synuclein -> PD spreads from lower brainstem up to cortex

• Terminology:

  • "Dementia with Lewy Bodies"

    •  If dementia develops before, concurrently with, or within 1 yr. of PD onset

  • “Parkinson Disease Dementia”

    • If PD has been present for at least 1 yr. before development of dementia

Describe HUNTINGTON DISEASE (HD)

• Genetics

• Anticipation

• Patho

• Clinical

• Morph.

HUNTINGTON DISEASE (HD)

• Genetics:

  • HTT gene on chromosome 4p encodes a protein “huntingtin”

    • encodes a polyglutamine tract in huntingtin

  • trinucleotide (CAG) repeat in coding region -> abnormal huntingtin

• Anticipation:

  • The greater the # of trinucleotide repeats, the earlier the onset of disease

  • # of CAG repeats in a mutated HTT gene tends to increase during spermatogenesis

• Pathogenesis:

  • Mutant huntingtin -> bind various trxn factors ->   transcriptional dysregulation

  • proteasomal and autophagic degradation pathways Disruption

---

• Clinical:

  • Choreoathetosis, 

  • affective disorder

  • Dementia

  • Progress to death in ≈ 15 yrs

• Morphology:

  •  caudate nucleus & putamen

    • Atrophy

    • Loss of neurons with gliosis

  • Atrophy of frontal cortex w/ 20 dilatation of the ventricles

  • Intranuclear inclusions in surviving neurons

  • Cortical neurons are less severely depleted

NOTE:

• Direct relationship between the degree of neuronal loss in the striatum & the severity of clinical Sx’s

Describe AMYOTROPHIC LATERAL SCLEROSIS (LOU GEHRIG’S DISEASE)

• What is it?

• STATs

• Genetic Factors

• Potential Proteins/Genes involved

• ENV factors

• Patho

• Clinical Manifestations

• What is it?

  • Worldwide degenerative disease of motor neurons  progressive muscle weakness

• STATs

  • incidence ≈2 per 100,000

  • Onset 5th decade or later, M/F 1.5-2 /1

• Genetic Factors:

  • Familial ALS accounts for up to 20% of cases

  • two dozen genetic loci 

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Potential Proteins/Genes involved

• Mutation in gene encoding SOD1: 20% of fam. Cases

  • SOD1 misfolds + aggregates -> death of motor neurons

    • Aggregation can occur w/o gene mutation

• These Proteins -> both ALS & FTLD simultaneously

  • C9orf72

    • (GGGGCC) repeat in noncoding region

    • 40% of familial ALS & 8-10% of sporadic ALS cases

  • TDP-43

  • FUS

---

Environmental Factors

• Pesticides

• Heavy metals

• beta-N-methylamino-L-alanine (BMAA)

  • produced by cyanobacteria (blue-green algae)

  • can be incorporated into proteins -> misfolding

---

Pathology:

• Loss of LMN in Ant. Horn of Spinal Cord

  • (Progressive Muscular Atrophy)

• Loss of UMN in motor cortex w/ 2° loss of axons in the lateral columns

  • (Primary Lateral Sclerosis)

• Involvement of CN motor nuclei 

  • (Progressive Bulbar Palsy)

• TDP-43 cytoplasmic inclusions

  • When C9orf72 & TDP-43 involved

---

Clinical:

• Weakness of hands 

  • often early symptom

• spasticity of extremities with + Babinski sign

• Progressive muscle weakness & wasting, fasciculations

• Difficulty with speech & swallowing

• Respiratory muscle weakness  

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NOTE:

• course is ≈ 3-5 yrs.

• Some ALS patients also have FTLD

Describe Spinocerebellar Degenerations

• What is it?

• MOA?

• What is Spinocerebellar ataxias

• What is it?

  • Group of degen diseases characterized by involvement of the:

    • Cerebellum

    • Spinal cord

    • Peripheral nerves

• MOA:

  • Loss of neurons in affected areas -> secondary degeneration of white-matter tracts

• Spinocerebellar ataxias

  • Group of AD inherited spinocerebellar degenerations

  • 35 distinct subtypes

  • Many subtypes caused by trinucleotide repeat expansion mutations

Describe Friedreich Ataxia

• STATs

• Patho

• Morphology

• Clinical

• Prognosis

STATs

• Most common inherited ataxia

Patho:

•  GAA repeated in 1st intron of the frataxin gene -> defective Frataxin -> MIt. Dysfunction

  • Involved in assembly of iron-sulfur clusters

  • Present in mit. enzyme complexes I and II

---

Morphology:

• Loss of dorsal root ganglion neurons  -> 2degree degen of dorsal roots and dorsal columns

• Loss of Betz cells ->  2degree degeneration of corticospinal tracts

• Loss of neurons in dorsal nucleus of Clarke  -> 2degree degeneration of spinocerebellar tracts

• Loss of neurons in the cerebellum & some cranial nerve nuclei

---

Clinical

• gait ataxia ->  hand clumsiness + dysarthria

  • Onset; first decade of lifeP

• Spastic weakness, + Babinski sign

• Joint position + vibratory sense impaired

• Decreased or absent DTRs

  • may have loss of sensation

• pes cavus 

• Kyphoscoliosis

• Cardiac Involvement

---

Prognosis

• Most patients become wheelchair-bound within 5 years of onset

• Life expectancy is 40 – 50 yrs.

Describe MS

• What is it?

• STATs

• Clinical Progression

• Symptoms

• Gross features

• Microscopic features

MULTIPLE SCLEROSIS (MS)

• What is it?

  • Autoimmune demyelinating disorder

• STATs

  • MC demyelinating disease

  • prevalence ≈ 3/1,000 in the US

  • Most commonly presents 20-40 yrs, mean ≈ 30 yrs

  • F/M ≈ 3:1

• Clinical Progression:

  • Chronic relapsing & remitting course

    • episodes of neurologic deficits over weeks to months, followed by partial recovery

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Symptoms:

• Unilateral visual impairment (optic neuritis)

• Internuclear ophthalmoplegia

• Facial weakness, 

• vertigo

• Ataxia

• sensation & spastic weakness, 

• bladder dysfunction

---

Gross

• Hallmark = Plaque

  • relatively firm well- circumscribed area of dark discoloration in the white matter

  • involves 

    • periventricular white matter (corona radiata), 

    • optic nerves & optic chiasm, 

    • spinal cord

    • others

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Microscopic

• Active plaques

  • ongoing myelin breakdown w/ numerous foamy macrophages 

    • (and some lymphocytes)

  • relative preservation of axons

• Inactive

  • few inflammatory cells, 

  • little to no myelin, 

  • dense gliosis, 

  • Decreased oligodendrocytes +  markedly  decreased axons

Describe MS

• Patho

• Diagnostic Feature

• Genetic Factors

• ENV factors

• Prognosis

Pathogenesis

• Autoimmune

  • Mediated by  CD4+ T cells (TH1 & TH17) -> against CNS antigens

  • Act. Macrophages/Microglial -> demyelination

---

Diagnostic Feature:

•  Oligoclonal bands (OCBs)

  • Restricted bands on CSF electrophoresis composed of IgG

    • Imp in diagnosis/prognosis

---

• Genetic factors

  • 15× higher if a 1st degree relative has the disease

  • Multiple immune system genes are associated with MS

  • HLA-DR15 haplotype = strongest genetic association 

• Environmental factors

  • latitude gradient

    • higher prevalence at higher latitudes both north & south

  • (EBV)

    • May trigger via molecular mimicry

• Prognosis

  • Significant variation in severity of relapses & rate of accumulation of neurologic deficits

  • average lifespan ≈ 7 years shorter than normal 

    • individuals who don’t have MS