Pathology of CNS Degenerative Disorders

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Pathology of CNS Degenerative Disorders Powered By Docstoc
					  “Each individual creature on this
  beautiful planet is here to fulfill a
particular role. We are all born with a
divine fire in us. Our efforts should be
 to give wings to this fire and fill the
 world with the glow of its goodness.
   - Wings of Fire: An Autobiography of Dr. APJ Abdul Kalam (1999)
CNS Degenerative disorders…

CPC 4.3.5 – Helena, 65y Fem.
   Helena is a 65 year old married local GP. She is
    known as a ‘pillar of the community’ and works
    full time as the senior partner at a GP surgery in
    Townsville. She is actively involved in many GP
    related educational activities. Her husband,
    Brad, is a local orthopedic surgeon. Although
    you have been their GP for sometime, they
    seldom consult you. Today they have booked a
    double appointment with you.
     Brad : ‘I’ve come with Helena to discuss some
      memory problems she seems to be having’
     Helena : “I hope it’s nothing; Brad has always been a

CNS Degenerative disorders…

CPC 4.3.5 – Helena, 65y Fem.
 I haven’t been sleeping so well so I think
  my memory is a bit worse- it’s a
  combination of stress and fatigue’
 she can’t remember where she parked the
 She has forgotten social arrangements
  several times
 Couldn’t remember their names …
 she is struggling with organizing…

CNS Degenerative disorders…

CPC 4.3.5 – Helena, 65y Fem.
 Duration of symptoms: ? about 6/12
 Mood: low, quite tearful at times; not
  enjoying life much.
 Concentration: poor, struggling to read
 Sleep: disrupted, often up during early
  hours of morning.
 Appetite and weight: no change
 I am very tired. It’s probably time for me to
CNS Degenerative disorders…

CPC 4.3.5 – Helena, 65y Fem.
 Physical Examination: NAD.
 Cranial nerves, muscle power & tone,
  sensation & reflexes normal.
 Co-ordination + proprioception normal
 MMSE : 30/30 ?, K10 : 36/50 ?
 Word list task : recall of 2 words after 20

CNS Degenerative disorders…

CPC 4.3.5 – Helena, 65y Fem.
   Differential diagnoses: Dementia
     Depression– reactive – family events ?
   Age related Mild cognitive impairement?
   Hormonal e.g. hypothyroidism, drugs etc.
   Alzheimer’s Disease ?
 Physical Examination: motor/sensory/reflexes.
   Investigations:
     FBC, Liver FT & Thyroid FT normal,
     HIV negative. ..?
     CT scan: no space occupying lesion..? some loss of
      grey matter with increased ventricular space. .?

CNS Degenerative disorders…

Brain: Functional areas.



Broca’s area - Cingulate and Parahippocampal gyri.
   Neuro Anatomy
Hippocampus: where
 short-term memories
 are converted to long-
 term memories
Thalamus: receives
 sensory and limbic
 information and sends
 to cerebral cortex
Hypothalamus: monitors
 and controls internal
 clock & other activities.
Limbic system: controls
 emotions and
 instinctive behavior
 (includes the
 hippocampus and parts
 of the cortex)
                       Slide 8
   CNS Degenerative disorders…

  Dendritic tree - vs - Intelligence

Rat CA1 pyramidal cell labeled with EGFP   Synaptic bouton in rat CA1 stratum
 (Two photon laser scanning microscopy)     radiatum (Electron microscopy)
             What is Success?

"To laugh often and much; to win the respect
   of intelligent people and the affection of
 children. To leave the world a better place.
  To know even one life has breathed easier
 because you have lived… that is success..!
            -- Ralph Waldo Emerson
   Pathology of
C.N.S. Degenerative

    Dr. Venaktesh M. Shashidhar
      A/Prof. & Head of Pathology
         James Cook University

CNS Degenerative disorders…

Age related / Senile degeneration:
   Dementia: All spheres of intellect
   Decreasing mass - Slow 4th
    decade – rapid 7th decade.
   progressive neuronal loss
    Neuronophagia. (hippocampus
    and cerebral cortex)
   reduction in size & numbers of
    dendritic branches in surviving
   Cortical atrophy, hydrocephalus.
   Thickening of leptomeninges.
   NF tangles, Aβ Amyloid plaques.
   increase in number of astrocytes
   Athero & artero sclerosis.

CNS Degenerative disorders…

CNS Degenerations: Classification
   Neuronal Degenerations.
     Primary            Degenerations:
           Global – Alzheimer & Lewibody
           Selective/System – Parkinsons, Huntingtons, MND

     Secondary               Degenerations:
           Toxic, metabolic(storage), infections, nutritional.
           Alcohol & B12 def.

   Disorders of Myelin:
     Demyelinating Disorders - Multiple sclerosis
     Dysmylinating disorders – Leukodystrophies.

CNS Degenerative disorders…

   Acquired global impairment of intellect-intact consciousness
   > 15% of adults over 80 are demented…! (>30y, >70y…!)
   Primary & secondary dementias
   Primary:
       Alzheimer's disease
       Diffuse Lewy body disease, Huntington's Dis, Pick's,
   Secondary:
       Cerebrovascular disease – stroke.
       Infections (e.g. Creutzfeldt-Jakob (CJD), syphilis, HIV)
       Neoplasms, haematoma, hydrocephalus.
       drugs and toxins (barbiturates, digoxin, alcohol, heavy metals)
       metabolic disorders (e.g. hypothyroidism, hypoparathyroidism,
        uraemia, hepatic failure)
       vitamin deficiencies (e.g. B1-Wernicke-Korsakoff sy., B2, B12)

CNS Degenerative disorders…

Alzheimer’s disease:
 Commonest cause of dementia in elderly
 insidious with mood and behavior change.
 Prevalence 1% in 6th to >40% 8th decade.
 Pathology:
     Significant cortical atrophy
     secondary ventricular enlargement
     Neurofibrillary tangles – Intracellular (Tau)
     Neuritic plaques (Aβ amyloid) – Extracellular.
     Amyloid angiopathy.

CNS Degenerative disorders…

Aloysius Alzheimer:
   German Psychiatrist.
   1901 - Auguste Deter
     51year male Patient.
     Behavioural abnormality
     Short term memory loss
   Colleague Franz Nissl
     silver
     Observed amyloid
      plaques & NF tangles.
   Case Presented at Berlin
   International Brain
    Research Organization.      Aloysius Alzheimer’s first Patient
CNS Degenerative disorders…

Alzheimer’s – Pathogenesis:
 Deposition of neurotoxic amyloid protein
  (peptide Aβ derived from APP) around
  blood vessels & neurons – extracellular
 Abnormal forms of axonal microtubule
  protein (protein tau) in neurons
  ‘neurofibrillary intracellular tangles’
 Leading to Atrophy of neurons, gliosis.

CNS Degenerative disorders…

Alzheimers Disease:

                                Neurofibrillary tangles &
                              Extraneuronal Neuritic plaques
         Cortical Atrophy
CNS Degenerative disorders…

Alzheimer’s disease: Genetics
   Autosomal dominant genetic pattern – rare.
   4 genes on chromosomes 1, 14, 19, and 21,
    influence initiation and progression.
   Chromosome 21 generates the precursor
    protein for the amyloid protein (APP). Trisomy
    21 produces early Alzheimer's disease in
    persons with Down syndrome.
   Chromosome 19 generates apolipoprotein (apo)
    3 allelic forms ε2, ε3, and ε4, resulting in six
    combinations, of these risk for Alzheimer's
    disease is high with ε4/ ε4 & low with ε2/ε2.

CNS Degenerative disorders…


      Generation of
      Amyloid (Aβ)

CNS Degenerative disorders…

Alzheimer’s - Amyloid Angiopathy

 Cerebrum stained with polyclonal antibody against βA4 peptide showing
 amyloid deposits in plaques in brain substance (arrow A) and in blood
 vessel walls (arrow

Neurons have an internal support structure partly made up of
microtubules. A protein called tau helps stabilize microtubules. In AD,
tau changes, causing microtubules to collapse, and tau proteins clump
together to form neurofibrillary tangles.                              Slide 18
   CNS Degenerative disorders…

  Neurofibrillary Tangles in AD:

C: Neurofibrillary tangles (arrowheads) are present within the neurons (H & E).
D: Silver stain showing a neurofibrillary tangle within the neuronal cytoplasm

CNS Degenerative disorders…

Alzheimer’s - Amyloid Angiopathy

 Congo Red stain & Polarised Microscopy showing apple
 green” birefringence
CNS Degenerative disorders…

Neuron degeneration- granulovcuolar.

  Several neurons display granulovacuolar degeneration of the cytoplasm. B.
  A neuron (center) contains an eosinophilic Hirano body (arrow).

CNS Degenerative disorders…

Cerebral atrophy in Alzheimer's:

                              A-Neuritic Plaque, B-Amyloid
CNS Degenerative disorders…

Cerebral atrophy in Alzheimer's:

CNS Degenerative disorders…

Cerebral atrophy in Alzheimer's:

CNS Degenerative disorders…

Cerebral atrophy in Alzheimer's:

               Severe cortical atrophy, narrow gyri, wider sulci.
White matter loss leading to dilated ventricles (compensatory hydrocephalus).
CNS Degenerative disorders…

          AD Morphology – Early / Preclinical

                              • Degenration starts in the
                                entorhinal cortex, then
                                proceed to hippocampus.
                              • Neuronal loss leads to
                              • Changes can begin 10-20
                                years before symptoms
                              • Memory loss is the first sign
                                of AD.

                                                            Slide 20
CNS Degenerative disorders…

         AD Morphology - Mild to Moderate

                              • Involves cerebral cortex
                              • Mild signs: Memory loss,
                                confusion, trouble handling
                                money, poor judgment, mood
                                changes, and anxiety.
                              • Moderate signs: increased
                                memory loss and confusion,
                                problems recognizing people,
                                difficulty with language and
                                thoughts, restlessness,
                                agitation, wandering, and
                                repetitive statements.
                                                               Slide 21
CNS Degenerative disorders…

                 AD Morphology: Severe AD

                              • Extreme shrinkage of brain.
                              • Patients are completely
                                dependent on others for care.
                              • Symptoms: weight loss,
                                seizures, skin infections,
                                groaning, moaning, or
                                grunting, loss of bladder and
                                bowel control.
                              • Death usually occurs from
                                aspiration pneumonia or other
                                                                Slide 22
   CNS Degenerative disorders…

  Neurofibrillary Tangles in AD:

Plaque around Blood Vessels.     Neurofibrillary Tangles-Intracellular
A β Protein Amyloid              tau protein – Microtubule.

CNS Degenerative disorders…

AD & Intelligence.…!
 In early life, higher skills in grammar and
  density of ideas are associated with
  protection against AD in late life.
 Mentally stimulating activity protects
  against AD.
 Use           it or loose it…..!

    CNS Degenerative disorders…

    Pick’s Disease:
   Severe, 40-65y, Rare.
   Selective Frontal &
    temporal lobe atrophy.
   Progressive aphasia /
    language dysfunction
   Behaviour & personality
   Preserved memory.
   Micro: Neurons with
    round intracytoplasmic
    Pick’s bodies (tau
    protein)                      36
CNS Degenerative disorders…

Knife blade Fronto-temporal atrophy in Picks.

CNS Degenerative disorders…

Knife blade Fronto-temporal atrophy in Picks.

CNS Degenerative disorders…

Picks Disease: Knife blade Fronto-temporal atrophy

    CNS Degenerative disorders…

    Lewibody Disease:
   Next common to AD.
   Dementia+hallucinations.

CNS Degenerative disorders…

CNS Degenerations: Classification
   Neuronal Degenerations.
     Primary            Degenerations:
           Global – Alzheimer & Lewibody
           Selective/System – Parkinsons, Huntingtons, MND

     Secondary               Degenerations:
             Toxic, metabolic(storage), infections, nutritional.
   Disorders of Myelin:
     Demyelinating Disorders - Multiple sclerosis
     Dysmylinating disorders – Leukodystrophies.

CNS Degenerative disorders…

Systemic Degenerations:
 Degeneration in functionally related areas
  of the CNS
 Neuronal death  neuronophagia 
  fibrillary gliosis
 Dementia: Intellectual disability.
 Several types with overlapping features:
 Many show neurotransmitter abnormalities
  (Parkinsons, Alzheimers )
 Mostly unknown Aetiology , some genetic
CNS Degenerative disorders…

   Dementia, depression,
    choreiform movement
    (Jerking dementia)
   5th decade. Autosomal dom.
   Huntington gene on 4p
   Excess CAG tandem repeats
    = severity.
   Atrophy of caudate &
    putamen with compensatory
    hydrocephalus of lateral

CNS Degenerative disorders…


CNS Degenerative disorders…

              Normal           -        Huntington’s


CNS Degenerative disorders…


CNS Degenerative disorders…


    CNS Degenerative disorders…

   "shaking palsy"
   Parkinsonism: Secondary / Clinical
     Drugs       (heroin), toxins, post encephalitis.
   Parkinson’s disease – Primary atrophy of
    substantia nigra. Dopaminergic system.
   Clinical features:
     Diminished    facial expressions, stooped posture,
     Slow voluntary movements, festinating gait, rigidity &
      fine rolling tremors.
     tremor, bradykinesia and rigidity (45-60 years)
     Inhibition of movement & dementia in some cases.

CNS Degenerative disorders…

Pathology of Parkinson’s disease:
   Gross: Loss of pigment in
    substantia nigra.
   Neuronal loss, degeneration,
   Loss of neurons replaced by
    gliosis (microglia)
   Micro: Lewy bodies (hyaline

    CNS Degenerative disorders…


Patient                                     Normal

   The pigmented neurones in the substantia nigra within the midbrain
   degenerate and die off in Parkinson's disease, giving a pale appearance in
   comparison to an age-matched normal control.

   CNS Degenerative disorders…


Surviving neurone in the
substantia nigra contains an
intracytoplasmic Lewy body (L).

CNS Degenerative disorders…

Vascular Dementia: (Multi-infarct)
 Second most common after AD. Different
  from senile dementia.
 Different pathophysiological types.
     Mild vascular cognitive impairment –
     Multi-infarct / single large infarct
     Hypertensive lacunar lesions.
     Binswanger disese – subcortical
      leukoencephalopathy - boxers, trauma.
     Mixed – AD+vascular.

    CNS Degenerative disorders…

   System Degenrations:
Disease                 Sites affected      Clinical features     Genetic basis
Friedreich's ataxia     Spinal cord         Ataxia                CAA triplet expansion in
                        Sensory nuclei      Sensory loss            frataxin gene on 9q
                        Cerebellum          Deafness
                                            Autosomal recessive
Autosomal               Purkinje cells      Ataxia                CAG triplet expansion in
dominant                Granular neurones   Nystagmus               ataxin-1 gene on 6p
cerebellar ataxia       Inferior olivary    Autosomal dominant
type 1                  nuclei              inheritance
Dentatorubro-           Dentate nucleus     Chorea                CAG triplet expansion in
pallidoluysial          Globus pallidus     Myoclonic epilepsy      gene on 12p
atrophy (DRPLA)         Subthalamus         Dementia
                        Red nucleus         Autosomal dominant
Multiple system         Substantia nigra    Ataxia                Unknown
atrophy (Shy-           Purkinje cells      Sensory loss
Drager syndrome)        Pontine nuclei      Tremor
                        Spinal autonomic    Orthostatic
                        nuclei              hypotension
The only real mistake is the one
from which we learn nothing.
CNS Degenerative disorders…

CNS Degenerations: Classification
   Neuronal Degenerations.
     Primary            Degenerations:
           Global – Alzheimer & Lewibody
           Selective/System – Parkinsons, Huntingtons, MND

     Secondary               Degenerations:
             Toxic, metabolic(storage), infections, nutritional.
   Disorders of Myelin:
     Demyelinating Disorders - Multiple sclerosis
     Dysmylinating disorders – Leukodystrophies.

CNS Degenerative disorders…

Demyelinating Disorders:
 Selective myelin damage - axon sparing.
 Defective transmission of impulse.
 Prognosis  repair & axon damage.
 Types & Classification
     Immune   – Multiple sclerosis
     Genetic – Metabolic, Leukodystrophy.
     Vitamin deficiency – Vit B12
     Infections – JC virus

CNS Degenerative disorders…

Multiple Sclerosis
   Commonest. CNS only.
   Autoimmune (Gen+Env+AI)
   Limb Weakness, paraesthesia
   Relapsing & remitting.
   Progressive  death in years.
   Multiple soft pink plaques of
    demyelination- periventricular.
   Inflammation, perivascular T
    lymphocytes & plasma cells.
   CSF - oligoclonal IgG.
   Reactive gliosis.

CNS Degenerative disorders…

  Multiple Sclerosis Plaque:

                              Section of fresh brain
                              showing brown plaque
                              around occipital horn of
                              the lateral ventricle.

CNS Degenerative disorders…

Multiple Sclerosis: Demyelinated plaques

   Microscopy showed loss of
   myelination with many lipid

CNS Degenerative disorders…

Multiple Sclerosis - plaques

CNS Degenerative disorders…

Multiple Sclerosis - plaques

CNS Degenerative disorders…

          MS – Periventricular plaque

                    Like patches of grey matter within white matter…!   62
CNS Degenerative disorders…

MS- Plaques – Myelin stain.

CNS Degenerative disorders…

Multiple Sclerosis – Chronic plaque
   Sharp area of
    myelin loss (white
    area in this blue
    myelin stain)
   Plaque contain
    fibrillary astrocytes.
    A few lymphocytes
    and macrophages
    are present around
    blood vessels (V)
   Normal myelinated
    white matter
    appears blue.

CNS Degenerative disorders…

Lewy body dementia:
   10-15% of Parkinsons with
   Dementia + Hallucinations.
   Lewy body (α-synuclein) in
    many part of cortex &
    substantia nigra.
   Atrophy of cortex like AD.

                                 cortical Lewy bodies (α-
                                 synuclein) special stain.

CNS Degenerative disorders…

Metabolic CNS Disorders:
   Alcoholism induced CNS
     Wernicke           syndrome (vit B1
     Central pontine
     Cortical atrophy
     Atrophy of vermis of the

 CNS Degenerative disorders…

Wernicke's encephalopathy:

Recurrent petechial hemorrhages in the hypothalamus, mamillary bodies
with atrophy.
Wernicke’s Sy: Altered Thermal regulation & consciousness,
ophthalmoplegia, nystagmus.
Korsokoff Psychosis: Loss of recent memory compensated by
CNS Degenerative disorders…

Korsakoff's disease:
                              Note: Shrunken, bodies brown
                              mammillary bodies indicating
                              chronic stage or Korsakoff's

                              Central pontine myelinolysis.
                              Demyelination of the center of the
                              basis pontis. Cause is unknown but
                              is usually in chronic alcoholics and
                              is often associated with rapid over-
                              correction of hyponatremia.

                              Alcoholic cerebellar atrophy.
                              Shrunken folia and widened fissures
                              of the anterior, superior vermis of
                              the cerebellum. Another change
                              which may be found in chronic

CNS Degenerative disorders…

Kernictirus – Neonatal hyperbilirubinemia
   Kern+Ictirus – yellow nuclei.
   Complication of Neonatal
       Polycythemia,
       Hemolytic disease of new born.
       Hemolytic anemia.

CNS Degenerative disorders…

ALS_Amyotrophic lateral sclerosis
   Progressive motor weakness
    leading to death.
   Degeneration of upper motor
    neurons (spastic paralysis).
   Middle age, men more,
   Familial & geographic
    (Guam, PNG, Japan.. )          Degeneration of lateral and ventral
                                    corticospinal tracts (myelin stain).
   Loss of motor neurons in           Degeneration of upper motor
    lateral and ventral               neurons and causes spasticity,
    corticospinal tracts.          brisk reflexes, and up-going plantar
                                    responses. Lower motor neurons
                                    and their axons are not involved.
                                       Therefore, there is no muscle

     Pathology of CNS degenerations:
   Disease            Lesion              Components            Location
Alzheimer         Senile plaques    β-Amyloid tau          Extracellular
   disease        &                                           Intracytoplasmic
Amyotrophic       Spheroids         Neurofilament          Intracytoplasmic
  lateral                           subunits/super-oxide
  sclerosis                         dismutase (SOD-1)
Dementia with     Lewy bodies       α-Synuclein            Intracytoplasmic
  Lewy bodies
Frontotemporal    Neurofibrillary   tau                    Intracytoplasmic
    dementias     tangles
(Pics disease)
Multiple system   Glial inclusions tau                     Intracytoplasmic
Parkinson         Lewy bodies       α-Synuclein            Intracytoplasmic
  Cells / Structure               Common Pathology
Purkinje cells          Alcoholism, carbon monoxide, Ischemia
Mammilaries, Purkinje   Wernicke's encephalopathy (alcoholism)
DM of thalamus          Korsakoff's psychosis (alcoholism)
Hippocampus             Alzheimer's, hypoxia, hypoglycemia
Retina                  Methanol toxicity
Anterior horn cells     Polio, lower-ALS
Globus pallidus         Carbon monoxide, Wilson's, Kernicterus.
Posterior columns       B12 deficiency, syphilis (tabes)
Caudate nucleus         Huntington's chorea
Fronto-temporal deg.    Pick's disease
Deep brain stem         Progressive supranuclear palsy
Substantia nigra        Parkinson‘s
Upper motor neurons     Upper-ALS (Amyotrophic Lateral Sclerosis)
Anybody who thinks money will
make you happy, hasn't got it….!
CNS Degenerative disorders…

CPC-3.6– CNS –Degenerations
   Pathology - Core Learning Issues:
     Pathology  & Pathogenesis of common
      Dementias/CNS degenerations.
     Overview of rare forms of degenerative CNS
     Dementia diagnosis & Laboratory investigations.

   Basic science - Core Learning Issues:
     Structure and function of brain
     Areas of brain dealing with higher cognitive function
     Age related changes in structure & function of brain.
      Senile dementia.

    38y recurrent limb weakness ? Diagnosis
1.    Multiple sclerosis
2.    Parkinsons
3.    Alzheimer’s
4.    Huntington’s
5.    Pick’s disease

0%     0%    0%    0%      0%

1       2     3      4      5
    38y depression, chorea ? Diagnosis
1.   Multiple sclerosis
2.   Parkinsons
3.   Alzheimer’s
4.   Huntington’s
5.   Pick’s disease

0%     0%   0%   0%   0%

1      2    3     4       5
 A 45-year-old woman is brought to the emergency room
after experiencing a generalized seizure. An x-ray film of
the skull reveals a lytic bone mass. A portion of the skull
and the adherent mass are removed. Microscopic image of
tumor is shown. Most likely diagnosis?
A.   Glioblastoma multiforme
B.   Hemangioblastoma
C.   Medulloblastoma
D.   Meningioma
E.   Oligodendroglioma

        0%   0%   0%   0%   0%

        A.   B.   C.   D.    E.
A 56-year-old man is rushed to the emergency room after
collapsing while shoveling snow. The patient has no pulse
on admission but is resuscitated. Laboratory studies show
elevated serum levels of cardiac-specific proteins, and ECG
confirms a transmural infarct of the left ventricle. The patient
expires 2 weeks later of cardiac tamponade. Examination of
the patient's brain at autopsy would most likely reveal
necrosis of Purkinje cells and selective loss of neurons in
which of the following regions?
                                  A.   Frontal lobes
                                  B.   Hippocampus
                                  C.   Hypothalamus
                                  D.   Occipital lobes
  0%    0%     0%    0%    0%
                                  E.   Thalamus
  A.     B.    C.     D.     E.
     38y female recurrent limb weakness. Image
     shows white mater stained for myelin.? Diagnosis

 A.    Multiple sclerosis
 B.    Parkinsons
 C.    Alzheimer’s
 D.    Huntington’s
 E.    Pick’s disease

0%       0%   0%    0%      0%

A.       B.    C.    D.      E.
72y Male progressive severe dementia,
Image shows amyloid stain of his brain.
? Diagnosis
1.       Pick’s disease.
2.       Huntington’s disease.
3.       Alzheimer’s disease.
4.       Multi-infarct dementia.
5.       Senile dementia.

     0%      0%    0%    0%    0%

     1       2      3     4        5
    38y fem recurrent tremor & limb weakness
    progressive over 13 years. ? Diag
1.    Multiple sclerosis
2.    Hypertensive-stroke.
3.    Alzheimer’s
4.    Huntington’s
5.    Pick’s disease

0%     0%   0%   0%    0%

1       2    3    4     5
A 60-year-old man with a 15-year history of diabetes mellitus
type II complains of deep burning pain and sensitivity to
touch over his hands and fingers. Nerve conduction studies
show slow transmission of impulses and diminished muscle
stretch reflexes in both ankles and knees. Sensations to
vibrations and light touch are also markedly diminished.
Laboratory analysis of CSF shows no biochemical
abnormalities. Which of the following is the most likely type
of peripheral nerve disease in this patient?
                                A.   Autonomic neuropathy
                                B.   Distal polyneuropathy
                                C.   Inflammatory neuropathy
                                D.   Mononeuropathy
                                E.   Paraproteinemic
  0%    0%    0%    0%    0%
  A.    B.    C.     D.    E.
     58y M, Progressive bradykinesia, dementia &
     Hallucinations ? Diagnosis
A.     Alzheimer’s
B.     Parkinson’s
C.     Motor neurone disease
D.     Syringomyelia
E.     Lewy body disease

0%      0%    0%   0%    0%

A.       B.   C.    D.    E.
A 35-year-old man with Down syndrome dies of acute
lympho-blastic leukemia. Gross examination of the patient's
brain at autopsy shows mild microcephaly and
underdevelopment of the superior temporal gyri. Histologic
examination would most likely show which of the following
neuropathologic changes?

                                 A.   AA amyloidosis
                                 B.   Lewy body dementia
                                 C.   Leukemic infiltrates
                                 D.   Neurofibrillary tangles
                                 E.   Old healed infarcts.
  0%    0%    0%    0%    0%

  A.    B.     C.    D.    E.
     38y fem, recurrent attacks of limb weakness, paraesthesia
     worsened over 7 years resulting in death due to respiratory
     failure. Image shows her brain specimen. What is the most
     likely Diagnosis?

1.    Multiinfarct dementia.
2.    Parkinsons disease.
3.    Multiple sclerosis
4.    Motor neurone disease.
5.    Lacunar infarcts.

0%       0%    0%    0%    0%

1         2     3     4      5
52y male, dementia, depression with choreiform movements.
Image of his brain(B) compared with normal (A) ?Diagnosis

A.    Binswanger disease
                              A                       B
B.    Parkinsons disease
C.    Alzheimers disease
D.    Pick’s disease
E.    Huntington’s disease

 0%     0%   0%    0%   0%

 A.     B.    C.   D.    E.
78y M, Dementia, memory loss and spacial
disorientation. Cortical biopsy. ? Diagnosis
1. Alzheimer’s
2. Parkinson’s
3. Lewy body disease
4. Huntington’s disease
5. Pick’s disease

                          Cortical biopsy - β amyloid immunostain

0%   0%   0%   0%   0%

1    2    3    4     5
78y, Dementia, Aphasia, Image shows
Hippocampus biopsy stained with anti tau stain.
? Diagnosis
A.   Multiple sclerosis
B.   Parkinsons
C.   Alzheimer’s
D.   Multi-infarct dementia
E.   Pick’s disease

0%    0%   0%    0%   0%

A.    B.    C.   D.    E.
78y Male progressive severe dementia,
Image shows amyloid stain of his brain.
? Identify structure A
1.       Neurofibrillary tangles.
2.       Amyloid plaques.
3.       Amyloid Angiopathy
4.       Astrocytes - Gliosis.
5.       Neuronophagia.

     0%      0%    0%     0%    0%

     1       2      3      4        5
 58y female vocalist difficulty remembering songs, depression,
 dementia & gait abnormality. Image shows brain biopsy.
 What is the most likely diagnosis?
  1.       Alzheimer’s disease.
  2.       Pick’s disease.
  3.       Huntington’s disease.
  4.       Lewy body disease.
  5.       Creutzfeldt-Jakob disease.

CJD: Spongiform degeneration (vacuoles) no inflammation - Slowly
progressive ataxia and dementia.
Prion protein (APrP amyloid) – form template to make more abnormal protein
(not a living being) Infection  From contaminated brain of infected animal.
      diseases: Kuru, CJD, Scrapie, and bovine spongiform encephalopathy
Prion0%       0%     0%      0%    0%

(mad cow disease).
       1       2     3     4       5
 38y progressive weakness, spasticity, dysphagia and loss
 of muscle mass. Image shows section of spinal cord
 stained for myelin. Diagnosis?
1.   Multiple sclerosis
2.   Parkinsons
3.   Motor neurone disease
4.   Syringomyelia
5.   Spinal cord infarction.

 0%     0%    0%    0%    0%

 1       2     3     4     5
30y F, 7 day history of mild tremor in her arms and impaired balance when
walking. Vital signs are normal. Her symptoms disappear the following week,
but recures several times over next 4 years gradually developed weakness
requiring assistance when walking. Neurologic examination reveals ataxia,
dysarthria, decreased vibratory sensation, absent abdominal reflexes,
increased deep tendon reflexes, and a Babinski sign on the left. Fifteen years
after the onset of symptoms, the patient becomes bedridden and dies. A
coronal section of the patient's brain at autopsy is stained for myelin (shown).
Which of the following histopathologic findings would be expected in the
lesions seen in the patient's brain?
A.        Astrogliosis
B.        Lewy bodies
C.        Myelin loss.
D.        Neuritic plaques
E.        Neuronophagia.

     0%       0%   0%    0%       0%

     A.       B.    C.       D.    E.
What is the best clinical description for the image?
1.   83y man – dementia, memory loss and disorientation.
2.   43y man -abnormal movements who committed suicide
3.   56y woman -progressive paralysis
4.   60y man -tremor, rigidity and dementia
5.   73y woman –Dementia aphasia but intact memory.

20%    20%   20%   20%   20%

 1      2     3     4     5
 What is the best clinical description for the image?
AD1.   83y man – dementia, memory loss and disorientation.
HD2.   43y man -abnormal movements who committed suicide
  3.   56y woman -progressive paralysis
PD4.   60y man -tremor, rigidity and dementia
  5.   73y woman –Dementia aphasia intact memory.

  0%     0%    0%   0%    0%

  1       2     3    4     5
CNS Degenerative disorders…

CPC-3.6– KFP Questions:
 Dementia – definition, classification.
 Primary:
     Alzheimer's, Pick's, Huntington's & Diffuse
        Lewy body disease.
   Secondary:
     CVD,    Infections, Neoplasms, haematoma,
        hydrocephalus.drugs and toxins metabolic,
        vitamin def. (e.g. B1, B2, B12).
   Demyelinating disorders:
     Multiple           sclerosis, MND,

The 10-10-10 rule.

"I wasn't living my life. My life was living me. I realised I made
many of my decisions as if I was watching from a moving car.
(decisions for instant pleasure…)

“I realised all I really had to do to reclaim my life was to Start
making decisions by considering their consequences in the
immediate present, near term and distant future.. i.e . In ten
months, in ten minutes and in ten years”.
                                                       -- Suzy Welch.

        10 – 10 – 10
        minutes             months                years
     "Education is for ‘life’..
      not for mere ‘living’

"The end of education is character"
CNS Degenerative disorders…

MND: Case study:
   A 25 year old woman developed progressive weakness of the left arm
    during the second trimester of her first pregnancy.Over the next few
    months she developed progressive weakness of the arms and later the
    legs and respiratory muscles. On examination she had reduced limb
    reflexes, with grade 1 power in the arms and grade 1 - 2 in the legs.
    Wasting and fasciculation were not seen. Sensation was normal. Nerve
    conduction studies showed evidence of axonal degeneration in motor
    nerves only. Normal investigations included MRI of the brain, cervical
    spine and brachial plexus, sural nerve biopsy, antiganglioside
    antibodies, CSF examination, lyme, syphilis and HIV serology, heavy
    metal levels, hexosaminidase levels, SOD-1 gene and mitochondrial
    DNA analyses. 10 months after the onset of her symptoms she required
    ventilation. Despite treatment with intravenous gammaglobulin, methyl
    prednisolone and plasma exchange her condition deteriorated and she
    became globally weak and areflexic, with involvement of bulbar muscles.
    Ocular movements were preserved until shortly before death. At times
    she appeared inappropriately cheerful, but cognition was normal.
    Sensation and autonomic function remained normal throughout the
    disease duration. She was ventilated for 27 months prior to death.

CNS Degenerative disorders…

MND: Atrophy of anterior nerve roots.

CNS Degenerative disorders…

Case study 1
 62-year-old minister is having trouble
  composing his sermons.
 wife tells that members of the church have
  complained that the pastor is making
  many mistakes. (Patient denies)
 "I can't grasp the profounder thoughts.“

CNS Degenerative disorders…

Case study 2
 A 73y widow, brought by daughter. She
  lives alone, and continues to drive.
 The daughter reports that her mother has
  become more disoriented during
  telephone conversations. Discussions with
  the mother's friends reveal memory lapses
  and inappropriate decisions.

CNS Degenerative disorders…

Case study 3
   A 62-year-old tool-and-die maker,
    accompanied by his wife, appears for an
    office visit. He has no physical complaints,
    but his wife reports a progressive decline
    in his short-term memory.

CNS Degenerative disorders…

Case study 4
   64y male, 2-year history severe depression. insomnia
    and early morning wakening. The patient typically woke
    feeling "unrefreshed", and the collateral history from the
    spouse suggested that the patient was "less active"
    during sleep, with reduced turning, and a tendency to
    sleep on his back throughout the night.
   attention and concentration were impaired, experiencing
    "slowing" and "difficulty getting going" with tasks. The
    patient reported feeling suspicious of others, and had
    concerns that people intended him harm. However, the
    patient did not describe any hallucinations.
   When questioned further, the patient reported that he
    was slower in his day-to-day activities, gait change,
    uncontrolled walking gait.. with a reduction in
    spontaneity and physical activity. He also reported a
    relatively recent onset of anxiety and irritability with
    associated tremor, which he thought was perhaps more
    marked on the left side. His appetite and weight were
    unchanged.                                                   103
CNS Degenerative disorders…

Neuropathies And Myopathies
 Neuronal / Muscular damage:
 Causes:
     Hereditary  Motor & Sensory neuropathies
     Inflammatory - Diphtheria,
     Infectious: HZV, HIV, Leprosy
     Acquired/ Metabolic: Diabetes, Uraemia
     Vitamin B12 def
     Toxins: Alcohol, Lead toxicity, Drugs

CNS Degenerative disorders…

 Diabetic Neuropathy
   Types:
     Distalsymmetric sensory neuropathy: tingling
      numbness, loss of pain in toes, hands, legs.
     Autonomic neuropathy
     Focal asymmetric neuropathy: cranial/
      peripheral nerve involvement
   Pathogenesis:
     Microangiopathy,  ischemia, Hyperosmolar cell
        damage by polyols, myelin loss in sensory

CNS Degenerative disorders…

Herpetic Neuralgia (HZ infection)
 Sensory ganglia of spinal cord & brain
 Reactivation of latent infection following
  decrease in cell mediated immunity.
 Painful vesicular lesions in the distribution
  of sensory dermatome, trigeminal nerve.
 Intranuclear inclusions are generally not
  found in the peripheral nerve lesions.

CNS Degenerative disorders…

                Inflammatory/ Immune Neuropathy
                              (Guillain-Barre Syndrome):

   Life threatening spinal neuropathy following an
    acute viral illness:
   Clinical Features:
     Distallimb weakness & paraesthesia which
      progresses to affect proximal muscles (Ascending
     Death usually due to respiratory paralysis
   Pathogenesis:
     T-cell mediated response, inflammation of peripheral
        nerves & segmental demyelination
   Pathology:
     CSF:        Albumino-Cytological dissociation

CNS Degenerative disorders…

     Muscular degeneration, weakness &
     3 main groups
     Muscular dystrophies – Abnormal structure.
     Myositis – Inflammation / immune.
     Myopathy- Degeneration. Usually sec to
      systemic disease: eg.Thyrotoxicosis or
      Neurogenic muscular atrophy.

 CNS Degenerative disorders…

       Brain Activity: PET Scan (language skills)

Hearing Words           Speaking Words   Seeing Words   Thinking about Words

 Different mental activities take place in different parts of the
 brain. Positron emission tomography (PET) scans can measure
 this activity.

Neuro Anatomy - Function
CNS Degenerative disorders…

Vitamin Def & Neuropathy:
   A - Benign intracranial
    hypertension (rare)
   B1Wernicke-Korsakoff
   B2Peripheral neuropathy,
   B6Convulsions in infants
   B12Weakness and
    paraesthesiae in the
    lower limbs (1 & 3)
   CScurvy
   EWeakness, sensory
    loss, ataxia, nystagmus

CNS Degenerative disorders…

Early atrophy in Alzheimer's: