Week 10: Schizophrenia,

Parkinson’s, Alzheimer’s
!  Schizophrenia
!  Dopamine Hypersecretion Theory
!  Parkinson’s
!  Dopamine Deficiency
!  Alzheimer’s
!  Neurofibrillary tangles Tau Protein
!  Beta Amyloid Plaques
!  Acetylcholine deficits
 Schizophrenia Outline
!   Basic Symptoms

!   Brain Volume Decreases

!   Hippocampus Specific Effects
!   Increase Ventricles

!   Dopamine Hypothesis and Drugs

!   Potential Causes
!   Neurodevelopmental
!   Maternal Immune Activation
 Schizophrenia
!   Positive Symptoms (things
in addition + to normal)
!   Hallucinations
!   Delusions

!   Negative Symptoms (things

subtracted – from normal)
!   Impaired cognition
!   Blunted Affect
Schizophrenia Brain Volume Decreases

Healthy Schizophrenic
Schizophrenia: Hippocampal Volume
Loss and Disorganization of Cells
Hippocampal atrophy!

A
Disorganization of
hippocampal neurons!
 Schizophrenia: Enlargement of
the Ventricles

Staal, W. G., Hulshoff Pol, H. E., Schnack, H. G., van Haren, N. E., Seifert, N., and
Kahn, R. S. (2001). Structural brain abnormalities in chronic schizophrenia at the
extremes of the outcome spectrum. Am J Psychiatry 158, 1140–1142.
 Schizophrenia: Excessive
Dopamine Hypothesis

Drugs that work

to treat
schizophrenia
antagonize
dopamine
receptor binding
 Schizophrenia: Dopamine Increasing
Drugs Mimic Schizophrenia
!   L-DOPA (used to treat
Parkinson’s) can cause
hallucinations and delusions

!   Amphetamine use can induce

schizophrenia-like symptoms
in healthy people and make
schizophrenia worse.

!   Antipsychotic medications that

block dopamine
neurotransmission treat
amphetamine-induced Amphetamine causes the release of
psychosis dopamine
Shoptaw, S. J., Kao, U., and Ling, W. W. (2008). Treatment for amphetamine psychosis. Cochrane Database Syst Rev

Sokolski, K. N., Cummings, J. L., Abrams, B. I., DeMet, E. M., Katz, L. S., and Costa, J. F. (1994). Effects of
substance abuse on hallucination rates and treatment responses in chronic psychiatric patients. J Clin Psychiatry
55, 380–387.
 Potential Causes
!   Possibly related to impaired neural development
!  Rare cases of childhood Schizophrenia associated with massive sleep disruptions during
development

!   Possibly related to maternal immune activation during pregnancy

A

Canetta, S. E., and Brown, A. S. (2012). PRENATAL INFECTION, MATERNAL IMMUNE ACTIVATION, AND RISK
FOR SCHIZOPHRENIA. Transl Neurosci 3, 320–327
 Parkinson’s Outline
!   Normal symptoms
!   Drug induced Parkinsonism
!   MPTP

!   L-DOPA (pretty great, for a while then

terrible)
!   Other pro-dopamine drugs also work
MAOI, COMT

!   Dopaminergic cell graft/transplant

treatments (not so great)
!   Deep Brain Stimulation treatment
(pretty great if you don’t mind wires in
your brain and neurosurgery)
Parkinson’s: Normal/Diagnostic
Symptoms
!   Primary Motor Symptoms
!   Resting Tremor
!   Brady-kinesia (slow-movement)
!   Rigidity
!   Postural Instability

!   Other Motor Symptoms

!   Freezing (inability to initiate movements)
!   Non-expressive Faces
!   Unwanted motor movements

!   Early (leading) symptoms may include

!   Loss of smell sensation
!   REM Behavior disorder
 Parkinson’s Movement Initiation
& Basal Ganglia: Simple look

Green arrows are excitatory. Red arrows are inhibitory. Dashed arrows are weakened,
bigger arrows are strengthened
 Parkinson’s Movement Initiation
& Basal Ganglia: Complex look

Indirect pathway:
Normally inhibits
thalamus when influenced
(excited) by the cortex
You are decreasing an
inhibitory influence on
this pathway from the
substantia nigra (pc),
thereby allowing the
indirect pathway to be
more active ! greater
inhibition on the thalamus
Direct pathway: Normally
excites thalamus when
influenced (excited) by the
cortex
You are decreasing an
excitatory influence on this
pathway from the
substantia nigra (pc),
thereby making the direct
pathway less active !
thalamus is inhibited
compared to usual
 MPTP- Induced Parkinson’s
!   Botched synthetic opiate
(with heroine-like effects)
destroys dopamine cells and
produces Parkinson’s
overnight

!   Patients respond to L-DOPA

for a while, then become
tolerant.

!   Patients respond to fetal

dopaminergic transplants
 More Modern Parkinson’s Treatment: Deep Brain
Stimulation of Subthalamic Nucleus & Globus Pallidus
(internal segment)

What exactly causes resting tremor in Parkinson’s is unknown.

Why Deep brain stimulation helps is unknown as well.
Successful treatment has resulted from subthalamic nucleus and Globus Pallidus internal segment implants

More info:
Lukins, T. R., Tisch, S., and Jonker, B. (2014). The latest evidence on target selection in deep brain stimulation for
Parkinson's disease. J Clin Neurosci 21, 22–27. doi:10.1016/j.jocn.2013.05.011.

Helmich, R. C., Hallett, M., Deuschl, G., Toni, I., and Bloem, B. R. (2012). Cerebral causes and consequences of
parkinsonian resting tremor: a tale of two circuits? Brain 135, 3206–3226. doi:10.1093/brain/aws023.
 Alzheimer’s Outline
!   Basic Symptoms

!   Biomarkers
!   Structural Degeneration
!   Beta Amyloid Plaques
!   Neurofibrillary Tangles
!   Blood Proteins

!   Neurotransmitters (Acetylcholine, Glutamate)

 Basic Symptoms
!   Progressive cognitive decline

!   Memory loss

!   Disorientation

!   Confusion

!   Emotion & Behavior Changes

!   Social Withdrawal

!   Difficulty moving, walking, swallowing (late stage)

 Structural Degeneration: Gross Brain

Figure 22.1 Sections through human brains. Left: Alzheimer’s patient; right: control brain
Source: Alfred Pasieka/Science Photo Library
 Structural Degeneration: Decreased White
Matter Integrity (Diffusion Tensor Imaging)

Amlien, I. K., and Fjell, A. M. (2014). Diffusion tensor imaging of white matter degeneration in Alzheimer's disease
and mild cognitive impairment. Neuroscience.
 Alzheimer’s:
Beta Amyloid Plaques
 Alzheimer’s: Amyloid Plaque Deposits

ALZ

Mild Cognitive
Impairment

Healthy

Hatashita, S., Yamasaki, H., Suzuki, Y., Tanaka, K., Wakebe, D., and Hayakawa, H. (2014).
[18F]Flutemetamol amyloid-beta PET imaging compared with [11C]PIB across the spectrum of
Alzheimer's disease. Eur. J. Nucl. Med. Mol. Imaging 41, 290–300. doi:10.1007/s00259-013-2564-y.
 Alzheimer’s:
Neurofibrillary tangles
 Acetylcholine Deficits in Alzheimer’s & Aricept

ChAT deficits in
Alzheimer’s
decreases
Acetylcholine
production from
precursors

Aricept inhibits
acetylcholinesterase
leaving more
acetylcholine in the
synapse for longer
increasing
neurotransmission
Neurotransmitter Disruptions &
Cellular Learning
!   Acetylcholine projections are major inputs in glutamate neurons in
the hippocampus

!   Glutamate and Long-term potentiation model of cellular learning

 Future Blood Panels for Early
Detection of future Alzheimer’s
Development???
!   Published 03/09/2014

!   ~Panel of 10 blood proteins reflecting cell membrane

integrity predict with 90% sensitivity/ 90% sensitivity who
will develop Alzheimer’s or Mild cognitive impairment

Mapstone, M., Cheema, A. K., Fiandaca, M. S., Zhong, X., Mhyre, T. R., MacArthur, L. H., Hall, W. J.,
Fisher, S. G., Peterson, D. R., Haley, J. M., et al. Plasma phospholipids identify antecedent memory
impairment in older adults. Nat Med advance online publication SP - EP . doi:10.1038/nm.3466.