Clinical examples of PET

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Alzheimer's Disease Example of Disordered
Flow-Metabolism Coupling? Albert Gjedde,
Center of Functionally Integrative
Neuroscience, Aarhus University, Aarhus, Denmark
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...all the elements of the cortex are
represented in it, and therefore it may be called
an elementary unit, in which, theoretically, the
whole process of the transmission of impulses
from the afferent fiber to the efferent axon may
be accomplished. Lorente de Nó (1938), in
Physiology of the Nervous System (Fulton, JB,
ed.), pp.291, London Oxford University Press.
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Gjedde A, Marrett S, Vafaee M (2002) Oxidative
and nonoxidative metabolism of excited neurons
and astrocytes. J Cereb Blood Flow Metab 22 1-14.
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CBF and CMRglc
CMRO2
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Low CBF and CMRglc
Low CMRO2
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Alzheimers patient Auguste D presented with the
current hallmarks of the disease, amnesia,
aphasia, agraphia, apraxia, and agnosia.
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1 Plaques and tangles are differentially
distributed, with far more tangles in the
anterior and medial temporal cortices, than in
the association areas of the temporal, occipital
and parietal lobes.
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The accurate diagnosis still is made by
neuropathological identification of the neuritic
plaques and neurofibrillary tangles.
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Arnold SE, Hyman BT, Flory J, Damasio AR, Van
Hoesen GW (1991) The topographical and
neuroanatomical distribution of neurofibrillary
tangles and neuritic plaques in the cerebral
cortex of patients with Alzheimers disease.
Cereb Cortex. 1 103-116.
Tangles are concentrated in hippocampus,
parahippocampal gyrus, entorhinal cortex, and
anterior temporal pole, while plaques are more
prominent in remaining areas of the temporal,
occipital and parietal lobes, except the primary
somatosensory, visual and auditory cortices.
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2 The differential distribution of plaques and
tangles reflects the input and output regions of
the hippocampus in the anterior and medial
temporal cortices and the temporal-occipital-parie
tal operculum.
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The association areas of the temporal, occipital
and parietal lobes are the sites of perceptual
activation of brain tissue in healthy individuals
who imagine, remember, or perceive an object of
consciousness, such as a face or a scene from the
past, present, or future.
Temporal-occipital-parietal operculum is
implicated in higher-order multimodal perception
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Ptito M, Kupers R, Faubert J, Gjedde A (2001)
Cortical representation of inward and outward
radial motion in man. Neuroimage 14 1409-1415.
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Johannsen P, Jakobsen J, Bruhn P, Hansen SB, Gee
A, Stødkilde-Jørgensen H, Gjedde A (1997)
Cortical sites of sustained and divided attention
in normal elderly humans. Neuroimage 6 145-55.
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Geday J, Gjedde A, Boldsen AS, Kupers R.
Emotional valence modulates activity in the
posterior fusiform gyrus and inferior medial
prefrontal cortex in social perception.
Neuroimage. 2003 18 675-84.
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Geday J, Gjedde A, Boldsen AS, Kupers R.
Emotional valence modulates activity in the
posterior fusiform gyrus and inferior medial
prefrontal cortex in social perception.
Neuroimage. 2003 18 675-84.
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3 The accumulation of plaques in the
temporal-occipital-parietal operculum and
posterior cingulate coincides with sites of
reduced blood flow and reduced glucose consumption
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The temporal-occipital-parietal operculum is the
most frequent site of significant reduction of
cerebral blood flow in patients suspected of
dementia of Alzheimers type (DAT) (Johannsen et
al. 2000).
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Johannsen P, Jakobsen J, Gjedde A (2000)
Statistical maps of cerebral blood flow deficits
in Alzheimer's disease. Eur J Neurol 7 385-92.
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Johannsen P, Jakobsen J, Gjedde A (2000)
Statistical maps of cerebral blood flow deficits
in Alzheimer's disease. Eur J Neurol 7 385-92.
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The presence of a CBF-deficit in the
temporal-occipital-parietal operculum raises the
certainty of a tentative diagnosis to 92, while
its absence reduces the certainty to 70 (Clark
Karlawish 2003).
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FDG
Also measure of glucose consumption reveals
opercular deficit FDG in 56-y/o woman with
dementia of Alzheimers type
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PET CBF (oxygen-15-labeled water)
MR relative CBF (spin echo)
Gyldensted et al., Aarhus 2003
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Studies of the response of the local circulation
to sensory or cognitive stimulation of the
temporal-occipital-parietal operculum reveal low
or no increase of blood flow in patients with
dementia of Alzheimers type (Johannsen et al.
1999, Clark Karlawish 2003).
controls
Johannsen P, Jakobsen J, Bruhn P, Gjedde A (1999)
Cortical responses to sustained and divided
attention in Alzheimer's disease. Neuroimage 10
269-81
DAT
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4 The accumulation of plaques in the inferior
medial prefrontal cortex coincides with sites of
reduction of blood flow and glucose during
activation of working memory.
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Decline of activity in orbital pre-frontal
cortex, Kupers et al., Aarhus PET Center 2003
Inferior medial prefrontal cortex is deactivated
by major memory task
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Geday J, Gjedde A, Boldsen AS, Kupers R.
Emotional valence modulates activity in the
posterior fusiform gyrus and inferior medial
prefrontal cortex in social perception.
Neuroimage. 2003 18 675-84.
Emotional valence (positive or negative) mediates
flow decline in inferior medial prefrontal cortex
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Beta-amyloid co-distributes with the serotonin
5HT1A receptors known to be involved in
neuro-plasticity
Control
WAY serotonin 5HT1A receptors (Møller et al.,
Aarhus PET Center, 2003
PIB - beta-amyloid imaging
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5 Structural damage to hippocampus is associated
with excessive release or presence of the
excitatory amino acid glutamate or analogs.
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activation of right posterior hippocampus in
London taxi drivers recalling routes
Maguire et al., 1997
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Maguire et al., 1999
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Blood flow to the right hippocampus has been
shown to be elevated in people suffering from
major depression who are at risk of developing
dementia, suggesting that excessive stimulation
of the medial temporal cortex can lead to cell
death (Videbech et al. 2001).
Major Depression relative to Normal
Videbech et al., PET Center Aarhus University
Hospitals
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The first known cases of domoic acid intoxication
were caused by ingestion of mussels from Prince
Edward Island in Montreal in the Fall of 1987.
More than 100 people developed symptoms of
intoxication, and four died. The most serious
symptom in those who survived was complete loss
of short-term memory. The toxin domoic acid
turned out to be a product of the algae
Pseudo-nitzschia multiseries. The loss of
short-term memory was permanent.
Amnesic shell fish poisoning
Gjedde A, Evans AC (1990) PET studies of domoic
acid poisoning in humans excitotoxic destruction
of brain glutamatergic pathways, revealed in
measurements of glucose metabolism by positron
emission tomography. Can Dis Wkly Rep. 16 Suppl
1E 105-109.
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Neuropathologic examination of the four patients
who died revealed necrosis and loss of cells
primarily in the amygdala and the H1 (CA1) region
of the hippocam-pus. Domoic acid is a glutamate
analog.
The mediator of the structural damage to the
hippocamus is likely to be the excitatory amino
acid glutamate when it is released in excessive
amounts from the presynaptic terminals of
afferent neurons.
Teitelbaum JS, Zatorre RJ, Carpenter S, Gendron
D, Evans AC, Gjedde A, Cashman NR (1990)
Neurological sequelae of domoic acid intoxication
due to ingestion of mussels from Prince Edward
Island. N Eng J Med 322 1781-1787.
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6 Excitotoxicity is associated with oxidative
stress.
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Volianskis A, Jensen MS (2003) Transient and
sustained types of long-term potentia-tion in the
CA1 area of the rat hippo-campus. J Physiol 550
459492
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Oxygen consump-tion declines more with age than
other measures (capillary density, glucose
consum-ption, oxygen extraction) OEF declines
least.
Peter Johannsen, Aarhus, and the MicroDAB Study
Group
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Cytochrome c oxidase and mitochondrial
F1F0-ATPase (ATP synthase) activities in
platelets and brain from patients with
Alzheimer's disease. Bosetti F, Brizzi F, Barogi
S, Mancuso M, Siciliano G, Tendi EA, Murri L,
Rapoport SI, Solaini G. Neurobiol Aging. 2002 23
371-376.
The activity of cytochrome c oxidase is low in
mid-temporal cortex of patients with dementia of
Alzheimers type, as is the amount of mRNA that
codes for the enzyme (Chandrasekan et al. 1996,
1997, Hatanpää et al. 1996, 1998, 1999, Rapoport
1999).
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West MJ, Coleman PD, Flood DG, Troncoso JC (1994)
Differences in the pattern of hippocampal
neuronal loss in normal ageing and Alzheimer's
disease. Lancet 344 769-772.
Unlike normal aging but like ischemic damage,
Alzheimers disease reveals loss of neurons in
the H1 (CA1) region of hippo-campus.
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Hevner Wong-Riley (1992) J Comp Neurol. 326
451-469
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Hevner Wong-Riley (1992) J Comp Neurol. 326
451-469
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Excessive Activity
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Excessive Activity
Oxidative Stress
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Excessive Activity
Oxidative Stress
Apoptosis
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Excessive Activity
Low CMRO2
Oxidative Stress
Apoptosis
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Low CBF and CMRglc
Excessive Activity
Low CMRO2
Oxidative Stress
Apoptosis
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Low CBF and CMRglc
Excessive Activity
Low CMRO2
Oxidative Stress
Apoptosis
Tangles
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Low CBF and CMRglc
Excessive Activity
Low CMRO2
Oxidative Stress
Apoptosis
Tangles
Plaques
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Low CBF and CMRglc
Medial and Anterior Temporal Lobe
Excessive Activity
Low CMRO2
Oxidative Stress
Apoptosis
Tangles
Plaques
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Low CBF and CMRglc
Medial and Anterior Temporal Lobe
Inferior Medial Prefrontal Cortex Temporo- Occipi
to- Parietal Operculum Posterior Cingulate
Excessive Activity
Low CMRO2
Oxidative Stress
Apoptosis
Tangles
Plaques
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Conclusions I The differential distributions of
neurofibrillary tangles and neuritic plaques
reflect the differential effects of oxidative
stress at the proximal and distal parts of a
functional network extending from the anterior
and metdial temporal lobe to the orbitofrontal
cortex, posterior operculum, and posterior
cingulate.
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Conclusions II The differential distributions of
neurofibrillary tangles and neuritic plaques
provide a rationale for the recently proposed
treatment of patients with Alzheimers disease
with NMDA-receptor antagonists.
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Conclusions III Cholinesterase inhibitors raise
acetylcholine levels, which may (or may not?)
cause nitric oxide tensions to rise and block
pathological cytochrome oxidase activity.
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Conclusions IV Specific or non-specific
cyclooxygenase inhibitors such as indomethacin
lower blood flow and may reduce oxygen tension
and the generation of reactive oxygen species in
conditions of deficient mitochondrial activity.
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The first five cases of Alzheimers disease were
reported as early as 1907-11 (Maurer et al. 1997,
Graeber Mehraein 1999) and presented with all
the current hallmarks of the diseases
symptomatology, the five As of amnesia, aphasia,
agraphia, apraxia, and agnosia.