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Alzheimer's Disease: Example of Disordered Flow-Metabolism Coupling? Albert Gjedde, Center of Functionally Integrative Neuroscience, Aarhus University,

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Presentation on theme: "Alzheimer's Disease: Example of Disordered Flow-Metabolism Coupling? Albert Gjedde, Center of Functionally Integrative Neuroscience, Aarhus University,"— Presentation transcript:

1 Alzheimer's Disease: Example of Disordered Flow-Metabolism Coupling? Albert Gjedde, Center of Functionally Integrative Neuroscience, Aarhus University, Aarhus, Denmark

2 ”...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.

3 Gjedde A, Marrett S, Vafaee M (2002) Oxidative and nonoxidative metabolism of excited neurons and astrocytes. J Cereb Blood Flow Metab 22: 1-14.

4 CMRO 2 CBF and CMR glc

5 Low CMRO 2 Low CBF and CMR glc

6 Alzheimer’s patient Auguste D presented with the current hallmarks of the disease, amnesia, aphasia, agraphia, apraxia, and agnosia.

7 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.

8 The accurate diagnosis still is made by neuropathological identification of the neuritic plaques and neurofibrillary tangles.

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11 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. 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 Alzheimer’s disease. Cereb Cortex. 1: 103-116.

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16 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-parietal operculum.

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20 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

21 Ptito M, Kupers R, Faubert J, Gjedde A (2001) Cortical representation of inward and outward radial motion in man. Neuroimage 14: 1409- 1415.

22 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.

23 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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25 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

26 The temporal- occipital-parietal operculum is the most frequent site of significant reduction of cerebral blood flow in patients suspected of dementia of Alzheimer’s type (DAT) (Johannsen et al. 2000).

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28 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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30 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).

31 Also measure of glucose consumption reveals opercular deficit: FDG in 56-y/o woman with dementia of Alzheimer’s type FDG

32 (mL/100mL tissue/min) Gyldensted et al., Aarhus 2003 PET CBF (oxygen-15-labeled water) MR relative CBF (spin echo)

33 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 Alzheimer’s type (Johannsen et al. 1999, Clark & Karlawish 2003). Johannsen P, Jakobsen J, Bruhn P, Gjedde A (1999) Cortical responses to sustained and divided attention in Alzheimer's disease. Neuroimage 10: 269-81 controls DAT

34 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.

35 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

36 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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38 Control WAY – serotonin 5HT 1A receptors (Møller et al., Aarhus PET Center, 2003 Beta-amyloid co-distributes with the serotonin 5HT 1A receptors known to be involved in neuro- plasticity PIB - beta-amyloid imaging

39 5 Structural damage to hippocampus is associated with excessive release or presence of the excitatory amino acid glutamate or analogs.

40 Mc Gill Maguire et al., 1997 activation of right posterior hippocampus in London taxi drivers recalling routes

41 Mc Gill Maguire et al., 1999

42 Videbech et al., PET Center Aarhus University Hospitals 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

43 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. 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. Amnesic shell fish poisoning

44 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. 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.

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46 6 Excitotoxicity is associated with oxidative stress.

47 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: 459–492

48 Peter Johannsen, Aarhus, and the MicroDAB Study Group Oxygen consump- tion declines more with age than other measures (capillary density, glucose consum- ption, oxygen extraction); OEF declines least.

49 The activity of cytochrome c oxidase is low in mid-temporal cortex of patients with dementia of Alzheimer’s 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). 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.

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51 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, Alzheimer’ s disease reveals loss of neurons in the H1 (CA1) region of hippo- campus.

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53 Hevner & Wong-Riley (1992) J Comp Neurol. 326: 451-469

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56 ExcessiveActivity

57 ExcessiveActivity Oxidative Stress

58 ExcessiveActivity Apoptosis

59 Low CMRO 2 ExcessiveActivity Oxidative Stress Apoptosis

60 Low CMRO 2 Low CBF and CMR glc ExcessiveActivity Oxidative Stress Apoptosis

61 Low CMRO 2 Low CBF and CMR glc Tangles ExcessiveActivity Oxidative Stress Apoptosis

62 Low CMRO 2 Low CBF and CMR glc Tangles Plaques ExcessiveActivity Oxidative Stress Apoptosis

63 Low CMRO 2 Low CBF and CMR glc Tangles Plaques Medial and AnteriorTemporalLobe ExcessiveActivity Oxidative Stress Apoptosis

64 Low CMRO 2 Low CBF and CMR glc Tangles Plaques Medial and AnteriorTemporalLobe InferiorMedialPrefrontalCortexTemporo-Occipito-ParietalOperculumPosteriorCingulate ExcessiveActivity Oxidative Stress Apoptosis

65 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.

66 Conclusions II The differential distributions of neurofibrillary tangles and neuritic plaques provide a rationale for the recently proposed treatment of patients with Alzheimer’s disease with NMDA- receptor antagonists.

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68 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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70 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.

71 The first five cases of Alzheimer’s disease were reported as early as 1907-11 (Maurer et al. 1997, Graeber & Mehraein 1999) and presented with all the current hallmarks of the disease’s symptomatol ogy, the five A’s of amnesia, aphasia, agraphia, apraxia, and agnosia.


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