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Functional brain imaging in subjects at genetic risk for Alzheimer's disease
s141
component of the adherens junction where it binds to the juxtamembrane region of N-cadherm. Our result\ suggest that Presenilin function extends beyond Notch processing to regulate the delivery of a multi-protein complex that regulates Armadillo trafficking between the adherens junction and the proteasome.
SEPARATION OF PRESENILIN FUNCTION IN AMYLOID P-PEPTIDE GENERATION AND ENDOPROTEOLYSIS OF NOTCH
Presenilins (PS) facihtate endoproteolysts of several substrates including the P-Amylotd precursor protem. and Notch. For this function two critical aspartate residues are required, which are located in trana-membrane domains (TM) 6 and 7. We demonstrate that the fun&on of PS proteins in the facilitated cleavage of Notch and pAPP can be separated. Expression of a natural occurring splice variant (PSI AexonX), which lacks the critical apartate residue 257 wthin TM6 inhibits Notch endoproteoly\is and Notch srgnaling. However. Abproduction i? not severely inhibited. This indicates that the two analyzed functions of PS proteins can be separated. Moreover, the natural occurring PSI splice variant may indirectly regulate Notch signaling. Separation of PS functions was further supported by the introduction of novel mutations at a previously identified site of a familial AD associated mutation. Upon introduction of negatively or positively charged amino acids incrtaed production of AP42 way ‘above the level of the natural occurring mutation was observed. This was paralleled by a dramatic reduction of Notch endoproteolysis. Moreover, the cytoplasmic domam of Notch was not transferred to the nucleus, and the holoprotein accumulated on the cell rurface. These results indicate that PS molecules may contain functionally distinct domains required for the specific binding of its substrates or that presenilins indrectly regulate the activity of distinct proteases.
Symposium:
Imaging
and Memory
Disorders
FUNCTIONAL BRAIN IMAGING IN SUBJECTS AT GENETIC RISK FOR ALZHEIMER’S DISEASE
Usmg flourodeoxyglucow (FDG) positron em&ion tomography. we previously found that late middle-aged, cognitively normal carriers of the apolipoprotem Ee4 alle. a common Alzheimer‘s susceptibility gene, have abnormally low brain activity in the same brain regions as patlents with Alrheimer’s dementia, the largest of which is in posterior cingulate cortex. We now find that the ~4 heterozygotes have Ggnificant two-year declines in regional bran activity, the largest of which is in temporal cortex, and that these reductions are significantly greater than those in the t4 non-carriers. We estimate that as few as 22 cogmtively normal, late-middle-aged ~4 heterorygotes are needed per active and placebo treatment group to test a candidate prevention therapy in a single year (gOBpower. p=O.OU5). Using FDG autoradiography. we find that aged PDAPP tranagenic mice have preferentially and progre\sively reduced activity in the posterior cingulate cortex and relative sparing in visual, wwximotor. cerebellar, and white matter regions. The reductions in posterior cingulate activity could be uwd to track disease progrescion, help clarify disease mechani?mr, and screen candidate treatments in these and other suitable laboratory animals. Functional brain imaging techniques could be wed to track the progression of Alzheimer’s disease in the abaebce of symptoms, help xreen candidate treatments in transgenic mice, and test candidate prevention therapies without having to study thousand5 of mdiwduals or wait many years to determine whether or when they develop symptoms.
METABOLIC AND PATHOLOGIC EAKLY ALZHEIMER’S DISEASE
Rcccnt pathologic and metabolic indicated discordance between versus that of glucose metabolic onset of chmcal dementia, PET
DISCORDANCE
IN VERY
studla of very early Alrheimer’s disease (AD) have the distribution of traditional pathologic changes abnormalities. In very early AD patients prior to the imaging with fluorodeoxyglucose demonstrated an
initial metabolic reduction in the posterior cingulate cortex as well as in the lateral association corticcs. Ncurofibrillruy tangles are known to appear initially in the entorhinal cortex that has glutamatergic output to the hippocampus as well as to the association cortices. Resection of the mesiotemporal lobe in humans resulted in consistent metabolic reductions in the thalamus and posterior cingulate cortex, but no reduction in the lateral pa&al or frontal association cottices as seen in very early AD. Baral forebrain cholinerglc neurons also are known to degenerate severely in AD. Image-based principal components analysis of cortical cholinesterase activity and glucose metabolism measured by PET and cortical atrophy measured by MRI revealed no robust correlation among these indices in the AD cortex. These findings suggest that neither the Ios’i of entorhinal efferents nor cholinergic deficits can account fully for all the metabolic features seen in very early AD. Metabolic reductions in the posterior cingulate cortex and lateral awxiation cort~~r are also not unique to AD. Dementia with Lewy bodies demonstrated cortical metabolic abnormalities similar to AD with the addition of a severe metabolic reduction in the occipital cortex. Recent insights into neuronal and glial mechanisms of glucose metabolism suggest that very early metabolic abnormalit& in AD probably retlect a \igniticant impairment of cortico-cortical glutamatergic projections in the association and paralimbic conices at a preclinical stage of the diseaw!. These projections may be part of a common pathologic pathway for interrelated dementing disorders.
pm/
MAGNETIC
RESONANCE SPECTROSCOPY
OF AD
MR spectroscopy provides brain biochemical information noninvaaively. Spectra may be obtained from individual brain volumes or the information may be spatially encoded to provide spectroxoplc images. There are several nuclei accessible by in viva MRS including lH, 3lP, l3C, 23Na and others. Proton MRS is most commonly it is used for clinical MRI employr this nucleus, thus the appropriate hardware i< in place. The proton MR spectrum prowdes information on molecules whose concentratron ranges from I to 20 mM. The most important component of the brain proton MR spectrum is n-acetylaspartate (NAA). This molecule is found exclusively in newons, and although its function is unknown, it serves as a neuronal marker. NAA concentration will diminish with neuronal loss and injury. In cases of temporary neuronal dysfunction, NAA has been ohhewed to diminish and then return to normal Icvels. However, an NAA decrease ia meveraible with neuronal loss. Correlative neuropathologlc studva have shown that decreased NAA IE associated with a decrease m synaptophysm suggesting that injury to the synaptodendrltic integrity is reflected in changes in NAA. It has been comistently demotxtrated that NAA is abnormally low m AD. The loss of NAA ia heterogeneous and follows the well known pathological progre\tion. For example, medIal temporal loss of NAA is typically more severe than other parts of the brain and the occipital lobe NAA concentration is normal. Becauw of these observations, NAA may be an ideal marker for therapy in AD: it may be used as a quantitative measure of neuronal preservation and neuronal regeneration. Two additional proton MRS resonances, myo-mositol (Ml) and choline (Cho), have been of interest to AD researchers. Both of these resonances have been observed to be elevated in AD. The reason for the elevations of these metabolites is not clear, but in animal studies they have been ahown to be elevated the course of astrogliow. GFAP has been rhown to related to an increase in the Cho resonance. With further advances in MR technology, especially increases in the field strength of magnets to 3T and beyond. MRS will likely become an extremely useful neuroimaging tool for early AD diagnori\ and therapeutic a\rewnent.
16391PREDICTION
OF AD USING MRIISPECT
Characteristic cerebral perfusion abnormalitie\ are frequently observed in patlent\ with a clinical diagnosis of Alzheimer’s disease (AD). Confidence in the clinical diagnoai\ of AD i\ improved when such abnormalities are found. and perfusion imaging with single photon emission computed tomography is used increasingly for this purpose. In order to examine the perfusion pattern of prodromal AD, subjec& have been identified either by genetic rusk factors, or by examining images of AD patients acquired several years prior to the clinical diagnosis of AD. Image analysis methods applied to these samples have included univariate maps, covariance matrix xormg, and MRI-guided volumetric perfusion measurement. These data suggest that specific brain region\ are requentially involved along a neuroanatomlc hierarchy which parallels disease symptomatology, and that progression from prodromal through chnical stages of dementia 1s accompanied by functional image abnormalities progressing from hmbic to neocortical nssoclation regions.
component of the adherens junction where it binds to the juxtamembrane region of N-cadherm. Our result\ suggest that Presenilin function extends beyond Notch processing to regulate the delivery of a multi-protein complex that regulates Armadillo trafficking between the adherens junction and the proteasome.
SEPARATION OF PRESENILIN FUNCTION IN AMYLOID P-PEPTIDE GENERATION AND ENDOPROTEOLYSIS OF NOTCH
Presenilins (PS) facihtate endoproteolysts of several substrates including the P-Amylotd precursor protem. and Notch. For this function two critical aspartate residues are required, which are located in trana-membrane domains (TM) 6 and 7. We demonstrate that the fun&on of PS proteins in the facilitated cleavage of Notch and pAPP can be separated. Expression of a natural occurring splice variant (PSI AexonX), which lacks the critical apartate residue 257 wthin TM6 inhibits Notch endoproteoly\is and Notch srgnaling. However. Abproduction i? not severely inhibited. This indicates that the two analyzed functions of PS proteins can be separated. Moreover, the natural occurring PSI splice variant may indirectly regulate Notch signaling. Separation of PS functions was further supported by the introduction of novel mutations at a previously identified site of a familial AD associated mutation. Upon introduction of negatively or positively charged amino acids incrtaed production of AP42 way ‘above the level of the natural occurring mutation was observed. This was paralleled by a dramatic reduction of Notch endoproteolysis. Moreover, the cytoplasmic domam of Notch was not transferred to the nucleus, and the holoprotein accumulated on the cell rurface. These results indicate that PS molecules may contain functionally distinct domains required for the specific binding of its substrates or that presenilins indrectly regulate the activity of distinct proteases.
Symposium:
Imaging
and Memory
Disorders
FUNCTIONAL BRAIN IMAGING IN SUBJECTS AT GENETIC RISK FOR ALZHEIMER’S DISEASE
Usmg flourodeoxyglucow (FDG) positron em&ion tomography. we previously found that late middle-aged, cognitively normal carriers of the apolipoprotem Ee4 alle. a common Alzheimer‘s susceptibility gene, have abnormally low brain activity in the same brain regions as patlents with Alrheimer’s dementia, the largest of which is in posterior cingulate cortex. We now find that the ~4 heterozygotes have Ggnificant two-year declines in regional bran activity, the largest of which is in temporal cortex, and that these reductions are significantly greater than those in the t4 non-carriers. We estimate that as few as 22 cogmtively normal, late-middle-aged ~4 heterorygotes are needed per active and placebo treatment group to test a candidate prevention therapy in a single year (gOBpower. p=O.OU5). Using FDG autoradiography. we find that aged PDAPP tranagenic mice have preferentially and progre\sively reduced activity in the posterior cingulate cortex and relative sparing in visual, wwximotor. cerebellar, and white matter regions. The reductions in posterior cingulate activity could be uwd to track disease progrescion, help clarify disease mechani?mr, and screen candidate treatments in these and other suitable laboratory animals. Functional brain imaging techniques could be wed to track the progression of Alzheimer’s disease in the abaebce of symptoms, help xreen candidate treatments in transgenic mice, and test candidate prevention therapies without having to study thousand5 of mdiwduals or wait many years to determine whether or when they develop symptoms.
METABOLIC AND PATHOLOGIC EAKLY ALZHEIMER’S DISEASE
Rcccnt pathologic and metabolic indicated discordance between versus that of glucose metabolic onset of chmcal dementia, PET
DISCORDANCE
IN VERY
studla of very early Alrheimer’s disease (AD) have the distribution of traditional pathologic changes abnormalities. In very early AD patients prior to the imaging with fluorodeoxyglucose demonstrated an
initial metabolic reduction in the posterior cingulate cortex as well as in the lateral association corticcs. Ncurofibrillruy tangles are known to appear initially in the entorhinal cortex that has glutamatergic output to the hippocampus as well as to the association cortices. Resection of the mesiotemporal lobe in humans resulted in consistent metabolic reductions in the thalamus and posterior cingulate cortex, but no reduction in the lateral pa&al or frontal association cottices as seen in very early AD. Baral forebrain cholinerglc neurons also are known to degenerate severely in AD. Image-based principal components analysis of cortical cholinesterase activity and glucose metabolism measured by PET and cortical atrophy measured by MRI revealed no robust correlation among these indices in the AD cortex. These findings suggest that neither the Ios’i of entorhinal efferents nor cholinergic deficits can account fully for all the metabolic features seen in very early AD. Metabolic reductions in the posterior cingulate cortex and lateral awxiation cort~~r are also not unique to AD. Dementia with Lewy bodies demonstrated cortical metabolic abnormalities similar to AD with the addition of a severe metabolic reduction in the occipital cortex. Recent insights into neuronal and glial mechanisms of glucose metabolism suggest that very early metabolic abnormalit& in AD probably retlect a \igniticant impairment of cortico-cortical glutamatergic projections in the association and paralimbic conices at a preclinical stage of the diseaw!. These projections may be part of a common pathologic pathway for interrelated dementing disorders.
pm/
MAGNETIC
RESONANCE SPECTROSCOPY
OF AD
MR spectroscopy provides brain biochemical information noninvaaively. Spectra may be obtained from individual brain volumes or the information may be spatially encoded to provide spectroxoplc images. There are several nuclei accessible by in viva MRS including lH, 3lP, l3C, 23Na and others. Proton MRS is most commonly it is used for clinical MRI employr this nucleus, thus the appropriate hardware i< in place. The proton MR spectrum prowdes information on molecules whose concentratron ranges from I to 20 mM. The most important component of the brain proton MR spectrum is n-acetylaspartate (NAA). This molecule is found exclusively in newons, and although its function is unknown, it serves as a neuronal marker. NAA concentration will diminish with neuronal loss and injury. In cases of temporary neuronal dysfunction, NAA has been ohhewed to diminish and then return to normal Icvels. However, an NAA decrease ia meveraible with neuronal loss. Correlative neuropathologlc studva have shown that decreased NAA IE associated with a decrease m synaptophysm suggesting that injury to the synaptodendrltic integrity is reflected in changes in NAA. It has been comistently demotxtrated that NAA is abnormally low m AD. The loss of NAA ia heterogeneous and follows the well known pathological progre\tion. For example, medIal temporal loss of NAA is typically more severe than other parts of the brain and the occipital lobe NAA concentration is normal. Becauw of these observations, NAA may be an ideal marker for therapy in AD: it may be used as a quantitative measure of neuronal preservation and neuronal regeneration. Two additional proton MRS resonances, myo-mositol (Ml) and choline (Cho), have been of interest to AD researchers. Both of these resonances have been observed to be elevated in AD. The reason for the elevations of these metabolites is not clear, but in animal studies they have been ahown to be elevated the course of astrogliow. GFAP has been rhown to related to an increase in the Cho resonance. With further advances in MR technology, especially increases in the field strength of magnets to 3T and beyond. MRS will likely become an extremely useful neuroimaging tool for early AD diagnori\ and therapeutic a\rewnent.
16391PREDICTION
OF AD USING MRIISPECT
Characteristic cerebral perfusion abnormalitie\ are frequently observed in patlent\ with a clinical diagnosis of Alzheimer’s disease (AD). Confidence in the clinical diagnoai\ of AD i\ improved when such abnormalities are found. and perfusion imaging with single photon emission computed tomography is used increasingly for this purpose. In order to examine the perfusion pattern of prodromal AD, subjec& have been identified either by genetic rusk factors, or by examining images of AD patients acquired several years prior to the clinical diagnosis of AD. Image analysis methods applied to these samples have included univariate maps, covariance matrix xormg, and MRI-guided volumetric perfusion measurement. These data suggest that specific brain region\ are requentially involved along a neuroanatomlc hierarchy which parallels disease symptomatology, and that progression from prodromal through chnical stages of dementia 1s accompanied by functional image abnormalities progressing from hmbic to neocortical nssoclation regions.