New Imaging Techniques Reveal Metabolism of the Aging Brain
New Imaging Techniques Reveal Metabolism of the Aging Brain
MCI is a transitional state between normal aging and dementia. MCI is a diagnosis given to individuals who experience memory problems greater than normally expected with typical aging, but who do not show other symptoms of dementia, such as impaired judgment or reasoning. A person with MCI is at an increased risk of developing AD, which is characterized by brain accumulation of senile Aβ plaques and hyperphosphorylated tau (neurofibrillary tangles) in the medial temporal lobe (MTL) and cortical areas of the brain.
Metabolic changes have been found in MCI using H-MRS. Elevated mI was detected in MCI and quantitative metabolite measures correlate with degrees of cognitive impairment in AD; NAA/mI ratio reduced in the MTL in MCI patients. Moreover, the level of NAA/mI reduction was correlated with the performance on visual recognition memory. Clinical follow-up data suggest that patients with impaired visual recognition memory are more likely to develop probable AD and MCI converters were found to have metabolic changes in the MTL at baseline in comparison to controls.
Instead of showing further reduction in glucose metabolism (CMRglc; determined by FDG-PET) compared with the normal aging, Cohen et al. has recently found that patients with MCI had a transient increase in CMRglc. They also found that the local elevations in glucose metabolism were found to be associated with Aβ plaque accumulation (determined by PIB-PET) at the MCI stage of AD. Specifically, CMRglc in anterior cingulate showed positive correlation with PIB in most brain areas in MCI, and CMRglc and PIB retention were positively correlated locally in the precuneus/parietal cortex. They suggested that, in MCI, higher basal metabolism could either be exacerbating Aβ deposition or increasing the level of Aβ necessary for cognitive impairment sufficient of the clinical diagnosis of AD. Only after extensive Aβ deposition has been present for longer period of time does Aβ become the driving force for decreased metabolism in clinical AD.
When the severity of hypometabolism of the parieto-temporal cortex and posterior cingulate cortex (PCC) is associated with that of MTL, FDG-PET is able to differentiate MCI patients from normal aging individuals with a 85% sensitivity and 71% specificity, and from AD patients with a 100% sensitivity and 77% specificity. FDG-PET is also able to predict the conversion rate of MCI to AD. In a recent study, Landau et al. followed-up patients with amnestic MCI (n = 85) for 1.9 ± 0.4 years and evaluated the predictors of subsequent conversion to AD and cognitive decline (Alzheimer's Disease Assessment Scale-Cognitive Subscale). They found that patients with MCI converted to AD at an annual rate of 17.2%. Subjects with MCI who had abnormal results on both FDG-PET and episodic memory were 11.7-times more likely to convert to AD than subjects who had normal results on both measures (p ≤ 0.02). Taken together, these results showed that FDG-PET can predict longitudinal cognitive decline, and baseline FDG-PET and episodic memory predict conversion to AD.
AD is the most common cause of dementia among the elderly and the seventh leading cause of death in the USA. In addition to the accumulation of senile Aβ plaques and hyperphosphorylated tau (neurofibrillary tangles), AD is a neurodegenerative disorder characterized by progressive memory deficits, cognitive impairments, and personality changes. Support for an early mitochondrial dysfunction that precedes the histopathological hallmarks described above in AD continues to increase. Perturbations of mitochondrial function in terms of altered morphology, compromised electron transfer complexes, and TCA cycle deficiencies have been long identified in post-mortem tissues of Alzheimer's patients.
Multiple levels of analyses indicate a dysfunction of glucose metabolism and mitochondrial bioenergetics as antecedents to the development of Alzheimer's pathology. A decline in brain glucose uptake (and metabolism) can appear decades prior to the onset of histopathological changes inherent in AD. A growing evidence has highlighted the importance of FDG-PET as a tool to distinguish AD from other dementias, predict and track decline from normal cognition to AD, and to identify individuals at risk for AD before the onset of cognitive decline (Figure 1). The FDG-PET results have shown that AD patients show consistent CMRglc deficits in the parietotemporal cortex and PCC and MTL. As the disease progresses, frontal association cortices become involved, while cerebellum, basal ganglia, striatum, primary visual and sensorimotor cortices remain preserved. The in vivo pattern of hypometabolism is found in the vast majority of clinically diagnosed AD patients, and in over 85% pathologically confirmed AD cases.
CMRglc is highly correlated with clinical disabilities in dementia. Clinical AD symptoms always occur accompanied with CMRglc reduction. Furthermore, the characteristic AD-pattern of CMRglc decreases yield high sensitivity in distinguishing AD from normal controls and from other types of dementia, including Lewy body, frontotemporal and cerebrovascular dementia. These findings suggest that FDG-PET is a powerful tool in differential diagnosis of the major neurodegenerative disorders.
MRS has also been used to differentiate AD from normal controls in the context of metabolic abnormality. Characteristic and consistent abnormalities in AD are decreased NAA and elevated mI in the medial temporal and parieto-occipital cortex. These are thought to represent neuronal loss/dysfunction and gliosis, in anatomic distributions that reflect early pathological involvement and atrophy patterns in AD. Less consistent disturbances of glutamine and glutamate, and Cho have also been reported. NAA/mI ratios of the PCC discriminate reliably between AD subjects and normal individuals, and provides a useful clinical test, as an adjunct to structural imaging.
In a pioneering study, Lin et al. infused three patients with [1-C] glucose and found a reduction of neuronal glucose oxidation and glutamate/glutamine neurotransmission rate in AD patients compared with age-matched controls, consistent with TCA impairment. They also reported that the C-MRS measures were significantly correlated with measures of neuronal integrity: reductions in NAA concentration, suggesting that impairment of TCA and neurotransmission may be a contributing factor in the cognitive impairment characteristic of AD.
Using a novel multivoxel P-MRS imaging experimental scheme and an advanced P signal processing technique, Mandal et al. determined the pH and neurochemicals from both hippocampal areas in young healthy individuals and patients with AD. They found that a significant decrease of PME and increase of PDE levels in the left and right hippocampus of AD patients was found compared with the control subjects. The pH in AD was found to be negatively correlated with phosphorus creatine level in AD subjects. In the left hippocampus, the increase in pH to alkaline range (in normal aging, pH is decreased to acidic range), significant increments of phosphorus creatine, γ-ATP and PDE, as well as a decrease of PME in AD subjects, provide additional crucial clinical information. They conclude that measures by P-MRS can be used as biomarkers for AD and potentially aid in the diagnosis.
Although not as direct a measure of metabolism as C and P MRS, H MRS has the potential of identifying alterations in aging.The H nucleus is the most sensitive for performing MRS studies and spectroscopic images of NAA and glutamate have been obtained with a spatial resolution as good as 5 mm in plane.H MRS studies have found reductions in NAA levels (reflex neuronal status) and increases in mI (reflect glial status) with healthy aging as well as in MCI, and AD.
In addition to significantly reduced brain metabolism, AD patients showed dramatic Aβ plaque deposition determined by PIB-PET (Figure 1). Several studies demonstrated significant PIB retention in AD patients as compared with normal controls and MCI, mostly in the frontal cortex, parietotemporal, PCC/precuneus, occipital lobes, thalamus and striatum, consistent with the known pattern of Aβ plaques deposition observed at post-mortem. However, the correlation between PIB retention and cognition does not appear to be as strong as with FDG-PET (i.e., glucose metabolism).
Despite the fact that in AD Aβ load and hypometabolism seem to spatially coincide in multiple brain regions, the lack of a direct correlation between the two measures is consistent with the finding that while FDG correlates reliably with the measures of cognitive decline, PIB does not. These reports are in line with longitudinal data on Aβ accumulation obtained with PIB, suggesting that Aβ levels remain relatively stable as cognitive functions deteriorate. There is a growing consensus in the field that once AD pathology is fully present, Aβ is no longer a driving factor of the continued cognitive decline. This is consistent with the notion that Aβ plaque distribution does not necessarily correlate with clinical symptoms in AD. As a result, neuroimaging related to metabolic profile, for example, FDG-PET and MRS, have advantages in clinical diagnosis in AD over PIB-PET.
As brain metabolism is critical to sustain brain functions and glucose metabolism is severely impaired in AD, alternative fuel substrate may be useful to maintain the energy balance and thus retard AD progression. In addition to glucose, brain cells use ketone bodies as energy sources (see). As a result, ketone bodies are the main replacement fuel for the brain when glucose availability is insufficient. Clinical studies have shown that the affected brain regions in AD are at least partially viable and that cognition can improve when exogenous supply of ketone bodies to the brain is increased. This suggests that although glucose metabolism (glycolysis) may be impaired in AD, other metabolic pathways (e.g., ketone metabolism) may be relatively normal in AD. This also implies that if brain hypometabolism in AD can be retarded or prevented, the clinical fallout may be reduced. The long-term metabolic and cognitive benefits of ketogenic therapies in AD may be further investigated using in vivo neuroimaging techniques, such as C MRS with 2,4-(13)C(2)-D-β-hydroxybutyrate infusion.
Brain Metabolism in Neurodegenerative Disorders
Mild Cognitive Impairment
MCI is a transitional state between normal aging and dementia. MCI is a diagnosis given to individuals who experience memory problems greater than normally expected with typical aging, but who do not show other symptoms of dementia, such as impaired judgment or reasoning. A person with MCI is at an increased risk of developing AD, which is characterized by brain accumulation of senile Aβ plaques and hyperphosphorylated tau (neurofibrillary tangles) in the medial temporal lobe (MTL) and cortical areas of the brain.
Metabolic changes have been found in MCI using H-MRS. Elevated mI was detected in MCI and quantitative metabolite measures correlate with degrees of cognitive impairment in AD; NAA/mI ratio reduced in the MTL in MCI patients. Moreover, the level of NAA/mI reduction was correlated with the performance on visual recognition memory. Clinical follow-up data suggest that patients with impaired visual recognition memory are more likely to develop probable AD and MCI converters were found to have metabolic changes in the MTL at baseline in comparison to controls.
Instead of showing further reduction in glucose metabolism (CMRglc; determined by FDG-PET) compared with the normal aging, Cohen et al. has recently found that patients with MCI had a transient increase in CMRglc. They also found that the local elevations in glucose metabolism were found to be associated with Aβ plaque accumulation (determined by PIB-PET) at the MCI stage of AD. Specifically, CMRglc in anterior cingulate showed positive correlation with PIB in most brain areas in MCI, and CMRglc and PIB retention were positively correlated locally in the precuneus/parietal cortex. They suggested that, in MCI, higher basal metabolism could either be exacerbating Aβ deposition or increasing the level of Aβ necessary for cognitive impairment sufficient of the clinical diagnosis of AD. Only after extensive Aβ deposition has been present for longer period of time does Aβ become the driving force for decreased metabolism in clinical AD.
When the severity of hypometabolism of the parieto-temporal cortex and posterior cingulate cortex (PCC) is associated with that of MTL, FDG-PET is able to differentiate MCI patients from normal aging individuals with a 85% sensitivity and 71% specificity, and from AD patients with a 100% sensitivity and 77% specificity. FDG-PET is also able to predict the conversion rate of MCI to AD. In a recent study, Landau et al. followed-up patients with amnestic MCI (n = 85) for 1.9 ± 0.4 years and evaluated the predictors of subsequent conversion to AD and cognitive decline (Alzheimer's Disease Assessment Scale-Cognitive Subscale). They found that patients with MCI converted to AD at an annual rate of 17.2%. Subjects with MCI who had abnormal results on both FDG-PET and episodic memory were 11.7-times more likely to convert to AD than subjects who had normal results on both measures (p ≤ 0.02). Taken together, these results showed that FDG-PET can predict longitudinal cognitive decline, and baseline FDG-PET and episodic memory predict conversion to AD.
Alzheimer's Disease
AD is the most common cause of dementia among the elderly and the seventh leading cause of death in the USA. In addition to the accumulation of senile Aβ plaques and hyperphosphorylated tau (neurofibrillary tangles), AD is a neurodegenerative disorder characterized by progressive memory deficits, cognitive impairments, and personality changes. Support for an early mitochondrial dysfunction that precedes the histopathological hallmarks described above in AD continues to increase. Perturbations of mitochondrial function in terms of altered morphology, compromised electron transfer complexes, and TCA cycle deficiencies have been long identified in post-mortem tissues of Alzheimer's patients.
Multiple levels of analyses indicate a dysfunction of glucose metabolism and mitochondrial bioenergetics as antecedents to the development of Alzheimer's pathology. A decline in brain glucose uptake (and metabolism) can appear decades prior to the onset of histopathological changes inherent in AD. A growing evidence has highlighted the importance of FDG-PET as a tool to distinguish AD from other dementias, predict and track decline from normal cognition to AD, and to identify individuals at risk for AD before the onset of cognitive decline (Figure 1). The FDG-PET results have shown that AD patients show consistent CMRglc deficits in the parietotemporal cortex and PCC and MTL. As the disease progresses, frontal association cortices become involved, while cerebellum, basal ganglia, striatum, primary visual and sensorimotor cortices remain preserved. The in vivo pattern of hypometabolism is found in the vast majority of clinically diagnosed AD patients, and in over 85% pathologically confirmed AD cases.
CMRglc is highly correlated with clinical disabilities in dementia. Clinical AD symptoms always occur accompanied with CMRglc reduction. Furthermore, the characteristic AD-pattern of CMRglc decreases yield high sensitivity in distinguishing AD from normal controls and from other types of dementia, including Lewy body, frontotemporal and cerebrovascular dementia. These findings suggest that FDG-PET is a powerful tool in differential diagnosis of the major neurodegenerative disorders.
MRS has also been used to differentiate AD from normal controls in the context of metabolic abnormality. Characteristic and consistent abnormalities in AD are decreased NAA and elevated mI in the medial temporal and parieto-occipital cortex. These are thought to represent neuronal loss/dysfunction and gliosis, in anatomic distributions that reflect early pathological involvement and atrophy patterns in AD. Less consistent disturbances of glutamine and glutamate, and Cho have also been reported. NAA/mI ratios of the PCC discriminate reliably between AD subjects and normal individuals, and provides a useful clinical test, as an adjunct to structural imaging.
In a pioneering study, Lin et al. infused three patients with [1-C] glucose and found a reduction of neuronal glucose oxidation and glutamate/glutamine neurotransmission rate in AD patients compared with age-matched controls, consistent with TCA impairment. They also reported that the C-MRS measures were significantly correlated with measures of neuronal integrity: reductions in NAA concentration, suggesting that impairment of TCA and neurotransmission may be a contributing factor in the cognitive impairment characteristic of AD.
Using a novel multivoxel P-MRS imaging experimental scheme and an advanced P signal processing technique, Mandal et al. determined the pH and neurochemicals from both hippocampal areas in young healthy individuals and patients with AD. They found that a significant decrease of PME and increase of PDE levels in the left and right hippocampus of AD patients was found compared with the control subjects. The pH in AD was found to be negatively correlated with phosphorus creatine level in AD subjects. In the left hippocampus, the increase in pH to alkaline range (in normal aging, pH is decreased to acidic range), significant increments of phosphorus creatine, γ-ATP and PDE, as well as a decrease of PME in AD subjects, provide additional crucial clinical information. They conclude that measures by P-MRS can be used as biomarkers for AD and potentially aid in the diagnosis.
Although not as direct a measure of metabolism as C and P MRS, H MRS has the potential of identifying alterations in aging.The H nucleus is the most sensitive for performing MRS studies and spectroscopic images of NAA and glutamate have been obtained with a spatial resolution as good as 5 mm in plane.H MRS studies have found reductions in NAA levels (reflex neuronal status) and increases in mI (reflect glial status) with healthy aging as well as in MCI, and AD.
In addition to significantly reduced brain metabolism, AD patients showed dramatic Aβ plaque deposition determined by PIB-PET (Figure 1). Several studies demonstrated significant PIB retention in AD patients as compared with normal controls and MCI, mostly in the frontal cortex, parietotemporal, PCC/precuneus, occipital lobes, thalamus and striatum, consistent with the known pattern of Aβ plaques deposition observed at post-mortem. However, the correlation between PIB retention and cognition does not appear to be as strong as with FDG-PET (i.e., glucose metabolism).
Despite the fact that in AD Aβ load and hypometabolism seem to spatially coincide in multiple brain regions, the lack of a direct correlation between the two measures is consistent with the finding that while FDG correlates reliably with the measures of cognitive decline, PIB does not. These reports are in line with longitudinal data on Aβ accumulation obtained with PIB, suggesting that Aβ levels remain relatively stable as cognitive functions deteriorate. There is a growing consensus in the field that once AD pathology is fully present, Aβ is no longer a driving factor of the continued cognitive decline. This is consistent with the notion that Aβ plaque distribution does not necessarily correlate with clinical symptoms in AD. As a result, neuroimaging related to metabolic profile, for example, FDG-PET and MRS, have advantages in clinical diagnosis in AD over PIB-PET.
As brain metabolism is critical to sustain brain functions and glucose metabolism is severely impaired in AD, alternative fuel substrate may be useful to maintain the energy balance and thus retard AD progression. In addition to glucose, brain cells use ketone bodies as energy sources (see). As a result, ketone bodies are the main replacement fuel for the brain when glucose availability is insufficient. Clinical studies have shown that the affected brain regions in AD are at least partially viable and that cognition can improve when exogenous supply of ketone bodies to the brain is increased. This suggests that although glucose metabolism (glycolysis) may be impaired in AD, other metabolic pathways (e.g., ketone metabolism) may be relatively normal in AD. This also implies that if brain hypometabolism in AD can be retarded or prevented, the clinical fallout may be reduced. The long-term metabolic and cognitive benefits of ketogenic therapies in AD may be further investigated using in vivo neuroimaging techniques, such as C MRS with 2,4-(13)C(2)-D-β-hydroxybutyrate infusion.
