Simply stated the Brain Hypometabolism Hypothesis (BHH) is
‘Brain hypometabolism leads to neuropathology’
This is a very simple but broad statement which is a starting point for elaboration.
What is the value for Brain Glucose Metabolism?
One of the key concepts in understanding brain glucose metabolism is the cerebral metabolic rate of glucose. This was calculated by comparing the glucose content of cerebral arterial and cerebral venous blood. When this difference is calculated it can be combined with the cerebral blood flow values to estimate the rate of glucose metabolism by the brain.
The value given in the article is (see Appendix A for calculations)
6–7 mg/100 g/min
31 μmol/100 g/min
What is the Link Between Alzheimer’s Disease and Brain Glucose Metabolism?
In their 2016 paper, Cunnane and colleagues outline several supporting lines of evidence as the basis for their paper
(i) Lower glucose uptake in the frontal cortex of older adults
(ii) Regional deficits in brain glucose uptake in younger adults at risk of Alzheimer’s Type Dementia
(iii) Preservation of ketone uptake in the brain
(iv) Further evidence on consequences of ketone based interventions.
Is there Lower Glucose Uptake in the Frontal Cortex of Older Adults?
Cannane and colleagues published a paper on brain metabolism and aging based on a database they had compiled using radioactive tracers for glucose and ketone metabolism in the brain.
Figure 2 from Cunnane and colleagues, CC BY
Is Insulin Resistance As a Risk Factor?
The Rotterdam study looked at insulin resistance in a large prospective cohort. Researchers found a correlation between insulin resistance and incident Alzheimer’s Type Dementia but only within the first three years.
However we know from Kuhn’s work on ‘The Structure of Scientific Revolutions‘ that central paradigms are successful even if there are lines of evidence that do not support the paradigm (as models are approximations to reality).
A Review of ‘The Structure of Scientific Revolutions’
Does atrophy in a brain region account for brain hypometabolism?
Cunnane and colleagues answer this question in two ways.
Firstly there is a specific research methodology that is able to answer this question – correction for atrophy. In their 2011 paper, Cunnane and colleagues review the literature on brain glucose metabolism studies in Alzheimer’s Type Dementia and summarise the results in Table 1 in the paper.
They note that in some studies, there is correction for atrophy and in those studies there is still a preservation of the relationship between Alzheimer’s Type Dementia and brain glucose hypometabolism.
Secondly Cunnane and colleagues also answer this question by referencing risk factors for Alzheimer’s Type Dementia where brain glucose hypometabolism occurs even in the absence of cognitive impairment
- Pre-senilin-1 mutation,
- Apolipoprotein E4 carrier status
- Matrilinear AD
- Cognitively healthy aging
- Insulin resistance
There are five lines of evidence for further investigation of the question above. However the relationship cited above looks at cognitive impairment. Cognitive impairment is a proxy marker. The key question is whether there is brain atrophy which is causing the brain hypometabolism.
So the question can be asked for each of the five risk factors identified above.
What is the Mechanism for Glucose Uptake in the Brain?
In their 2011 paper, Cunnane and colleagues note that there are three separate isoforms of GLUT1 that facilitate glucose uptake in the brain
(1) One isoform facilitates glucose uptake across the blood-brain barrier
(2) Another isoform facilitates glucose uptake in astrocytes
(3) A third isoform facilitates glucose uptake in neurons
There are however other mechanisms for glucose uptake in the brain.
Appendix A – Calculations for Unit Conversion
A mole is 6 x 10²³ molecules.
The molecular weight for glucose is 180.1559 g per mole.
Therefore 31 μmol of glucose is equivalent to 180.1559 g x 31/1000000
= 0.00558 g
= 5.58 mg
which is in the range described above.
There is also a conversion calculator here.
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