I think you need to refine your question, but lets start with "what does BOLD measure ?". BOLD measure a magnetic gradient between oxygenated and de-oxygenated hemoglobin in the blood. Areas of the brain that are more active than other areas during a task will have a higher use of oxygen, and therefore a change in BOLD signal. All of these measures are in reference to a resting state BOLD signal, and that resting state signal is qualitative between individuals, between magnets, and between time points.

Is it possible that there are chemical and proteins in the brain that affect the BOLD signal? Yes, if they affect either the overall magnetic signal or they affect the amount of oxygen that is passed across the blood brain barrier. What are those chemicals or proteins? Caffeine is one but there are probably many others.

But there are many other possible reasons for changes in BOLD signal with age. An incomplete list of those variables are: Partial Volume Effects due to atrophy, changes in vascular permeability, changes in blood flow, changes in red blood cell count, and decreases in oxygen exchange.

I hope this helps.

Phil Greer

Phil J Greer Appreciated your detailed explanation and time.

By your explanation i came to know that further need to understand role of oxygenated and de oxgenated hemoglobin with respect to chemicals and proteins

specially in Alzheimers disease ( patients having severe AD).

the following details is helpful to understand chemicals and proteins affected in AD.

beta-amyloid 42, is thought to be especially toxic. In the Alzheimer’s brain, abnormal levels of this naturally occurring protein clump together to form plaques that collect between neurons and disrupt cell function.

Neurofibrillary tangles are abnormal accumulations of a protein called tau that collect inside neurons ...Alzheimer’s-related brain changes may result from a complex interplay among abnormal tau and beta-amyloid proteins and several other factors.

chronic inflammation may be caused by the buildup of glial cells... In Alzheimer’s, microglia fail to clear away waste, debris, and protein collections, including beta-amyloid plaques.

Astrocytes—another type of glial cell—are signaled to help clear the buildup of plaques and other cellular debris left behind. These microglia and astrocytes collect around the neurons but fail to perform their debris-clearing function. In addition, they release chemicals that cause chronic inflammation and further damage the neurons they are meant to protect.

Nowadays mainly researchers are focusing on early detection of neurodegeneration diseases.... as in Alzheimers the categories divided as Early MCI, MCI and AD

During the early stages activation increases in some stages and decreases in coming stages.... the point is NO SEQUENCE ( in early stages) as shown in attached images ..

The first image (stages.png) of brain region(1) show that stage 4 fMRI activation is higher than stage 2 and stage 3 , but still less than baseline ( stage 1 ).... so the finding show that increase in activation then earlier stages.... how ?

In second image (Stages2.png) brain region (2).... increase in activations ( stage 2, stage 3 and stage 4) then its baseline (stage1) but somehow activation in stage 2 , stage3 and stage 4 are closed... WHY ?

if we do comparision of brain region (1) and brain region (2)....

Activation in brain region (1)

stage 1 (base line)

stage 2 (decrease)

Stage 3 (decrease)

stage 4 (increase)

Activation in brain region (2)

stage 1 (baseline)

stage 2 (increase)

stage 3 (increase)

stage 4 ( decrease then stage 2 and stage 3 but still more than stage 1 activation)

key point is same chemicals... same protiens and other substances but showing different activition in different brain regions... that is something interesting to understand more deeply and as research gap...

YES, these points are important to consider, changes in BOLD signal with age is also an important indicator similarly as mentioned by you the variables like Partial Volume Effects due to atrophy, changes in vascular permeability, changes in blood flow, changes in red blood cell count, and decreases in oxygen exchange have their own importance to understand neurodegenration

Thank You Very Much... Your explanation is immensely appreciated !

As the discussion is also started on social media group... i am sharing here views of MR. Marek Bartoň ... he also shared very useful knowledge regarding those technical QUESTIONS

"" Hello, I think these questions are very hard to answer exactly since there is (afaik) very limited research on that.

Anyway, it's interesting - have you observed such effect across whole group of cognitively declining individuals?

edit: next thing which is important to consider - the level of baseline vs. variation (percentual change) of the signal... there may be some effect of the basic image contrast (baseline), but this doesn't have necessarily to be linked to variation/magnitude of BOLD signal (which reflect neural activation, neurovascular coupling etc.) ""

Marek Bartoň Than Afaik will create research gap as you mentionted very limited research on that.

"""" have you observed such effect across whole group of cognitively declining individuals? """"

yes i checked it on individuals and as a whole group.... the above images showing results of whole group activations.

""""next thing which is important to consider - the level of baseline vs. variation (percentual change) of the signal... there may be some effect of the basic image contrast (baseline), but this doesn't have necessarily to be linked to variation/magnitude of BOLD signal (which reflect neural activation, neurovascular coupling etc.)""""

thats a Good Point.... the question rises here is how to observe variations by PERCENTUAL CHANGE... if i understand your point then i like to share that all stages have same patients and all pateints have the same image preprocessing and statistical steps... but YES still there is external and internal variations exist...

Mr. Marek Bartoň :

1, "baseline" - simple mean of all the time points in a given voxel

2, "variation" - signal fluctuations, let's say standard deviation of the signal from a given voxels (must be quantified relatively to baseline, so std(signal) divided by mean(signal))

1, If you observe different means (it's apparent from your graphs), it may be just different magnetic properties of the tissue ("independent" on measured neural activity) due to (?)degeneration.

2, If you observe different variation/baseline (std divided by mean) - you probably have different BOLD activity (whatever it means).

I want to say - if you have just different baselines across stages but the fluctuations are comparable, there might not be necessary to do "fMRI", because the differences are not reflected in BOLD signal, rather in general magnetic susceptibility changes of the brain. If you have different BOLD amplitudes (normal, low, low, high) relative to the mean, then it's different story again (probably complex, multifactorial, moreover when assuming you have also different means).

Thanks for providing the kind of help that I needed.

i have 105 scans for each subjects... so 105 voxels intensity values/ time points .... later i added all subjects, and get "" Mean voxels"" of the group... this mean voxels presented in graph as shown in above figures.... i am attaching descriptive statistics of MEAN voxels with (MEAN AND STANDARD DEVIATION, Minimum mean voxel intensity, Maximum mean voxel intensity) with 4 stages... of two brain regions

Mr. Marek Bartoň:

By the way, have you tried to correlate the fMRI signal intensity with some measure of atrophy? The cerebrospinal fluid has high signal intensity on BOLD-weighted images, so if there is more CSF in sulci and ventricles, it may result in higher fMRI signal (it may has also "longer-range" effects if you smooth your images during preprocessing)...