Abnormalities in Cerebral Perfusion

From: <a href="https://link.springer.com/article/10.1007/s12035-017-0598-z">A Comparison of Neuroimaging Abnormalities in Multiple Sclerosis, Major Depression and Chronic Fatigue Syndrome (Myalgic Encephalomyelitis): is There a Common Cause? | SpringerLink</a>

Most of the SPECT studies investigating potential CBF abnormalities in CFS have reported areas of significant cerebral hypoperfusion, at either a global [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR20">20</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR192">192</a>] or regional level [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR193">193</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR194">194</a>] compared with unaffected controls. However, a minority of researchers reported no significant CBF impairments in comparison with unaffected controls or MDD participants [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR195">195</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR196">196</a>]. The reasons for such discrepant findings are unclear, but fewer participants and differences in selection methods may be relevant. The much larger studies conducted by Ichise, Schwartz, Costa and Goldstein, and their colleagues [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR20">20</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR192">192</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR193">193</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR194">194</a>] appear worthy of particular consideration as they examined multiple brain regions and perhaps even more importantly, apart from Ichise and others [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR192">192</a>], examined differences in patterns of abnormal perfusion between participants with CFS and MDD, which is currently a contentious area.

Ischise et al. compared rCBF in 60 CFS participants and 14 healthy controls and reported significant reductions in cortical/cerebellar rCBF ratios in the frontal, temporal, parietal and occipital lobes, providing objective evidence of widespread functional impairment of the brain in the vast majority of their CFS subjects [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR192">192</a>]. Schwartz et al. examined SPECT data differences in terms of regional perfusional deficits and mid-cerebral uptake indices between 45 CFS participants, 14 MDD participants, 27 participants with AIDS dementia complex (ADC) and 38 healthy controls [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR20">20</a>]. These authors noted more areas of impaired frontal and temporal perfusion in the ADC group compared with those with CFS or MDD. However, the mid-cerebral uptake index was lower in patients with ADC and CFS than in the MDD and healthy controls groups [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR20">20</a>].

The largest study examining potential 99mTc-HMPAO SPECT differences between CFS and MDD patients was carried out by Costa and others [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR193">193</a>]. It included 40 healthy participants, 67 CFS participants (both with and without psychiatric co-morbidity) and 29 early- and late-onset MDD participants [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR193">193</a>]. These authors reported significantly greater global and brain-stem hypoperfusion in CFS participants free of psychiatric symptoms compared with controls and MDD participants, which was not apparent in CFS participants displaying symptoms of anxiety and depression [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR193">193</a>]. Goldstein and others compared high-resolution 99mTc-HMPAO SPECT imaging patterns of rCBF in 33 CFS subjects (55 ± 10 years), 26 age-matched MDD participants and 19 healthy participants in an attempt to investigate the potential pathophysiology of CFS [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR194">194</a>]. Importantly, they reported dorsofrontal hypoperfusion as the dominant profile in CFS while hypoperfusion seen in MDD was predominantly in the right orbitofrontal lobe, left temporal lobe and, in particular, the left anterior frontal lobes [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR194">194</a>].

More recent research using xenon-computed tomography, ASL and high-resolution SPECT reported consistently impaired CBF at a global and regional level at rest and during exercise [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR197">197</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR198">198</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR199">199</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR200">200</a>]. Yoshiuchi and others reported reduced CBF in the right and left hemisphere in CFS participants free of psychiatric comorbidity compared with healthy controls but also noted that hypoperfusion in CFS patients with psychiatric comorbidity appeared to be exclusively limited to the left hemisphere [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR198">198</a>]. These results have been broadly replicated by Biswal and others who reported impaired regional and global CBF in the vast majority of their participants with evidence of regional hyperperfusion in a minority [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR197">197</a>]. Evidence of hyperperfusion in some CFS subjects has also been supplied by Machale and others who reported significantly increased hyperperfusion in the left thalamus in CFS compared with a pattern of hyperperfusion in the left prefrontal cortex of MDD [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR200">200</a>]. Finally, Patrick-Neary and others reported significantly decreased CBF in CFS participants during maximal exercise compared with healthy controls which they suggested as a cause of the profound disability experienced by many patients [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR199">199</a>].

The potential capacity of SPECT to differentiate CFS from MDD may be highly significant as CFS is a purely descriptive diagnosis reliant on phenotype only, and there is accumulating evidence that the diagnosis identifies a clinically and aetiologically heterogeneous syndrome rather than a discrete biological entity even when such a diagnosis is made via the application of international guidelines [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR1">1</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR3">3</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR201">201</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR202">202</a>]. Unsurprisingly, research in this area has been bedevilled by a lack of reproducibility which is also the case in many other areas where diagnostic categories are descriptive and homogeneity of causation is assumed (reviewed in [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR203">203</a>]). This issue in ‘CFS research’ is even more complex because of the frequent use of unvalidated criteria which only mandate the presence of chronic mental and physical tiredness [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR204">204</a>] or where a diagnosis is based on the presence of intermittent symptoms based on a population study of fatigue in a localised population [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR205">205</a>]. Hence, a method for increasing the homogeneity of a study population and excluding patients with MDD is to be welcomed. The question of heterogeneity is also relevant to the next section of this paper which briefly examines mechanisms whereby systemic inflammation could be a major element initiating and maintaining neuropathology in different illnesses even though investigation with an array of neuroimaging techniques produces very different and often illness-specific results.

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<h2 class="Heading" data-role="collapsible-handle">Factors Affecting Severity and Specificity of Neuropathology</h2>

There is widespread agreement that the relationship between the presence of systemic inflammation and various dimensions of neuropathology is established via the conveyance of inflammatory signals to the brain through a range of humoral and neural routes culminating in the activation of microglia and astrocytes [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR206">206</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR207">207</a>]. Once activated, these glial cells secrete a range of inflammatory molecules such as pro-inflammatory cytokines, reactive oxygen species, reactive nitrogen species, prostaglandins and quinolinic acid [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR208">208</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR209">209</a>]. These are well-documented effects and have been described in a number of detailed reviews [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR210">210</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR211">211</a>].

Another source of neuropathology is more indirect however and stems from the loss or corruption of the regulatory functions exerted by these glial cells via a sophisticated communication system with neurones and oligodendrocytes founded on the secretion of exosomes containing mRNAs, miRNAs, caspases and P2X7 (reviewed in [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR212">212</a>]). This is a highly complex area, but the key point from the perspective of this paper is that abnormally expressed microglial exosomal miRNAs appear to be independent contributors to the development maintenance and illness-specific patterns of neuroinflammation seen in many different neurodegenerative and neuroprogressive disorders [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR213">213</a>]. Thus, microglial activation following prolonged systemic inflammation could produce an illness-specific or at least a range of characteristic WM abnormalities depending on a particular signature of abnormally expressed miRNAs. The mechanisms underpinning this phenomenon are currently unknown but may lie in the recently discovered capacity of at least some miRNAs to activate toll-like receptors and are another mechanism underpinning ‘sterile’ immune activation [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR214">214</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR215">215</a>].

Microglia also display distinct regional differences in density and transcriptional identity particularly in bioenergetic and immunoregulatory pathways [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR216">216</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR217">217</a>]. This underpins observations of region-specific sensitivities to microglial dysfunction and in particular responses to different pathogen-associated molecular patterns [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR216">216</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR217">217</a>]. Hence, this provides another mechanism whereby systemic inflammation could produce geographically variable neuropathology. Another highly pertinent example of the role of microglial genetics in creating unique patterns of abnormalities can be found from recent data in MS, where microglia deficient in the production of caspase-8 are considered to be the source of necroptotic markers seen in active plaques of MS patients. These glial cells are likely one of the main drivers of neuronal and oligodendrocyte destruction seen in this illness [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR218">218</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR219">219</a>]. The heterogeneous responses of microglia to external or internal stimuli are also under epigenetic regulation involving DNA methylation, histone acetylation and the expression of a wide range of miRNAs [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR220">220</a>]. It is also noteworthy that different genomic patterns of DNA methylation within and outside glial cells are associated with different patterns of neuropathology in distinct brain regions [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR221">221</a>].

Predictably, astrocytes also display extensive variability in biochemical, biophysical and immunoregulatory properties in distinct brain regions (reviewed in [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR222">222</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR223">223</a>]). The signalling pathways orchestrated by astrocytes are also strongly influenced by genetics [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR224">224</a>]. Importantly, some of the neuroprotective functions of astrocytes are also under epigenetic control. Reactive microglia also compromise astrocytic function and survival in an inflammatory environment with the latter property resulting from a decrease of histone acetylation in astrocytes and a silencing of Nrf-2-mediated antioxidant defences [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR225">225</a>].

Antioxidant defence systems also demonstrate pronounced regional differences in composition and efficacy. For example, thioredoxin and thioredoxin reductase levels vary in different brain regions [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR226">226</a>]. This is also true of glutathione transferase, glutathione reductase and glutathione peroxidase, with the former two enzymes being reduced in the striatum, neocortex, cerebellum and hippocampus, whereas expression of the last enzyme appears to be reduced in the striatum, cerebellum, cortex and corpus callosum [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR227">227</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR228">228</a>]. The expression and activity of NADPH oxidases also displays considerable variation in different brain regions [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR229">229</a>]. Selenium distribution across different brain regions is also heterogeneous, with the highest concentrations being in the parietal inferior lobule, putamen and occipital cortex and the lowest levels in the cerebellum and medulla [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR230">230</a>].

Different discrete neuronal populations existing in different brain regions display differential susceptibility to neurodegenerative stressors which is a phenomenon often described as selective neuronal vulnerability (SNV). Well-documented examples include neurones in the entorhinal cortex, frontal cortex, hippocampal CA1 region and amygdala, which are the most susceptible to neurodegenerative death in populations of neurones most sensitive to the neurodegeneration associated with Alzheimer’s disease [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR231">231</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR232">232</a>]. The increased susceptibility of dopaminergic neurones of the substantia nigra to neurodegenerative destruction in Parkinson’s disease is equally well documented [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR233">233</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR234">234</a>]. It should be stressed that the pattern and extent of neural damage seen in different neurodegenerative disease is not just dependent on SNV but also stems from specific factors unique to the aetiology of the illness (reviewed in [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR235">235</a>]). SNV also exists within populations in the same brain region. For example, the hippocampal CA1 neurones are much more vulnerable than are CA3 neurones to global cerebral ischaemia [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR236">236</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR237">237</a>] and oxidative stress [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR238">238</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR239">239</a>].

Brain volume and structure are strongly influenced by genetic factors [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR240">240</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR241">241</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR242">242</a>] and resting-state functional connectivity [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR243">243</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR244">244</a>], GM and WM volume [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR245">245</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR246">246</a>] and CBF [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR247">247</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR248">248</a>] are sensitive to environmentally induced epigenetic changes in gene methylation and/or acetylation and/or changes in the expression of a wide range of miRNAs. These factors may also produce heterogeneity in neuroimaging phenotypes between individuals with the same illness or between illnesses even if systemic inflammation is a major driver of neuropathology in each instance.

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