CCSVI in Parkinson’s, Alzheimer’s and other neurological disorders (ONDs)
CCSVI in ONDs: Quick Facts
In the four years since Dr. Paolo Zamboni first published his discovery of chronic cerebrospinal venous insufficiency (CCSVI) as a venous disease specific to multiple sclerosis (MS), other international researchers, imaging specialists, and physicians have published and discussed their findings of CCSVI in other neurological disorders (ONDs).
The very first correlation of CCSVI to ONDs was made by Dr. Robert Zivadinov and his imaging team at Buffalo Neuroimaging Center (BNAC). BNAC has been involved in researching CCSVI since 2008, and recruited over 499 enrolled participants in their CTEVD (combined transcranial and extracranial venous doppler) study. BNAC utilized Dr. Zamboni’s doppler protocol and found CCSVI and venous irregularities in 42.3% of patients with other neurological disease, including Parkinson’s. 
The International Society for Neurovascular Disease (ISNVD) is a group committed to understanding the role of altered venous return in OND and aging and elucidating how ONDs share many facets related to neurodegeneration and cerebral blood flow. In his welcoming Letter as the President for the 2nd Annual ISNVD conference, held in Orlando, Florida during February 2012, Dr. Zivadinov commented on the scientific sessions of the conference, which were “focused on better understanding venous involvement in neurological disorders, the abnormalities in multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, Sturge-Weber Syndrome, normal pressure hydrocephalus and aging.” 
A member of the ISNVD and founding President, Dr. Mark Haacke, presented research at the 2nd Annual ISNVD conference. His paper, which has been submitted for publication , looked at 21 patients with Parkinson’s. These participants were imaged by MRV, and 15 of them (71%) had abnormal venous structures and/or blood flow. All participants with CCSVI exhibited the same pattern: reduced flow on the left side and abnormal left transverse sinus and jugular vein, with the right internal jugular carrying most of the flow out of the brain. This work was stimulated in part by the fact that iron deposition in the MS population has similar locations to that seen in Parkinson's patients. So the question that came to mind was: "Could these effects have similar associations with CCSVI?" Further, Prof. Haacke has studied more than 2000 cases and recently published a paper on 323 MS cases to show that there is clearly abnormal flow in MS patients . However, the type of flow abnormalities appears to be different with Parkinson's cases, possibly explaining why Parkinson’s disease develops so much later than MS.
Other members of the ISNVD, Dr. CP Chung and Dr. HY Hsu, neurologists at the Chung Shan Medical University in Taiwan, have been studying jugular vein reflux in relation to neurological disorders and aging for the past decade. 
Dr. Peter Stys, neurologist and stroke researcher at the University of Calgary and recipient of a $3.8 million grant from the MS Society in Canada to research the degenerative aspect of MS, has recently published a review of the literature defining MS as a disease of primary neurodegeneration with secondary inflammation, or what he calls an “inside-out mechanism.”
Although Stys’ research does not refer to venous return or CCSVI specifically, he does compare MS to other diseases of neurodegeneration, including Alzheimer’s and Parkinson’s disease. Stys considers these diseases within the spectrum of “cytodegeneration”--or cellular death. He posits that the difference between these diseases may be age of onset, since MS begins earlier in life, and “immune responsiveness” is more acute in younger individuals. Included below is a section from a recent review by Dr. Stys, entitled “Will the real multiple sclerosis please stand up?” 
One might reasonably ask why other common neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease, do not also result in relapsing–remitting neuroinflammation. In fact, both diseases do exhibit inflammation in pathologically vulnerable regions 83,84. Indeed, in these research fields there is also an ongoing debate about whether inflammation is a reaction to, or cause of, ongoing degeneration.
Because diseases such as Alzheimer’s and Parkinson’s have a much more prominent degenerative rather than inflammatory phenotype, the initial assumption was that a degenerative mechanism (or mechanisms) was primarily responsible, with inflammation perhaps a secondary, but possibly important, consequence of the degeneration.
In MS, the situation is reversed: inflammation occurs early and is very prominent in many patients, so it was naturally assumed that autoimmunity might be causal; but, as we argue throughout this Perspective, such an assumption may be incorrect.
If MS is primarily a degenerative disorder in line with an inside-out mechanism, why would this disease be unique in engendering such prominent and cyclic inflammation? The differences may be related to age: Alzheimer’s disease and Parkinson’s disease present decades later than MS, and immune responsiveness wanes with age through a process of ‘immune senescence’ (REFS 21,87). Indeed, the responsiveness of T cells, which are known to be centrally involved in the immunopathogenesis of MS88, appears to be particularly altered with age87. Moreover, it is conceivable that the putative cytodegeneration involving the myelinating unit (oligodendroglia, their processes and myelin) in MS releases debris that is more antigenic35,36,66 than the debris that is shed from the mainly synaptic and neuronal degeneration in Alzheimer’s disease and other traditional neurodegenerative disorders.
Hypoperfusion as a cause of neurodegeneration in Multiple Sclerosis and ONDs
A potential mechanism behind the neurodegenerative process which is currently being studied is hypoperfusion, or slowed cerebral blood flow.
Hypoperfusion in the brain parenchyma has been linked to the severity of CCSVI. In a blinded study undertaken by Dr. Zamboni and Dr. Zivadinov’s research labs, healthy controls and people with MS received doppler analysis and perfusion MRIs. There was a correlation noted between venous hemodynamic insufficiency and reduced cerebral blood flow.
This pilot study is the first to report a significant relationship between the severity of CCSVI and hypoperfusion in the brain parenchyma. These preliminary findings should be confirmed in a larger cohort of MS patients to ensure that they generalize to the MS population as a whole. Reduced perfusion could contribute to the known mechanisms of virtual hypoxia in degenerated axons. 
The following studies have found a connection between slowed cerebral bloodflow and diseases of neurodegeneration. Most of these studies note that hypoperfusion appears to precede the degenerative process.
1. Cerebral hypoperfusion is linked to neurodegeneration in Alzheimer’s and appears to precede the hypometabolic, cognitive and degenerative pathology.
Chronic cerebral hypoperfusion has been associated with cognitive decline in aging and Alzheimer's disease. Moreover, the pattern of cerebral blood flow in mild cognitive impairment has emerged as a predictive marker for the progression into Alzheimer's disease. 
Mounting clinical and experimental evidence indicates that Alzheimer’s disease (AD) can be caused by vascular-related factors that directly reduce cerebral perfusion to a critical level of dysfunction. This evidence can be summarized as follows:
(1) epidemiological studies show that risk factors thus far described for AD have a vascular basis;
(2) most of the risk factors for AD are also associated with vascular dementia (VaD);
(3) practically all drugs reported to slow the development of AD improve or increase cerebral perfusion;
(4) development of AD can be predicted preclinically by measuring regional cerebral perfusion deficits;
(5) clinical evidence exists that AD symptoms are related to brain microvascular hemodynamic pathology;
(6) clinical symptomatology is similar in AD and VaD;
(7) cerebrovascular pathological lesions often overlap in AD and VaD; and
The collective data presented in this review strongly support the concept that sporadic AD is a vascular disorder.
Our experiments reveal that total cerebral blood flow was 20% lower in the Alzheimer’s Disease group than in the Normal Nondemented Controls group, and that these values were directly correlated with pulse pressure and cognitive measures. The AD group had a significantly lower pulse pressure (mean AD 48, mean NDC 71; P = 0.0004). A significant group difference was also observed in their hippocampal volumes. Composite z-scores for clinical, psychometric, hippocampal volume, and hemodynamic data differed between the AD and NDC subjects, with values in the former being significantly lower (t = 12.00, df = 1, P = 0.001) than in the latter.
These results indicate an association between brain hypoperfusion and the dementia of AD. Cardiovascular disease combined with brain hypoperfusion may participate in the pathogenesis/pathophysiology of neurodegenerative diseases. Future longitudinal and larger-scale confirmatory investigations measuring multidomain parameters are warranted.
2. Cerebral hypoperfusion is found early in Parkinson’s Disease.
In this work, arterial spin labeled perfusion MRI was employed to quantify absolute cerebral blood flow in a group of early-to-moderate Parkinson's disease patients and age-matched healthy controls. Perfusion comparisons between the two groups showed that Parkinson's disease is characterized by wide-spread cortical hypoperfusion. Subcortically, hypoperfusion was also found in the caudate nucleus. This pattern of hypoperfusion could be related to cognitive dysfunctions that have been previously observed even at the disease early stages. 
Region of interest analysis of absolute perfusion values revealed that the Parkinson’s disease pattern was characterized by decreased perfusion in posterior parieto- ococcipital cortex, precuneus and cuneus, and middle frontal gyri compared with healthy controls. 
3. Hypoperfusion and reduced cerebral blood flow cause neurodegeneration in a mouse model characterizing vascular cognitive impairment and white matter changes.
Introduction: Reduced cerebral blood flow is associated with neurodegenerative disorders and dementia, in particular. Experimental evidence has demonstrated the initiating role of chronic cerebral hypoperfusion in neuronal damage to the hippocampus, the cerebral cortex, the white matter areas and the visual system. Permanent, bilateral occlusion of the common carotid arteries of rats (two vessel occlusion - 2VO) has been introduced for the reproduction of chronic cerebral hypoperfusion as it occurs in Alzheimer’s disease and human aging. Increased generation of free radicals through lipid peroxidation can damage neuronal cell membrane. Markers of lipid peroxidation have been found to be elevated in brain tissues and body fluids in neurodegenerative diseases, including Alzheimer’s disease, Parkinson disease and amyotrophic lateral sclerosis. 
Recent evidence indicates that BBB dysfunction is associated with the accumulation of several vasculotoxic and neurotoxic molecules within brain parenchyma, a reduction in cerebral blood flow, and hypoxia. Together, these vascular-derived insults might initiate and/or contribute to neuronal degeneration. 
CCSVI Alliance views the discovery of CCSVI in other neurological disorders as further emphasizing the importance of the venous system and cerebral perfusion to brain health. We encourage neurologists to work with vascular doctors and imaging specialists in considering cerebral blood flow in neurodegenerative disease.
We also encourage patients and caretakers of those with other neurodegenerative diseases to stay abreast of developments and support the ongoing exploration of CCSVI. If MS is a primary disease of neurodegeneration, like Alzheimer’s and Parkinson’s, it is essential to understand how cerebral blood flow, cerebrospinal fluid, and perfusion are related to brain health.
CCSVI Alliance invites those with a connection to Parkinson’s, Alzheimer’s and ONDs to support the Alliance. We also ask you to encourage further research into neurodegenerative diseases by contacting patient advocacy groups, governmental representatives and local universities in order to expedite research into the connection between neurodegeneration and CCSVI. This research is in the early stages but needs to be continued, and funding is essential.
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- Habib CA, Liu M, Bawany N, Garbern J, Krumbein I, Mentzel HJ, Reichenbach J, Magnano C, Zivadinov R, Haacke EM. Assessing Abnormal Iron Content in the Deep Gray Matter of Patients with Multiple Sclerosis versus Healthy Controls. AJNR Am J Neuroradiol. 2012 Feb. Vol. 33 (Issue 2): Pages 252-258. Epub 2011 Nov 24. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/22116106
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