Omental Transposition to the Brain for Alzheimer’s Disease H A R R Y S. GOLDSMITH” University o,f Nevada School of Medicine, Reno, Nevada, USA ABSTRACT: Omental transposition (OT) to revascularize the brain was first performed in animals in the late 1960s, where it was shown that blood vessels originating from the omentum crossed through the omental-cerebral interface prior to developing into large-sized vessels that penetrated directly and deeply into the underlying brain. The additional cerebral blood flow coming from the omentum was of sufficicnt volume to protect an animal’s brain from cerebral infarction even in the prescnce of middle cerebral artery ligation. It was also learned that the umentum was a rich source for neurotransmitters and omentum-derived nerve growth substance. O T to the brain is now being done for a variety of conditions which include strokes, TlAs, epilepsy, and Parkinson’s disease. Of recent interest is the published information that OT may play some role in Alzheimer’s disease (AD). The placement of the omentum on an AD brain has led to a profound decrease in senile plaque formation. The omentum may ultimately prove to be beneficial in reversing or at least stabilizing the dementia associated with the devastation of AD. Alzheimer’s disease has become one of the most devastating problems confronting medicine today with 4 million Americans suffering from a disease that is estimated will cost up t o 50-100 billion dollars by early in the next century.’ Alois Alzheimer, in 1907, was the first t o identify the disease that now bears his name in a %-yearold woman who suffered from progressive dementia.’ He observed the presence of abnormal nerve cells within the cerebral cortex which containcd tangles of fibers that are classified as neurofibrillary tangles. Also identified by Akheimer were degenerated nerve endings, which he classified as senile plaques. It remained unclear over subsequcnt years whether these neuropathogenic structures reported by Alzheimer were responsible for the dementia that occurred in Alzheimer’s disease (AD). However, a direct relationship was eventually established bctween the number o f senilc plaques that are present within thc cerebral cortex and an individual’s cognitive performance.? BACKGROUND The neurodcgenerative effects of AD are well known, but the devastating cognitive results o f the disease have not been clarified as to their cause. Without this knowledge it continues t o remain difficult to develop therapeutic designs to treat the diseasc. Recent publications, however, have suggested that placing an intact ‘I Addrcss for correspondence: Harry S. Goldmiith, M.D., P.O. Box 493, Glcnbrook, Nevada 89413. Phone, 702/749-5801; fax, 702/749-.5Xhl. 323 324 ANNALS NEW YORK ACADEMY OF SCIENCES pedicled omental graft o n thc brain of an AD patient led to improved cognitive and neurological function4and neuropathologic findings? The operation was carried out in the hope of success on the basis of two characteristics of the omentum: its cerebrovascular potential and its cholinergic potential, both of which represent biological activities that are deficient in AD. During thc mid-1960s interest was raised in my laboratory to learn whether an intact omcntal pedicle could be lengthened and mobilized to reach a dog's brain, with thc subsequent development of vascular connections at the omental-cerebral interface. It was theorized that if this could be accomplished, it might lead to a surgical procedure that would add an extracerebral source of blood to an ischemic brain. Thc surgical technique for omental lengthening was developed and the vascular connections that devclopcd between the omentum and the brain were confirmed by injecting fluorcsccin and India ink into an omental artery within the peritoneal cavity that supplied the omental pediclc to the brain." In order to be absolutely certain that the injected dye markers reached the brain only by way of the omcntal pedicle, the neck of the animal was completely severed from its body except for the intact omental pedicle coming from the peritoneal cavity. The dye markers were subsequently seen on the brain surfacc, in major cerebral blood vessels and in deep portions of both cerebral hemisphcrcs. These findings of widespread cerebrovascular perfusion originating from the omcntum were later confirmed by radioisotopic studies? After it had been demonstrated that vascular connections developed at the interface between the omentum and thc brain (FIG.l), the next step in developing the operation was to learn whether it was possible to increase cerebral perfusion from the omenfum to the brain in sufficient volume to protcct the brain from a severe ischemic insult. The experimental model used to show this was accomplishcd by creating a cerebral infarction in the dog' and in the monkey' by ligating the middle cerebral artery (MCA). Omental placement on the brain just days prior to subsequent MCA ligation confirmed in these studies that omental transposition could supply sufficient extracerebral blood flow to the brain to prevent ccrcbral infarction. These experiments took place in the 1970s, and by the 1980s other laboratory studies from around the world began to appear, reporting favorably on the effects of transposing the omentum to the brain. These experiments included the confirmation that the brain had its CBF maintained by the omentum after MCA occlusion'" with preservation of neuronal conduction activity within the brain as measured by somatosensory evoked potentials." The original idea that the omentum might benefit patients with AD stemmed from two early experimental papers. One of these publications reported that placing the omentum on the surface of the brain prior to MCA ligation prevented the marked depression in cortical levels of biogenic amines that routinely occurs aftcr MCA occlusion." The other paper showed that protein synthesis within the brain was maintained by the omentum even in the presence of MCA occl~sion.'~ These obscrvations, plus the thcn known ability of the omentum to increase CBF, raised the questions as to whether the omcntum had the biological potential to stop, or at least slow down, the linear destruction of neurons that is the hallmark of AD. But it was a decade before this question was addressed. On the basis of favorable laboratory experiments that had accumulated from around the world, omental transposition was approved for human trial. It was felt that the best patients to whom to offer the operation wcre those suffering from transient ischemic attacks (TIA). However, institutional authorities gave permission to perform the procedure only on patients who had already sustained a cerebral infarction. The operation was first carried out in 1978 on a small group of palients GOLDSMITH OMENTAL TRANSPOSITION TO BRAJN 325 FIGURE 1. Blood vessel development at the omental-cerebral interface. Omental blood vessels filled with India ink are shown penetrating deep into underlying brain. The blood-brain barrier is broken by this development, which could allow drug therapy to the brain. 326 ANNALS NEW YORK ACADEMY OF SCIENCES who had suffered a stroke years earlier.I4I’ Since that time there have been a number of publications showing the beneficial effects of omcntal transposition to the brain in treating a variety of neurological conditions.’”-’’ SURGICAL PROCEDURE A gcneral surgeon and a neurosurgeon work as a team to transpose a pedicled omental graft to the surface of the brain. The general surgeon is responsible for performing a laparotomy, elongating the omentum into a long pedicle and developing an extensive subcutaneous tunnel up the chest and neck to the head. The neurosurgeon is responsible for performing the craniotomy and securing the omentum on the brain.” The technique for lengthening the omentum begins by separating the omentum from the transverse colon. This is followed by removing the omentum from its proximal and central attachments to the stomach, which is done directly on the greater curvature ol the stomach leaving the gastroepiploic vessels intact within FIGURE 2. The omental apron is divided to gain increased Iength, with artcrial supply being maintained primarily along the periphery. GOLDSMITH OMENTAL TRANSPOSITION TO BRAIN 321 FIGURE: 3. Omentum has been brought through a long subcutancous tunnel dcveloped hetwccn incisions along chcst and antcrolatcral neck, where it exits behind the ear and is placed directly on thc brain. the omental apron. The left gastroepiploic vessels are then divided to gain increasing omental length. In order to get sufficient length to reach the brain, the omcntal apron is surgically tailored, with care being taken to preserve intact at least one major artery and vein within the structure (FIG.2). At the end of the omental lengthening process, the blood vessels that maintain the vascular integrity of the omental pedicle are the right gastroepiploic artery and vein. The viability of thc pedicled omental graft depends on the preservation of these vessels. Once the omentum has been sufficiently lengthened to reach the brain without any tension, incisions are made along the chcst wall which are connected by a long subcutaneous tunnel. The omentum is brought through this tunnel, with the omentum exiting behind the ear and beneath thc base of thc scalp flap previously dissected in making the initial craniotomy incision on the head (FIG.3). The dura mater is opened over the cerebral hemisphere and picccs of arachnoid mcmbrane are carefully removed. The omcntum is then laid on the brain surface and secured to the edges of the surrounding dura with absorbable suturcs. Some surgeons do not use this pedicled omental technique, but employ a free omental graft which rcquires microvascular anastomoses o f the gastroepiploic artery and vein to the 328 ANNALS NEW YORK ACADEMY OF SCIENCES superficial temporal vessels or other vascular connections. This latter technique is more surgically demanding than thc pcdiclc mcthod, hut of greatcr significance is the tendency €or a vascularized free omental graft to allow edematous fluid to accumulate within the cranial vault. I believe that the reason fluid accumulation occurs with a free vascularized omental graft, which I have never seen with a pedicled omental graft, is that a free graft markedly diminishes a major characteristic of the omentum, namely, it5 enormous edema-absorptive capacity. The loss of this absorption capability is a reflection of a non- or poorly functioning omental graft probably because all lymphatic vessels are divided when an isolatcd piccc of omcntum is taken and developed into a free graft. During the early 198Os, omentum transposition was performed with increasing frequency on the human brain, with the most common indication for the operation being to treat the neurcilogical sequelae of patients who had sustained a previous cerebral infarction. 11 was never expected that omental transposition would have any effect on infarcted brain lissue, but what was theorized was that increased CBF originating from the omentum might stimulate the viable hut ischemic depressed neurons located in the zone surrounding the infarct (penumbra). Favorable clinical results have been subsequently published following the performance of omental transposition for post-stroke and TIA Theory In view of favorable published experimental data and encouraging clinical results after omental placemcnt onto a previously infarcted brain, it was theorized that the omentum might have the potential to maintain the viability of neurons still functioning in an AD patient. This sccmcd even more likely if the omentum could be placed on the brain early in the disease process. The main reason for believing the omentum might be helpful in this situation was based on two unfavorable characteristics in AD-a decrease in CBF and depressed intracerebral cholinergic activity. Vascular and Cholinergic Concepts It has been established that there is a decrease in the CBF of AD patients, but it has remained unclear as to whether diminished cerebrovascular perfusion occurs as a result of neuronal damage which lowers the neuron’s metabolic requircmcnts, or whether the lowered CBF results in decreased neuronal activity. Recent ultrastructural studies of the AD brain have suggested the latter possibility as thc more likely because extensive architectural distortion of capillaries in the brain have bccn identificd that may limit vital nutrient delivery to ischemic-scnsitive neurons over an extended period?” It was felt that omental transposition to an AD brain could improve this vascular situation. FIGURE 4. Top: preoperative SPECT scan. Coronal slices with imagcs displaycd in an anterior to posterior position with color scale on left side. A major preoperative perfusion defect is seen in right parietal-occipital location. Bottom: postoperative SPECT examination 10 months after surgery. Reperfusion has occurred in right parietal-occipital area. (From Goldsmith! Reproduced by permission.) 330 ANNALS NEW YORK ACADEMY OF SCIENCES Another reason for believing omental transposition to the brain might help AD patients was based on the decrease in acetylcholine (ACh) activity that occurs in AD. This cholinergic loss is reflected in the 40-90% decrease in brain levels of choline acetyltransferase (ChAT), which is the cnzyme that catalyzes the reaction for ACh synthesis in the brain?‘,” Case Report Because of a significant decrease in ChAT activity that has been reported near senile plaque formations that have been associated with decreased intellectual performance: a pedicled omental graft, with its increased vascular and cholinergic activity,?‘was placed on the brain of an A D patient who had an eight-year-history of a progressive decline in neuropsychological function. The patient and his family elected to undergo the operation in thc hope that the procedure might stabilize his mental deterioration. The opcration was performed in 1993. Postoperative Course:The patient showed subjective and objective improvement in his cognitive and neurological condition for one year after the operation? The postoperative cerebral angiogenic activity originating from of the omentum became clearly evident, as shown by a global increase in CBF as demonstrated by comparison of pre- and postoperative SPECT examinations (FIGS.4 top and bottom), with the greatest increase in CBF occurring in the cerebral hemisphere located directly beneath the overlying omental graft (FIGS.5 top and bottom). After the first postoperative year, the patient began to show a neurological decline in association with deterioration in neuropsychological testing. The cognitive loss continued, with an associated decline in his physical condition resulting from chronic cardiopulmonary problems. Of special interest, however, was the rctention of his short-term memory. The patient died 31 months after surgery from unrelated chronic medical problems. Autopsy Findings: An autopsy was authorized which confirmed the diagnosis of AD, as demonstrated by the presence of neocortical senile plaques, neurofibrillary tangles, and amyloid deposition. At the time of surgery, the omentum had bcen placed on the patient’s right cerebral hemisphcre since his cerebral perfusion deficit was most prominent on the right side of the brain and his neurological findings most prominent on the left side or his body, evidence indicating that the right cerebral hemisphere was the location most affected by the AD process. Autopsy confirmed this, with increased numbers of senile plaques and neurofibrillary tangles being seen in the right cercbral hemisphere compared with the left. This right-left brain asymmetry found at autopsy correlated with preoperative clinical and SPECT findings, which indicated greater dysfunction in the right cerebral hemisphere. Two major neuropathological observations were made at autopsy which were totally uncxpectcd.5 One was a significant decrease in the number of senile plaques found in the cerebral cortex at the crest of the gyri subjacent to the omentum compared to an increased number of senile plaques located in the contiguous depths of the sulci (Ficis. 6 top and bottom). This finding strongly suggested that the omentum played a role in this phenomenon, especially since no comparable gradient of neurofibrillary tangles was observed adjacent to the omentum. The second significant neuropathological finding made at the time of autopsy occurred directly below the omental transplant in the upper cortical lamina. Numerous hypertrophic astrocytcs were observed which contained fine granules of Prussian blue-positive cytoplasmic hemosiderin. Also noted was an inverse rcla- GOLDSMITH: OMENTAL TRANSPOSITION TO BRAIN 33 1 FIGURE 5. Pre- (dark bars) and postoperative (lighter burs) activity ratios of cerebrovascular perfusion derived from SPECT scans (FIG.4). Activity ratios compiled from measured perfusion in cerebral regions of interest are compared lo ipsilatcral cerebellar perfusion used as a standard. Omental placement was on right ccrcbral hemisphere. Top: right brain; bottom: lcft brain. DL = deep left lfrontal]. 332 ANNALS NEW YORK ACADEMY OF SCIENCES GOLDSMITH. OMENTAL TRANSPOSITION TO BRAIN 333 tionship between the presence of these hemosiderin-filled astrocytes, which are not a normal finding in AD, and a significant decrease in the number of senile plaques in the area. Careful examination of multiple cortical regions of the right and left cerebral hemispheres failed to reveal either hemosiderin inclusions or decreased numbers of senile plaques except for the area where the omentum had been located. DISCUSSION The idea that placing the omentum on an AD brain could be clinically beneficial was initially based on the idea that the biological activity of the omentum might interrupt or at least slow down the progressive destruction of cerebral neurons that is observed in an AD brain. Asked another way, would increasing CBF and possibly cholinergic activity in the brain of an A D patient enhance the neuroelectrical and neurochemical activity of still viable neurons prior to their expected destruction? This question came into sharper focus when it was suggested that the etiology of AD was secondary to decreased blood flow to ischemic-sensitive neurons caused by an extensive distortion of cerebral capillaries which create abnormal hemodynamic patterns that impair the CBF and energy supply to the As these cerebral capillaries become progressively kinked, looped, and twisted in shape, it was postulated that they decrease the glucose, oxygen, and other micronutrient delivery across the blood-brain barrier and limit the egress of catabolic products from the brain.” The known suboptimal utilization of 022’ and glucose2xin an AD brain would be expected to cause a continuing decline of neuronal activity since glucose is the main substrate for glycolysis and oxygen is necessary for oxidative phosphorylation and ATP production. As the decreased glucose and O2 levels in the brain persist, ischemic-sensitive neurons cannot meet necessary energy demands because of decreased CBF and the lowered energy supply. This pathophysiological situation eventually leads to a slow but continuing decline in neuronal activity, which has been postulated to lead to cognitive decline and the development of senile plaques and neurofibrillary tangle^.'^ Since this process is predicated on a hemodynamic abnormality caused by cerebral microvascular distortion, it was felt that omental transposition to the brain of an AD patient would improve cerebrovascular function:’ which might increase the energy effectiveness of ischemic-sensitive neurons. Omental transposition was also theorized to benefit patients with AD by improving the defective cholinergic transmission that occurs in AD. The omentum has neurotransmitters incorporated into its tissues3”which include ChAT, the enzyme that is responsible for the formation of acetylcholine (ACh) from choline and acctyl coenzyme A and is the marker for cholinergic activity.*”Since the omentum has ChAT activity, which is depressed in the AD brain and has been correlated with the density of senile plaques,’the question was asked as to whether any acetylcholine in omental tissue might be transported through vascular connections at the omcntalcerebral interface causing increased brain levels of acetylcholine. Even if omental FIGURE 6. Sections of right parietal neocortex underlying the transposed umcntum. (Bielschowsky silver stain; X40). Top: middle cortical laminae in the depth of a sulcus showing numerous senile plaqucs and neurofibrillary tangles. Bolturn: crest of gyrus contiguous with regions shown above. Conspicuously fewer senile plaques are evident. Occasional hypertrophic astrocytes containing hemosiderin are present throughout the section. (From Relkin? Reproduced by permission.) 334 ANNALS NEW YORK ACADEMY OF SCIENCES ACh proved insufficient to fully supplement cercbral ACh levels, there might be partial protection since omental transposition has been shown t o maintain neurotransmitter levels in the brain even in the presence of severe cerebral ischemia caused by middle cerebral artery occlusion.” Additionally, nerve growth substances in thc omentum” might also benefit A D patients by increasing neurite growth into neuroactivity-deficient areas of the brain. Other ideas were raised as to why omciital transposition to the brain had the potential to hclp AD patients. For example, the omentum on the brain might increase cerebral ACh levels simply by elevating cerebral glucose concentrations by way of the additional CBF originating from the omentum. CBF, glucose and oxygen metabolism are diminished in AD, with the lowest levels of glucose and O2metabolism occurring in cerebral regions that have the greatest A D pathol~gy.’~.’~ Since decreased CBF is one of the earliest markers for the presence of AD>3 cven a small increase in C B F might be clinically important since hypoglycemia has been shown to dramatically decrease cerebral ACh levels.34Further support for thc idea that increasing glucose levels in an AD brain by way of the omentum might bc beneficial is suggested by the study that showed that administered glucose diminishes atropine-induced ACh depletion in the brain.3s An increased C B F originating from the omentum might also benefit AD patients just by increasing the availability of ACh precursors (choline and acetyl-coenzyme A) that are presented t o the brain. How the omentum affects the brain of AD patients awaits further elucidation. 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