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 Reports from recent DLB biomarker conference and AD/PD conf 
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Post Reports from recent DLB biomarker conference and AD/PD conf
The Alzheimer Research Forum has posted five parts of a nine-part series on an international AD/PD conference held in March '09 in Prague and on an international DLB/PDD conference held a few days earlier in Prague. The DLB/PDD conference focused on biomarkers. At least two LBDA Scientific Advisory Council (SAC) members attended the conferences -- Dr. Jim Galvin, neurologist from Washington University (St. Louis, MO) and Dr. Ian McKeith, psychiatrist from University of Newcastle upon Tyne (Newcastle, UK). This nine-part series summarizes what was discussed at these conferences. It seems that the remaining four parts will be posted over the next several days.

I've copied four of the parts below -- Part 1, Part 3, Part 4, and Part 5. You can read all of these online. Part 1 is about overlaps between neurodegenerative diseases, proteins, genetics, and biomarkers. Part 3 will be of interest to more of you; it's about diagnosing and researching DLB. Part 4 is about the interplay between two proteins in DLB. Part 5 is about imaging biomarkers.

Here are some excerpts from Part 3 about the challenges of diagnosing and researching DLB:

* The DLB consensus diagnostic criteria "have not widely penetrated community geriatric, neurology, or primary care settings where many patients are still seen, and both the rate and accuracy of DLB diagnosis remain low. 'We are very bad at diagnosing DLB. Up to half of cases diagnosed as DLB turn out at autopsy to have had AD. Misdiagnosis of DLB as AD occurs, as well,' said David Brooks of Imperial College, London. This has serious consequences."

* "The U.S. Food and Drug Administration, for example, does not formally recognize DLB as a distinct disorder. The agency has a point, Galvin concedes. 'They ask: Is it AD? Is it PD? What exactly is it? They ask: Do doctors recognize DLB as separate? No? Then how can you run drug trials, and how can you get doctors to prescribe a future DLB drug?' Galvin said."

* "Part of the reason why more research groups have not taken up focused study of DLB is its complexity. DLB is marked by overlap with AD and PD on the clinical level and on the postmortem pathology level."

* "Clinicians agree that people with mixed pathologies suffer faster and more severe disease. Pure Lewy body pathology exists in 10 to 20 percent of cases with clinical DLB, but the majority of patients also have amyloid pathology and many have tangles to varying degrees, as well. ... Several groups have found that when they looked at postmortem pathology and compared the clinical and cognitive course of the respective patients during their lives, the mixed cases always performed more poorly and progressed faster. Time to nursing home placement, time to death, visuospatial deterioration—whatever the outcome, the mixed cases fared worse. 'Pure and mixed clearly are different diseases,' Galvin said."

* "David Salmon of the University of California, San Diego, showed in Kassel that despite some general similarities between DLB and PDD, PDD is marked by deficits in psychomotor speed and attention, which probably arise as alpha-synuclein pathology spreads from the brainstem via limbic structures and across the cortex. As long as alpha-synuclein pathology in the cortex remains mild, PD patients tend to stay cognitively intact. DLB has in common with AD verbal memory deficits driven by these diseases’ shared amyloid and tau pathologies. That is another point of distinction from PDD."

* "DLB differs from AD by showing pronounced deficits in visuospatial and executive function that Salmon attributes to a unique combination of cortical amyloid and alpha-synuclein pathology. These differences are useful early on in disease; in late stages the clinical picture of these diseases increasingly merges. Overall, visuospatial tests seemed the most useful for picking out patients with DLB, and these tended to be the people most likely to deteriorate quickly. They also tended to be the ones who suffered visual hallucinations."

* "Galvin and colleagues recently developed cognitive profiles that distinguish AD from healthy brain aging. Compared against these profiles, a group of DLB patients performed quite differently from AD, as well. Combining these cognitive data with clinical and amyloid imaging data, Galvin has devised a clinical risk score that detects LBD."

* "The goal is to be able eventually to define preclinical DLB. This would work such that a person who is positive for brain amyloid by PET imaging but is cognitively normal could receive CSF biochemistry testing for Abeta/tau and for alpha-synuclein to determine whether (s)he will likely go on to develop AD or DLB."

And here are the four parts in their entirety, with links to the webpages on the AlzForum.

Robin



http://www.alzforum.org/new/detail.asp?id=2142

Part 1 - Spectrum of Neurodegeneration Comes to the Fore

28 May 2009. Sometimes in science, a concept lingers unattended in the collective back of researchers’ minds for years; they sense there’s something important to it but aren’t ready to grasp it head-on. Then something changes and, voila, the concept moves front and center. Such was the case with the issue of overlap in the major neurodegenerative diseases at the 9th International Conference AD/PD held 11-15 March in the Czech capital city of Prague. Previous AD/PD conferences had reflected the de-facto separation in the daily work of most scientists and clinicians in this field. Even though they spent days under the same roof, by and large the movement disorder people went to one meeting and the dementia people to another. But Prague was different. Rather than being treated as an inconvenient side issue that blurred boundaries, the extensive and multitudinous overlap between Alzheimer and Parkinson diseases (and also the frontotemporal dementias) was the focus of presentations and hallway discussion. Much of the buzz about this topic had spilled over into Prague from a preceding workshop in the former Royal German city of Kassel that had focused on dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD). These are two underappreciated conditions that occupy a large area of overlap between AD and PD. From 8-10 March, co-organizer Brit Mollenhauer of the Paracelsus-Elena-Klinik in Kassel had convened a group of investigators around the goals of sharing the latest insight and hammering out a research agenda to speed progress and fight for recognition of these betwixt diseases.

Once the overlap between two neurodegenerative diseases, not their differences, becomes the center of attention, the story changes in many ways, scientists said. Individual cases are comfortably seen as falling on a spectrum rather than having to fit into this box or that, and the view of the diagnosing physician changes such that (s)he expects and accommodates large numbers of mixed cases. Perhaps most importantly, the search for protein-based biomarkers—from fluid biochemistry to imaging—to tease out which underlying proteins drive a given person’s disease, assumes paramount importance.

Traditionally, neurodegenerative diseases have been classified clinically, as physicians grouped them into boxes based on the preponderance of signs their patient presented—movement abnormalities in PD, cognitive deficits in AD at its simplest. Separately, pathologists described postmortem brain abnormalities and tried to match them up with symptoms. That clinico-pathological pairing is descriptive, and it has been refined in recent years. But in reality, the pathology, seen years after diagnosis, often poorly matches the clinical diagnosis a patient had received. Or it even calls the diagnosis into question when, for example, a patient diagnosed as having AD turns out to have had extensive alpha-synuclein but little tau pathology in the brain.

“There has been a conceptual shift in neurodegeneration research. Until recently the focus was on factors that distinguish between these disorders. But now we recognize that there is extensive overlap at the pathological level and the clinical level, which does not fully match the genetics. So it is difficult to distinguish cleanly by means of clinical, pathological, or genetic determination alone,” said Kristel Sleegers of VIB in Belgium.

As science advances, the diagnosis of neurodegenerative diseases beyond AD itself will become increasingly molecular in an effort to pin down the pathogenic proteins that drive an individual person’s disease rather than focus primarily on the symptoms. “In time, we will shift away from relying on clinical categorization to make diagnoses,” said James Galvin of Washington University, St. Louis. “We will make protein diagnoses. The way to get there is to understand underlying pathways and to develop a range of biomarkers.”

The need for protein markers (and eventually also RNA- and lipid-based markers) as sorting tools is evident from even a cursory look at how varied these diseases can be. For example, scientists are realizing that what looks like a single clinical entity has multiple causes. To quote but one emerging example, new studies of Parkinson disease patients are fingering the gene for Gaucher disease, as well as a high-expression variant of the protein tau (see Part 2 in this series). Vice versa, a single pathogenic mutation, for example, in the gene progranulin, has been reported to manifest itself in the form of frontotemporal dementia, Parkinson’s, or even Alzheimer’s in affected members of one and the same family.

Confused already? Read on; there’s more. DLB and PDD define a spectrum going from AD to PD that hinges on the specifics of aggregation of Abeta, tau, and alpha-synuclein, but it is not the only spectrum at play. There is also a spectrum going from frontotemporal dementias to amyotrophic lateral sclerosis that hinges on loss of progranulin protein and accumulation of ubiquitin and TAR DNA-binding protein 43 (TDP43). Deposits of the latter have been reported in a significant fraction of AD cases, even, though whether they are mechanistically important to disease is entirely unclear at this point. And, of course, it matters greatly where a pathologic protein acts. For example, of the wide range of disorders blamed on alpha-synuclein—the Lewy body diseases—one particularly severe one called multiple system atrophy stands out by exhibiting this pathology primarily in oligodendroglia, not neurons. Yet another spectrum talks of tauopathy in parkinsonism (see Part 2 of this series.) The number of invoked spectra conjure up a mental image less of a linear continuum between, say, blue and green, but more of a color wheel. Scientists readily agree that there are many more examples for heterogeneity at the clinical, pathological, and genetic levels.

“People are talking in terms of spectra now because the pure forms of these diseases are less common than we used to think, and the overlap is incredibly large,” said Galvin. “Once you focus on patients in the overlap, you see that they are different from those with the pure forms of disease. That is why molecular diagnoses are going to be critical for this field.”

Molecular diagnoses will require fluid or imaging markers based on individual proteins that drive disease either alone or in various combinations. The range of candidates is expanding well beyond the known ones such as amyloid-beta, tau, to now include alpha-synuclein, progranulin, TDP43, glucocerebrosidase, and brain imaging based on neurotransmitter transporters (see Part 5 of this series). Such tests are being aggressively pursued in different labs.

Besides offering a more precise diagnosis, such tests may help scientists define what molecular interactions underlie yet another phenomenon scientists emphasized both in Kassel and in Prague—namely that when two of these proteins go awry in one person, they tend to heat up the pathogenic process and worsen the resulting clinical disease in a given person. “There’s an emerging realization that whenever two pathologies occur together, they accelerate disease,” said Michael Schlossmacher of the University of Ottawa, Canada. This, in turn, has created interest in studying possible links between the underlying proteins at the monomeric and oligomeric level (see Part 4 of this series).

The esteemed reader trying to keep track of these blurring boundaries might take solace in remembering that this added layer of complexity comes on top of a much simpler, underlying rule that has found wide acceptance across the field of neurodegeneration. It is that for the established, major proteins causing neurodegeneration when they aggregate —Abeta/amyloidoses, alpha-synuclein/synucleinopathies, tau/tauopathies, prp/prion diseases—mutations or duplication of the gene cause familial forms, whereas overproduction alleles raise the risk of sporadic forms. “This blindingly simple categorization is true for all of these diseases. The more you make of these proteins, the earlier you get the disease,” John Hardy of University College, London, UK, said in Prague. And as a possible yang to this yin, the opposite trend is just beginning to emerge for progranulin and perhaps even the newest neurodegenerative disease protein, glucocerebrosidase. There, early indications are that disease risk goes up the less a person makes of the protein.—Gabrielle Strobel.



http://www.alzforum.org/new/detail.asp?id=2147

Part 3 - Neither Fish Nor Fowl—Dementia With Lewy Bodies Often Missed

1 June 2009. Perhaps the biggest, and quintessential, representative of a spectrum neurodegenerative disease is dementia with Lewy bodies (DLB). By some counts, this disease is the second most common form of dementia after Alzheimer disease (AD), with patient estimates for its various forms ranging between one and two million in the U.S. (Aarsland et al., 2008; Weisman and McKeith 2007). All the same, DLB has struggled for recognition and research dollars, being squeezed uncomfortably between its two large neighbors AD and Parkinson disease (PD). “DLB research is an unappreciated field,” said Brit Mollenhauer of the Paracelsus-Elena-Klinik in Kassel, Germany.

DLB is a double whammy of a disease. People with DLB have behavioral and memory problems as in AD and, to a varying extent, also suffer motor symptoms as seen in PD. However, the cognitive symptoms of people with DLB tend to fluctuate frequently, their motor symptoms are milder than in PD, and DLB patients often have vivid visual hallucinations and particular visuospatial deficits. In short, DLB is neither AD nor PD, and yet defining its distinct identity has been a challenge. At the 9th International Conference AD/PD held last March in Prague, ample discussion about DLB resonated from an immediately preceding workshop on this disease and its cousin, Parkinson disease dementia (PDD). Co-organized by Mollenhauer and Richard Dodel, the workshop tried to put DLB more firmly on the research map (see Part 1 of this series).

“Scientists who study DLB think it is a very important disease,” said James Galvin of Washington University, St. Louis. “As a set of independent groups, we and others have worked to increase its face time in the dementia world. We fight a battle because given the limited time and resources funders and reviewers have available to cover related conditions, DLB tends to get the short end of the stick.”

Why is that? Part of the reason is that carving distinct disease categories out of a continuum of symptoms and pathologies is inherently arbitrary. Part of it is that multiple labels being advanced by different investigators for multiple similar variants have not helped the branding. In Prague, several scientists noted that if its awkward name was part of DLB’s identity problem, one solution might be to name it after Kenji Kosaka of Houyuu Hospital in Yokohama, Japan (Kosaka et al., 1980). “Kosaka himself called it a different name, but he really described the clinico-pathological entity that we nowadays diagnose as DLB,” said Michael Schlossmacher of Ottawa University, Canada. “Alzheimer disease, Parkinson disease, Kosaka disease would sound consistent and recognizable to me.”

The Kassel workshop was the latest in a series of small international meetings by a consortium of groups interested in DLB and PDD. In 1995, researchers led by Ian McKeith of Newcastle General Hospital met in Newcastle-upon-Tyne, UK, to hammer out consensus diagnostic criteria (McKeith et al., 1996). This spurred diagnosis in specialty settings and provided a basis for gathering incidence and prevalence data there (Zaccai et al. 2005). But the consensus criteria have not widely penetrated community geriatric, neurology, or primary care settings where many patients are still seen, and both the rate and accuracy of DLB diagnosis remain low. “We are very bad at diagnosing DLB. Up to half of cases diagnosed as DLB turn out at autopsy to have had AD. Misdiagnosis of DLB as AD occurs, as well,” said David Brooks of Imperial College, London.

This has serious consequences. The U.S. Food and Drug Administration, for example, does not formally recognize DLB as a distinct disorder. The agency has a point, Galvin concedes. “They ask: Is it AD? Is it PD? What exactly is it? They ask: Do doctors recognize DLB as separate? No? Then how can you run drug trials, and how can you get doctors to prescribe a future DLB drug?” Galvin said.

With their series of DLB/PDD workshops, McKeith’s and other groups aim to forge a common research agenda that can move their nascent field forward in a concerted way. Subsequent to Newcastle, workshops in the Dutch city of Amsterdam and Yokohama, Japan, continued the effort; and this year’s gathering in Kassel was to lead up to an official centenary workshop in 2012 that will celebrate Frederick Henry Lewey’s first description of Lewy bodies in 1912. (Born in Berlin as Fritz Heinrich Lewy, this German Jewish neurologist-cum-pathologist in his early years worked with Emil Kraepelin and Alois Alzheimer (see Centennial Alzheimer story), but was forced in 1933 emigrate to England and then the U.S.) This year’s workshop designated working groups for biomarkers and for clinical trials, said Mollenhauer. It also included representatives from national DLB societies and patient groups in an effort to help these lay groups beef up their operations such that they can become larger funders of research and lobby for federal funding and recognition, akin to what the Alzheimer’s Association has accomplished for its disease.

Below are some of the main problems, and points of consensus, about DLB from the Kassel and Prague meetings. Part of the reason why more research groups have not taken up focused study of DLB is its complexity. DLB is marked by overlap with AD and PD on the clinical level and on the postmortem pathology level. But clinic and pathology do not match up to a clean picture, leaving the scientist to juggle a welter of descriptive facts that for many fail to “gel” into a tangible entity. Eventually, the solution to this problem will come with new biomarker-driven diagnoses (see Part 5 of this series, but even in the meantime, clinico-pathological correlations have come a long way, the Kassel workshop made clear.

Clinicians agree that people with mixed pathologies suffer faster and more severe disease. Pure Lewy body pathology exists in 10 to 20 percent of cases with clinical DLB, but the majority of patients also have amyloid pathology and many have tangles to varying degrees, as well. Some even have aggregates of TDP43, though whether that is functionally important is not known yet (Arai et al., 2009; Nakashima-Nasuda et al., 2007). It is beyond dispute, however, that mixed pathologies compound each other. Several groups have found that when they looked at postmortem pathology and compared the clinical and cognitive course of the respective patients during their lives, the mixed cases always performed more poorly and progressed faster. Time to nursing home placement, time to death, visuospatial deterioration—whatever the outcome, the mixed cases fared worse. “Pure and mixed clearly are different diseases,” Galvin said.

In the year 2005, the 1996 DLB consensus criteria were revised to focus on the spectrum of Lewy body disorders and to explain more clearly the links between symptoms and pathology. The clinical aspects that set DLB apart from AD, for example, were ascribed to alpha-synuclein pathology. In a nutshell, this is what the criteria said: DLB and AD share amyloid pathology; people with DLB have alpha-synuclein pathology, as well, but generally few neurofibrillary tangles. The more tangles a person has, the more their clinical picture overlaps with AD; the fewer tangles they have, the more it diverges from AD.

In the past four years, several groups have further sharpened the cognitive profile of DLB. The goal is to separate DLB not just from AD but also from PDD, where a patient first has Parkinson disease for some years and then develops dementing symptoms. For example, David Salmon of the University of California, San Diego, showed in Kassel that despite some general similarities between DLB and PDD, PDD is marked by deficits in psychomotor speed and attention, which probably arise as alpha-synuclein pathology spreads from the brainstem via limbic structures and across the cortex. As long as alpha-synuclein pathology in the cortex remains mild, PD patients tend to stay cognitively intact (Jellinger, 2009). DLB has in common with AD verbal memory deficits driven by these diseases’ shared amyloid and tau pathologies. That is another point of distinction from PDD (Filoteo et al., 2009). But DLB differs from AD by showing pronounced deficits in visuospatial and executive function that Salmon attributes to a unique combination of cortical amyloid and alpha-synuclein pathology. These differences are useful early on in disease; in late stages the clinical picture of these diseases increasingly merges. Overall, visuospatial tests seemed the most useful for picking out patients with DLB, and these tended to be the people most likely to deteriorate quickly (Hamilton et al., 2008). They also tended to be the ones who suffered visual hallucinations. Beyond these means, disentangling in more detail which clinical features arise from AD pathology and which ones from alpha-synuclein pathology will require alpha-synuclein-based and AD pathology-based biomarkers (see also Lippa et al., 2007).

For his part, Galvin and colleagues recently developed cognitive profiles that distinguish AD from healthy brain aging (Johnson et al., 2008). Compared against these profiles, a group of DLB patients performed quite differently from AD, as well. Combining these cognitive data with clinical and amyloid imaging data, Galvin has devised a clinical risk score that detects LBD. “This gives us a good separation. We find that some people who were clinically diagnosed with AD turn out to probably have DLB,” Galvin said. In the laboratory, his group is working on cerebrospinal alpha-synuclein detection to support this prediction. The goal is to be able eventually to define preclinical DLB. This would work such that a person who is positive for brain amyloid by PET imaging but is cognitively normal could receive CSF biochemistry testing for Abeta/tau and for alpha-synuclein to determine whether (s)he will likely go on to develop AD or DLB. “We have great confidence in predicting AD based on the PIB/CSF Abeta-tau combination. We want to achieve the same confidence to predict DLB,” Galvin said.—Gabrielle Strobel.



http://www.alzforum.org/new/detail.asp?id=2150

Part 4 - Like DLB, Like AD—Do Oligomers Stir Up the Trouble?

2 June 2009. Current work on distinguishing Alzheimer disease from its cousin dementia with Lewy bodies (DLB, see Part 3 of this series) has underscored one intriguing similarity between the two. In DLB, researchers increasingly note that many people, indeed up to half in some patient series, remain neurologically intact despite having abundant Lewy body pathology in their brains. In AD, florid amyloid pathology in the brains of people who died cognitively normal has for years sustained doubt about the amyloid hypothesis. In DLB now as formerly in AD, the pathologic observation raises questions about whether Lewy bodies are toxic or even relatively protective compared with even more toxic oligomeric aggregates of alpha-synuclein that remain invisible to the stains typically used on brain slices.

At the Kassel workshop preceding the 9th International Conference AD/PD, Laura Parkkinen of the Institute of Neurology, London, UK, broached this issue in a clinico-pathological talk. Similarly, Walther Schulz-Schaeffer of the University of Goettingen, Germany, proposed that not Lewy bodies, but smaller alpha-synuclein aggregates at synapses, are the real culprits (Kramer and Schulz-Schaeffer et al., 2007; Kramer et al., 2008). And at AD/PD in Prague, Maria-Grazia Spillantini of Cambridge University, UK, previewed data from a new mouse model of alpha-synucleinopathy that pinned early pathogenic changes on mislocalization of monomeric alpha-synuclein within presynaptic terminals (see also Watson et al., 2009). Spillantini proposed that the neurons seen laden with Lewy bodies in autopsy tissue might represent those cells that were the latest to have gotten sick, i.e., that have withstood a disease process driven by smaller assemblies.

Mice are also the model of choice to try to understand whether different pathogenic proteins interact, perhaps as oligomers, before they form their signature microscopic deposits. Eliezer Masliah of the University of California, San Diego, has for some time explored molecular interactions between Abeta and alpha-synuclein, showing first that Abeta potentiates the deposition of alpha-synuclein in transgenic mice (Masliah et al., 2001) and more recently that these two proteins can form mixed ring-like oligomers in membranes (Tsigelny et al., 2008 on ARF related news story). In Kassel and in Prague, Masliah expanded on the theme. He introduced several different unpublished mouse systems that combine transgenic lines and lentiviral injection. Together, these build a body of data suggesting that Abeta42 promotes alpha-synuclein aggregation, worsens learning deficits, and can drive neurodegeneration in these mixed models. This happens regardless of whether APP is added to an alpha-synuclein transgenic background or alpha-synuclein is added to an APP-transgenic background.

Most likely, Abeta is upstream of alpha-synuclein, researchers agreed. This creates a parallel with older Alzheimer’s research placing Abeta upstream of tau, and it puts alpha-synuclein and tau on a par in a sense. Expressed in mice, the mutant human tau that causes frontotemporal dementia leads to tangles and a behavioral phenotype mostly in the spinal cord (Lewis et al., 2000), but when these mice cross-breed with APP transgenic mice, the Abeta in the resulting offspring greatly amplifies tau pathology in the cortex (Lewis et al., 2001; also Goetz et al., 2001). The idea is that, similarly, the co-occurrence of Abeta might help alpha-synuclein pathology spread in the human brain.

“The idea of one pathology augmenting another is accepted in AD, and now comes up in DLB, as well,” noted John Hardy of University College, London, UK. Other scientists agreed that amyloid pathology probably deposits first in people, before inciting either tau or alpha-synuclein pathology. More than two pathogenic proteins can be at play, as some scientists suspect tau heating up alpha-synuclein pathology downstream of amyloid. “In the mixed pathologies, we know that amyloid deposits first. Then there occurs some unknown step that we need to understand much better,” said Galvin.

This point drew wide notice in Prague. “Broadly, the idea that one of those proteins can influence aggregation of another is gaining prominence,” said Charles Glabe of University of California, Irvine, who mentioned collaborative work with a German group indicating that therapeutic removal of amyloid can draw down alpha-synuclein inside cells. “The big question is how that happens, whether directly at the membrane or through activating autophagy.”

Interaction between Abeta and alpha-synuclein might imply that upstream (read anti-amyloid) therapies might benefit downstream alpha-synuclein pathology (read DLB patients), as well. Masliah showed data suggesting that anti-Abeta immunotherapies treat synucleinopathy and attendant functional deficits quite nicely in transgenic mice. Alas, the known trials and tribulations of translating mouse treatments to humans apply. Other scientists cautioned that diseases marked in large part by pathologies downstream of Abeta amyloid might at some point become independent of that amyloid once disease is established, such that removing the initial offender no longer helps the patient very much because it leaves in place an active tauopathy or synucleinopathy.

Antibodies against alpha-synuclein are under construction in Masliah’s laboratory. In Prague, Brian Spencer in Masliah’s lab presented a poster showing a lentivirus single-chain antibody against alpha-synuclein oligomers. When injected into the brain of alpha-synuclein transgenic mice, the antibody rescued neurodegeneration in these animals. The mechanism, Masliah believes, is not so much microglial clearance but activation of the autophagy pathway of protein degradation. This, if it could be revved up safely, might just offer a new therapy development avenue to pursue against both AD and DLB.—Gabrielle Strobel.



http://www.alzforum.org/new/detail.asp?id=2151

Part 5 - Ordnung, Please—Can Biomarkers Tame a Bewildering Overlap?

3 June 2009. Faced with a complicated landscape of mixed disease at all levels of observation, scientists at the 9th International Conference AD/PD last March in Prague made one point abundantly clear. Even as the recognition that neurodegeneration occurs on a spectrum is gaining prominence throughout the field, tangible progress in dealing with spectrum diseases will remain limited until the field comes up with more and better biomarkers of their component proteins. “It is apparent that the next phase of refinements to clinical classification will need to incorporate the use of biological markers of underlying disease process, since clinical presentation alone is an unreliable witness of pathology,” is how Ian McKeith of Newcastle General Hospital in Newcastle upon Tyne, put it in his opening abstract to a workshop in Kassel, Germany, that preceded AD/PD. The same challenge applies to the spectrum of progranulin diseases. Protein-based markers could address the common problem of mis-diagnosis of dementia with Lewy bodies (DLB). In clinical testing, biomarkers could avoid several problems, for example that of trials recruiting patients with different underlying diseases into a single treatment group, or the problem of enrolling patients with simmering preclinical disease into control groups, or of enrolling a person with, e.g., a progranulin-driven dementia into an anti-amyloid drug trial.

What, then, do scientists have in hand? In short, they have candidates in various stages of refinement but no officially validated winners yet. This conference story will summarize some of the imaging markers currently under study for use in diseases of the alpha-synuclein and progranulin spectrum. The next story will summarize fluid markers.

First, brain imaging. And first, the bad news. Numerous groups are working on contrast agents and radioligands that would find and label aggregates of alpha-synuclein and also tau, (see ARF related Eibsee story) but no one appears to have a candidate ready for trial in humans. Michael Pontecorvo of the molecular imaging company AVID Radiopharmaceuticals Inc. is usually a fluent speaker with the polish of a company pitchman. But when asked where things stood on a PET ligand for tau, all he could say was, “We are not close.” For a-synuclein? “Working on it.” How about Abeta oligomers? “Nope… I wish.”

Pontecorvo was more loquacious about dopamine transporter imaging. SPECT scans using ligands for this molecule are already in routine clinical use to diagnose Parkinson disease. In Prague, Pontecorvo presented phase 1 data on an experimental PET ligand for essentially the same purpose. AVID sees advantages because the new agent labels a presymptomatic vesicular monoamine transporter, VMAT2. Its levels decrease with disease but are not up-or downregulated in response to L-Dopa treatment, Pontecorvo said. Called 18F-AV-133 at present, the new ligand enters and leaves the brain rapidly, meaning it could be imaged sooner after the patient receives the injection and would shorten the time the patient has to lie still in the scanner. In a small pilot study, AV-133 distinguished Alzheimer disease (AD) from DLB, Pontecorvo said in Prague. PD and DLB patients both showed a reduction in requisite brain areas, whereas participants even with fairly advanced AD looked like controls. The company also has an amyloid imaging ligand, AV-45 aka Florpiramine, which at present is in a Phase 3 trial and serves as a biomarker in some AD drug trials, though it has no peer-reviewed papers in the scientific literature (see ARF related HAI story). Avid hopes eventually to sell the dopamine transporter ligand and Florpiramine to support differential diagnosis along the spectrum going from AD, DLB, PDD, to PD. “You could scan the same person with both compounds on the same day in three to four hours,” Pontecorvo said.

For his part, David Brooks, who works both at Hammersmith Hospital and for G.E. Healthcare, the commercial developer of Pittsburgh compound B (PIB), reviewed brain imaging approaches for this disease spectrum more broadly. Regarding dopamine transporters (DAT), Brooks cited an older study showing that DAT scans of the striatum distinguish DLB from AD during a person’s life (Walker et al., 2002). Since then, postmortem follow up of people who had undergone DAT scans have shown that whenever the pathologist definitively diagnosed DLB, the person’s DAT scan had been abnormal, whereas when the definitive diagnosis said AD the DAT scan had been normal. A phase 3 multicenter trial further validated this method (see McKeith et al., 2007).

By contrast, on a different method advanced for distinguishing DLB from AD, Brooks noted that his group was unable to reproduce previous data by others. That data had suggested that measuring atrophy in the medial temporal lobe might discriminate (e.g., Burton et al., 2009). This imaging method is more valuable for following disease progression, Brooks said.

Amyloid imaging can be one component of a DLB diagnosis, Brooks said. New Abeta radioligands are joining an increasingly competitive field. The latest is perhaps AstraZeneca’s 11CAZD2184 compound, which Samuel Svensson debuted in Prague (see also Johnson et al., 2009; Svensson comment) These new compounds are just beginning to be tested on a broader scale. The older compound PIB (“older” meaning all of five years) has since 2004 been used at a growing number of independent institutions. It has by now generated a critical mass of data to indicate that, overall, a small majority of patients diagnosed with DLB have brain amyloid loads approaching those of people with AD, Brooks said.

A much smaller percentage of people diagnosed with PDD are PIB-positive. In contrast to DLB, which causes both motor and mental symptoms from the get-go, PDD is a dementia that develops when PD progresses and spreads outward from the nigrostriatal system. PET studies following the fate of dopaminergic and cholinergic neurons show that PDD manifests itself as neuron loss expands from the motor cortex to the parietal and frontal cortex. This causes both a dopaminergic and sweeping cholinergic loss (e.g., Hilker et al., 2005). The former is responsible for increasing disability, the latter for cognitive decline, Brooks concluded. It is clear, however, that “in PDD, the dementia is not caused by amyloid,” he added.

the next few years, FDG PET of neuronal activity in cortical areas of the brain appears helpful. Inflammation as imaged with the microglial activation marker 11C-PK11195 also precedes dementia in PD, Brooks said in Prague. Up to 80 percent of people with PD suffer this fate, but typically not before having lived with PD for a decade or more.—Gabrielle Strobel.


Wed Jun 03, 2009 9:19 pm
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Please let us know if the MIND folks can enlighten us on any of this!
Robin


Thu Jun 04, 2009 1:05 pm
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