PART 5: Ordnung, Please -- Can Biomarkers Tame a Bewildering Overlap?

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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 α-synuclein and progranulin spectrum. The next story will summarize fluid markers (see Part 6 of this series).

First, brain imaging. And first, the bad news. Numerous groups are working on contrast agents and radioligands that would find and label aggregates of α-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 Aβ 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 Aβ 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.

ARF related Eibsee story: http://www.alzforum.org/new/detail.asp?id=2010

ARF related HAI story: http://www.alzforum.org/new/detail.asp?id=2129

Burton EJ, Barber R, Mukaetova-Ladinska EB, Robson J, Perry RH, Jaros E, Kalaria RN, O'Brien JT. Medial temporal lobe atrophy on MRI differentiates Alzheimer's disease from dementia with Lewy bodies and vascular cognitive impairment: a prospective study with pathological verification of diagnosis. Brain. 2009 Jan;132(Pt 1):195-203.

Hilker R, Thomas AV, Klein JC, Weisenbach S, Kalbe E, Burghaus L, Jacobs AH, Herholz K, Heiss WD. Dementia in Parkinson disease: functional imaging of cholinergic and dopaminergic pathways. Neurology. 2005 Dec 13;65(11):1716-22.

Johnson AE, Jeppsson F, Sandell J, Wensbo D, Neelissen JA, Juréus A, Ström P, Norman H, Farde L, Svensson SP. AZD2184: a radioligand for sensitive detection of beta-amyloid deposits. J Neurochem. 2009 Mar;108(5):1177-86.

McKeith I, O'brien J, Walker Z, Tatsch K, Booij J, Darcourt J, Padovani A, Giubbini R, Bonuccelli U, Volterrani D, Holmes C, Kemp P, Tabet N, Meyer I, Reininger C, DLB Study Group. Sensitivity and specificity of dopamine transporter imaging with 123I-FP-CIT SPECT in dementia with Lewy bodies: a phase III, multicentre study. Lancet Neurol. 2007 Apr;6(4):305-13.

Rosen RF, Walker LC, Levine H. PIB binding in aged primate brain: Enrichment of high-affinity sites in humans with Alzheimer's disease. Neurobiol Aging. 2009 Mar 27;

Svensson comment: AstraZeneca presented the preclinical data on [18F]AZD4694 at the 9th International AD/PD meeting in Prague. In our preclinical studies, AZD4694 shows high affinity to amyloid plaque with very low non-specific interactions with white matter regions devoid of amyloid plaque. This low non-specific background provides a higher contrast and should support the potential to detect very low levels of amyloid. AZD4694 is currently in a Phase 1 study (in collaboration with Karolinska Institutet, Stockholm) with the objective to test clinical utility of this ligand. Our first data look very promising. We are supportive of ADNI, which has already made significant contributions to the field, and we have planned to make our ligand available for the sites in ADNI 2. The elegant study by Rosen et al., 2009, showing that PIB may be selective for pathological human-specific conformation of aggregated Aβ, indicates that we should be cautious when comparing results from different methods for evaluating Aβ plaque load in vitro (i.e., in vitro PET tracer binding, ELISA for insoluble Aβ, and IHC). The data from Rosen et al. suggest that one should include PIB or another amyloid selective PET tracer when evaluating plaque load in vitro, to support translation to the in-vivo situation. Clearly more work is needed to unravel the molecular mechanism of amyloid ligand binding.

Walker Z, Costa DC, Walker RW, Shaw K, Gacinovic S, Stevens T, Livingston G, Ince P, McKeith IG, Katona CL. Differentiation of dementia with Lewy bodies from Alzheimer's disease using a dopaminergic presynaptic ligand. J Neurol Neurosurg Psychiatry. 2002 Aug;73(2):134-40.


This is Part 5 of a nine-part series. See also Part 1, Part 2, Part 3, Part 4, Part 6, Part 7, Part 8, Part 9.