“Earlier” seems to be the new mantra in Alzheimer’s research. With biomarker data indicating that amyloid pathology begins up to 20 years before symptoms appear, many researchers now believe that treatment should start in the preclinical phase. This shift in thinking demands new ways to recognize the disease in its preliminary stages. In an Alzheimer’s disease press conference at the Society for Neuroscience 2012 annual meeting, held 13-17 October in New Orleans, Louisiana, researchers presented three novel approaches to early detection. These included using positron emission tomography (PET) to detect subtle functional changes a decade before diagnosis, imaging oligomeric forms of Aβ in living brains, and identifying an epigenetic signature of AD that distinguishes it from related disorders. Although promising, all of these strategies are under development and not yet viable as diagnostics. Two additional talks at the press conference focused on treatment, with researchers discussing insights gleaned from animal models (see Part 2).

With brain pathology accumulating up to two decades before diagnosis, Lori Beason-Held at the National Institute on Aging, Baltimore, Maryland, wondered whether changes in brain function would also be detectable at preclinical stages. To answer this, Beason-Held and colleagues looked at resting-state PET imaging of oxygen-15-labeled water to measure cerebral blood flow. About 120 people in the Baltimore Longitudinal Study of Aging participated. The study began while they were cognitively healthy, and continued with annual scans and cognitive tests. About one in six participants developed cognitive impairment, which surfaced an average of 11 years after the study began.

Over the first seven years of the study, the researchers saw significantly greater changes in blood flow patterns in people who developed memory problems compared to those who maintained good cognitive function. Prior to cognitive impairment, blood flow dropped in parietal and occipital cortices and the thalamus, but surged in several anterior brain regions such as the orbitofrontal and medial frontal cortex and the anterior cingulate. These frontal regions affect memory, attention, and executive function, all faculties that falter in AD, Beason-Held noted. Amyloid and tau pathology emerge early in affected brain regions as well, suggesting that changes in blood flow may reflect underlying pathology. Importantly, these changes take place several years before cognitive decline begins. Although the finding holds potential for flagging people at risk for decline, at the moment the changes only reach significance at the population level, Beason-Held said. In other words, researchers do not yet know what amount of blood flow change would signify increased risk for an individual. Ultimately, a combination of biomarkers may provide the best measure of those at risk for the disease, Beason-Held told the audience.

One difficulty in diagnosing AD is distinguishing it from other neurodegenerative diseases with overlapping symptoms, such as Parkinson’s disease and dementia with Lewy bodies. Paula Desplats at the University of California, San Diego, wondered if unique epigenetic alterations to DNA might characterize these diseases (see ARF related news story). To examine this, Desplats and colleagues compared frontal cortex autopsy samples from people with AD, PD, and DLB, as well as from healthy, age-matched controls. Each group contained about seven samples. The researchers focused on 84 genes that affect DNA structure, such as histone deacetylases (HDACs) and histone lysine methyltransferases. Several other studies have fingered HDACs and other epigenetic modifiers as therapeutic targets in AD (see, e.g., ARF related news story; ARF news story; and ARF news story).

The researchers found that 13 to 20 genes in each disease significantly changed expression compared to controls. While several genes showed similar changes in two or three of the disorders, about six unique genes also characterized each disease. The results provide a molecular signature of the three disorders, Desplats said. To make this into a useful biomarker, however, researchers will need to detect these changes in living people. If the epigenetic modifications occur systemically and not just in the brain, they might be detectable with a simple blood test, Desplats suggested. If so, clinicians could potentially use this method to help sharpen diagnosis and start patients on the correct treatment regimen earlier. The findings may also point to new therapeutic targets for each disease, Desplats noted.

Current imaging and fluid biomarkers provide glimpses into the early stages of AD, but these methods have some limitations, said William Klein at Northwestern University, Evanston, Illinois. For example, while scientists can visualize amyloid plaques in the brain using PET radioligands that bind to aggregated forms of Aβ (see, e.g., ARF related news story and ARF news story), plaque load correlates poorly with clinical symptoms, whereas synapse loss associates closely with cognitive decline (see, e.g., ARF related news story and ARF news story). Many researchers now believe that soluble, oligomeric forms of Aβ are most toxic to synapses and perhaps initiate the disease. Researchers need a way to visualize this synaptotoxic species, Klein said. He noted that the concentration of Aβ oligomers in AD brain shoots up to about seven times that of control brain before plaques form. This suggests that the presence of oligomers could make a good early diagnostic, Klein said.

To develop a probe, Klein and colleagues conjugated magnetic nanoparticles to antibodies specific for oligomeric forms of synthetic Aβ known as Aβ-derived diffusible ligands (ADDLs) (see ARF related news story and ARF news story). The resulting probe produces a strong magnetic resonance imaging (MRI) signal. In solutions and cell cultures, the compound binds to these Aβ oligomers with high affinity and specificity, Klein reported. The researchers incubated the probe with slices from human frontal cortex, and showed the MRI signal could clearly distinguish between AD and aged control brains.

Large molecules such as antibodies poorly penetrate the blood-brain barrier, presenting a problem for in-vivo use. To enhance uptake, the researchers delivered the antibody to transgenic AD mice via intranasal injections. In these experiments, they conjugated the antibody to a wheat germ protein rather than the magnetic nanoprobe. Treated mice were spared the cognitive declines seen in untreated animals, suggesting the antibody enters the brain and mops up Aβ oligomers, Klein said. The researchers are now working on a way to deliver probe-conjugated antibody to people by using a nasal spray. Preliminary experiments suggest that the probe enters the brain within six hours, allowing it to be used as a diagnostic. People at the press conference wondered how this diagnostic tool turns out to prevent cognitive decline in mouse models. Klein noted that the antibody is an example of “theranostics,” where the same agent could be used for both diagnosis and therapy. In addition, the probe could also evaluate the efficacy of early-stage drugs designed to lower Aβ levels, Klein suggested. Other groups are developing similar theranostics that recognize oligomeric forms of Aβ (see ARF related news story).—Madolyn Bowman Rogers.

This is Part 1 of a two-part series. See also Part 2.

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  1. Long before AD symptoms, perhaps even in childhood (congenital causes cannot be excluded), people with a high likelihood of acquiring AD show degeneration of the brain capillary bed (1,2). This is manifested in reduction of the capillaries in the temporal and frontoparietal regions, which at some point leads to reduction of capillary blood flow in these areas (2,3). Further reduction of the capillary bed leads to the opening of arteriovenous shunts in these areas, and to early dumping of arterial blood into the venous system of the brain (2,4). During ultrasound and PET examination, these changes of hemodynamics may look like increased blood flow, but this does not happen in reality, as the blood is just dumped into the veins without going through the capillary bed, and examination shows blood flow in arteriovenous shunts (4). This process, in turn, leads to disruption of the process of deposition and clearance of amyloid-β, and as a result contributes to AD development (5,6,7). Early identification of these changes is essential for the diagnosis of preclinical AD (2,4,6,7).

    References:

    . The Importance of Early Diagnosis of Dyscircular Angiopathy of Alzheimer's Type in the Study of Heredity of Alzheimer's Disease. J Alzheimer's & Dementia, 6, 4, Supp. e 4, July 2010

    . Vascular factors in Alzheimer’s disease. J. Health. 4, Special Issue I, 735-742.

    . The vascular factor in Alzheimer's disease: A study in Golgi technique and electron microscopy. J Neurol Sci. 2012 Nov 15;322(1-2):117-21. PubMed.

    . Endovascular Application of Low-Energy Laser in the Treatment of Dyscirculatory Angiopathy of Alzheimer’s Type. Journal of Behavioral and Brain Science. 2:67-81. (2012)

    . The Tomography Dementia Rating Scale (TDR)—the Rating Scale of Alzheimer's Disease Stages. . J. Health. 4;Special Issuec (2012)

    . Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer's disease. Acta Neuropathol. 2009 Jul;118(1):103-13. PubMed.

    . Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci. 2011 Dec;12(12):723-38. PubMed.

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References

News Citations

  1. Animal Model Redux: New Lessons From Old Transgenics?
  2. Bethesda: "Ome" Sweet "Ome"—Epigenome Joins Genome, Proteome
  3. Does Epigenetic Modification by Aβ Offer New Take on Therapy?
  4. Histone Acetylation: Epigenetic Achilles’ Heel of Memory in Aging
  5. DC: Developing But Debatable—Deacetylase Inhibitors for CNS Disease?
  6. Paper Alert: PIB-PET, Brain Biopsies Match Well for Detecting Aβ
  7. FDA Approves Amyvid for Clinical Use
  8. Post-Conference News: Oligomers, Protofibrils, and Fibrils—They Are All Bad
  9. Synapses Sizzle in Limelight of Symposium Preceding Neuroscience Conference, Orlando: Day 2
  10. Orlando: Adding to ADDLs: Where Are They; What Might They Be Doing?
  11. Orlando: ADDLing Pieces to the Amyloid Puzzle; Oligomers Increase in AD Brain
  12. An Oligomer Test for PD—Could One for AD Be Close Behind?

Further Reading

News

  1. Post-Conference News: Oligomers, Protofibrils, and Fibrils—They Are All Bad
  2. Synapses Sizzle in Limelight of Symposium Preceding Neuroscience Conference, Orlando: Day 2
  3. Orlando: Adding to ADDLs: Where Are They; What Might They Be Doing?
  4. Orlando: ADDLing Pieces to the Amyloid Puzzle; Oligomers Increase in AD Brain
  5. Heavy Methyl—DNA, Protein Modification Affect Memory, APP, and Tau
  6. Paper Alert: PIB-PET, Brain Biopsies Match Well for Detecting Aβ
  7. Overworked HDACs Leave Transcriptional Posts to Push DNA Repair
  8. Histone Acetylation: Epigenetic Achilles’ Heel of Memory in Aging
  9. Bethesda: "Ome" Sweet "Ome"—Epigenome Joins Genome, Proteome
  10. An Oligomer Test for PD—Could One for AD Be Close Behind?
  11. Does Epigenetic Modification by Aβ Offer New Take on Therapy?
  12. DC: Developing But Debatable—Deacetylase Inhibitors for CNS Disease?
  13. It’s an HDAC2 Wrap— Memory-suppressing DNA Modifier Identified
  14. St. Louis: Imaging Preclinical AD—Can You See it Coming in the Brain?
  15. San Diego: Pre-AD Brain Changes May Allow Early Diagnosis
  16. FDA Approves Amyvid for Clinical Use
  17. The Human Connectome Project: Deciphering the Brain’s Wiring
  18. The Many Faces of LRRK2