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Longitudinal Data Say: Nope, CSF Markers Do Not Track Progression

Series - Alzheimer's Association International Conference 2017:

Part 2 of a two-part story.

As longitudinal biomarker data begin to roll in, they challenge some previous assumptions about Alzheimer’s disease progression. Researchers at the Alzheimer’s Association International Conference 2017, held July 16–20 in London, presented data from studies of familial and sporadic AD that, on the face of it, contradict previous cross-sectional findings. While progression models based on the latter propose that most biomarkers change gradually during the preclinical phase of the disease, in-person serial data from familial AD show instead that several biomarkers change abruptly around the time symptoms begin (see Part 1 of this story). Serial studies of sporadic AD painted yet a different picture. Researchers reported no difference in how quickly CSF biomarkers changed between controls and AD patients, confirming the idea that these markers do not track progression. Imaging showed more promise for this. Amyloid PET suggested that plaques appeared first in frontal and only later in posterior brain regions. FDG PET and structural MRI pinned down the earliest neurodegeneration in ApoE4 carriers to about 10 years before age at onset. MRI also indicated that so-called “superagers,” older adults who maintain the memory skills of youngsters, preserve cortical thickness. But don’t take all this to the bank. Speakers stressed that some of these findings are based on only two or three time points, and that more data may change the picture. Even so, these preliminary data may help researchers pick biomarkers to use in clinical trials. 

Frontal First. Amyloid PET of cognitively healthy people finds the earliest amyloid accumulation (red lines) in frontal (left) rather than posterior regions (right). Gray lines represent those with stable/declining amyloid. [Courtesy of Michelle Farrell, AAIC 2017.]

Imaging Pins Down Early Changes
In London, several scientists focused on early imaging changes in AD. Previous neuropathology and imaging studies suggested that amyloid plaques first begin to deposit in the frontal cortex (see Braak and Braak, 1991; Villemagne et al., 2011). Specifically, the earliest accumulation may occur in the orbitofrontal cortex, claimed Michelle Farrell of the University of Texas at Dallas. She analyzed longitudinal data from 83 cognitively healthy participants in the Dallas Lifespan Brain Study. Participants ranged from 30 to 89 years old, and only 15 of them were amyloid-positive at baseline. They underwent amyloid PET and structural MRI and took cognitive tests at baseline and four years later. 

Farrell examined the PET signal in frontal and posterior brain regions and distinguished people who accumulated amyloid from those who remained stable (see image above). Looking just at the accumulators, she found that those who started out as amyloid-negative had their first sign of accumulation in frontal regions, namely the lateral and medial orbitofrontal cortex and the pars orbitalis. That suggests these are the first regions to lay down plaques, and that an amyloid PET signal in the OFC might serve as a very early biomarker of AD, Farrell said. Intriguingly, accumulation in the lateral OFC predicted a decline in reasoning on follow-up testing, but no effect on memory or processing speed. This makes sense because the pars orbitalis plays a role in reasoning, Farrell noted. Others at AAIC suggested that the finding of early OFC accumulation could help explain the presence of olfactory dysfunction in the very early stages of AD (Jan 2010 news). 

On the other hand, people who were already amyloid-positive at baseline accumulated further amyloid in both frontal and posterior regions, namely the precuneus, posterior cingulate, and isthmus cingulate. This group tended to be older than the frontal accumulators. Amyloid deposition in the precuneus predicted a drop in episodic memory upon follow-up, but did not affect reasoning or processing speed. This is in keeping with the role of the precuneus in memory, Farrell said. The SUVR changes in this study were small and often in the amyloid-negative range, but others at AAIC noted that accumulation can still be measured in this way. “It is quite reasonable to look for rising SUVRs even at levels below threshold,” William Jagust of the University of California at Berkeley told Alzforum.

Richard Caselli of the Mayo Clinic in Scottsdale, Arizona, reported on longitudinal changes in ApoE4 carriers. They tend to accumulate amyloid in the brain faster than noncarriers, and some studies have shown that they can have subtle metabolic or functional deficits in their 30s or even younger (Apr 2009 news; Oct 2015 news). Despite these early signs, neurodegeneration in ApoE4 carriers begins late in life, just as in noncarriers, Caselli said.

He selected 36 cognitively healthy ApoE4 carriers and 10 noncarriers from a larger cohort who attended clinics in the Phoenix area. All were over 50 and had a first-degree relative with dementia. Although the study was not specifically designed to study ApoE4 carriers, it was highly enriched for people with this risk factor, Caselli noted. To spot early brain changes, Caselli tracked changes in cognition as well as in brain volume and metabolism every two years for an average 14-year follow-up time. During this time, 12 of the carriers and three of the noncarriers progressed to MCI.

Caselli found that rates of hippocampal atrophy accelerated in ApoE4 carriers about 10 years before an MCI diagnosis. Deficits in verbal memory appeared seven years prior to diagnosis, and hypometabolism in posterior regions at six. On average, these declines started when people were in their 60s, suggesting that the deficits reported in the literature for young ApoE4 carriers may reflect differences in brain development and are not progressive.

Researchers also believe superagers can help them understand what goes on in the aging brain (Rogalski et al., 2013). Studies have reported greater cortical thickness in these lucky folks than in peers with age-related decline, but it was unclear if superagers start out with bigger brains, or simply maintain their brain volume (Oct 2016 news). Hamid Sohrabi of Edith Cowan University in Perth, Australia, investigated this by following 21 superagers and 24 typical agers older than 60 enrolled in the Australian Imaging, Biomarkers & Lifestyle (AIBL) study. Superagers were defined as having a baseline memory performances on the second edition of the California Verbal Learning Test that matched those of 30- to 44-year-olds. Participants underwent five MRI scans and took four cognitive assessments over six years.

Surprisingly, the baseline cortical thicknesses of superagers resembled those of the typical agers. Super- and typical agers also had the same degree of amyloid pathology as seen by PET.

Over time, however, the superagers maintained their cortical thickness, particularly in the median cingulate, paracingulate gyri, and superior occipital gyrus, while their peers with age-related cognitive decline lost brain volume at typical aging rates (Salat et al., 2004). Superagers kept more volume than typical agers in 25 of 34 brain regions examined. This study represents some of the first longitudinal data on volume changes in superagers, and the data need to be replicated, Sohrabi said. He speculated that genetic factors allow some people to resist the losses associated with aging. In future work, Sohrabi will look for genetic differences that might support this idea.

Nothing Much to See in CSF
Many researchers investigate the utility of CSF biomarkers for trials. CSF analysis costs less than brain imaging and allows researchers to monitor numerous biological processes. In London, Alberto Lleó of the Hospital de Sant Pau, Barcelona, Spain, reported CSF findings from the longitudinal BioMark APD study, which tracks volunteers at 45 centers across 19 European countries and Canada. Lleó analyzed data from a subset comprising 154 cognitively healthy people, 75 with subjective cognitive decline, 128 with mild cognitive impairment, and 111 people with clinical late-onset AD. Most were in their 60s. Participants took the MMSE and donated CSF at baseline, and gave CSF again during at least one follow-up visit about two years later.

At baseline, the findings matched other studies: People with mild cognitive impairment (MCI) or AD had lower CSF Aβ42, and higher total tau and p-tau, than the other groups. Inflammatory and injury markers such as YKL-40 and NfL also ran high in CSF of people with clinical symptoms.

Over time, however, no differences emerged between diagnostic groups in how fast biomarker levels changed. CSF Aβ42 levels rose slightly, but at the same rate, in all four groups. Inflammatory markers also climbed similarly in all groups. By contrast, CSF tau markers remained stable over time, with one exception: In people with AD who did not carry an ApoE4 allele, CSF total tau and p-tau dropped. The reason for this is still not clear. Possibly, the patterns of AD biomarker changes in people without an ApoE4 allele are shifted compared to those with ApoE4, so that they represent different time frames despite similar clinical status, the researchers said. Intriguingly, at AAIC researchers reported that CSF total tau levels stayed flat in people with familial AD in the Dominantly Inherited Alzheimer Network (DIAN), too, but CSF p-tau dropped close to disease onset. Researchers saw this drop as a sign p-tau was getting swept into neurofibrillary tangles in the brain (see Part 1 of this story). 

What explains the static biomarker signatures in sporadic AD? Daniel Alcolea at Sant Pau’s noted that the study’s two-year time span may be too short to capture true long-term change. “Longer follow-up periods, and a special focus on preclinical stages might give us more information about the relevance of these changes,” Alcolea wrote to Alzforum.

Meanwhile, the lack of longitudinal change over the short term casts fresh doubt on the ability of CSF markers to serve as outcome measures for clinical trials, as others have noted (Aug 2017 conference news). Lleó suggested that CSF markers might best track progression early in disease. In preliminary analyses of people with preclinical AD, he does see a rise in p-tau in this group, he told Alzforum. “The main changes in core CSF biomarkers occur during the asymptomatic phase of AD. Our study supports the idea that these biomarkers are not very dynamic during the symptomatic phase of the disease,” Lleó wrote.—Madolyn Bowman Rogers

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References

News Citations

  1. Data from DIAN Revise Familiar Biomarker Trajectories
  2. Blunted Sense of Smell Parallels Pathology in AD, PD
  3. ApoE4 Linked to Default Network Differences in Young Adults
  4. Young ApoE4 Carriers Wander Off the ‘Grid’ — Early Predictor of Alzheimer’s?
  5. The Making of a “Superager”: New Research Examines Neuroanatomy that Keeps Older Adults Sharp
  6. CSF and Brain Markers Highlight Different Facets of Dementia

Paper Citations

  1. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239-59. PubMed.
  2. Villemagne VL, Pike KE, Chételat G, Ellis KA, Mulligan RS, Bourgeat P, Ackermann U, Jones G, Szoeke C, Salvado O, Martins R, O'Keefe G, Mathis CA, Klunk WE, Ames D, Masters CL, Rowe CC. Longitudinal assessment of Aβ and cognition in aging and Alzheimer disease. Ann Neurol. 2011 Jan;69(1):181-92. PubMed.
  3. Rogalski EJ, Gefen T, Shi J, Samimi M, Bigio E, Weintraub S, Geula C, Mesulam MM. Youthful memory capacity in old brains: anatomic and genetic clues from the Northwestern SuperAging Project. J Cogn Neurosci. 2013 Jan;25(1):29-36. PubMed.
  4. Salat DH, Buckner RL, Snyder AZ, Greve DN, Desikan RS, Busa E, Morris JC, Dale AM, Fischl B. Thinning of the cerebral cortex in aging. Cereb Cortex. 2004 Jul;14(7):721-30. Epub 2004 Mar 28 PubMed.

External Citations

  1. Dallas Lifespan Brain Study
  2. BioMark APD

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