07 Aug 2015

The Alzheimer’s Association International Conference, held July 18 to 23 in Washington, D.C., showcased a growing interest in early brain changes beyond the established markers of amyloid, tau, and brain volume that anchor the diagrams of successive biomarker change in the pathogenesis of presymptomatic Alzheimer’s disease. What else changes in the brain? Could new measures fill in what happens in those long years between the first amyloid deposits and shrinkage? What other curves can scientists fit into the pathologic staging model of AD? “We want to detect changes earlier than volumetry does, before the neurons are gone,” said Natalie Ryan of University College London.

Something is Crumbling Early in White Matter
Conspicuously absent from the current staging diagram are white-matter hyperintensities (WMH). These bright areas on MRI scans have received plenty of research attention in recent years, but their role in Alzheimer’s is unclear. They are thought to represent damaged small vessels such as capillaries and arterioles, sometimes in connection with microbleeds, demyelination, or gliosis. Scientists typically think of them as a result of ischemic injury arising from a number of different underlying factors. There is debate about whether these lesions are truly a part of AD. To some, they are an independent comorbidity separate from Alzheimer’s core pathologies of plaques and tangles. To others, they predict the clinical onset and course of AD (e.g., Brickman et al., 2014; Tosto et al., 2015).

Because age-related comorbidities make it difficult to study the emergence of WMH in late-onset Alzheimer’s disease (LOAD), Adam Brickman of Columbia University, New York, turned to the purer form of autosomal-dominant AD (ADAD). Mutation carriers do not have the hypertension, elevated cholesterol, or diabetes that heighten dementia risk by way of independently acquired cerebrovascular disease in old people. For this reason they enable scientists to dissect more cleanly which changes are genuinely part of the AD cascade itself. 

At AAIC, Brickman reported an analysis of baseline scans from 299 DIAN participants, 184 of whom were mutation carriers. (One hundred of these people and their relatives traveled to Washington for a one-day workshop before the AAIC conference.) Seventy percent were still asymptomatic. The scans showed an inflection point six years before symptoms, when WMH became larger. What’s more, by using an estimated age at onset model for ADAD, Brickman was able to see that these lesions began to crop up in selected regions of the brain up to 22 years prior. In fact, WMH start to appear soon after amyloid deposits. Correlating the WMH with other biomarkers captured in the DIAN dataset suggests that amyloid deposits might cause them, not tau. “We observed a definitive relationship between WMH and amyloid markers of ADAD,” Brickman said.

“This greatly changes how we think about AD pathogenesis,” said Tammie Benzinger of Washington University, St. Louis. “We used to think about Alzheimer’s as a gray-matter disease, but there is something about these white-matter changes that is also a primary AD pathology. At least in ADAD, it is not a second hit.” When DIAN researchers first spotted WHM in this cohort in 2013, they realized that WMH were not due to independent diseases such as age-related hypertension; however, they still could have been a late step in the pathogenic process. Now, Brickman’s analysis suggests it is a primary step connected early on to amyloid.

The finding renews questions about amyloid-related imaging abnormalities, aka ARIA, in response to amyloid removal. The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) will yield important information on that, Benzinger noted. If longitudinal observation shows that the WMH in the carriers progress over time, that might explain ARIA upon removal of amyloid in later stages of the pathogenic process. On the flip side, removing amyloid earlier, before the white-matter disease has progressed as much, might become possible without causing ARIA-H, Benzinger said. One issue to watch is whether the DIAN-TU trial of gantenerumab, an antibody that did cause ARIA in the SCarlet RoAD trial, causes less of it in these earlier-stage patients or not. Speaking in general terms, Bateman told DIAN families that the ongoing DIAN-TU trial thus far has had no safety concerns.

ARIAs are grouped into two types, E for edema and H for microhemorrhage. Microbleeds are a related manifestation of small-vessel disease, and they can be imaged with MRI, as well. Not only do microbleeds and white-matter hyperintensities tend to appear in the same DIAN participants, they also fall into a specific pattern depending on which presenilin 1 mutation a carrier has inherited, Nelly Joseph-Mathurin of Benzinger's lab reported at AAIC. Previous histological studies had suggested a curious dichotomy whereby people with PS1 mutations before codon 200 have worse parenchymal but milder vascular amyloid pathology, whereas people with mutations after codon 200 have milder parenchymal but worse vascular amyloid pathology. Would brain imaging bear out this genotype-phenotype relationship? Among 157 PS1 mutation carriers, it did. As a group, the carriers whose mutation was before codon 200 accumulated amyloid faster but were only one-third as likely to have microbleeds as the carriers of a PS1 mutation after codon 200, Joseph-Mathurin said.

Early Fissures in Gray Matter?
“Micro” was a recurrent theme in brain imaging at AAIC. Researchers are searching for ways to detect subtler changes that precede the wholesale contraction of the whole brain or the hippocampus as neurons die off in droves. For example, a pair of talks by University College London colleagues Phil Weston and Natalie Ryan showed how they are learning to capture finer presymptomatic changes by MRI. First, Weston adapted from LOAD to ADAD a method of detecting a specific regional signature of cortical thinning originally developed by Brad Dickerson at Massachusetts General Hospital. This work was not done within DIAN; rather, it drew on 43 mutation carriers and 42 non-carrying relatives from UCL’s longstanding observational cohort of ADAD families, some of whom are also in DIAN. 

Weston divided the presymptomatic carriers into an early group of people in their 30s who were about a decade younger than their family’s expected age at onset and an older, late presymptomatic group of people in their 40s who were only three years away. Using longitudinal measurements of MRI and cognition, Weston found that a similar cortical signature as that in LOAD showed detectable thinning more than three years prior to symptom onset. Consisting of entorhinal, parietal, superior frontal, supramarginal cortex plus precuneus, this signature was able to distinguish presymptomatic carriers from healthy aging controls. Of these regions, the precuneus started to subtly thin out first, around nine years prior to onset. “Besides separating groups, this cortical signature was quite effective at identifying presymptomatic people who are likely to go on to develop symptoms,” Weston said.

Weston’s colleague Ryan picked up from there to see if the researchers could apply new MRI analyses to quantify tiny changes within the microarchitecture in the regions that would later thin out. Much like looking for hairline fissures that form inside a wall before the wall comes down, Ryan hoped to detect microchanges years earlier than outright macro-shrinkage of the width of cortex. To that end, she measured mean diffusivity in the same group of early presymptomatic and late presymptomatic mutation carriers. Mean diffusivity is measured with diffusion-weighted imaging, an advanced MRI technique that has been analyzed most widely as diffusion tensor imaging to capture changes in water diffusion in white matter. Rather than measure changes in the directed diffusion along fiber tracts, however, Weston and Ryan in this study analyzed the diffusion-weighted MRI data to quantify the average degree of diffusion in all directions in gray matter—basically measuring random Brownian motion as water molecules bump around within and between cells.

The London scientists acquired T1 and diffusion-weighted MRI of the ADAD cortical signature regions, and saw that mean diffusivity went up as people neared their expected age of symptom onset. This could be because cell and organelle membranes in those brain areas were breaking down as neurons started to degenerate, leaving fewer barriers to hinder diffusion. Intriguingly, mean diffusivity was somewhat lower in carriers at earlier presymptomatic stages than normal controls. Perhaps, Ryan speculated, this might be because prior to degeneration, glial proliferation and swelling of inflamed brain cells press them more closely together, hindering the diffusion of water. Weston and Ryan do not yet have amyloid scans in all those volunteers to see how the initial decrease and subsequent increase in water diffusion relates to the presence of amyloid deposits.

Ryan cautioned that this was a small, initial study mainly concerned with learning whether diffusion-weighted MRI might be a feasible way to capture presymptomatic processes in AD. Technical improvements, correlation with known biomarkers, and longitudinal observation in larger and independent samples still stand between this data and mean diffusivity becoming an established marker. An added caveat is that a number of different biological processes could underlie changes in diffusivity, as the measure itself is not tied to amyloid or tau pathology. That said, measuring microdamage might eventually offer an earlier marker of change than the atrophy curve that is part of the Alzheimer’s staging model.

What Does the Pathologist See?
Curiously, the suspected vascular micropathology that Brickman saw in the form of white-matter hyperintensities does not appear to develop into overt vascular damage of the sort that would show up in a postmortem exam. Also at AAIC, Nigel Cairns of Washington University, who runs the neuropathology core for both ADNI and DIAN, presented results from his direct comparison of 34 deceased AD patients in ADNI to 22 deceased relatives of DIAN families. Besides amyloid and tau pathology, LOAD and ADAD had in common that about half of the patients also had Lewy body pathology. But there were also clear differences. The amyloid and tau pathology were more intense in ADAD. Absent from these younger people’s brains were abundant comorbidities that marked the brains of people who had died of LOAD. TDP-43 proteinopathy, the tauopathy argyrophilic grain disease, hippocampal sclerosis, and cerebrovascular disease with infarcts were present in LOAD but absent in ADAD.

“From a pathological standpoint, ADAD is a purer form of the disease,” Cairns said. Cerebral amyloid angiopathy—where amyloid deposits lodge in blood vessel walls—is variable in a similar way between ADAD and LOAD, Cairns noted, with both types of AD having very severe and very mild cases of accompanying CAA. Microhemorrhages, too, are similar in ADAD and LOAD in that their number is comparable in symptomatic people of both types of AD. In that sense, both CAA and microhemorrhages appear not to be caused by independent diseases but to be an integral part of AD itself. —Gabrielle Strobel

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References

Conference Coverage Series Citations

1. Alzheimer's Association International Conference 2015: ADAD Family Conference 7 Aug 2015

Therapeutics Citations

1. Gantenerumab

Paper Citations

1. Brickman AM, Zahodne LB, Guzman VA, Narkhede A, Meier IB, Griffith EY, Provenzano FA, Schupf N, Manly JJ, Stern Y, Luchsinger JA, Mayeux R. Reconsidering harbingers of dementia: progression of parietal lobe white matter hyperintensities predicts Alzheimer's disease incidence. Neurobiol Aging. 2015 Jan;36(1):27-32. Epub 2014 Jul 21 PubMed.
2. Tosto G, Zimmerman ME, Hamilton JL, Carmichael OT, Brickman AM, Alzheimer's Disease Neuroimaging Initiative. The effect of white matter hyperintensities on neurodegeneration in mild cognitive impairment. Alzheimers Dement. 2015 Jun 13; PubMed.

Further Reading

No Available Further Reading