eFAD Research Surprise: In Mutation Carriers, Amyloid Starts in Striatum

The striatum does not have a place of notoriety in Alzheimer disease research. Sure, this brain region shows amyloid pathology at postmortem, but so do many others by the time AD has run its course. After all, the cerebral cortex and the hippocampal formation are where memory and thinking happens, whereas the striatum is best known for its role in movement control. And yet, the striatum is precisely where amyloid pathology starts to build up in some healthy people who are genetically destined to develop AD. It pops up there in the mid-thirties, many years before the person is expected to develop symptoms and many years before any cortical amyloid deposits show up. That is the surprising conclusion of a study out today in the Journal of Neuroscience. In it, a collaborative team of scientists from five different research institutions, led by William Klunk of University of Pittsburgh School of Medicine, report that 10 mutation carriers from two separate families with autosomal-dominant AD caused by presenilin 1 mutations all show a focal signal of PIB retention in their striatum. Strikingly, the asymptomatic people had good striatal function even though their PIB retention in that area was very high.

The study is the first to use amyloid imaging in asymptomatic carriers of presenilin 1 mutations. The paper reports results of the first round of imaging from a longitudinal study designed to monitor the natural history of amyloid deposition in early onset familial AD (eFAD). The study employs PIB-PET, a brain imaging method that uses the amyloid tracer Pittsburgh compound B originally developed by Klunk and his colleague and co-author Chester Mathis. The study participants are invited to return annually for repeat scans, and for accompanying neurological, psychiatric, and neuropsychological assessments. The study is a long-term effort to track how amyloid pathology spreads in advance of symptoms and, for some participants, relative to their symptoms.

Some prior postmortem studies have suggested that amyloid pathology develops years before people begin noticing cognitive problems. Part of the excitement around PIB has been that, unlike postmortem observation alone, it allows scientists to “look” inside a person’s brain and address that question directly. Almost by definition, presymptomatic cases of AD are difficult to find among the general population. This study became possible through the willingness of two groups of siblings and cousins, who know from genetic testing that they will develop AD, to devote time and effort to AD research.

The paper reports on 12 members of two families with eFAD, one afflicted with the C410Y mutation and one with the A426P mutation, both in presenilin 1. In each family, one person who had not inherited the mutation, plus five relatives who had, volunteered for the study. The 10 carriers ranged in age from 35 to 49. Five of them had a clinical dementia rating (CDR) of 0. Four had a CDR of 0.5/MCI (though one of these had been diagnosed with a learning disorder in school and was not declining yet, according to the family), and one relative had a CDR of 1. Two siblings met clinical criteria for AD. On a neuropsychological battery, the carriers ranged from normal to mildly impaired, roughly in step with their clinical picture. The mildly symptomatic siblings were all from the A426P family; the carriers from the C410Y were younger than their family’s mean age of onset and asymptomatic. The scientists compared the participants’ PIB-PET data with that from 12 sporadic AD patients and 18 cognitively normal controls of the same age range.

The PIB-PET scans of all 10 carriers showed a consistent pattern of intense amyloid deposition almost exclusively in the striatum. Some of the symptomatic carriers also retained more PIB in cortex than did controls, but much less than do sporadic cases of MCI or mild AD. The scans of the two most impaired carriers with diagnosed AD looked more like those of their asymptomatic fellow carriers than those of sporadic AD cases. Overall, at this asymptomatic to early symptomatic stage, the PS1 carriers had a strikingly different PIB retention pattern than is known from sporadic MCI and AD, with striatal PIB retention being the defining feature.

Other evidence suggests that the finding is real. A previous study has verified that PIB retention during life correlates with amyloid deposition after death (Bacskai et al., 2007). In this study, postmortem pathology of two affected parents from the C410Y family showed extensive amyloid deposition in the striatum along with the typical cortical deposition, the authors report. By contrast, emerging data from cognitively normal older people who begin to show elevated PIB retention do not point to an early start in the striatum (Mintun et al., 2006). Taken together, this suggests that by the time of death, eFAD brains resemble sporadic AD brains in terms of amyloid deposition, but early on they are different.

What does the striatal pathology mean? FDG PET showed no hypometabolism in the striatum. The carriers had no overt motor symptoms and did not appear to suffer from early Parkinson’s, though the authors will continue to pursue hints of subtle impairments in tasks calling on the striatum. The striatal amyloid pathology of the affected C410Y parents was different from their cortical amyloid pathology in that the density of plaques in the striatum was actually greater, but the striatal plaques were not neuritic. Striatal plaques apparently cause no dystrophic damage in their vicinity, the authors note.

At an amyloid imaging symposium held on May 4 in Boston, Klunk presented these data and offered them for discussion. Some scientists suspected that perhaps the striatum can withstand accumulating amyloid pathology better than other brain areas because it has fewer of the type of glutamate receptors that are thought to be the target of oligomeric Aβ toxicity. Other scientists suggested that eFAD might be more strongly driven by Aβ oligomers than sporadic AD, such that people meet clinical criteria for AD before fibrillar amyloid deposition as visible by PIB has spread throughout large swaths of the cerebral cortex. At the conference, AD scientists called on the imaging field to develop PET tracers for Aβ oligomers, but imaging experts noted that technical challenges, such as the small physiological concentration of toxic oligomers, were still considerable. With no information on tangle pathology in these volunteers, a major piece of AD pathogenesis is missing from this picture.

Prior imaging studies have found evidence of brain changes in asymptomatic eFAD carriers, for example, hippocampal atrophy (Ridha et al., 2006), and metabolism in the temporoparietal cortex (Matsushita et al., 2002). The research teams who collaborated on the present study, besides Klunk’s, were those of Daniel Pollen at University of Massachusetts Medical School in Worcester, Keith Johnson at Massachusetts General Hospital, Carol Lippa at Drexel University College of Medicine in Philadelphia, and Dorene Rentz at Brigham and Women’s Hospital in Boston.

Klunk and colleagues note that asymptomatic eFAD mutation carriers offer an opportunity to study experimental medicines at the very early stages of disease at which those therapies may stand a greater chance of making a difference before neurofibrillary changes and neuronal death set in yet. At the conference, Klunk said, “We can image the pathology. Now let’s image the cure.”—Gabrielle Strobel

Comments

  1. A provocative paper providing new insights into the onset of Abeta amyloidosis in FAD. It also raises intriguing questions as to whether or not FAD and sporadic AD and Down syndrome evolve in the same locations and same manner. It also raises question about we are how to understand the disconnection between striatal Abeta deposits and the lack of clinical symptoms, signficant neuron loss, and tau pathology linked to striatal accumulations of Abeta deposits.

    View all comments by John Trojanowski

  2. These findings suggest more a loss of function of APP/AICD than a gain of toxic function, since there is no correlation between the precise early distribution of amyloid and clinical impairment.

    View all comments by Andre Delacourte

  3. The work by Klunk and coworkers (2007) demonstrates how incomplete our understanding is of the early neuropathobiological events that occur in both FAD as well as sporadic AD. Interestingly, we recently demonstrated an age-related increase in striatal amyloid-containing plaques associated with neuritic pathology in APPswe/PS1δE9 mice (Perez et al., 2005). Whether striatal plaque pathology is a very early event compared to cortical and hippocampal pathology in these mice remains an unanswered question. If so, then this mutant may be a putative animal model for both AD and FAD as well as the investigation of early treatment strategies.

    References:

    Klunk WE, Price JC, Mathis CA, Tsopelas ND, Lopresti BJ, Ziolko SK, Bi W, Hoge JA, Cohen AD, Ikonomovic MD, Saxton JA, Snitz BE, Pollen DA, Moonis M, Lippa CF, Swearer JM, Johnson KA, Rentz DM, Fischman AJ, Aizenstein HJ, Dekosky ST. Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees. J Neurosci. 2007 Jun 6;27(23):6174-84. PubMed.

    Perez SE, Lazarov O, Koprich JB, Chen EY, Rodriguez-Menendez V, Lipton JW, Sisodia SS, Mufson EJ. Nigrostriatal dysfunction in familial Alzheimer's disease-linked APPswe/PS1DeltaE9 transgenic mice. J Neurosci. 2005 Nov 2;25(44):10220-9. PubMed.

    View all comments by Elliott Mufson

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References

Paper Citations

  1. Bacskai BJ, Frosch MP, Freeman SH, Raymond SB, Augustinack JC, Johnson KA, Irizarry MC, Klunk WE, Mathis CA, Dekosky ST, Greenberg SM, Hyman BT, Growdon JH. Molecular imaging with Pittsburgh Compound B confirmed at autopsy: a case report. Arch Neurol. 2007 Mar;64(3):431-4. PubMed.
  2. Mintun MA, Larossa GN, Sheline YI, Dence CS, Lee SY, Mach RH, Klunk WE, Mathis CA, Dekosky ST, Morris JC. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology. 2006 Aug 8;67(3):446-52. PubMed.
  3. Ridha BH, Barnes J, Bartlett JW, Godbolt A, Pepple T, Rossor MN, Fox NC. Tracking atrophy progression in familial Alzheimer's disease: a serial MRI study. Lancet Neurol. 2006 Oct;5(10):828-34. PubMed.
  4. Matsushita S, Arai H, Okamura N, Ohmori T, Takasugi K, Matsui T, Maruyama M, Iwatsubo T, Higuchi S. Clinical and biomarker investigation of a patient with a novel presenilin-1 mutation (A431V) in the mild cognitive impairment stage of Alzheimer's disease. Biol Psychiatry. 2002 Nov 1;52(9):907-10. PubMed.

Other Citations

  1. genetic testing

External Citations

  1. C410Y mutation
  2. A426P mutation

Further Reading

No Available Further Reading

Primary Papers

  1. Klunk WE, Price JC, Mathis CA, Tsopelas ND, Lopresti BJ, Ziolko SK, Bi W, Hoge JA, Cohen AD, Ikonomovic MD, Saxton JA, Snitz BE, Pollen DA, Moonis M, Lippa CF, Swearer JM, Johnson KA, Rentz DM, Fischman AJ, Aizenstein HJ, Dekosky ST. Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees. J Neurosci. 2007 Jun 6;27(23):6174-84. PubMed.

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