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July 17, 2012; 79 (3) Articles

Low PiB PET retention in presence of pathologic CSF biomarkers in Arctic APP mutation carriers

Michael Schöll, Anders Wall, Steinunn Thordardottir, Daniel Ferreira, Nenad Bogdanovic, Bengt Långström, Ove Almkvist, Caroline Graff, Agneta Nordberg
First published June 13, 2012, DOI: https://doi.org/10.1212/WNL.0b013e31825fdf18
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Abstract

Objective: To investigate the particular pathology of the Arctic APP (APParc) early-onset familial Alzheimer disease (eoFAD) mutation for the first time in vivo with PET in comparison with other eoFAD mutations and sporadic Alzheimer disease (sAD).

Methods: We examined 2 APParc mutation carriers together with 5 noncarrier siblings cross-sectionally with 11C-labeled Pittsburgh compound B (PiB) and 18F-fluorodeoxyglucose (FDG) PET, as well as MRI, CSF biomarkers, and neuropsychological tests. Likewise, we examined 7 patients with sAD, 1 carrier of a presenilin 1 (PSEN1) mutation, 1 carrier of the Swedish APP (APPswe) mutation, and 7 healthy controls (HCs).

Results: Cortical PiB retention was very low in the APParc mutation carriers while cerebral glucose metabolism and CSF levels of Aβ1-42, total and phosphorylated tau were clearly pathologic. This was in contrast to the PSEN1 and APPswe mutation carriers revealing high PiB retention in the cortex and the striatum in combination with abnormal glucose metabolism and CSF biomarkers, and the patients with sAD who showed typically high cortical PiB retention and pathologic CSF levels as well as decreased glucose metabolism when compared with HCs.

Conclusions: The lack of fibrillar β-amyloid (Aβ) as visualized by PiB PET in APParc mutation carriers suggests, given the reduced glucose metabolism and levels of Aβ1-42 in CSF, that other forms of Aβ such as oligomers and protofibrils are important for the pathologic processes leading to clinical Alzheimer disease.

GLOSSARY

Aβ=
β-amyloid;
AD=
Alzheimer disease;
APParc=
Arctic APP;
APPswe=
Swedish APP mutation carrier;
CAA=
cerebral amyloid angiopathy;
eoFAD=
early-onset familial Alzheimer disease;
FDG=
18F-fluorodeoxyglucose;
MCI=
mild cognitive impairment;
MMSE=
Mini-Mental State Examination;
p-tau=
phosphorylated tau;
PiB=
Pittsburgh compound B;
sAD=
sporadic Alzheimer disease;
t-tau=
total tau;
varAD=
variant AD

The rare autosomal dominantly inherited early-onset familial Alzheimer disease (eoFAD) can be caused by over 200 different mutations in the presenilin 1 (PSEN1), the presenilin 2 (PSEN2), and the β-amyloid (Aβ) precursor protein genes (APP). These mutations alter the processing and turnover of Aβ in the brain, a major pathologic hallmark of Alzheimer disease (AD).1

The introduction of PET amyloid imaging agents such as N-methyl-[11C] 2-(4′-methylaminophenyl)-6-hydroxy-benzothiazole (Pittsburgh compound B [PiB]) has made in vivo visualization of fibrillar Aβ pathology possible.2,3 Few studies have investigated Aβ pathology in eoFAD mutation carriers with PiB PET, generally showing high tracer retention predominantly in the striatum along with pathologic cortical levels.4,–,7

Seven pathogenic APP mutations within the sequence encoding the Aβ peptide have been discovered: the Dutch, Flemish, Italian, IA, A671V, E693Δ, and Arctic APP (APParc) mutations. Of these, only the E693Δ and the APParc mutation (E693G) result in a clinical presentation typical of AD.8,–,10 A Swedish and an American pedigree with the APParc mutation have previously been described clinically and neuropathologically. Carriers of the mutation presented with ring-shaped Aβ plaques without the distinct amyloid cores that are associated with typical sporadic AD (sAD).9

To study this pathology further in vivo, we investigated brain fibrillar Aβ burden with PiB PET in the context of 18F-fluorodeoxyglucose (FDG) PET, MRI measures of atrophy, together with CSF levels of Aβ1-42, total tau (t-tau), and phosphorylated tau (p-tau), as well as cognitive performance in carriers of the APParc mutation. These were compared with noncarriers from the same family, a PSEN1 mutation carrier, a Swedish APP (APPswe) mutation carrier, patients with sAD, and healthy controls (HCs).

METHODS

Subjects.

Clinical examinations and routine clinical assessments (MRI, cognitive testing, and CSF sampling) were performed at the Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden, except for 1 APParc mutation carrier (APParc-1) who was clinically assessed and underwent all examinations except for PET imaging at the Department of Geriatric Medicine, Umeå University Hospital, Umeå, Sweden. The eoFAD family members were recruited blind to mutation status as part of a larger longitudinal study on eoFAD and regularly followed up.

In this study, we included 7 members of the Swedish APParc (p.E693G) mutation family (APParc-1–7), 1 subject, previously examined,11 from the PSEN1 (p.H163Y) mutation family (PSEN1-1), and 1 subject from the Swedish APPswe family (APPswe-1). Sequencing revealed the presence of the APParc, the PSEN1 H163Y, and the APPswe mutations in the subjects APParc-1, APParc-2, PSEN1-1, and APPswe-1. PET, MRI, CSF, and neuropsychological data were compared with those from a group of 7 demographically matched cognitively healthy controls, who were recruited among the mutation noncarriers from the above-mentioned eoFAD families, and a group of 7 patients with sAD. The mutation carriers APParc-1, PSEN1-1, as well as the subjects with sAD fulfilled the National Institute of Neurological and Communicative Disorders and Stroke– Alzheimer's Disease and Related Disorders Association criteria for a clinical diagnosis of AD12; APPswe-1 was diagnosed with amnestic mild cognitive impairment (MCI) based on clinical observation in agreement with the criteria defined by Petersen et al.13

APParc-1Embedded Image7 descend from a family from northern Sweden that harbors the Arctic APP mutation. Carrier APParc-1 initially reported word-finding difficulties when Mini-Mental State Examination (MMSE) was 28/30 and neuropsychological tests showed impairment of verbal and spatial episodic memory. Nine years later she was diagnosed with AD (MMSE 23/30) and treatment with galantamine was started to which later memantine was added. Rapid cognitive decline led to an MMSE score of 11/30 at the time of the PET investigation 2 years later. APParc-2 reported subjective occasional difficulties following conversations.

Demographic data are shown in table 1. Age and level of education for APParc-1–7 are displayed as mean ± SD, and age of APPswe-1 is not shown for confidentiality reasons.

View this table:
Table 1

Demography and neuropsychology data

Standard protocol approvals, registrations, and patient consents.

All subjects provided written informed consent to participate in the study that was conducted according to the Declaration of Helsinki and subsequent revisions and approved by the Regional Human Ethics Committee of Stockholm, and the Isotope Committee of Uppsala University, Sweden.

PET and MRI.

All PET investigations were performed between 2009 and 2011 at Uppsala PET Center, Uppsala, Sweden, on ECAT EXACT HR+ (Siemens/CTI) or Discovery PET/CT (General Electric) scanners. For each PiB emission scan, 24 frames over 60 minutes, and for each FDG emission scan, 21 frames over 45 minutes, were acquired. After reconstruction and realignment of the frames, 40–60 minutes PiB sum images and 30–45 minutes FDG sum images were created and used for subsequent analysis. Patients were required to fast for 4 hours preceding the FDG scan. The mean injected doses for each tracer were PiB = 208 ± 68 MBq and FDG = 229 ± 50 MBq.

All patients underwent a structural T1 MRI scan with a magnetization-prepared rapid gradient echo sequence at 3 T (Siemens Trio scanner) at the Karolinska University Hospital Huddinge, Stockholm, Sweden, except for one scan that was performed on a 3 T Philips scanner at the Umeå University Hospital, Umeå, Sweden.

All subsequent data analyses was performed blindly with respect to genotype or clinical phenotype.

PET image processing and analysis.

The PET scans were coregistered to their corresponding T1 MRI using SPM8 (Functional Imaging Laboratory, Wellcome Department of Imaging Neuroscience, UCL, London, UK). The MRI were then segmented into gray and white matter tissue using SPM.14 From the resultant probabilistic gray matter map, a binary gray matter mask was created. As part of the segmentation algorithm an inverse nonlinear transform parameter file was generated, enabling transformation of data in Montreal Neurological Institute space back into native image space. This was used to transform a simplified digital probabilistic atlas,15 consisting of 29 brain regions, into individual space and multiplied by the corresponding binary gray matter mask resulting in a gray matter specific digital atlas for each participant.

Since earlier neuropathologic studies in subjects with eoFAD have reported amyloid plaques in the cerebellum,16 the pons was chosen as a reference region to create a ratio by dividing the PiB and FDG sum images by the measured activity in the pons.

MRI processing and analysis.

Cortical reconstruction and volumetric segmentation was performed with the Freesurfer image analysis suite (http://surfer.nmr.mgh.harvard.edu).17 This processing includes motion correction, removal of nonbrain tissue, segmentation of the subcortical white matter and deep gray matter structures, tessellation of the gray/white matter boundary, surface deformation to place the gray/white matter and gray matter/CSF borders, parcellation of the cerebral cortex into units based on gyral and sulcal structure, and creation of surface-based data. The method uses both intensity and continuity information from the 3D MRI volumes in segmentation and deformation processes to produce representations of cortical thickness. The maps are created using spatial intensity gradients across tissue classes and are therefore not only reliant on absolute signal intensity. The analysis included measures of bilateral hippocampal volume and bilateral thickness of the entorhinal cortex as these regions are suggested to be most affected in AD.18 Finally, an experienced radiologist evaluated degrees of white matter changes visually.

CSF sampling.

CSF samples were collected by lumbar puncture at the Karolinska University Hospital and the Umeå University Hospital. A volume of 12 mL CSF was collected and stored in polypropylene tubes. CSF samples with more than 500 erythrocytes/μL were excluded. All samples were centrifuged for 10 minutes at 3,000 g and 4°C immediately after collection. The supernatant was aliquoted after careful mixing to avoid gradient effects, and stored at −80°C pending biochemical analysis, without being thawed or refrozen. Levels of Aβ1-42, t-tau, and p-tau were analyzed using the INNO-BIA AlzBio3 assay, as described previously in detail,19 or with ELISA Innotest β-amyloid, hTAU Ag, and Phospho-tau (181P) (Innogenetics, Ghent, Belgium). CSF data were unavailable for 4 HCs and APParc-6.

Cognitive function.

Clinical routine neuropsychological assessment was performed on all participants. Global cognition was assessed by the MMSE and a summary measure including 9 tests tapping verbal (Information, Similarities), visuospatial (Block design, Rey-Osterrieth copy), working memory (Digit Span, Corsi Span), and attention/executive domains (Digit Symbol, Trail Making Test A and B). In addition, episodic memory was assessed by 3 subtests (Rey-Auditory Verbal Learning Test learning and retention, Rey-Osterrieth retention). Raw scores of the neuropsychological test results were transformed into z scores in relation to a large reference group from the Department of Geriatric Medicine, Karolinska University Hospital Huddinge.20

Statistical analysis.

All PET, MRI, and CSF data were converted into z scores (not shown) based on data from the 7 HCs for comparisons at the individual level. The Mann-Whitney U Test was used for group comparisons using absolute, not converted data.

RESULTS

PET examinations.

Sections from all FDG, PiB PET, and MRI scans are shown in figure 1. Figure 2 A furthermore displays PiB retention levels and figure 2B glucose metabolism levels in selected brain regions. For detailed bilateral regional PiB and FDG PET data and statistics, refer to tables e-1 and e-2 on the Neurology® Web site at www.neurology.org, respectively. All 7 APParc family members, mutation carriers as well as noncarriers, presented with PiB scans comparable to the HC scans, reflecting very low retention of PiB in all cortical and subcortical brain regions. Symptomatic APParc-1, clinically diagnosed with AD, and presymptomatic APParc-2 showed marginally higher levels of PiB retention than HCs in the cerebellum, bilateral parahippocampal gyrus, and hippocampus (only APParc-1). However, APParc-1 revealed significantly lower glucose metabolism than HCs in almost all examined brain regions except for the striatum and cerebellum. Carrier APParc-2 showed significantly decreased glucose metabolism in regions typically affected in AD such as the temporal, posterior cingulate, and parahippocampal cortex, as well as the hippocampus. Glucose metabolism in the 5 APParc noncarriers APParc-3–7 was on average comparable to HCs' levels although values varied with age within the group of noncarriers. The group of patients with sAD showed significantly higher PiB retention than the HCs in all regions except for the cerebellum and bilateral hippocampus, and significantly lower glucose metabolism in all typically affected brain regions. EoFAD patient PSEN1-1 revealed PiB retention levels comparable with the patients with sAD except for elevated values in the striatum. Cerebral glucose metabolism was significantly lower than in HCs in almost all examined brain regions. APPswe-1, clinically diagnosed with MCI, also presented with high cortical and subcortical PiB retention, exceeding the patients with sADs' levels particularly in the striatum, the thalamus, and the hippocampus. Cerebral glucose metabolism was comparable with values in HCs. Rotating 3D reconstructions of the PiB PET scans of APParc-1 and -2 and PSEN1-1 are available online (videos 1, 2, and 3).

Figure 1
Figure 1 Individual PET and MRI scans

Transaxial sections of individual MRI (upper row), Pittsburgh compound B (PiB) (middle row), and 18F-fluorodeoxyglucose (FDG) PET (lower row) scans of all participants. Images of patients with sporadic Alzheimer disease (sAD) and healthy controls (HCs) are mean images. The Arctic APP (APParc) mutation carriers APParc-1 and APParc-2 showed very low cortical PiB retention, comparable with the 5 noncarriers APParc 3–7 and HCs. APParc-1 revealed globally decreased glucose metabolism and brain atrophy, and APParc-2 regionally decreased glucose metabolism. MCI = mild cognitive impairment.

Figure 2
Figure 2 Regional Pittsburgh compound B (PiB) and 18F-fluorodeoxyglucose (FDG) PET data

PiB retention (A) and FDG uptake (B) divided by pons ratios in selected regions. Means of left and right hemispheres. Striatum: composite of caudate nucleus and putamen. Sporadic Alzheimer disease (sAD) and healthy controls (HCs): mean ± SD. The Arctic APP (APParc) mutation carriers showed PiB retention comparable to noncarriers and HCs in all examined brain regions while the carriers of the PSEN1 mutations and Swedish APP mutation carriers (APPswe) demonstrated PiB retention patterns similar to the patients with sAD with notably higher levels in the striatum and, for APPswe-1, in hippocampus (A). Glucose metabolism was globally clearly reduced in symptomatic APParc-1; presymptomatic APParc-2 showed reduced glucose metabolism in regions typically affected early in Alzheimer disease (AD) (B).

MRI examinations.

Bilateral hippocampal volume and entorhinal cortical thickness were significantly reduced in APParc-1 compared to HCs, as were these measures in the patients with sAD (table 2). APParc-2 did not show any atrophic changes in these areas. Slight pathologic white matter changes were observed in both APParc mutation carriers. Hippocampal volume and entorhinal cortical thickness of ArcAPP-3–7 were comparable with those in HCs. Hippocampal volume in PSEN1-1 was bilaterally significantly smaller than in HCs but not entorhinal cortical thickness. No signs of white matter pathology were demonstrated. APPswe-1 showed no distinct hippocampal or entorhinal atrophy but substantial white matter changes and clear signs of hemorrhages predominantly in left temporo-occipital and bilateral parietal cortical brain regions.

View this table:
Table 2

MRI data

CSF biomarkers.

APParc-1, APParc-2, the patients with sAD, and PSEN1-1 showed clearly pathologic CSF levels of Aβ1-42, t-tau, and p-tau compared to HCs (figure 3). APParc-3–7 presented with normal CSF findings. APPswe-1 demonstrated deviant CSF levels of Aβ1-42 and p-tau but not t-tau.

Figure 3
Figure 3 CSF data

CSF levels of Aβ1-42 (A), total tau (B), and phosphorylated tau (C). Significantly different from healthy controls (HCs): (a) p < 0.05 (Mann-Whitney U test), (b) z score < −1.645 (α < 0.05), (c) z score > 1.645 (α < 0.05). Both Arctic APP (APParc) mutation carriers APParc-1 and APParc-2 showed pathologically low Aβ1-42, and high total and phosphorylated tau, respectively. AD = Alzheimer disease; APPswe = Swedish APP mutation carrier; MCI = mild cognitive impairment; sAD = sporadic Alzheimer disease.

Cognitive function.

Composite z scores of neuropsychological test results are presented in table 1. APParc-1 had test z scores below normal levels in all tested cognitive domains while APParc-2 only showed a trend toward isolated impaired episodic memory functions. APParc-3–7 performed within normal range. The patients with sAD performed generally better than APParc-1 and PSEN1-1 but had test z scores lower than −1.645 in all cognitive domains. PSEN1-1 also scored below normal levels throughout all neuropsychological tests. APPswe-1 showed neuropsychological test results in the lower end of the normal range.

DISCUSSION

Amyloid imaging with PiB PET has proven qualities as an early potential diagnostic marker for AD and a prognostic marker for the conversion to AD.21,–,23 Typically, patients with sAD display increased PiB retention in most cortical areas, such as frontal, parietal, temporal, and occipital cortex, and the striatum, compared to healthy controls.3,24 PiB retention patterns in eoFAD deviate slightly from that. Studies in presymptomatic and symptomatic PSEN1 mutation carriers showed significantly elevated levels eminently in the striatum,4,5,11 while PiB retention in other brain regions varied both with the time from the expected age at disease onset and with different kinds of PSEN1 mutations.6

Few studies have examined APP mutation carriers with PiB PET. One presymptomatic carrier of an APP V717I mutation was examined as part of one of the above-mentioned studies, showing particularly increased striatal PiB retention with globally higher levels than cognitively matched PSEN1 mutation carriers.5 Another study in members of Finnish kindred harboring an APP locus duplication also revealed the eminent striatal PiB retention accompanied by high levels in the posterior cingulate.7

In the current study we observed that carriers of the Arctic APP mutation did not demonstrate fibrillar amyloid pathology as visualized by in vivo PiB PET imaging in contrast to what is known about sAD and from the previous reports on eoFAD mutation carriers.2,4,5 In fact, PiB retention was comparably low in APParc mutation carriers, the mutation noncarriers, and the HCs. This was despite otherwise clearly impaired glucose metabolism, MRI and cognitive measures, and decreased levels of CSF Aβ1-42 and increased levels of CSF t-tau and p-tau in mutation carrier APParc-1 and pathologic CSF and FDG measures in carrier APParc-2. Both the patient with AD carrying a PSEN1 mutation and the patient with MCI with an APPswe mutation showed, in accordance with the above-mentioned previous studies, significantly higher PiB retention in all examined brain regions compared with the HCs, with particularly high levels in the striatum.

The absence of cortical PiB retention in the APParc mutation carriers might be explained by the lack of β-pleated sheet fibrils of Aβ. A postmortem brain examination of another member of the APParc family who had shown a clinical and neuropsychological picture compatible with AD before death9 and a re-examination of the same brain tissue for the current study revealed ring-formed Aβ plaques devoid of congophilic Aβ cores, indicating lack of β-pleated sheet formation (figure e-1). A recent detailed postmortem study of plaque pathology associated with the APParc mutation reported the presence of C- and N-terminally truncated forms of Aβ that were specific for the “Arctic” plaques.25 However, the presence of β-pleated sheet fibrils of Aβ cannot be excluded solely due to the lack of in vivo PiB retention. PiB binding has been shown to be associated with certain forms of Aβ, such as AβN3-pyroglutamate,26 or high-affinity binding sites,27 which might not be present in the APParc mutation.

Another aberrant form of Aβ plaque has been found in carriers of different PSEN1 mutations that present with variant AD (varAD) with spastic paraparesis.28 These so-called cotton wool plaques are immunoreactive for Aβ but are weakly neuritic and show no distinct core. A PiB PET study in varAD showed high striatal and cortical PiB retention. However, besides cotton-wool plaques, diffuse plaque pathology was abundant in these regions.29

Similar to our results, very low levels of PiB retention were found in a Japanese pedigree with an amino acid deletion (p.E693Δ) in the same amino acid position as the APParc mutation. This deletion has been suggested to cause a recessively inherited AD type dementia by enhanced formation of synaptotoxic Aβ oligomers.10 The levels of PiB retention were thereby markedly lower than in patients with sAD.30 The Arctic APP mutation leads to a replacement of the glutamic acid at codon 22 in the Aβ peptide by glycine, which has been shown to promote Aβ protofibril formation at high levels.8

Increasing evidence supports the idea that soluble Aβ oligomers, also termed Aβ -derived diffusible ligands, rather than Aβ fibrils, might be important molecular pathogens that trigger synaptic dysfunction and memory deterioration observed in AD.31 A differing pattern of oligomer conformations has recently been demonstrated between early-onset AD and late-onset AD in autopsy brain tissue.32 A significant negative correlation was also observed between levels of different oligomers and choline acetyltransferase activity and the number of nicotinic acetylcholine receptors, respectively.32 This supports the assumption that synaptic loss and the degree of cognitive impairment show a strong correlation with levels of soluble nonfibrillar Aβ in AD brains.33,–,35

High immunoreactivity of Aβx-42 was observed postmortem in the previously examined APParc case (figure e-1), which complies with the finding of low CSF levels of Aβ1-42 in the presently examined cases. Although low levels of CSF Aβ1-42 correlate with high levels of fibrillar Aβ in most previous PiB PET studies of sporadic AD,36,37 this was not the case here. Similarly, a recent study found low CSF levels of Aβ1-42 but negative PiB PET imaging in an autopsy-confirmed sAD case, suggesting that certain levels of fibrillar Aβ must be reached to be detected by PiB PET.38

Interestingly, severe cerebral amyloid angiopathy (CAA) was found at autopsy in the above-mentioned APParc case (figure e-1). PiB PET can detect CAA,39,40 which was not the case in the mutation carriers examined in the present study. However, the presence of CAA stained with congo red in 1 case examined postmortem does not necessarily imply that the subjects examined here with PiB PET have developed the same pathology. If CAA pathology was abundant in those subjects, it might not have reached levels detectable by PiB PET.

The APParc mutation differs from most other so far examined eoFAD mutations as well as the sporadic form of AD in that low PiB retention was measured in the presence of AD-typical pathologic changes in CSF biomarkers, cerebral glucose metabolism, and medial temporal lobe atrophy as well as severe cognitive impairment. Our findings suggest that the intra-Aβ APParc mutation alters Aβ properties in a way that precludes in vivo PiB retention in the presence of pathologic other biomarkers typical for AD.

AUTHOR CONTRIBUTIONS

Dr. Schöll participated in drafting/revising the manuscript, study concept or design, analysis or interpretation of data, acquisition of data, and statistical analysis. Dr. Wall participated in drafting/revising the manuscript and acquisition of data. Dr. Thordardottir participated in drafting/revising the manuscript and acquisition of data. D. Ferreira participated in drafting/revising the manuscript and analysis or interpretation of data. Dr. Bogdanovic participated in drafting/revising the manuscript, acquisition of data, and analysis or interpretation of data. Dr. Långström participated in drafting/revising the manuscript. Dr. Graff participated in drafting/revising the manuscript, study supervision or coordination, analysis or interpretation of data, and obtaining funding. Dr. Nordberg participated in drafting/revising the manuscript, study concept or design, analysis or interpretation of data, study supervision or coordination, and obtaining funding.

DISCLOSURE

M. Schöll received research support from the Gun and Bertil Stohne's Foundation, the Old Servants Foundation, and the Sigurd and Elsa Goljes Foundation. A. Wall, S. Thordardottir, and D. Ferreira report no disclosures. N. Bogdanovic is employed by Pfizer Inc. B. Långström and O. Almkvist report no disclosures. C. Graff has received/receives research support from the Swedish Research Council (project 21738), Swedish Brain Power, the Marianne and Marcus Wallenberg Foundation, the King Gustaf V and Queen Victoria's Foundation of Freemasons, the Old Servants Foundation, the Gun and Bertil Stohne's Foundation, and the Swedish Alzheimer Foundation and the Regional Agreement on Medical Training and Clinical Research (ALF) between Stockholm County Council and the Karolinska Institutet and received honoraria for a lecture from Lundbeck AB. A. Nordberg has received/receives research support from the Knut and Alice Wallenberg foundation, the Swedish Research Council (project 05817), the Strategic Research Program in Neuroscience at Karolinska Institutet, Swedish Brain Power, the Swedish Brain Foundation, the Swedish Alzheimer Foundation, the Gun and Bertil Stohne's Foundation, Novartis, GE Healthcare, Johnson & Johnson, GSK, Bayer, and Schering, served as a scientific board member at Lundbeck AB, Pfizer Sweden, Elan, Baxter, and GE Healthcare, and received honoraria for lectures from Novartis and Pfizer. Go to Neurology.org for full disclosures.

ACKNOWLEDGMENT

The authors thank all participants for making this study possible; Dr. Rasmuson and Dr. Byström (Umeå University Hospital) for clinical assessment and acquisition of CSF of one family member; Dr. Stephen Carter and Dr. Gabriela Spulberg (Karolinska Institutet) and the staff at the Umeå Center for Functional Brain imaging (Umeå University) for their help with PET data analysis, MRI acquisition, and data processing; Dr. Maria Kristoffersen Wiberg for evaluating the MR scans; Dr. Niels Andreasen and Professor Maria Eriksdotter-Jönhagen for clinical examinations of eoFAD family members; and Dr. Anne Kinhult Ståhlbom and Mrs. Agneta Lindahl for administrative work. This study made use of the SMILE medical imaging laboratory at Karolinska University Hospital, Stockholm, Sweden.

Footnotes

  • Study funding: Supported by grants from the Knut and Alice Wallenberg Foundation, the Strategic Research Program in Neuroscience at Karolinska Institutet, the Swedish Research Council (project 05817 and 21738), the Swedish Brain Power, the Marianne and Marcus Wallenberg Foundation, the King Gustaf V and Queen Victoria's Foundation of Freemasons, the Old Servants Foundation, the Gun and Bertil Stohne's Foundation, the Brain Foundation, the Swedish Alzheimer Foundation, and the Regional Agreement on Medical Training and Clinical Research (ALF) between Stockholm County Council and the Karolinska Institutet.

  • Editorial, page 206

  • Supplemental data at www.neurology.org

  • Received September 2, 2011.
  • Accepted December 1, 2011.

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