Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: A case-control study
Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USAThe Lancet Neurology (Impact Factor: 21.9). 11/2012; 11(12). DOI: 10.1016/S1474-4422(12)70228-4
BACKGROUND: We have previously characterised functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's disease. To gain further knowledge on the preclinical phase of Alzheimer's disease, we sought to characterise structural and functional MRI, CSF, and plasma biomarkers in a cohort of young adults carrying a high-penetrance autosomal dominant mutation that causes early-onset Alzheimer's disease. METHODS: Between January and August, 2010, 18-26-year-old presenilin 1 (PSEN1) E280A mutation carriers and non-carriers from the Colombian Alzheimer's Prevention Initiative Registry in Medellín Antioquia, Colombia, had structural MRI, functional MRI during associative memory encoding and novel viewing and control tasks, and cognitive assessments. Consenting participants also had lumbar punctures and venepunctures. Outcome measures were task-dependent hippocampal or parahippocampal activations and precuneus or posterior cingulate deactivations, regional grey matter reductions, CSF Aβ(1-42), total tau and phospho-tau(181) concentrations, and plasma Aβ(1-42) concentrations and Aβ(1-42):Aβ(1-40) ratios. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to Alzheimer's disease. Cognitive and fluid biomarkers were compared using Mann-Whitney tests. FINDINGS: 44 participants were included: 20 PSEN1 E280A mutation carriers and 24 non-carriers. The carrier and non-carrier groups did not differ significantly in their dementia ratings, neuropsychological test scores, or proportion of apolipoprotein E (APOE) ɛ4 carriers. Compared with non-carriers, carriers had greater right hippocampal and parahippocampal activation (p=0·001 and p<0·014, respectively, after correction for multiple comparisons), less precuneus and posterior cingulate deactivation (all p<0·010 after correction), and less grey matter in several parietal regions (all p<0·002 uncorrected and corrected p=0·009 in the right parietal search region). In the 20 participants (ten PSEN1 E280A mutation carriers and ten non-carriers) who had lumbar punctures and venepunctures, mutation carriers had higher CSF Aβ(1-42) concentrations (p=0·008) and plasma Aβ(1-42) concentrations (p=0·01) than non-carriers. INTERPRETATION: Young adults at genetic risk for autosomal dominant Alzheimer's disease have functional and structural MRI findings and CSF and plasma biomarker findings consistent with Aβ(1-42) overproduction. Although the extent to which the underlying brain changes are either neurodegenerative or developmental remain to be determined, this study shows the earliest known biomarker changes in cognitively normal people at genetic risk for autosomal dominant Alzheimer's disease. FUNDING: Banner Alzheimer's Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Boston University Department of Psychology, Colciencias, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the State of Arizona.
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- "Whole brain analyses also demonstrated that PSEN1 mutation carriers had greater activation in the posterior parietal cortex during successful encoding, compared to non-carriers. In our previous work , we reported a similar finding with a younger cohort. This increased parietal activation in regions known to be less active during cognitive tasks may suggest a failure to deactivate the default network regions, which is likely related to the accumulation of brain amyloid. "
ABSTRACT: Background: Brain regions critical to episodic memory are altered during the preclinical stages of Alzheimer's disease (AD). However, reliable means of identifying cognitively-normal individuals at higher risk to develop AD have not been established. Objective: To examine whether functional MRI can detect early functional changes associated with scene encoding in a group of presymptomatic presenilin-1 (PSEN1) E280A mutation carriers. Methods: Participants were 39 young, cognitively-normal individuals from an autosomal dominant early-onset AD kindred, located in Antioquia, Colombia. Participants performed a functional MRI scene encoding task and a post-scan subsequent memory test. Results: PSEN1 mutation carriers exhibited hyperactivation within medial temporal lobe regions (hippocampus, parahippocampal formation) during successful scene encoding compared to age-matched non-carriers. Conclusion: Hyperactivation in medial temporal lobe regions during scene encoding is seen in individuals genetically-determined to develop AD years before their clinical onset. Our findings will guide future research with the ultimate goal of using functional neuroimaging in the early detection of preclinical AD.
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- "The discrepancies in the results can be due to small sample sizes and differences in the age of included subjects between studies. The studies by Fortea et al.  and Reiman et al.  mentioned above, respectively showing increased cortical thickness in MC and increased CSF A␤ 42 levels in MC, might reflect pathological changes appearing very early in the preclinical stage and therefore do not need to be in disagreement with results from other groups. Then there is a possibility that differences in the sequence of pathological events in different FAD mutations explain some of the variable observations. "
ABSTRACT: Objective: To compare cerebrospinal fluid (CSF) biomarkers and brain structure in preclinical mutation carriers (MC) and non-carriers (NC) from families with familial Alzheimer disease (FAD). Methods: The study included members from four Swedish families at risk for carrying an APPswe, APParc, PSEN1 H163Y or PSEN1 I143T mutation. Magnetic resonance imaging (MRI) scans were obtained from 13 MC and 20 NC and analyzed using vertex-based analyses of cortical thickness and volume. CSF was collected from 10 MC and 12 NC and analyzed for Aβ42, tau-protein and phospho-tau. Results: The MC had significantly lower levels of CSF Aβ42 and higher levels tau-protein and phospho-tau than the NC. There was a trend showing a decrease in Aβ42 15 – 20 years before expected onset of clinical symptoms, while a trend of increasing tau-protein and phospho-tau was observed closer to expected onset. The MC had decreased volume on MRI in the left precuneus, superior temporal gyrus and fusiform gyrus. Conclusions: Aberrant biomarker levels in CSF as well as regional brain atrophy are present in preclinical FAD, several years before the expected onset of clinical symptoms.Journal of Alzheimer's disease: JAD 08/2014; In-press. · 4.15 Impact Factor
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- "DS patients have decreased levels of CSF Ab1-42 already in mid life, likely reflecting sequestration of Ab monomers into plaques (Tamaoka et al. 1999; Tapiola et al. 2001). This is consistent with biomarker results from patients with other types of autosomal dominant early onset AD where the disease is believed to be caused by Ab overproduction or an increase in the Ab1-42/ Ab1-40 ratio (Karran et al. 2011; Reiman et al. 2012). However, besides the altered CSF Ab42 levels, little is known about APP and Ab metabolism in DS. "
ABSTRACT: Down's syndrome (DS) patients develop early Alzheimer's disease pathology with abundant cortical amyloid plaques, likely due to overproduction of the amyloid precursor protein (APP), which subsequently leads to amyloid β (Aβ) aggregation. This is reflected in cerebrospinal fluid (CSF) levels of the 42-amino acid long Aβ peptide (Aβ1-42), which are increased in young DS patients and decreases with age. However, it is unclear whether DS also affects other aspects of Aβ metabolism, including production of shorter C- and N-terminal truncated Aβ peptides, and production of peptides from the amyloid precursor-like protein 1 (APLP1), which is related to APP, and cleaved by the same enzymatic processing machinery. APLP1-derived peptides may be surrogate markers for Aβ1-42 production in the brain. Here, we used hybrid immunoaffinity-mass spectrometry and enzyme-linked immunosorbent assays to monitor several Aβ and APLP1 peptides in CSF from DS patients (n = 12) and healthy controls (n = 20). CSF levels of Aβ1-42 and three endogenous peptides derived from APLP1 (APL1β25, APL1β27 and APL1β28) were decreased in DS compared with controls, while a specific Aβ peptide, Aβ1-28, was increased in a majority of the DS individuals. This study indicates that DS causes previously unknown specific alterations of APP and APLP1 metabolism.Neuromolecular medicine 04/2014; 16(2). DOI:10.1007/s12017-014-8302-1 · 3.68 Impact Factor
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