Clinical and biomarker investigation of a patient with a novel presenilin-1 mutation (A431V) in the mild cognitive impairment stage of Alzheimer’s Disease

Matsushita, Satoru; Arai, Hiroyuki; Okamura, Nobuyuki; Ohmori, Tomohiro; Takasugi, Keiichi; Matsui, Toshifumi; Maruyama, Masahiro; Iwatsubo, Takeshi; Higuchi, Susumu

doi:10.1016/s0006-3223(02)01386-0

Cited by 20 publications

(11 citation statements)

References 14 publications

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“…In both symptomatic and presymptomatic APP , PSEN1 and PSEN2 mutation carriers, the majority of the studies found a decrease in Aβ 42 and an increase in both t-tau and p-tau levels when compared with healthy control individuals, consistent with a typical AD profile [7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26] (table 1). In some cases, 1 or more markers were found to be unchanged compared to controls [27,28,29,30].…”

Section: Resultsmentioning

confidence: 99%

Cerebrospinal Fluid Biomarkers in Familial Forms of Alzheimer's Disease and Frontotemporal Dementia

Rostgaard

Waldemar

Nielsen

et al. 2015

Dement Geriatr Cogn Disord

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As dementia is a fast-growing health care problem, it is becoming an increasingly urgent need to provide an early diagnosis in order to offer patients the best medical treatment and care. Validated biomarkers which reflect the pathology and disease progression are essential for diagnosis and are important when developing new therapies. Today, the core protein biomarkers amyloid-β₄₂, total tau and phosphorylated tau in the cerebrospinal fluid (CSF) are used to diagnose Alzheimer's disease (AD), because these biomarkers have shown to reflect the underlying amyloid and tau pathology. However, the biomarkers have proved insufficient predictors of dementias with a different pathology, e.g. frontotemporal dementia (FTD); furthermore, the biomarkers are not useful for early AD diagnosis. Familial dementias with a known disease-causing mutation can be extremely valuable to study; yet the biomarker profiles in patients with familial dementias are not clear. This review summarizes CSF biomarker findings from studies on symptomatic and presymptomatic individuals carrying a mutation in one of the genes known to cause early-onset familial AD or FTD. In conclusion, the biomarker profile of inherited AD is quite similar between carriers of different mutations as well as similar to the profile found in sporadic AD, whereas familial FTD does not seem to have a clear biomarker profile. Hence, new biomarkers are needed for FTD.

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Section: Resultsmentioning

confidence: 99%

Cerebrospinal Fluid Biomarkers in Familial Forms of Alzheimer's Disease and Frontotemporal Dementia

Rostgaard

Waldemar

Nielsen

et al. 2015

Dement Geriatr Cogn Disord

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“…Full sagittal and transaxial slices are included at the bottom to show the marked striatal focality in the PS1 mutation carrier compared with the extensive cortical involvement in the sporadic AD subject. (Kennedy et al, 1995;Rossor et al, 1996;Wahlund et al, 1999;Matsushita et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Amyloid Deposition Begins in the Striatum of Presenilin-1 Mutation Carriers from Two Unrelated Pedigrees

Klunk¹,

Price²,

Mathis³

et al. 2007

Journal of Neuroscience

374

333

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The amyloid cascade hypothesis suggests that the aggregation and deposition of amyloid-␤ protein is an initiating event in Alzheimer's disease (AD). Using amyloid imaging technology, such as the positron emission tomography (PET) agent Pittsburgh compound-B (PiB), it is possible to explore the natural history of preclinical amyloid deposition in people at high risk for AD. With this goal in mind, asymptomatic (n ϭ 5) and symptomatic (n ϭ 5) carriers of presenilin-1 (PS1) mutations (C410Y or A426P) that lead to early-onset AD and noncarrier controls from both kindreds (n ϭ 2) were studied with PiB-PET imaging and compared with sporadic AD subjects (n ϭ 12) and controls from the general population (n ϭ 18). We found intense and focal PiB retention in the striatum of all 10 PS1 mutation carriers studied (ages 35-49 years). In most PS1 mutation carriers, there also were increases in PiB retention compared with controls in cortical brain areas, but these increases were not as great as those observed in sporadic AD subjects. The two PS1 mutation carriers with a clinical diagnosis of early-onset AD did not show the typical regional pattern of PiB retention observed in sporadic AD. Postmortem evaluation of tissue from two parents of PS1C410Y subjects in this study confirmed extensive striatal amyloid deposition, along with typical cortical deposition. The early, focal striatal amyloid deposition observed in these PS1 mutation carriers is often is not associated with clinical symptoms.

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“…In addition, a good correlation between neuropathological features and CSF biomarkers has been established [8] . In FAD, symptomatic mutation carriers (SMC) present the typical CSF AD signature [9] . However, there are very few studies analyzing CSF biomarkers in asymptomatic mutation carriers (AMC), and they are not completely concordant [10][11][12] .…”

Section: I S E a S E Smentioning

confidence: 99%

Cerebrospinal Fluid Biomarkers in Alzheimer’s Disease Families with <i>PSEN1</i> Mutations

et al. 2011

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Background/Aims: Familial Alzheimer’s disease allows studies in the preclinical phases of the disease. We studied cerebrospinal fluid (CSF) amyloid β1–42 (Aβ1–42), total tau (t-tau) and phospho-tau181 (p-tau) levels in PSEN1 families and correlated the results with the genetic status, age and clinical stage. Methods: Thirteen subjects from 3 families with 2 PSEN1 mutations (L286P, M139T) were recruited from the genetic counseling program for familial dementia. Eight mutation carriers (MC) and 5 noncarriers (NC) underwent clinical and cognitive evaluations. CSF concentrations were obtained by ELISA methodology. Results: Symptomatic MC presented reduced CSF Aβ1–42 (mean = 175 pg/ml) and elevated t-tau (mean = 635 pg/ml) compared to controls, but not asymptomatic MC (mean = 684 and 255 pg/ml, respectively) at a median of –12.8 years from the predicted disease onset (adjusted age). Aβ1–42 levels presented an inverse correlation with the adjusted age (r = –1, p < 0. 01) in asymptomatic MC, but not in symptomatic MC or NC. t-tau presented a trend towards a negative correlation with Mini Mental State Examination (MMSE; r = –0.949, p = 0.051) in symptomatic MC but not in asymptomatic MC. In the whole group of MC, t-tau presented a significant positive correlation with Clinical Dementia Rating sum of boxes (r = 0.913, p = 0.002) and a negative correlation with MMSE (r = –0.946, p < 0.001). Conclusions: CSF Aβ1–42 levels correlate with time to disease onset in asymptomatic MC to reach floor levels when symptoms appear. CSF t-tau levels become elevated in symptomatic MC and correlate with clinical severity. These findings may suggest that the changes in Aβ1–42 precede t-tau elevation in PSEN1 MC.

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Clinical and biomarker investigation of a patient with a novel presenilin-1 mutation (A431V) in the mild cognitive impairment stage of Alzheimer’s Disease

Cited by 20 publications

References 14 publications

Cerebrospinal Fluid Biomarkers in Familial Forms of Alzheimer's Disease and Frontotemporal Dementia

Cerebrospinal Fluid Biomarkers in Familial Forms of Alzheimer's Disease and Frontotemporal Dementia

Amyloid Deposition Begins in the Striatum of Presenilin-1 Mutation Carriers from Two Unrelated Pedigrees

Cerebrospinal Fluid Biomarkers in Alzheimer’s Disease Families with <i>PSEN1</i> Mutations

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