Publications by authors named "Martin Cook"

200 Publications

Higher CSF sTREM2 attenuates ApoE4-related risk for cognitive decline and neurodegeneration.

Mol Neurodegener 2020 10 8;15(1):57. Epub 2020 Oct 8.

Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig Maximilian University (LMU), Munich, Germany.

Background: The Apolipoprotein E ε4 allele (i.e. ApoE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). TREM2 (i.e. Triggering receptor expressed on myeloid cells 2) is a microglial transmembrane protein brain that plays a central role in microglia activation in response to AD brain pathologies. Whether higher TREM2-related microglia activity modulates the risk to develop clinical AD is an open question. Thus, the aim of the current study was to assess whether higher sTREM2 attenuates the effects of ApoE4-effects on future cognitive decline and neurodegeneration.

Methods: We included 708 subjects ranging from cognitively normal (CN, n = 221) to mild cognitive impairment (MCI, n = 414) and AD dementia (n = 73) from the Alzheimer's disease Neuroimaging Initiative. We used linear regression to test the interaction between ApoE4-carriage by CSF-assessed sTREM2 levels as a predictor of longitudinally assessed cognitive decline and MRI-assessed changes in hippocampal volume changes (mean follow-up of 4 years, range of 1.7-7 years).

Results: Across the entire sample, we found that higher CSF sTREM2 at baseline was associated with attenuated effects of ApoE4-carriage (i.e. sTREM2 x ApoE4 interaction) on longitudinal global cognitive (p = 0.001, Cohen's f = 0.137) and memory decline (p = 0.006, Cohen's f = 0.104) as well as longitudinally assessed hippocampal atrophy (p = 0.046, Cohen's f = 0.089), independent of CSF markers of primary AD pathology (i.e. Aβ, p-tau). While overall effects of sTREM2 were small, exploratory subanalyses stratified by diagnostic groups showed that beneficial effects of sTREM2 were pronounced in the MCI group.

Conclusion: Our results suggest that a higher CSF sTREM2 levels are associated with attenuated ApoE4-related risk for future cognitive decline and AD-typical neurodegeneration. These findings provide further evidence that TREM2 may be protective against the development of AD.
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http://dx.doi.org/10.1186/s13024-020-00407-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545547PMC
October 2020

SOX10 is as specific as S100 protein in detecting metastases of melanoma in lymph nodes and is recommended for sentinel lymph node assessment.

Eur J Cancer 2020 09 8;137:175-182. Epub 2020 Aug 8.

Section of Pathological Anatomy, Department of Health Sciences, University of Florence, Florence, Italy.

Background: Sentinel lymph node (SLN) biopsy remains crucial for melanoma staging. The European Organisation for Research and Treatment of Cancer Melanoma Group recommends performing immunohistochemical stainings for reproducible identification of melanoma metastases. S100 protein (pS100) is a commonly used melanocytic antigen because of its high sensitivity in spite of relatively low specificity. SRY-related HMG-box 10 protein (SOX10) is a transcription factor characterising neural crest-derived cells. It is uniformly expressed mostly in the nuclei of melanocytes, neural, and myoepithelial cells. Pathologists sometimes prefer SOX10 as a melanoma marker, but it has not yet been investigated on a large-scale to confirm that it is reliable and recommendable for routine SLN evaluation.

Methods: Four hundred one treatment-naïve lymph node (LN) metastatic melanomas were included in high-density tissue microarrays and were assessed for the presence of SOX10 and pS100 by immunohistochemistry. The slides were digitalised, shared and evaluated by a panel of experienced melanoma pathologists.

Results: The vast majority of melanomas were double-positive for pS100 and SOX10 (93.2%); a small percentage of the cases (3.9%) were double-negative melanomas. Discordance between the two markers was observed: 1.9% pS100(-)/SOX10(+) and 0.75% pS100(+)/SOX10(-). SOX10 was not expressed by immune cell types in the LN, resulting in a less controversial interpretation of the staining.

Conclusions: SOX10 is as equally specific as pS100 for the detection of melanoma metastases in LNs. The interpretation of SOX10 staining is highly reproducible among different centres and different pathologists because of the absence of staining of immune cells.
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http://dx.doi.org/10.1016/j.ejca.2020.06.037DOI Listing
September 2020

Neuropathologic features associated with basal forebrain atrophy in Alzheimer disease.

Neurology 2020 09 6;95(10):e1301-e1311. Epub 2020 Jul 6.

From the German Center for Neurodegenerative Diseases (DZNE) (S.J.T., M.J.G.); Department of Psychosomatic Medicine (S.J.T., H.-C.F.), University Medicine Rostock, Germany; and Instituto de Biomedicina de Sevilla (IBiS) (M.J.G.), Unidad de Trastornos del Movimiento, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Spain.

Objective: To study the neuropathologic correlates of cholinergic basal forebrain (BF) atrophy as determined using antemortem MRI in the Alzheimer disease (AD) spectrum.

Methods: We determined associations between BF volume from antemortem MRI brain scans and postmortem assessment of neuropathologic features, including neuritic plaques, neurofibrillary tangles (NFTs), Lewy body (LB) pathology, and TDP-43, in 64 cases of the Alzheimer's Disease Neuroimaging Initiative cohort. For comparison, we assessed neuropathologic features associated with hippocampal and parahippocampal gyrus atrophy. In addition to region of interest-based analysis, we determined the association of neuropathologic features with whole brain gray matter volume using regionally unbiased voxel-based volumetry.

Results: BF atrophy was associated with Thal amyloid phases (95% confidence interval [CI] -0.49 to -0.01, = 0.049) and presence of LB pathology (95% CI -0.54 to -0.06, = 0.015), as well as with the degree of LB pathology within the nucleus basalis Meynert (95% CI -0.54 to -0.07, = 0.025). These effects were no longer significant after false discovery rate (FDR) correction. Hippocampal atrophy was significantly associated with the presence of TDP-43 pathology (95% CI -0.61 to -0.17, = 0.003; surviving FDR correction), in addition to dentate gyrus NFT load (95% CI -0.49 to -0.01, = 0.044; uncorrected). Voxel-based analysis confirmed spatially restricted effects of Thal phases and presence of LB pathology on BF volume.

Conclusions: These findings indicate that neuropathologic correlates of regional atrophy differ substantially between different brain regions that are typically involved in AD-related neurodegeneration, including different susceptibilities to common comorbid pathologies.
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http://dx.doi.org/10.1212/WNL.0000000000010192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538215PMC
September 2020

Stroma remodeling and reduced cell division define durable response to PD-1 blockade in melanoma.

Nat Commun 2020 02 12;11(1):853. Epub 2020 Feb 12.

Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Manchester, UK.

Although immune checkpoint inhibitors (ICIs) have achieved unprecedented results in melanoma, the biological features of the durable responses initiated by these drugs remain unknown. Here we show the genetic and phenotypic changes induced by treatment with programmed cell death-1 (PD-1) blockade in a genetically engineered mouse model of melanoma driven by oncogenic BRAF. In this controlled system anti-PD-1 treatment yields responses in ~35% of the tumors, and prolongs survival in ~27% of the animals. We identify increased stroma remodeling and reduced expression of proliferation markers as features associated with prolonged response. These traits are corroborated in two independent early on-treatment anti-PD-1 melanoma patient cohorts. These insights into the biological responses of tumors to ICI provide a strategy for identification of durable response early during the course of treatment and could improve patient stratification for checkpoint inhibitory drugs.
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http://dx.doi.org/10.1038/s41467-020-14632-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015935PMC
February 2020

A Novel Joint Brain Network Analysis Using Longitudinal Alzheimer's Disease Data.

Sci Rep 2019 12 20;9(1):19589. Epub 2019 Dec 20.

Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Ga, 30322, USA.

There is well-documented evidence of brain network differences between individuals with Alzheimer's disease (AD) and healthy controls (HC). To date, imaging studies investigating brain networks in these populations have typically been cross-sectional, and the reproducibility of such findings is somewhat unclear. In a novel study, we use the longitudinal ADNI data on the whole brain to jointly compute the brain network at baseline and one-year using a state of the art approach that pools information across both time points to yield distinct visit-specific networks for the AD and HC cohorts, resulting in more accurate inferences. We perform a multiscale comparison of the AD and HC networks in terms of global network metrics as well as at the more granular level of resting state networks defined under a whole brain parcellation. Our analysis illustrates a decrease in small-worldedness in the AD group at both the time points and also identifies more local network features and hub nodes that are disrupted due to the progression of AD. We also obtain high reproducibility of the HC network across visits. On the other hand, a separate estimation of the networks at each visit using standard graphical approaches reveals fewer meaningful differences and lower reproducibility.
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http://dx.doi.org/10.1038/s41598-019-55818-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925181PMC
December 2019

Exercise Training in Amnestic Mild Cognitive Impairment: A One-Year Randomized Controlled Trial.

J Alzheimers Dis 2019 ;71(2):421-433

Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas, Dallas, TX, USA.

Background: The current evidence is inconclusive to support the benefits of aerobic exercise training (AET) for preventing neurocognitive decline in patients with amnestic mild cognitive impairment (aMCI).

Objective: To examine the effect of a progressive, moderate-to-high intensity AET program on memory and executive function, brain volume, and cortical amyloid-β (Aβ) plaque deposition in aMCI patients.

Methods: This is a proof-of-concept trial that randomized 70 aMCI patients to 12 months of AET or stretching and toning (SAT, active control) interventions. Primary neuropsychological outcomes were assessed by using the California Verbal Learning Test-second edition (CVLT-II) and the Delis-Kaplan Executive Function System (D-KEFS). Secondary outcomes were the global and hippocampal brain volumes and the mean cortical and precuneus Aβ deposition.

Results: Baseline cognitive scores were similar between the groups. Memory and executive function performance improved over time but did not differ between the AET and SAT groups. Brain volume decreased and precuneus Aβ plaque deposition increased over time but did not differ between the groups. Cardiorespiratory fitness was significantly improved in the AET compared with SAT group. In amyloid positive patients, AET was associated with reduced hippocampal atrophy when compared with the SAT group.

Conclusion: The AET and SAT groups both showed evidence of slightly improved neuropsychological scores in previously sedentary aMCI patients. However, these interventions did not prevent brain atrophy or increases in cortical Aβ deposition over 12 months. In amyloid positive patients, AET reduced hippocampal atrophy when compared with the SAT group.
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http://dx.doi.org/10.3233/JAD-181175DOI Listing
November 2020

Non-coding variability at the APOE locus contributes to the Alzheimer's risk.

Nat Commun 2019 07 25;10(1):3310. Epub 2019 Jul 25.

Division of Life Science, State Key Laboratory of Molecular Neuroscience and Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.

Alzheimer's disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.
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http://dx.doi.org/10.1038/s41467-019-10945-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658518PMC
July 2019

An updated European Organisation for Research and Treatment of Cancer (EORTC) protocol for pathological evaluation of sentinel lymph nodes for melanoma.

Eur J Cancer 2019 06 17;114:1-7. Epub 2019 Apr 17.

Department of Surgical Oncology, Netherlands Cancer Institute Antoni van Leeuwenhoek, Amsterdam, the Netherlands.

The sentinel lymph node (SLN) biopsy is a highly accurate staging procedure and the most important prognostic factor in melanoma patients. The European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group aimed to design an updated evolved SLN protocol for the histopathological workup and reporting. We herein recommend extending the distance between steps according to the short axis dimension of the lymph node and optimise both conventional sectioning and staining procedures including immunohistochemistry. We also provide guidance on the description of the spatial localisation of melanoma deposits in a SLN. The histopathological features to be reported include the following: presence or absence of the metastasis, the intranodal location of the metastasis (subcapsular, parenchymal, combined, extensive confluent and extensive multifocal), the number of the metastatic deposits (1, 2-5, 6-10, 11-20 and >20), the maximum dimension of the largest metastasis (indicating its site) and the presence of extracapsular extension and of naevus cells. This updated EORTC protocol is expected to clarify and simplify the existing procedures, ensuring a reasonable workload for the laboratory and for the pathologists resulting in cost saving with no loss, and possible increase, in accuracy.
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http://dx.doi.org/10.1016/j.ejca.2019.03.010DOI Listing
June 2019

The BIN1 rs744373 SNP is associated with increased tau-PET levels and impaired memory.

Nat Commun 2019 04 16;10(1):1766. Epub 2019 Apr 16.

Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Feodor-Lynen Straße 17, 81377, Munich, Germany.

The single nucleotide polymorphism (SNP) rs744373 in the bridging integrator-1 gene (BIN1) is a risk factor for Alzheimer's disease (AD). In the brain, BIN1 is involved in endocytosis and sustaining cytoskeleton integrity. Post-mortem and in vitro studies suggest that BIN1-associated AD risk is mediated by increased tau pathology but whether rs744373 is associated with increased tau pathology in vivo is unknown. Here we find in 89 older individuals without dementia, that BIN1 rs744373 risk-allele carriers show higher AV1451 tau-PET across brain regions corresponding to Braak stages II-VI. In contrast, the BIN1 rs744373 SNP was not associated with AV45 amyloid-PET uptake. Furthermore, the rs744373 risk-allele was associated with worse memory performance, mediated by increased global tau levels. Together, our findings suggest that the BIN1 rs744373 SNP is associated with increased tau but not beta-amyloid pathology, suggesting that alterations in BIN1 may contribute to memory deficits via increased tau pathology.
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http://dx.doi.org/10.1038/s41467-019-09564-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467911PMC
April 2019

Validation of Whole-slide Digitally Imaged Melanocytic Lesions: Does Z-Stack Scanning Improve Diagnostic Accuracy?

J Pathol Inform 2019 21;10. Epub 2019 Feb 21.

Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: Accurate diagnosis of melanocytic lesions is challenging, even for expert pathologists. Nowadays, whole-slide imaging (WSI) is used for routine clinical pathology diagnosis in several laboratories. One of the limitations of WSI, as it is most often used, is the lack of a multiplanar focusing option. In this study, we aim to establish the diagnostic accuracy of WSI for melanocytic lesions and investigate the potential accuracy increase of z-stack scanning. Z-stack enables pathologists to use a software focus adjustment, comparable to the fine-focus knob of a conventional light microscope.

Materials And Methods: Melanocytic lesions ( = 102) were selected from our pathology archives: 35 nevi, 5 spitzoid tumors of unknown malignant potential, and 62 malignant melanomas, including 10 nevoid melanomas. All slides were scanned at a magnification comparable to use of a ×40 objective, in z-stack mode. A ground truth diagnosis was established on the glass slides by four academic dermatopathologists with a special interest in the diagnosis of melanoma. Six nonacademic surgical pathologists subspecialized in dermatopathology examined the cases by WSI.

Results: An expert consensus diagnosis was achieved in 99 (97%) of cases. Concordance rates between surgical pathologists and the ground truth varied between 75% and 90%, excluding nevoid melanoma cases. Concordance rates of nevoid melanoma varied between 10% and 80%. Pathologists used the software focusing option in 7%-28% of cases, which in 1 case of nevoid melanoma resulted in correcting a misdiagnosis after finding a dermal mitosis.

Conclusion: Diagnostic accuracy of melanocytic lesions based on glass slides and WSI is comparable with previous publications. A large variability in diagnostic accuracy of nevoid melanoma does exist. Our results show that z-stack scanning, in general, does not increase the diagnostic accuracy of melanocytic.
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http://dx.doi.org/10.4103/jpi.jpi_46_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415522PMC
February 2019

Type 2 diabetes mellitus, brain atrophy, and cognitive decline.

Neurology 2019 02 23;92(8):e823-e830. Epub 2019 Jan 23.

From the Department of Medicine (C.M., R.B., W.W., M.C., V.S.), Peninsula Clinical School, Central Clinical School, Monash University; Departments of Medicine and Geriatric Medicine (C.M., V.S.), Peninsula Health; Department of Aged Care (C.M.), Caulfield Hospital, Alfred Health; Developmental Imaging (R.B.), Murdoch Children's Research Institute, Melbourne; and Menzies Institute for Medical Research (M.C., V.S.), University of Tasmania, Hobart, Australia.

Objective: To study longitudinal relationships between type 2 diabetes mellitus (T2DM), cortical thickness, and cognitive function in older people with normal cognition, mild cognitive impairment, and Alzheimer disease (AD).

Methods: The sample was derived from the Alzheimer's Disease Neuroimaging Initiative cohort who underwent brain MRI and cognitive tests annually for 5 years. Presence of T2DM was based on fasting blood glucose ≥7.0mml/L or the use of glucose-lowering agents. We used latent growth curve modeling to explore longitudinal relationships between T2DM, cortical thickness, and cognitive function, adjusting for relevant covariates and testing for interactions.

Results: There were 124 people with T2DM (mean age 75.5 years, SD 6.2) and 693 without T2DM (mean age 75.1 years, SD 6.9) with at least 1 MRI available. AD and lower cortical thickness at study entry was associated with a lower chance of having a MRI available at each follow-up phase (all < 0.001). T2DM was associated with lower baseline cortical thickness ( = 0.01). We found no direct effect of T2DM on decline in cortical thickness or cognitive function, but there was an indirect pathway linking T2DM and cognitive decline via baseline cortical thickness (β = -0.17, = 0.022). There was an interaction between T2DM and education whereby the negative effect of T2DM on baseline cortical thickness was reduced in those with greater education (β = 0.34, = 0.037). These associations changed minimally when adjusted for baseline cognitive diagnosis.

Conclusions: In an older cohort with low cerebrovascular disease burden, T2DM contributes to cognitive decline via neurodegeneration. Prior brain and cognitive reserve may protect against this effect.
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http://dx.doi.org/10.1212/WNL.0000000000006955DOI Listing
February 2019

Publisher Correction: Ultraviolet radiation-induced DNA damage is prognostic for outcome in melanoma.

Nat Med 2019 Feb;25(2):350

Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.

In the version of this article originally published, Extended Data Fig. 3 was incorrect. A duplicate of Extended Data Fig. 4 was uploaded in place of Extended Data Fig. 3. Extended Data Fig. 3 has now been uploaded. The error has been fixed in the PDF and HTML versions of this article.
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http://dx.doi.org/10.1038/s41591-018-0325-yDOI Listing
February 2019

Ultraviolet radiation-induced DNA damage is prognostic for outcome in melanoma.

Nat Med 2019 02 3;25(2):221-224. Epub 2018 Dec 3.

Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.

The melanoma genome is dominated by ultraviolet radiation (UVR)-induced mutations. Their relevance in disease progression is unknown. Here we classify melanomas by mutation signatures and identify ten recurrently mutated UVR signature genes that predict patient survival. We validate these findings in primary human melanomas; in mice we show that this signature is imprinted by short-wavelength UVR and that four exposures to UVR are sufficient to accelerate melanomagenesis.
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http://dx.doi.org/10.1038/s41591-018-0265-6DOI Listing
February 2019

Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference.

Nat Commun 2018 10 15;9(1):4273. Epub 2018 Oct 15.

Centre for Medical Image Computing, University College London, London, WC1E 6BT, UK.

The heterogeneity of neurodegenerative diseases is a key confound to disease understanding and treatment development, as study cohorts typically include multiple phenotypes on distinct disease trajectories. Here we introduce a machine-learning technique-Subtype and Stage Inference (SuStaIn)-able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies. Results from imaging studies in two neurodegenerative diseases reveal subgroups and their distinct trajectories of regional neurodegeneration. In genetic frontotemporal dementia, SuStaIn identifies genotypes from imaging alone, validating its ability to identify subtypes; further the technique reveals within-genotype heterogeneity. In Alzheimer's disease, SuStaIn uncovers three subtypes, uniquely characterising their temporal complexity. SuStaIn provides fine-grained patient stratification, which substantially enhances the ability to predict conversion between diagnostic categories over standard models that ignore subtype (p = 7.18 × 10) or temporal stage (p = 3.96 × 10). SuStaIn offers new promise for enabling disease subtype discovery and precision medicine.
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http://dx.doi.org/10.1038/s41467-018-05892-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189176PMC
October 2018

Nodular Melanoma: A Histopathologic Entity?

Acta Derm Venereol 2018 Apr;98(4):460-462

Cancer and Population Studies Group, QIMR Berghofer Medical Research Institute, Locked Bag 2000 Royal Brisbane Hospital, Brisbane, Queensland 4029, Australia.

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http://dx.doi.org/10.2340/00015555-2855DOI Listing
April 2018

In vivo staging of regional amyloid deposition.

Neurology 2017 Nov 18;89(20):2031-2038. Epub 2017 Oct 18.

From the German Center for Neurodegenerative Diseases (DZNE) (M.J.G., M.D., S.J.T.), Rostock; Department of Nuclear Medicine (H.B., O.S.), University of Leipzig, Germany; Gordon Center for Medical Imaging (J.S.), Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston; Athinoula A. Martinos Center for Biomedical Imaging (J.S.), Charlestown, MA; and Department of Psychosomatic Medicine (S.J.T.), University of Rostock, Germany.

Objectives: To estimate a regional progression pattern of amyloid deposition from cross-sectional amyloid-sensitive PET data and evaluate its potential for in vivo staging of an individual's amyloid pathology.

Methods: Multiregional analysis of florbetapir (F-AV45)-PET data was used to determine individual amyloid distribution profiles in a sample of 667 participants from the Alzheimer's Disease Neuroimaging Initiative cohort, including cognitively normal older individuals (CN) as well as patients with mild cognitive impairment and Alzheimer disease (AD) dementia. The frequency of regional amyloid positivity across CN individuals was used to construct a 4-stage model of progressing amyloid pathology, and individual distribution profiles were used to evaluate the consistency of this hierarchical stage model across the full cohort.

Results: According to a 4-stage model, amyloid deposition begins in temporobasal and frontomedial areas, and successively affects the remaining associative neocortex, primary sensory-motor areas and the medial temporal lobe, and finally the striatum. Amyloid deposition in these brain regions showed a highly consistent hierarchical nesting across participants, where only 2% exhibited distribution profiles that deviated from the staging scheme. The earliest in vivo amyloid stages were mostly missed by conventional dichotomous classification approaches based on global florbetapir-PET signal, but were associated with significantly reduced CSF Aβ42 levels. Advanced in vivo amyloid stages were most frequent in patients with AD and correlated with cognitive impairment in individuals without dementia.

Conclusions: The highly consistent regional hierarchy of PET-evidenced amyloid deposition across participants resembles neuropathologic observations and suggests a predictable regional sequence that may be used to stage an individual's progress of amyloid pathology in vivo.
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http://dx.doi.org/10.1212/WNL.0000000000004643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5711511PMC
November 2017

genotype and early β-amyloid accumulation in older adults without dementia.

Neurology 2017 Sep 9;89(10):1028-1034. Epub 2017 Aug 9.

From the Florey Institute of Neuroscience and Mental Health (Y.Y.L.), The University of Melbourne, Parkville, Australia; and the Department of Neurology and Neurological Sciences (E.C.M.), Stanford University, CA.

Objective: To clarify associations between ε4 allele and age on longitudinal rates of β-amyloid (Aβ) accumulation within Aβ+ and Aβ- older individuals without dementia.

Methods: We analyzed 595 older adults without dementia classified cross-sectionally as Aβ- (n = 325) and Aβ+ (n = 270) using longitudinal florbetapir PET. The influence of age and genotype on longitudinal accumulation of Aβ was examined with linear mixed models.

Results: ε4 and older age were associated with higher risk of being classified as Aβ+ at baseline. The annual rate of Aβ accumulation was significantly greater than zero for Aβ- ε3 (0.0021 ± 0.0007 standardized uptake value ratio [SUVR] units) and Aβ- ε4 (0.0044 ± 0.0010 SUVR units), as well as Aβ+ ε3 (0.0141 ± 0.0019 SUVR units) and Aβ+ ε4 (0.0126 ± 0.0018 SUVR units). Aβ accumulation was significantly faster in Aβ- ε4 compared to Aβ- ε3 and Aβ- ε2. Rates of Aβ accumulation did not differ significantly between Aβ+ groups. Older age was associated with higher rates of Aβ accumulation in the Aβ- group.

Conclusions: ε4 carriage and older age were predictors of longitudinal Aβ accumulation within the Aβ- group but not the Aβ+ group. ε2 carriage was protective against longitudinal Aβ accumulation within the Aβ- group. genotype in conjunction with chronologic age may aid in participant selection for primary prevention trials aimed at halting Aβ accumulation before abnormal levels are reached.
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http://dx.doi.org/10.1212/WNL.0000000000004336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589795PMC
September 2017

Four simple recommendations to encourage best practices in research software.

F1000Res 2017 13;6. Epub 2017 Jun 13.

Software Sustainability Institute, Web and Internet Science, University of Southampton, Southampton, UK.

Scientific research relies on computer software, yet software is not always developed following practices that ensure its quality and sustainability. This manuscript does not aim to propose new software development best practices, but rather to provide simple recommendations that encourage the adoption of existing best practices. Software development best practices promote better quality software, and better quality software improves the reproducibility and reusability of research. These recommendations are designed around Open Source values, and provide practical suggestions that contribute to making research software and its source code more discoverable, reusable and transparent. This manuscript is aimed at developers, but also at organisations, projects, journals and funders that can increase the quality and sustainability of research software by encouraging the adoption of these recommendations.
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http://dx.doi.org/10.12688/f1000research.11407.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490478PMC
June 2017

New insights into naevoid melanomas: a clinicopathological reassessment.

Histopathology 2017 Dec 2;71(6):943-950. Epub 2017 Oct 2.

Members of EORTC Melanoma Group Pathology Working Group, Florence, Italy.

Aims: Because the term 'naevoid melanoma' has variable clinical and pathological interpretations, we aimed to clarify the features of melanomas referred to as naevoid.

Methods And Results: A review was undertaken of 102 melanomas diagnosed histopathologically as naevoid melanomas and ascertained by European Organization for Research and Treatment of Cancer Melanoma Group Subcommittee pathologists from their records. We found these could be classified morphologically into three groups. Thirteen melanomas were overlying genuine naevi and were therefore excluded. Of the 89 melanomas considered to be naevoid, 11 presented clinically as exophytic papillomatous nodules with little junctional component and composed of small atypical cells showing numerous mitoses and no change with depth; we termed these 'papillomatous naevoid' melanomas. The other 78 were flat or only slightly raised, and had a superficial spreading melanoma-like component with maturation to a small cell, but still an atypical, dermal component; we termed these 'maturing naevoid' melanomas. We showed that papillomatous and maturing naevoid melanomas also have differing immunochemical profiles. Preliminary clinical follow-up suggested different outcomes for these two naevoid melanoma types.

Conclusions: Melanomas that have been classified as naevoid melanomas comprise two types with distinct clinical, histopathological and immunohistochemical features that may also be prognostically significant.
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http://dx.doi.org/10.1111/his.13317DOI Listing
December 2017

BioCIDER: a Contextualisation InDEx for biological Resources discovery.

Bioinformatics 2017 Aug;33(16):2607-2608

ELIXIR Hub, The European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton CB10 1SD, UK.

Summary: The vast, uncoordinated proliferation of bioinformatics resources (databases, software tools, training materials etc.) makes it difficult for users to find them. To facilitate their discovery, various services are being developed to collect such resources into registries. We have developed BioCIDER, which, rather like online shopping 'recommendations', provides a contextualization index to help identify biological resources relevant to the content of the sites in which it is embedded.

Availability And Implementation: BioCIDER (www.biocider.org) is an open-source platform. Documentation is available online (https://goo.gl/Klc51G), and source code is freely available via GitHub (https://github.com/BioCIDER). The BioJS widget that enables websites to embed contextualization is available from the BioJS registry (http://biojs.io/). All code is released under an MIT licence.

Contact: carlos.horro@earlham.ac.uk or rafael.jimenez@elixir-europe.org or manuel@repositive.io.
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http://dx.doi.org/10.1093/bioinformatics/btx213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870719PMC
August 2017

Robust Identification of Alzheimer's Disease subtypes based on cortical atrophy patterns.

Sci Rep 2017 03 9;7:43270. Epub 2017 Mar 9.

School of Biomedical Engineering, Korea University, Seoul, Republic of Korea.

Accumulating evidence suggests that Alzheimer's disease (AD) is heterogenous and can be classified into several subtypes. Here, we propose a robust subtyping method for AD based on cortical atrophy patterns and graph theory. We calculated similarities between subjects in their atrophy patterns throughout the whole brain, and clustered subjects with similar atrophy patterns using the Louvain method for modular organization extraction. We applied our method to AD patients recruited at Samsung Medical Center and externally validated our method by using the AD Neuroimaging Initiative (ADNI) dataset. Our method categorized very mild AD into three clinically distinct subtypes with high reproducibility (>90%); the parietal-predominant (P), medial temporal-predominant (MT), and diffuse (D) atrophy subtype. The P subtype showed the worst clinical presentation throughout the cognitive domains, while the MT and D subtypes exhibited relatively mild presentation. The MT subtype revealed more impaired language and executive function compared to the D subtype.
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http://dx.doi.org/10.1038/srep43270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5343676PMC
March 2017

Multimodal characterization of older APOE2 carriers reveals selective reduction of amyloid load.

Neurology 2017 02 6;88(6):569-576. Epub 2017 Jan 6.

From the German Center for Neurodegenerative Diseases (M.J.G., M.D.), Rostock, Germany; Douglas Mental Health University Institute (S.V.), Research Centre, Verdun; Department of Psychiatry (S.V.), McGill University, Montreal, Quebec, Canada; Department of Medicine (D.B.-F.), Faculty of Medicine and Health Sciences, University of Barcelona, Spain; and NeuroCure Clinical Research Center (M.W.) and Department of Neurology, Charité-Universitätsmedizin Berlin, Germany.

Objective: To comprehensively assess neurobiological effects of the protective APOE2 allele in the aged brain using a cross-sectional multimodal neuroimaging approach.

Methods: Multimodal neuroimaging data were obtained from a total of 572 older individuals without dementia (cognitively normal and mild cognitive impairment) enrolled in the Alzheimer's Disease Neuroimaging Initiative and included assessments of regional amyloid load with AV45-PET, glucose metabolism with fluorodeoxyglucose-PET, and gray matter volume with structural MRI. Imaging indexes of APOE2 carriers were contrasted to risk-neutral APOE3 homozygotes, and analyses were controlled for age, sex, education, and clinical diagnosis. Additional models examined genotype-specific effects of age on the imaging markers.

Results: In region-of-interest-based analyses, APOE2 carriers had significantly less precuneal amyloid pathology and did not show the typical age-related increase in amyloid load, although the age × genotype interaction was only trend-level significant. In contrast, parietal metabolism and hippocampal volume did not differ between APOE2 and APOE3 genotypes, and both groups showed comparable negative effects of age on these markers. The amyloid specificity of APOE2-related brain changes was corroborated in 2 complementary analyses: spatially unbiased voxel-wise analyses showing widespread reductions in amyloid deposition but no differences in gray matter volume or metabolism and an analysis of CSF-based biomarkers showing a significant effect on amyloid but not on tau pathology.

Conclusions: Regarding the range of Alzheimer disease biomarkers considered in the present study, the APOE2 allele appears to have a relatively selective effect on reduced accumulation of amyloid pathology in the aged brain.
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http://dx.doi.org/10.1212/WNL.0000000000003585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5304459PMC
February 2017

Basal forebrain degeneration precedes and predicts the cortical spread of Alzheimer's pathology.

Nat Commun 2016 11 4;7:13249. Epub 2016 Nov 4.

Laboratory of Brain and Cognition, Department of Human Development, Human Neuroscience Institute, Cornell University, Martha Van Rensselaer Hall G62C, Ithaca, New York 14853, USA.

There is considerable debate whether Alzheimer's disease (AD) originates in basal forebrain or entorhinal cortex. Here we examined whether longitudinal decreases in basal forebrain and entorhinal cortex grey matter volume were interdependent and sequential. In a large cohort of age-matched older adults ranging from cognitively normal to AD, we demonstrate that basal forebrain volume predicts longitudinal entorhinal degeneration. Models of parallel degeneration or entorhinal origin received negligible support. We then integrated volumetric measures with an amyloid biomarker sensitive to pre-symptomatic AD pathology. Comparison between cognitively matched normal adult subgroups, delineated according to the amyloid biomarker, revealed abnormal degeneration in basal forebrain, but not entorhinal cortex. Abnormal degeneration in both basal forebrain and entorhinal cortex was only observed among prodromal (mildly amnestic) individuals. We provide evidence that basal forebrain pathology precedes and predicts both entorhinal pathology and memory impairment, challenging the widely held belief that AD has a cortical origin.
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http://dx.doi.org/10.1038/ncomms13249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5097157PMC
November 2016

Reduced global brain metabolism but maintained vascular function in amnestic mild cognitive impairment.

J Cereb Blood Flow Metab 2017 Apr 1;37(4):1508-1516. Epub 2016 Jan 1.

1 Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Amnestic mild cognitive impairment represents an early stage of Alzheimer's disease, and characterization of physiological alterations in mild cognitive impairment is an important step toward accurate diagnosis and intervention of this condition. To investigate the extent of neurodegeneration in patients with mild cognitive impairment, whole-brain cerebral metabolic rate of oxygen in absolute units of µmol O/min/100 g was quantified in 44 amnestic mild cognitive impairment and 28 elderly controls using a novel, non-invasive magnetic resonance imaging method. We found a 12.9% reduction ( p = 0.004) in cerebral metabolic rate of oxygen in mild cognitive impairment, which was primarily attributed to a reduction in the oxygen extraction fraction, by 10% ( p = 0.016). Global cerebral blood flow was not found to be different between groups. Another aspect of vascular function, cerebrovascular reactivity, was measured by CO-inhalation magnetic resonance imaging and was found to be equivalent between groups. Therefore, there seems to be a global, diffuse diminishment in neural function in mild cognitive impairment, while their vascular function did not show a significant reduction.
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http://dx.doi.org/10.1177/0271678X16658662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453471PMC
April 2017

Polygenic risk of Alzheimer disease is associated with early- and late-life processes.

Neurology 2016 Aug 6;87(5):481-8. Epub 2016 Jul 6.

From the Departments of Neurology (E.C.M., R.A.S.) and Radiology (R.A.S.), Massachusetts General Hospital, Harvard Medical School, Charlestown; Center for Alzheimer Research and Treatment, Department of Neurology (R.A.S.), and Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry (P.L.D.), Brigham and Women's Hospital, Harvard Medical School (P.L.D.), Boston, MA; Department of Psychology (A.J.H.), Yale University, New Haven, CT; Department of Psychiatry (A.J.H.), Massachusetts General Hospital, Harvard Medical School, Boston; Athinoula A. Martinos Center for Biomedical Imaging (A.J.H.) and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research (J.W.S.), Massachusetts General Hospital, Boston; Department of Psychology and Center for Brain Science (R.L.B.), Harvard University, Cambridge; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology (R.L.B., M.R.S.), Massachusetts General Hospital, Charlestown; Program in Medical and Population Genetics (P.L.D.), Broad Institute; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard (J.W.S.); and Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge.

Objective: To examine associations between aggregate genetic risk and Alzheimer disease (AD) markers in stages preceding the clinical symptoms of dementia using data from 2 large observational cohort studies.

Methods: We computed polygenic risk scores (PGRS) using summary statistics from the International Genomics of Alzheimer's Project genome-wide association study of AD. Associations between PGRS and AD markers (cognitive decline, clinical progression, hippocampus volume, and β-amyloid) were assessed within older participants with dementia. Associations between PGRS and hippocampus volume were additionally examined within healthy younger participants (age 18-35 years).

Results: Within participants without dementia, elevated PGRS was associated with worse memory (p = 0.002) and smaller hippocampus (p = 0.002) at baseline, as well as greater longitudinal cognitive decline (memory: p = 0.0005, executive function: p = 0.01) and clinical progression (p < 0.00001). High PGRS was associated with AD-like levels of β-amyloid burden as measured with florbetapir PET (p = 0.03) but did not reach statistical significance for CSF β-amyloid (p = 0.11). Within the younger group, higher PGRS was associated with smaller hippocampus volume (p = 0.05). This pattern was evident when examining a PGRS that included many loci below the genome-wide association study (GWAS)-level significance threshold (16,123 single nucleotide polymorphisms), but not when PGRS was restricted to GWAS-level significant loci (18 single nucleotide polymorphisms).

Conclusions: Effects related to common genetic risk loci distributed throughout the genome are detectable among individuals without dementia. The influence of this genetic risk may begin in early life and make an individual more susceptible to cognitive impairment in late life. Future refinement of polygenic risk scores may help identify individuals at risk for AD dementia.
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http://dx.doi.org/10.1212/WNL.0000000000002922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970660PMC
August 2016

Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis.

Nat Commun 2016 06 21;7:11934. Epub 2016 Jun 21.

Department of Neurology &Neurosurgery, McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, Quebec, Canada H3A 2B4.

Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD-abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions.
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http://dx.doi.org/10.1038/ncomms11934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919512PMC
June 2016

Evaluation of the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) classification scheme for diagnosis of cutaneous melanocytic neoplasms: Results from the International Melanoma Pathology Study Group.

J Am Acad Dermatol 2016 Aug 14;75(2):356-63. Epub 2016 May 14.

Department of Pathology, Institut Curie and Faculty of Medicine, University of Paris Descartes, Paris, France.

Background: Pathologists use diverse terminology when interpreting melanocytic neoplasms, potentially compromising quality of care.

Objective: We sought to evaluate the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) scheme, a 5-category classification system for melanocytic lesions.

Methods: Participants (n = 16) of the 2013 International Melanoma Pathology Study Group Workshop provided independent case-level diagnoses and treatment suggestions for 48 melanocytic lesions. Individual diagnoses (including, when necessary, least and most severe diagnoses) were mapped to corresponding MPATH-Dx classes. Interrater agreement and correlation between MPATH-Dx categorization and treatment suggestions were evaluated.

Results: Most participants were board-certified dermatopathologists (n = 15), age 50 years or older (n = 12), male (n = 9), based in the United States (n = 11), and primary academic faculty (n = 14). Overall, participants generated 634 case-level diagnoses with treatment suggestions. Mean weighted kappa coefficients for diagnostic agreement after MPATH-Dx mapping (assuming least and most severe diagnoses, when necessary) were 0.70 (95% confidence interval 0.68-0.71) and 0.72 (95% confidence interval 0.71-0.73), respectively, whereas correlation between MPATH-Dx categorization and treatment suggestions was 0.91.

Limitations: This was a small sample size of experienced pathologists in a testing situation.

Conclusion: Varying diagnostic nomenclature can be classified into a concise hierarchy using the MPATH-Dx scheme. Further research is needed to determine whether this classification system can facilitate diagnostic concordance in general pathology practice and improve patient care.
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http://dx.doi.org/10.1016/j.jaad.2016.04.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958559PMC
August 2016

Accelerating rates of cognitive decline and imaging markers associated with β-amyloid pathology.

Neurology 2016 05 15;86(20):1887-96. Epub 2016 Apr 15.

From the Center for Imaging of Neurodegenerative Diseases (P.S.I., R.S.M., R.L.N., D.T., M.W.W.), Department of Veterans Affairs Medical Center, San Francisco; Departments of Radiology and Biomedical Imaging (P.S.I., D.T., M.W.W.) and Psychiatry (R.S.M.), University of California, San Francisco; Clinical Memory Research Unit, Faculty of Medicine (P.S.I., N.M.), Lund University; Memory Clinic (N.M.) and Department of Neurology (N.M.), Skåne University Hospital, Lund University; MedTech West and the Department of Clinical Neuroscience and Rehabilitation (M.S.), University of Gothenburg, Sweden; Department of Neurology (M.C.D., P.S.A.), Keck School of Medicine, University of Southern California, Los Angeles; Helen Wills Neuroscience Institute (W.J.J.), University of California, Berkeley; and Life Sciences Division (M.S., W.J.J.), Lawrence Berkeley National Laboratory, Berkeley CA.

Objective: To estimate points along the spectrum of β-amyloid pathology at which rates of change of several measures of neuronal injury and cognitive decline begin to accelerate.

Methods: In 460 patients with mild cognitive impairment (MCI), we estimated the points at which rates of florbetapir PET, fluorodeoxyglucose (FDG) PET, MRI, and cognitive and functional decline begin to accelerate with respect to baseline CSF Aβ42. Points of initial acceleration in rates of decline were estimated using mixed-effects regression.

Results: Rates of neuronal injury and cognitive and even functional decline accelerate substantially before the conventional threshold for amyloid positivity, with rates of florbetapir PET and FDG PET accelerating early. Temporal lobe atrophy rates also accelerate prior to the threshold, but not before the acceleration of cognitive and functional decline.

Conclusions: A considerable proportion of patients with MCI would not meet inclusion criteria for a trial using the current threshold for amyloid positivity, even though on average, they are experiencing cognitive/functional decline associated with prethreshold levels of CSF Aβ42. Future trials in early Alzheimer disease might consider revising the criteria regarding β-amyloid thresholds to include the range of amyloid associated with the first signs of accelerating rates of decline.
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http://dx.doi.org/10.1212/WNL.0000000000002683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873684PMC
May 2016

Better verbal memory in women than men in MCI despite similar levels of hippocampal atrophy.

Neurology 2016 04 16;86(15):1368-1376. Epub 2016 Mar 16.

From the Einstein Aging Study and the Department of Neurology (E.E.S., R.B.L.) and the Department of Epidemiology and Population Health (W.M.), Albert Einstein College of Medicine, Bronx; Department of Neurology (A.B.), State University of New York, Stony Brook; Department of Psychiatry (L.H.R., P.M.M.), University of Illinois at Chicago; and Helen Wills Neuroscience Institute (S.L.), University of California, Berkeley.

Objective: To examine sex differences in the relationship between clinical symptoms related to Alzheimer disease (AD) (verbal memory deficits) and neurodegeneration (hippocampal volume/intracranial volume ratio [HpVR]) across AD stages.

Methods: The sample included 379 healthy participants, 694 participants with amnestic mild cognitive impairment (aMCI), and 235 participants with AD and dementia from the Alzheimer's Disease Neuroimaging Initiative who completed the Rey Auditory Verbal Learning Test (RAVLT). Cross-sectional analyses were conducted using linear regression to examine the interaction between sex and HpVR on RAVLT across and within diagnostic groups adjusting for age, education, and APOE ε4 status.

Results: Across groups, there were significant sex × HpVR interactions for immediate and delayed recall (p < 0.01). Women outperformed men among individuals with moderate to larger HpVR, but not among individuals with smaller HpVR. In diagnosis-stratified analyses, the HpVR × sex interaction was significant in the aMCI group, but not in the control or AD dementia groups, for immediate and delayed recall (p < 0.01). Among controls, women outperformed men on both outcomes irrespective of HpVR (p < 0.001). In AD dementia, better RAVLT performance was independently associated with female sex (immediate, p = 0.04) and larger HpVR (delayed, p = 0.001).

Conclusion: Women showed an advantage in verbal memory despite evidence of moderate hippocampal atrophy. This advantage may represent a sex-specific form of cognitive reserve delaying verbal memory decline until more advanced disease stages.
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http://dx.doi.org/10.1212/WNL.0000000000002570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831033PMC
April 2016

Amyloid negativity in patients with clinically diagnosed Alzheimer disease and MCI.

Neurology 2016 Apr 11;86(15):1377-1385. Epub 2016 Mar 11.

From Helen Wills Neuroscience Institute (S.M.L., A.H., W.J.J.), University of California, Berkeley; and Life Sciences Division (S.M.L., A.F., W.J.J.), Lawrence Berkeley National Laboratory, CA.

Objective: To examine the clinical and biomarker characteristics of patients with amyloid-negative Alzheimer disease (AD) and mild cognitive impairment (MCI) from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a prospective cohort study.

Methods: We first investigated the reliability of florbetapir- PET in patients with AD and patients with MCI using CSF-Aβ1-42 as a comparison amyloid measurement. We then compared florbetapir- vs florbetapir+ patients with respect to several AD-specific biomarkers, baseline and longitudinal cognitive measurements, and demographic and clinician report data.

Results: Florbetapir and CSF-Aβ1-42 +/- status agreed for 98% of ADs (89% of MCIs), indicating that most florbetapir- scans were a reliable representation of amyloid status. Florbetapir- AD (n = 27/177; 15%) and MCI (n = 74/217, 34%) were more likely to be APOE4-negative (MCI 83%, AD 96%) than their florbetapir+ counterparts (MCI 30%, AD 24%). Florbetapir- patients also had less AD-specific hypometabolism, lower CSF p-tau and t-tau, and better longitudinal cognitive performance, and were more likely to be taking medication for depression. In MCI only, florbetapir- participants had less hippocampal atrophy and hypometabolism and lower functional activity questionnaire scores compared to florbetapir+ participants.

Conclusions: Overall, image analysis problems do not appear to be a primary explanation of amyloid negativity. Florbetapir- ADNI patients have a variety of clinical and biomarker features that differ from their florbetapir+ counterparts, suggesting that one or more non-AD etiologies (which may include vascular disease and depression) account for their AD-like phenotype.
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http://dx.doi.org/10.1212/WNL.0000000000002576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831042PMC
April 2016