Browsing by Author "Xiong, Chengjie"
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Item 15 Years of Longitudinal Genetic, Clinical, Cognitive, Imaging, and Biochemical Measures in DIAN(medRxiv, 2024-08-09) Daniels, Alisha J.; McDade, Eric; Llibre-Guerra, Jorge J.; Xiong, Chengjie; Perrin, Richard J.; Ibanez, Laura; Supnet-Bell, Charlene; Cruchaga, Carlos; Goate, Alison; Renton, Alan E.; Benzinger, Tammie L. S.; Gordon, Brian A.; Hassenstab, Jason; Karch, Celeste; Popp, Brent; Levey, Allan; Morris, John; Buckles, Virginia; Allegri, Ricardo F.; Chrem, Patricio; Berman, Sarah B.; Chhatwal, Jasmeer P.; Farlow, Martin R.; Fox, Nick C.; Day, Gregory S.; Ikeuchi, Takeshi; Jucker, Mathias; Lee, Jae-Hong; Levin, Johannes; Lopera, Francisco; Takada, Leonel; Sosa, Ana Luisa; Martins, Ralph; Mori, Hiroshi; Noble, James M.; Salloway, Stephen; Huey, Edward; Rosa-Neto, Pedro; Sánchez-Valle, Raquel; Schofield, Peter R.; Roh, Jee Hoon; Bateman, Randall J.; Dominantly Inherited Alzheimer Network; Neurology, School of MedicineThis manuscript describes and summarizes the Dominantly Inherited Alzheimer Network Observational Study (DIAN Obs), highlighting the wealth of longitudinal data, samples, and results from this human cohort study of brain aging and a rare monogenic form of Alzheimer's disease (AD). DIAN Obs is an international collaborative longitudinal study initiated in 2008 with support from the National Institute on Aging (NIA), designed to obtain comprehensive and uniform data on brain biology and function in individuals at risk for autosomal dominant AD (ADAD). ADAD gene mutations in the amyloid protein precursor (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2) genes are deterministic causes of ADAD, with virtually full penetrance, and a predictable age at symptomatic onset. Data and specimens collected are derived from full clinical assessments, including neurologic and physical examinations, extensive cognitive batteries, structural and functional neuro-imaging, amyloid and tau pathological measures using positron emission tomography (PET), flurordeoxyglucose (FDG) PET, cerebrospinal fluid and blood collection (plasma, serum, and whole blood), extensive genetic and multi-omic analyses, and brain donation upon death. This comprehensive evaluation of the human nervous system is performed longitudinally in both mutation carriers and family non-carriers, providing one of the deepest and broadest evaluations of the human brain across decades and through AD progression. These extensive data sets and samples are available for researchers to address scientific questions on the human brain, aging, and AD.Item A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's disease(Springer Nature, 2021) Salloway, Stephen; Farlow, Martin; McDade, Eric; Clifford, David B.; Wang, Guoqiao; Llibre-Guerra, Jorge J.; Hitchcock, Janice M.; Mills, Susan L.; Santacruz, Anna M.; Aschenbrenner, Andrew J.; Hassenstab, Jason; Benzinger, Tammie L.S.; Gordon, Brian A.; Fagan, Anne M.; Coalier, Kelley A.; Cruchaga, Carlos; Goate, Alison A.; Perrin, Richard J.; Xiong, Chengjie; Li, Yan; Morris, John C.; Snider, B. Joy; Mummery, Catherine; Surti, G. Mustafa; Hannequin, Didier; Wallon, David; Berman, Sarah B.; Lah, James J.; Jimenez-Velazquez, Ivonne Z.; Roberson, Erik D.; van Dyck, Christopher H.; Honig, Lawrence S.; Sánchez-Valle, Raquel; Brooks, William S.; Gauthier, Serge; Galasko, Douglas R.; Masters, Colin L.; Brosch, Jared R.; Hsiung, Ging-Yuek Robin; Jayadev, Suman; Formaglio, Maité; Masellis, Mario; Clarnette, Roger; Pariente, Jérémie; Dubois, Bruno; Pasquier, Florence; Jack, Clifford R., Jr.; Koeppe, Robert; Snyder, Peter J.; Aisen, Paul S.; Thomas, Ronald G.; Berry, Scott M.; Wendelberger, Barbara A.; Andersen, Scott W.; Holdridge, Karen C.; Mintun, Mark A.; Yaari, Roy; Sims, John R.; Baudler, Monika; Delmar, Paul; Doody, Rachelle S.; Fontoura, Paulo; Giacobino, Caroline; Kerchner, Geoffrey A.; Bateman, Randall J.; Dominantly Inherited Alzheimer Network–Trials Unit; Neurology, School of MedicineDominantly inherited Alzheimer's disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4-7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aβ targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses.Item Amyloid-Related Imaging Abnormalities in the DIAN-TU-001 Trial of Gantenerumab and Solanezumab: Lessons from a Trial in Dominantly Inherited Alzheimer Disease(Wiley, 2022) Joseph-Mathurin, Nelly; Llibre-Guerra, Jorge J.; Li, Yan; McCullough, Austin A.; Hofmann, Carsten; Wojtowicz, Jakub; Park, Ethan; Wang, Guoqiao; Preboske, Gregory M.; Wang, Qing; Gordon, Brian A.; Chen, Charles D.; Flores, Shaney; Aggarwal, Neelum T.; Berman, Sarah B.; Bird, Thomas D.; Black, Sandra E.; Borowski, Bret; Brooks, William S.; Chhatwal, Jasmeer P.; Clarnette, Roger; Cruchaga, Carlos; Fagan, Anne M.; Farlow, Martin; Fox, Nick C.; Gauthier, Serge; Hassenstab, Jason; Hobbs, Diana A.; Holdridge, Karen C.; Honig, Lawrence S.; Hornbeck, Russ C.; Hsiung, Ging-Yuek R.; Jack, Clifford R., Jr.; Jimenez-Velazquez, Ivonne Z.; Jucker, Mathias; Klein, Gregory; Levin, Johannes; Mancini, Michele; Masellis, Mario; McKay, Nicole S.; Mummery, Catherine J.; Ringman, John M.; Shimada, Hiroyuki; Snider, B. Joy; Suzuki, Kazushi; Wallon, David; Xiong, Chengjie; Yaari, Roy; McDade, Eric; Perrin, Richard J.; Bateman, Randall J.; Salloway, Stephen P.; Benzinger, Tammie L. S.; Clifford, David B.; Dominantly Inherited Alzheimer Network Trials Unit; Neurology, School of MedicineObjective: To determine the characteristics of participants with amyloid-related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD). Methods: 142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, β-amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross-sectional and longitudinal analyses evaluated potential ARIA-related risk factors. Results: Eleven participants developed ARIA-E, including 3 with mild symptoms. No ARIA-E was reported under solanezumab while gantenerumab was associated with ARIA-E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE-ɛ4 carriers were more likely to develop ARIA-E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA-E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. At first ARIA-E occurrence, all ARIA-E participants were amyloid-PET+, 60% were CDR >0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA-H. Most ARIA-E radiologically resolved after dose adjustment and developing ARIA-E did not significantly increase odds of trial discontinuation. ARIA-E was more frequently observed in the occipital lobe (90%). ARIA-E severity was associated with age at time of ARIA-E. Interpretation: In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA-E risk, with additional risk for individuals APOE-ɛ4(+) or with microhemorrhage. ARIA-E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation.Item Association of BDNF Val66Met With Tau Hyperphosphorylation and Cognition in Dominantly Inherited Alzheimer Disease(American Medical Association, 2022-03-01) Lim, Yen Ying; Maruff, Paul; Barthélemy, Nicolas R.; Goate, Alison; Hassenstab, Jason; Sato, Chihiro; Fagan, Anne M.; Benzinger, Tammie L. S.; Xiong, Chengjie; Cruchaga, Carlos; Levin, Johannes; Farlow, Martin R.; Graff-Radford, Neill R.; Laske, Christoph; Masters, Colin L.; Salloway, Stephen; Schofield, Peter R.; Morris, John C.; Bateman, Randall J.; McDade, Eric; Dominantly Inherited Alzheimer Network; Neurology, School of MedicineImportance: Allelic variation in the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism moderates increases in cerebrospinal fluid (CSF) levels of tau and phosphorylated tau 181 (p-tau181), measured using immunoassay, and cognitive decline in presymptomatic dominantly inherited Alzheimer disease (DIAD). Advances in mass spectrometry show that CSF tau phosphorylation occupancy at threonine 181 and 217 (p-tau181/tau181, p-tau217/tau217) increases with initial β-amyloid (Aβ) aggregation, while phosphorylation occupancy at threonine 205 (p-tau205/tau205) and level of total tau increase when brain atrophy and clinical symptoms become evident. Objective: To determine whether site-specific tau phosphorylation occupancy (ratio of phosphorylated to unphosphorylated tau) is associated with BDNF Val66Met in presymptomatic and symptomatic DIAD. Design, setting, and participants: This cross-sectional cohort study included participants from the Dominantly Inherited Alzheimer Network (DIAN) and Aβ-positive cognitively normal older adults in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Data were collected from 2009 through 2018 at multicenter clinical sites in the United States, United Kingdom, and Australia, with no follow-up. DIAN participants provided a CSF sample and completed clinical and cognitive assessments. Data analysis was conducted between March 2020 and March 2021. Main outcomes and measures: Mass spectrometry analysis was used to determine site-specific tau phosphorylation level; tau levels were also measured using immunoassay. Episodic memory and global cognitive composites were computed. Results: Of 374 study participants, 144 were mutation noncarriers, 156 were presymptomatic mutation carriers, and 74 were symptomatic carriers. Of the 527 participants in the network, 153 were excluded because their CSF sample, BDNF status, or both were unavailable. Also included were 125 Aβ-positive cognitively normal older adults in the ADNI. The mean (SD) age of DIAD participants was 38.7 (10.9) years; 43% were women. The mean (SD) age of participants with preclinical sporadic AD was 74.8 (5.6) years; 52% were women. In presymptomatic mutation carriers, compared with Val66 homozygotes, Met66 carriers showed significantly poorer episodic memory (d = 0.62; 95% CI, 0.28-0.95), lower hippocampal volume (d = 0.40; 95% CI, 0.09-0.71), and higher p-tau217/tau217 (d = 0.64; 95% CI, 0.30-0.97), p-tau181/tau181 (d = 0.65; 95% CI, 0.32-0.99), and mass spectrometry total tau (d = 0.43; 95% CI, 0.10-0.76). In symptomatic mutation carriers, Met66 carriers showed significantly poorer global cognition (d = 1.17; 95% CI, 0.65-1.66) and higher p-tau217/tau217 (d = 0.53; 95% CI, 0.05-1.01), mass spectrometry total tau (d = 0.78; 95% CI, 0.28-1.25), and p-tau205/tau205 (d = 0.97; 95% CI, 0.46-1.45), when compared with Val66 homozygotes. In preclinical sporadic AD, Met66 carriers showed poorer episodic memory (d = 0.39; 95% CI, 0.00-0.77) and higher total tau (d = 0.45; 95% CI, 0.07-0.84) and p-tau181 (d = 0.46; 95% CI, 0.07-0.85). Conclusions and relevance: In DIAD, clinical disease stage and BDNF Met66 were associated with cognitive impairment and levels of site-specific tau phosphorylation. This suggests that pharmacological strategies designed to increase neurotrophic support in the presymptomatic stages of AD may be beneficial.Item Autosomal dominant and sporadic late onset Alzheimer's disease share a common in vivo pathophysiology(Oxford University Press, 2022) Morris, John C.; Weiner, Michael; Xiong, Chengjie; Beckett, Laurel; Coble, Dean; Saito, Naomi; Aisen, Paul S.; Allegri, Ricardo; Benzinger, Tammie L. S.; Berman, Sarah B.; Cairns, Nigel J.; Carrillo, Maria C.; Chui, Helena C.; Chhatwal, Jasmeer P.; Cruchaga, Carlos; Fagan, Anne M.; Farlow, Martin; Fox, Nick C.; Ghetti, Bernardino; Goate, Alison M.; Gordon, Brian A.; Graff-Radford, Neill; Day, Gregory S.; Hassenstab, Jason; Ikeuchi, Takeshi; Jack, Clifford R.; Jagust, William J.; Jucker, Mathias; Levin, Johannes; Massoumzadeh, Parinaz; Masters, Colin L.; Martins, Ralph; McDade, Eric; Mori, Hiroshi; Noble, James M.; Petersen, Ronald C.; Ringman, John M.; Salloway, Stephen; Saykin, Andrew J.; Schofield, Peter R.; Shaw, Leslie M.; Toga, Arthur W.; Trojanowski, John Q.; Vöglein, Jonathan; Weninger, Stacie; Bateman, Randall J.; Buckles, Virginia D.; Dominantly Inherited Alzheimer Network; Alzheimer’s Disease Neuroimaging and Initiative; Neurology, School of MedicineThe extent to which the pathophysiology of autosomal dominant Alzheimer's disease corresponds to the pathophysiology of 'sporadic' late onset Alzheimer's disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer's disease to late onset Alzheimer's disease. We compared brain MRI and amyloid PET data, as well as CSF concentrations of amyloid-β42, amyloid-β40, tau and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer's disease from the Dominantly Inherited Alzheimer Network, with corresponding data from 559 participants from the Alzheimer's Disease Neuroimaging Initiative. Imaging data and CSF samples were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer's disease, allowing the alignment of the ∼30-year age difference between the cohorts on a clinically meaningful anchor point, namely the participant age at symptomatic onset. Biomarker profiles were similar for both autosomal dominant Alzheimer's disease and late onset Alzheimer's disease. Both groups demonstrated accelerated rates of decline in cognitive performance and in regional brain volume loss after symptomatic onset. Although amyloid burden accumulation as determined by PET was greater after symptomatic onset in autosomal dominant Alzheimer's disease than in late onset Alzheimer's disease participants, CSF assays of amyloid-β42, amyloid-β40, tau and p-tau181 were largely overlapping in both groups. Rates of change in cognitive performance and hippocampal volume loss after symptomatic onset were more aggressive for autosomal dominant Alzheimer's disease participants. These findings suggest a similar pathophysiology of autosomal dominant Alzheimer's disease and late onset Alzheimer's disease, supporting a shared pathobiological construct.Item Autosomal Dominantly Inherited Alzheimer Disease: Analysis of genetic subgroups by Machine Learning(Elsevier, 2020-06) Castillo-Barne, Diego; Su, Li; Ramírez, Javier; Salas-Gonzalez, Diego; Martinez-Murcia, Francisco J.; Illan, Ignacio A.; Segovia, Fermin; Ortiz, Andres; Cruchaga, Carlos; Farlow, Martin R.; Xiong, Chengjie; Graff-Radford, Neil R.; Schofield, Peter R.; Masters, Colin L.; Salloway, Stephen; Jucker, Mathias; Mori, Hiroshi; Levin, Johannes; Gorriz, Juan M.; Neurology, School of MedicineDespite subjects with Dominantly-Inherited Alzheimer's Disease (DIAD) represent less than 1% of all Alzheimer's Disease (AD) cases, the Dominantly Inherited Alzheimer Network (DIAN) initiative constitutes a strong impact in the understanding of AD disease course with special emphasis on the presyptomatic disease phase. Until now, the 3 genes involved in DIAD pathogenesis (PSEN1, PSEN2 and APP) have been commonly merged into one group (Mutation Carriers, MC) and studied using conventional statistical analysis. Comparisons between groups using null-hypothesis testing or longitudinal regression procedures, such as the linear-mixed-effects models, have been assessed in the extant literature. Within this context, the work presented here performs a comparison between different groups of subjects by considering the 3 genes, either jointly or separately, and using tools based on Machine Learning (ML). This involves a feature selection step which makes use of ANOVA followed by Principal Component Analysis (PCA) to determine which features would be realiable for further comparison purposes. Then, the selected predictors are classified using a Support-Vector-Machine (SVM) in a nested k-Fold cross-validation resulting in maximum classification rates of 72-74% using PiB PET features, specially when comparing asymptomatic Non-Carriers (NC) subjects with asymptomatic PSEN1 Mutation-Carriers (PSEN1-MC). Results obtained from these experiments led to the idea that PSEN1-MC might be considered as a mixture of two different subgroups including: a first group whose patterns were very close to NC subjects, and a second group much more different in terms of imaging patterns. Thus, using a k-Means clustering algorithm it was determined both subgroups and a new classification scenario was conducted to validate this process. The comparison between each subgroup vs. NC subjects resulted in classification rates around 80% underscoring the importance of considering DIAN as an heterogeneous entity.Item Avoid or Embrace? Practice Effects in Alzheimer’s Disease Prevention Trials(Frontiers Media, 2022-06-16) Aschenbrenner, Andrew J.; Hassenstab, Jason; Wang, Guoqiao; Li, Yan; Xiong, Chengjie; McDade, Eric; Clifford, David B.; Salloway, Stephen; Farlow, Martin; Yaari, Roy; Cheng, Eden Y. J.; Holdridge, Karen C.; Mummery, Catherine J.; Masters, Colin L.; Hsiung, Ging-Yuek; Surti, Ghulam; Day, Gregory S.; Weintraub, Sandra; Honig, Lawrence S.; Galvin, James E.; Ringman, John M.; Brooks, William S.; Fox, Nick C.; Snyder, Peter J.; Suzuki, Kazushi; Shimada, Hiroyuki; Gräber, Susanne; Bateman, Randall J.; Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU); Neurology, School of MedicineDemonstrating a slowing in the rate of cognitive decline is a common outcome measure in clinical trials in Alzheimer's disease (AD). Selection of cognitive endpoints typically includes modeling candidate outcome measures in the many, richly phenotyped observational cohort studies available. An important part of choosing cognitive endpoints is a consideration of improvements in performance due to repeated cognitive testing (termed "practice effects"). As primary and secondary AD prevention trials are comprised predominantly of cognitively unimpaired participants, practice effects may be substantial and may have considerable impact on detecting cognitive change. The extent to which practice effects in AD prevention trials are similar to those from observational studies and how these potential differences impact trials is unknown. In the current study, we analyzed data from the recently completed DIAN-TU-001 clinical trial (TU) and the associated DIAN-Observational (OBS) study. Results indicated that asymptomatic mutation carriers in the TU exhibited persistent practice effects on several key outcomes spanning the entire trial duration. Critically, these practice related improvements were larger on certain tests in the TU relative to matched participants from the OBS study. Our results suggest that the magnitude of practice effects may not be captured by modeling potential endpoints in observational studies where assessments are typically less frequent and drug expectancy effects are absent. Using alternate instrument forms (represented in our study by computerized tasks) may partly mitigate practice effects in clinical trials but incorporating practice effects as outcomes may also be viable. Thus, investigators must carefully consider practice effects (either by minimizing them or modeling them directly) when designing cognitive endpoint AD prevention trials by utilizing trial data with similar assessment frequencies.Item Awareness of Genetic Risk in the Dominantly Inherited Alzheimer Network (DIAN)(Wiley, 2020-01) Aschenbrenner, Andrew J.; James, Bryan D.; McDade, Eric; Wang, Guoqiao; Lim, Yen Ying; Benzinger, Tammie L.S.; Cruchaga, Carlos; Goate, Alison; Xiong, Chengjie; Perrin, Richard; Buckles, Virginia; Allegri, Ricardo; Berman, Sarah B.; Chhatwal, Jasmeer P.; Fagan, Anne; Farlow, Martin; O'Connor, Antoinette; Ghetti, Bernardino; Graff-Radford, Neill; Goldman, Jill; Gräber, Susanne; Karch, Celeste M.; Lee, Jae-Hong; Levin, Johannes; Martins, Ralph N.; Masters, Colin; Mori, Hiroshi; Noble, James; Salloway, Stephen; Schofield, Peter; Morris, John C.; Bateman, Randall J.; Hassenstab, Jason; Neurology, School of MedicineIntroduction: Although some members of families with autosomal dominant Alzheimer's disease mutations learn their mutation status, most do not. How knowledge of mutation status affects clinical disease progression is unknown. This study quantifies the influence of mutation awareness on clinical symptoms, cognition, and biomarkers. Methods: Mutation carriers and non-carriers from the Dominantly Inherited Alzheimer Network (DIAN) were stratified based on knowledge of mutation status. Rates of change on standard clinical, cognitive, and neuroimaging outcomes were examined. Results: Mutation knowledge had no associations with cognitive decline, clinical progression, amyloid deposition, hippocampal volume, or depression in either carriers or non-carriers. Carriers who learned their status mid-study had slightly higher levels of depression and lower cognitive scores. Discussion: Knowledge of mutation status does not affect rates of change on any measured outcome. Learning of status mid-study may confer short-term changes in cognitive functioning, or changes in cognition may influence the determination of mutation status.Item Axonal damage and inflammation response are biological correlates of decline in small-world values: a cohort study in autosomal dominant Alzheimer's disease(Oxford University Press, 2024-10-09) Vermunt, Lisa; Sutphen, Courtney L.; Dicks, Ellen; de Leeuw, Diederick M.; Allegri, Ricardo F.; Berman, Sarah B.; Cash, David M.; Chhatwal, Jasmeer P.; Cruchaga, Carlos; Day, Gregory S.; Ewers, Michael; Farlow, Martin R.; Fox, Nick C.; Ghetti, Bernardino; Graff-Radford, Neill R.; Hassenstab, Jason; Jucker, Mathias; Karch, Celeste M.; Kuhle, Jens; Laske, Christoph; Levin, Johannes; Masters, Colin L.; McDade, Eric; Mori, Hiroshi; Morris, John C.; Perrin, Richard J.; Preische, Oliver; Schofield, Peter R.; Suárez-Calvet, Marc; Xiong, Chengjie; Scheltens, Philip; Teunissen, Charlotte E.; Visser, Pieter Jelle; Bateman, Randall J.; Benzinger, Tammie L. S.; Fagan, Anne M.; Gordon, Brian A.; Tijms, Betty M.; Pathology and Laboratory Medicine, School of MedicineThe grey matter of the brain develops and declines in coordinated patterns during the lifespan. Such covariation patterns of grey matter structure can be quantified as grey matter networks, which can be measured with magnetic resonance imaging. In Alzheimer's disease, the global organization of grey matter networks becomes more random, which is captured by a decline in the small-world coefficient. Such decline in the small-world value has been robustly associated with cognitive decline across clinical stages of Alzheimer's disease. The biological mechanisms causing this decline in small-world values remain unknown. Cerebrospinal fluid (CSF) protein biomarkers are available for studying diverse pathological mechanisms in humans and can provide insight into decline. We investigated the relationships between 10 CSF proteins and small-world coefficient in mutation carriers (N = 219) and non-carriers (N = 136) of the Dominantly Inherited Alzheimer Network Observational study. Abnormalities in Amyloid beta, Tau, synaptic (Synaptosome associated protein-25, Neurogranin) and neuronal calcium-sensor protein (Visinin-like protein-1) preceded loss of small-world coefficient by several years, while increased levels in CSF markers for inflammation (Chitinase-3-like protein 1) and axonal injury (Neurofilament light) co-occurred with decreasing small-world values. This suggests that axonal loss and inflammation play a role in structural grey matter network changes.Item Cerebral amyloidosis associated with cognitive decline in autosomal dominant Alzheimer disease(American Academy of Neurology, 2015-09) Wang, Fen; Gordon, Brian A.; Ryman, Davis C.; Ma, Shengmei; Xiong, Chengjie; Hassenstab, Jason; Goate, Alison; Fagan, Anne M.; Cairns, Nigel J.; Marcus, Daniel S.; McDade, Eric; Ringman, John M.; Graff-Radford, Neill R.; Ghetti, Bernardino; Farlow, Martin R.; Sperling, Reisa; Salloway, Steve; Schofield, Peter R.; Masters, Colin L.; Martins, Ralph N.; Rossor, Martin N. N.; Jucker, Mathias; Danek, Adrian; Förster, Stefan; Lane, Christopher A.S.; Morris, John C.; Benzinger, Tammie L. S.; Bateman, Randall J.; Department of Neurology, IU School of MedicineOBJECTIVE: To investigate the associations of cerebral amyloidosis with concurrent cognitive performance and with longitudinal cognitive decline in asymptomatic and symptomatic stages of autosomal dominant Alzheimer disease (ADAD). METHODS: Two hundred sixty-three participants enrolled in the Dominantly Inherited Alzheimer Network observational study underwent neuropsychological evaluation as well as PET scans with Pittsburgh compound B. One hundred twenty-one participants completed at least 1 follow-up neuropsychological evaluation. Four composite cognitive measures representing global cognition, episodic memory, language, and working memory were generated using z scores from a battery of 13 standard neuropsychological tests. General linear mixed-effects models were used to investigate the relationship between baseline cerebral amyloidosis and baseline cognitive performance and whether baseline cerebral amyloidosis predicts cognitive change over time (mean follow-up 2.32 years ± 0.92, range 0.89-4.19) after controlling for estimated years from expected symptom onset, APOE ε4 allelic status, and education. RESULTS: In asymptomatic mutation carriers, amyloid burden was not associated with baseline cognitive functioning but was significantly predictive of longitudinal decline in episodic memory. In symptomatic mutation carriers, cerebral amyloidosis was correlated with worse baseline performance in multiple cognitive composites and predicted greater decline over time in global cognition, working memory, and Mini-Mental State Examination. CONCLUSIONS: Cerebral amyloidosis predicts longitudinal episodic memory decline in presymptomatic ADAD and multidomain cognitive decline in symptomatic ADAD. These findings imply that amyloidosis in the brain is an indicator of early cognitive decline and provides a useful outcome measure for early assessment and prevention treatment trials.