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Patients with early-onset Alzheimer's disease (EOAD) are commonly excluded from large-scale observational and therapeutic studies due to their young age, atypical presentation, or absence of pathogenic mutations. The goals of the Longitudinal EOAD Study (LEADS) are to (1) define the clinical, imaging, and fluid biomarker characteristics of EOAD; (2) develop sensitive cognitive and biomarker measures for future clinical and research use; and (3) establish a trial-ready network. LEADS will follow 400 amyloid beta (Aβ)-positive EOAD, 200 Aβ-negative EOnonAD that meet National Institute on Aging-Alzheimer's Association (NIA-AA) criteria for mild cognitive impairment (MCI) or AD dementia, and 100 age-matched controls. Participants will undergo clinical and cognitive assessments, magnetic resonance imaging (MRI), [18 F]Florbetaben and [18 F]Flortaucipir positron emission tomography (PET), lumbar puncture, and blood draw for DNA, RNA, plasma, serum and peripheral blood mononuclear cells, and post-mortem assessment. To develop more effective AD treatments, scientists need to understand the genetic, biological, and clinical processes involved in EOAD. LEADS will develop a public resource that will enable future planning and implementation of EOAD clinical trials.

We report on the initial 17 (11 male:6 female) brain autopsies from across Europe and the United States in the Parkinson's Progression Markers Initiative (PPMI). Clinical diagnoses were Parkinson's disease (n = 15), multiple system atrophy (n = 1), and Dementia with Lewy bodies (n = 1); average age of death = 72 ± 8 yr. Cognitive assessment at last evaluation was 5 with normal cognition, 7 with mild cognitive impairment, and 5 with dementia. Genetic assessment showed 4 participants were heterozygous or homozygous for GBA N370S and 3 were heterozygous carriers for LRRK2 R1441G or G2019S; 1 was an APOE ε2 carrier and 5 were APOE ε4 carriers. Longitudinal DAT neuroimaging as well as CSF and plasma biomarker data are summarized. Neuropathologic examination confirmed all clinical diagnoses and showed the expected frequencies of common comorbidities; no evidence of chronic traumatic encephalopathy was observed. Thus, brain autopsy data can provide confirmation, clarification, and new insights into the PD progression observed during life. As it grows, the PPMI brain autopsy program will provide a deeply-annotated research resource to the community of investigators focused on developing biomarkers for PD progression.

Author(s): Alcalay, Roy N; Wolf, Pavlina; Chiang, Ming Sum Ruby; Helesicova, Karolina; Zhang, Xiaokui Kate; Merchant, Kalpana; Hutten, Samantha J; Scherzer, Clemens; Caspell-Garcia, Chelsea; Blauwendraat, Cornelis; Foroud, Tatiana; Nudelman, Kelly; Gan-Or, Ziv; Simuni, Tanya; Chahine, Lana M; Levy, Oren; Zheng, Dandi; Li, Gen; Sardi, Sergio Pablo; Parkinson’s Progression Markers Initiative | Abstract: ObjectiveReduction in glucocerebrosidase (GCase; encoded by GBA) enzymatic activity has been linked to Parkinson's disease (PD). Here, we correlated GCase activity and PD phenotype in the Parkinson's Progression Markers Initiative (PPMI) cohort.MethodsWe measured GCase activity in dried blood spots from 1559 samples of participants in the inception PPMI cohort, collected in four annual visits (from baseline visit to Year-3). Participants (PD, nn=n392; controls, nn=n175) were fully sequenced for GBA variants by means of genome-wide genotyping arrays, whole-exome sequencing, whole-genome sequencing, Sanger sequencing, and RNA-sequencing.ResultsFifty-two PD participants (13.4%) and 13 (7.4%) controls carried a GBA variant. GBA status was strongly associated with GCase activity. Among noncarriers, GCase activity was similar between PD and controls. Among GBA p.E326K carriers (PD, nn=n20; controls, nn=n5), activity was significantly lower in PD carriers than control carriers (9.53nµmol/L/h vs. 11.68nµmol/L/h, Pn=n0.035). Glucocerebrosidase activity was moderately (rn=n0.45) associated with white blood cell (WBC) count. Next, we divided the noncarriers with PD to tertiles based on WBC count-corrected enzymatic activity. Members of the lower tertile had higher MDS-Unified Parkinson's Disease Rating Scale motor score in the "off" medication examination at year-III exam. Longitudinal analyses demonstrated slight reduction of activity in samples collected earlier on in the study, likely because of longer storage time.InterpretationGCase activity is associated with GBA genotype, WBC count, and among p.E326K variant carriers, with PD status. Reduced activity may also be associated with worse phenotype but longer follow up is required to confirm this observation.

In this case report, we discuss a patient presenting with parkinsonism followed by a non-amnestic dementia with aphasic clinical features, as well as frontal dysexecutive syndrome. There was a family history of dementia with an autopsy diagnosis of “Pick’s disease” in the proband’s father. Neuroimaging of the patient revealed focal and severe temporal lobe and lesser frontoparietal lobe atrophy. At autopsy, there was severe frontotemporal lobar degeneration. Histologic evaluation revealed an absence of tau or transactivation response DNA-binding protein of 43 kDa (TDP) pathology but rather severe Lewy body deposition in the affected cortices. Genetic phenotyping revealed a novel missense mutation (p.E83Q) in exon 4 of the gene encoding α-synuclein (SNCA). This case study presents a patient with a novel SNCA E83Q mutation associated with widespread Lewy body pathology with prominent severe atrophy of the frontotemporal lobes and corresponding cognitive impairment.

INTRODUCTION Abnormal gene expression patterns may contribute to the onset and progression of late-onset Alzheimer's disease (LOAD). METHODS We performed transcriptome-wide meta-analysis (N = 1440) of blood-based microarray gene expression profiles as well as neuroimaging and cerebrospinal fluid (CSF) endophenotype analysis. RESULTS We identified and replicated five genes (CREB5, CD46, TMBIM6, IRAK3, and RPAIN) as significantly dysregulated in LOAD. The most significantly altered gene, CREB5, was also associated with brain atrophy and increased amyloid beta (Aβ) accumulation, especially in the entorhinal cortex region. cis-expression quantitative trait loci mapping analysis of CREB5 detected five significant associations (P < 5 × 10-8 ), where rs56388170 (most significant) was also significantly associated with global cortical Aβ deposition measured by [18 F]Florbetapir positron emission tomography and CSF Aβ1-42 . DISCUSSION RNA from peripheral blood indicated a differential gene expression pattern in LOAD. Genes identified have been implicated in biological processes relevant to Alzheimer's disease. CREB, in particular, plays a key role in nervous system development, cell survival, plasticity, and learning and memory.

To estimate dopaminergic dysfunction in patients with Parkinson disease (PD) during the premotor stage and to investigate the effect of genetic factors on the trajectories. Using longitudinal dopamine transporter single-photon emission computed tomography data from 367 sporadic PD (sPD), 72 LRRK2 (G2019S), and 39 GBA (N370S) PD patients in the Parkinson’s Progression Markers Initiative (PPMI) study, we estimated the temporal trajectories of putaminal-specific binding ratios using an integrating function between baseline values and their annual change rates. In order to test reproducibility, we computed another trajectory for sPD using positron emission tomography data of 38 sPD patients at Gangnam Severance Hospital (GSH). Temporal trajectories of sPD were compared between the groups separated by age at onset (AAO) and polygenic load for common PD risk variants, and also compared with genetic PD. sPD patients in both the PPMI and GSH cohorts showed similar onset of dopaminergic degeneration around 10 years before motor onset. Early-onset PD patients exhibited later onset of degeneration and a faster decline in dopaminergic activity during the premotor period than late-onset patients. sPD patients with high polygenic load were associated with earlier onset and slower progression of dopaminergic dysfunction. Compared to the sPD and LRRK2 PD groups, GBA PD patients exhibited faster deterioration of dopaminergic function during the premotor stage. Dopaminergic dysfunction in PD appears to start about 10 years before motor onset. Genetic factors may be contributing to the heterogeneity of dopaminergic deterioration during the premotor stage.

BACKGROUND Sleep disturbance and genetic profile are risks for cognitive decline in noncancer populations, yet their role in cancer-related cognitive problems remains understudied. This study examined whether sleep disturbance was associated with worse neurocognitive outcomes in breast cancer survivors and whether sleep effects on cognition varied by genotype. METHODS Newly diagnosed female patients (n = 319) who were 60 years old or older and had stage 0 to III breast cancer were recruited from August 2010 to December 2015. Assessments were performed before systemic therapy and 12 and 24 months later. Neuropsychological testing measured attention, processing speed, executive function, learning, and memory; self-perceived cognitive functioning was also assessed. Sleep disturbance was defined by self-report of routine poor or restless sleep. Genotyping included APOE, BDNF, and COMT polymorphisms. Random effects fluctuation models tested associations of between-person and within-person differences in sleep, genotype, and sleep-genotype interactions and cognition and controlled for age, reading level, race, site, and treatment. RESULTS One-third of the patients reported sleep disturbances at each time point. There was a sleep-APOE e4 interaction (P = .001) in which patients with the APOE e4 allele and sleep disturbances had significantly lower learning and memory scores than those who were APOE e4-negative and without sleep disturbances. There was also a sleep disturbance-COMT genotype interaction (P = .02) in which COMT Val carriers with sleep disturbances had lower perceived cognition than noncarriers. CONCLUSIONS Sleep disturbance was common and was associated with worse cognitive performance in older breast cancer survivors, especially those with a genetic risk for cognitive decline. Survivorship care should include sleep assessments and interventions to address sleep problems.

Introduction While telomere shortening, a marker of cellular aging, may impact the progression of age-related neurodegenerative diseases, its association with cognition is unclear, particularly in the context of Alzheimer's disease (AD) pathology. Methods Telomere, cognitive, and CSF data from 482 participants in the AD Neuroimaging Initiative (148 cognitively normal, 283 mild cognitive impairment, 51 AD) was leveraged to assess telomere length associations with cognition (measured by memory and executive function) and interactions with CSF amyloid-β, tau, and APOE-e4. Secondary analyses assessed brain volume and thickness outcomes. Results Longer telomeres at baseline were associated with faster executive function decline. Amyloid-β and tau interacted with telomere length on cognition, with longer telomeres related to faster decline among biomarker-positive individuals. Discussion Telomere associations with cognition shift with AD progression, with longer telomeres related to worse outcomes as pathology increases, highlighting the need for further investigation of telomere length along the AD neuropathological cascade.

BackgroundAlzheimer’s disease (AD) is a chronic progressive neurodegenerative disease impacting an estimated 44 million adults worldwide. The causal pathology of AD (accumulation of amyloid-beta and tau), precedes hallmark symptoms of dementia by more than a decade, necessitating development of early diagnostic markers of disease onset, particularly for new drugs that aim to modify disease processes. To evaluate differentially methylated positions (DMPs) as novel blood-based biomarkers of AD, we used a subset of 653 individuals with peripheral blood (PB) samples in the Alzheimer’s disease Neuroimaging Initiative (ADNI) consortium. The selected cohort of AD, mild cognitive impairment (MCI), and age-matched healthy controls (CN) all had imaging, genetics, transcriptomics, cerebrospinal protein markers, and comprehensive clinical records, providing a rich resource of concurrent multi-omics and phenotypic information on a well-phenotyped subset of ADNI participants.ResultsIn this manuscript, we report cross-diagnosis differential peripheral DNA methylation in a cohort of AD, MCI, and age-matched CN individuals with longitudinal DNA methylation measurements. Epigenome-wide association studies (EWAS) were performed using a mixed model with repeated measures over time with aPvalue cutoff of 1 × 10−5to test contrasts of pairwise differential peripheral methylation in AD vs CN, AD vs MCI, and MCI vs CN. The most highly significant differentially methylated loci also tracked with Mini Mental State Examination (MMSE) scores. Differentially methylated loci were enriched near brain and neurodegeneration-related genes (e.g.,BDNF, BIN1, APOC1) validated using the genotype tissue expression project portal (GTex).ConclusionsOur work shows that peripheral differential methylation between age-matched subjects with AD relative to healthy controls will provide opportunities to further investigate and validate differential methylation as a surrogate of disease. Given the inaccessibility of brain tissue, the PB-associated methylation marks may help identify the stage of disease and progression phenotype, information that would be central to bringing forward successful drugs for AD.

Background There are limited data on the phenotypic and dopamine transporter (DAT) imaging characterization of the Parkinson's disease (PD) patients with leucine rich kinase 2 (LRRK2) and glucosylceramidase beta (GBA) mutations. Objective The objective of this study was to examine baseline clinical and DAT imaging characteristics in GBA and LRRK2 mutation carriers with early PD compared with sporadic PD. Methods The Parkinson's Progression Markers Initiative is an ongoing observational longitudinal study that enrolled participants with sporadic PD, LRRK2 and GBA PD carriers from 33 sites worldwide. All participants are assessed annually with a battery of motor and nonmotor scales, 123-I Ioflupane DAT imaging, and biologic variables. Results We assessed 158 LRRK2 (89% G2019S), 80 GBA (89 %N370S), and 361 sporadic PD participants with the mean (standard deviation) disease duration of 2.9 (1.9), 3.1 (2.0), and 2.6 (0.6) years, respectively. When compared with sporadic PD, the GBA PD patients had no difference in any motor, cognitive, or autonomic features. The LRRK2 PD patients had less motor disability and lower rapid eye movement behavior disorder questionnaire scores, but no meaningful difference in cognitive or autonomic features. Both genetic cohorts had a higher score on the impulse control disorders scale when compared with sporadic PD, but no difference in other psychiatric features. Both genetic PD cohorts had less loss of dopamine transporter on DAT imaging when compared with sporadic PD. Conclusions We confirm previous reports of milder phenotype associated with LRRK2-PD. A previously reported more aggressive phenotype in GBA-PD is not evident early in the disease in N370s carriers. This observation identifies a window for potential disease-modifying interventions. Longitudinal data will be essential to define the slope of progression for both genetic cohorts. Trial registration ClinicalTrials.gov (NCT01141023). © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Author(s): Power, Melinda C; Mormino, Elizabeth; Soldan, Anja; James, Bryan D; Yu, Lei; Armstrong, Nicole M; Bangen, Katherine J; Delano-Wood, Lisa; Lamar, Melissa; Lim, Yen Ying; Nudelman, Kelly; Zahodne, Laura; Gross, Alden L; Mungas, Dan; Widaman, Keith F; Schneider, Julie | Abstract: ObjectiveOur objectives were to characterize the inter-relation of known dementia-related neuropathologies in one comprehensive model and quantify the extent to which accumulation of neuropathologies accounts for the association between age and dementia.MethodsWe used data from 1,362 autopsied participants of three community-based clinicopathological cohorts: the Religious Orders Study, the Rush Memory and Aging Project, and the Minority Aging Research Study. We estimated a series of structural equation models summarizing a priori hypothesized neuropathological pathways between age and dementia risk individually and collectively.ResultsAt time of death (mean age, 89 years), 44% of our sample had a clinical dementia diagnosis. When considered individually, our vascular, amyloid/tau, neocortical Lewy body, and TAR DNA-binding protein 43 (TDP-43)/hippocampal sclerosis pathology pathways each accounted for a substantial proportion of the association between age and dementia. When considered collectively, the four pathways fully accounted for all variance in dementia risk previously attributable to age. Pathways involving amyloid/tau, neocortical Lewy bodies, and TDP-43/hippocampal sclerosis were interdependent, attributable to the importance of amyloid beta plaques in all three. The importance of the pathways varied, with the vascular pathway accounting for 32% of the association between age and dementia, wheraes the remaining three inter-related degenerative pathways together accounted for 68% (amyloid/tau, 24%; the Lewy body, 1%; and TDP-43/hippocampal sclerosis, 43%).InterpretationAge-related increases in dementia risk can be attributed to accumulation of multiple pathologies, each of which contributes to dementia risk. Multipronged approaches may be necessary if we are to develop effective therapies. Ann Neurol 2018;84:10-22.

Purpose To describe the impact of chemotherapy-induced peripheral neuropathy symptoms (CIPN-sx) on breast cancer survivors’ (BCS) perceived ability to work post-treatment. Methods The sample included 22 chemotherapy-treated (Ctx+) and 22 chemotherapy-naïve (Ctx−) female BCS. Data was collected at the following three time points: baseline (post-surgery, pre-chemotherapy), 1 month (1 M) post-chemotherapy, and approximately 1 year (1 Y) later. The presence, frequency, number, and severity of CIPN-sx were self-reported using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Neurotoxicity questionnaire (FACT/GOG-Ntx) version 4, a validated 11-item CIPN measure. Perceived ability to work was measured using an item from the Functional Well-Being subscale of the FACT/GOG-Ntx. Results At 1 Y, more than 50 % of Ctx+ reported discomfort, numbness, or tingling in their hands or feet; weakness; or difficulty feeling small objects. The presence, number, and severity of these symptoms were correlated with being less able to work for Ctx+ at 1 M but not 1 Y. Results of a regression analysis using CIPN-sx to predict work ability found that models combining (1) hand numbness and trouble feeling small objects, (2) trouble buttoning buttons and trouble feeling small objects, (3) foot numbness and foot pain, (4) foot numbness and trouble walking, and (5) trouble hearing and hand pain each predicted survivors who were “not at all” able to work at 1 M. Conclusions Unresolved CIPN-sx may play a role in challenges working for BCS post-treatment. These findings highlight the need for research to explore the impact that CIPN-sx have on BCS’ ability to work, as well as the development of interventions to improve work function in BCS with CIPN-sx.

New neurons are generated throughout adulthood in two regions of the brain, the olfactory bulb and dentate gyrus of the hippocampus, and are incorporated into the hippocampal network circuitry; disruption of this process has been postulated to contribute to neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. Known modulators of adult neurogenesis include signal transduction pathways, the vascular and immune systems, metabolic factors, and epigenetic regulation. Multiple intrinsic and extrinsic factors such as neurotrophic factors, transcription factors, and cell cycle regulators control neural stem cell proliferation, maintenance in the adult neurogenic niche, and differentiation into mature neurons; these factors act in networks of signaling molecules that influence each other during construction and maintenance of neural circuits, and in turn contribute to learning and memory. The immune system and vascular system are necessary for neuronal formation and neural stem cell fate determination. Inflammatory cytokines regulate adult neurogenesis in response to immune system activation, whereas the vasculature regulates the neural stem cell niche. Vasculature, immune/support cell populations (microglia/astrocytes), adhesion molecules, growth factors, and the extracellular matrix also provide a homing environment for neural stem cells. Epigenetic changes during hippocampal neurogenesis also impact memory and learning. Some genetic variations in neurogenesis related genes may play important roles in the alteration of neural stem cells differentiation into new born neurons during adult neurogenesis, with important therapeutic implications. In this review, we discuss mechanisms of and interactions between these modulators of adult neurogenesis, as well as implications for neurodegenerative disease and current therapeutic research. © 2016 Wiley Periodicals, Inc.

Although Alzheimer's disease (AD) is an international health research priority for our aging population, little therapeutic progress has been made. This lack of progress may be partially attributable to disease heterogeneity. Previous studies have identified an inverse association of cancer and AD, suggesting that cancer history may be one source of AD heterogeneity. These findings are particularly interesting in light of the number of common risk factors and two-hit models hypothesized to commonly drive both diseases. We reviewed the ten hallmark biological alterations of cancer cells to investigate overlap with the AD literature and identified overlap of all ten hallmarks in AD, including (1) potentially common underlying risk factors, such as increased inflammation, deregulated cellular energetics, and genome instability; (2) inversely regulated mechanisms, including cell death and evading growth suppressors; and (3) functions with more complex, pleiotropic mechanisms, some of which may be stage-dependent in AD, such as cell adhesion/contact inhibition and angiogenesis. Additionally, we discuss the recent observation of a biological link between cancer and AD neuropathology. Finally, we address the therapeutic implications of this topic. The significant overlap of functional pathways and molecules between these diseases, some similarly and some oppositely regulated or functioning in each disease, supports the need for more research to elucidate cancer-related AD genetic and functional heterogeneity, with the aims of better understanding AD risk mediators, as well as further exploring the potential for some types of drug repurposing towards AD therapeutic development.

Alzheimer’s disease (AD) is a major public health threat; however, despite decades of research, the disease mechanisms are not completely understood, and there is a significant dearth of predictive biomarkers. The availability of systems biology approaches has opened new avenues for understanding disease mechanisms at a pathway level. However, to the best of our knowledge, no prior study has characterized the nature of pathway crosstalks in AD, or examined their utility as biomarkers for diagnosis or prognosis. In this paper, we build the first computational crosstalk model of AD incorporating genetics, antecedent knowledge, and biomarkers from a national study to create a generic pathway crosstalk reference map and to characterize the nature of genetic and protein pathway crosstalks in mild cognitive impairment (MCI) subjects. We perform initial studies of the utility of incorporating these crosstalks as biomarkers for assessing the risk of MCI progression to AD dementia. Our analysis identified Single Nucleotide Polymorphism-enriched pathways representing six of the seven Kyoto Encyclopedia of Genes and Genomes pathway categories. Integrating pathway crosstalks as a predictor improved the accuracy by 11.7% compared to standard clinical parameters and apolipoprotein E ε4 status alone. Our findings highlight the importance of moving beyond discrete biomarkers to studying interactions among complex biological pathways.

Purpose To investigate the longitudinal relationship between chemotherapy-induced peripheral neuropathy (CIPN) symptoms (sx) and brain perfusion changes in patients with breast cancer. Interaction of CIPN-sx perfusion effects with known chemotherapy-associated gray matter density decrease was also assessed to elucidate the relationship between CIPN and previously reported cancer treatment–related brain structural changes. Methods Patients with breast cancer treated with (n = 24) or without (n = 23) chemotherapy underwent clinical examination and brain magnetic resonance imaging at the following three time points: before treatment (baseline), 1 month after treatment completion, and 1 year after the 1-month assessment. CIPN-sx were evaluated with the self-reported Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Neurotoxicity four-item sensory-specific scale. Perfusion and gray matter density were assessed using voxel-based pulsed arterial spin labeling and morphometric analyses and tested for association with CIPN-sx in the patients who received chemotherapy. Results Patients who received chemotherapy reported significantly increased CIPN-sx from baseline to 1 month, with partial recovery by 1 year (P < .001). CIPN-sx increase from baseline to 1 month was significantly greater for patients who received chemotherapy compared with those who did not (P = .001). At 1 month, neuroimaging showed that for the group that received chemotherapy, CIPN-sx were positively associated with cerebral perfusion in the right superior frontal gyrus and cingulate gyrus, regions associated with pain processing (P < .001). Longitudinal magnetic resonance imaging analysis in the group receiving chemotherapy indicated that CIPN-sx and associated perfusion changes from baseline to 1 month were also positively correlated with gray matter density change (P < .005). Conclusion Peripheral neuropathy symptoms after systemic chemotherapy for breast cancer are associated with changes in cerebral perfusion and gray matter. The specific mechanisms warrant further investigation given the potential diagnostic and therapeutic implications.

Cerebral structural and functional alterations have been reported after chemotherapy for non-CNS cancers, yet the causative mechanism behind these changes remains unclear. This study employed a novel, non-invasive, MRI-based neuroimaging measure to provide the first direct longitudinal measurement of resting cerebral perfusion in breast cancer patients, which was tested for association with changes in cognitive function and gray matter density. Perfusion was measured using pulsed arterial spin labeling MRI in women with breast cancer treated with (N = 27) or without (N = 26) chemotherapy and matched healthy controls (N = 26) after surgery before other treatments (baseline), and one month after chemotherapy completion or yoked intervals. Voxel-based analysis was employed to assess perfusion in gray matter; changes were examined in relation to overall neuropsychological test performance and frontal gray matter density changes measured by structural MRI. Baseline perfusion was not significantly different across groups. Unlike control groups, chemotherapy-treated patients demonstrated significantly increased perfusion post-treatment relative to baseline, which was statistically significant relative to controls in the right precentral gyrus. This perfusion increase was negatively correlated with baseline overall neuropsychological performance, but was not associated with frontal gray matter density reduction. However, decreased frontal gray matter density was associated with decreased perfusion in bilateral frontal and parietal lobes in the chemotherapy-treated group. These findings indicate that chemotherapy is associated with alterations in cerebral perfusion which are both related to and independent of gray matter changes. This pattern of results suggests the involvement of multiple mechanisms of chemotherapy-induced cognitive dysfunction. Additionally, lower baseline cognitive function may be a risk factor for treatment-associated perfusion dysregulation. Future research is needed to clarify these mechanisms, identify individual differences in susceptibility to treatment-associated changes, and further examine perfusion change over time in survivors.