ABSTRACT
Histiocytic neoplasms are a heterogeneous group of clonal haematopoietic disorders that are marked by diverse mutations in the mitogen-activated protein kinase (MAPK) pathway1,2. For the 50% of patients with histiocytosis who have BRAFV600 mutations3-5, RAF inhibition is highly efficacious and has markedly altered the natural history of the disease6,7. However, no standard therapy exists for the remaining 50% of patients who lack BRAFV600 mutations. Although ERK dependence has been hypothesized to be a consistent feature across histiocytic neoplasms, this remains clinically unproven and many of the kinase mutations that are found in patients who lack BRAFV600 mutations have not previously been biologically characterized. Here we show ERK dependency in histiocytoses through a proof-of-concept clinical trial of cobimetinib, an oral inhibitor of MEK1 and MEK2, in patients with histiocytoses. Patients were enrolled regardless of their tumour genotype. In parallel, MAPK alterations that were identified in treated patients were characterized for their ability to activate ERK. In the 18 patients that we treated, the overall response rate was 89% (90% confidence interval of 73-100). Responses were durable, with no acquired resistance to date. At one year, 100% of responses were ongoing and 94% of patients remained progression-free. Cobimetinib treatment was efficacious regardless of genotype, and responses were observed in patients with ARAF, BRAF, RAF1, NRAS, KRAS, MEK1 (also known as MAP2K1) and MEK2 (also known as MAP2K2) mutations. Consistent with the observed responses, the characterization of the mutations that we identified in these patients confirmed that the MAPK-pathway mutations were activating. Collectively, these data demonstrate that histiocytic neoplasms are characterized by a notable dependence on MAPK signalling-and that they are consequently responsive to MEK inhibition. These results extend the benefits of molecularly targeted therapy to the entire spectrum of patients with histiocytosis.
Subject(s)
Azetidines/therapeutic use , Histiocytic Disorders, Malignant/drug therapy , Histiocytic Disorders, Malignant/enzymology , Histiocytosis/drug therapy , Histiocytosis/enzymology , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Piperidines/therapeutic use , Azetidines/pharmacology , Histiocytic Disorders, Malignant/genetics , Histiocytic Disorders, Malignant/pathology , Histiocytosis/genetics , Histiocytosis/pathology , Humans , MAP Kinase Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 2/antagonists & inhibitors , MAP Kinase Kinase 2/genetics , MAP Kinase Signaling System/drug effects , Mutation , Piperidines/pharmacology , Progression-Free Survival , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins c-raf/geneticsABSTRACT
PURPOSE: Glioblastoma (GBM) is a devastating neuro-oncologic disease with invariably poor prognosis. Despite this, research shows patients have unrealistic perceptions of their prognosis, which may relate in part to communication patterns between patients, caregivers and oncologists. The purpose of this study was to examine communication processes and goals among patients, caregivers, and oncologists to elucidate drivers of prognostic understanding (PU) in the context of recurrent GBM. METHODS: This was a prospective, multi-center study enrolling adult patients with GBM, caregivers, and oncologists, who independently reported the content of a specific discussion involving the disclosure of GBM recurrence. Communication processes and goals were characterized for each participant, and concordance between all dyads and patient-caregiver-oncologist triads were calculated. RESULTS: Seventeen patient, caregiver, and oncologist triads were analyzed. At the individual level, three (17.6%) patients and 8 (47.1%) caregivers reported having discussed prognosis during the clinical encounter, as compared to ten oncologists (58.8%). Seven patients (41.2%) and 5 caregivers (29.4%), versus thirteen oncologists (76.5%) reported ever discussing prognosis or life expectancy at previous appointments. Generally, patient-caregiver concordance (i.e., both answered the same) regarding communication goals and processes was low. Triads showed limited concordant responses in discussing curability (n = 5), prognosis (n = 4), end-of-life treatment goals (n = 4), and ever discussing prognosis (n = 3). CONCLUSION: Patients, caregivers and oncologists had discordant views regarding communication processes and prognostic goals, even when recalling a single discussion. This study highlights the importance of clear and frequent communication about prognosis, and the need for further research on communication and PU in the neuro-oncology setting.
Subject(s)
Glioblastoma , Neoplasms , Oncologists , Adaptation, Psychological , Adult , Caregivers , Glioblastoma/therapy , Humans , Neoplasms/therapy , Physician-Patient Relations , Prognosis , Prospective StudiesABSTRACT
OBJECTIVES: The aim of this study was to [1] characterize distribution of Erdheim-Chester Disease (ECD) by 18F-FDG PET/CT and [2] determine the utility of metabolic (18F-FDG PET/CT) imaging versus anatomic imaging (CT or MRI) in evaluating ECD patients for clinical trial eligibility. METHODS: 18F-FDG PET/CT and corresponding CT or MRI studies for ECD patients enrolled in a prospective registry study were reviewed. Sites of disease were classified as [1] detectable by 18F-FDG PET only, CT/MRI only, or both and as [2] measurable by modified PERCIST (mPERCIST) only, RECIST only, or both. Descriptive analysis was performed and paired t test for between-group comparisons. RESULTS: Fifty patients were included (mean age 51.5 years; range 18-70 years). Three hundred thirty-three disease sites were detected among all imaging modalities, 188 (56%) by both 18F-FDG PET and CT/MRI, 67 (20%) by 18F-FDG PET only, 75 (23%) by MRI brain only, and 3 (1%) by CT only. Of 178 disease sites measurable by mPERCIST or RECIST, 40 (22%) were measurable by both criteria, 136 (76%) by mPERCIST only, and 2 (1%) by RECIST only. On the patient level, 17 (34%) had mPERCIST and RECIST measurable disease, 30 (60%) had mPERCIST measurable disease only, and 0 had RECIST measurable disease only (p < 0.0001). CONCLUSION: Compared with anatomic imaging, 18F-FDG PET/CT augments evaluation of disease extent in ECD and increases identification of disease sites measurable by formal response criteria and therefore eligibility for clinical trials. Complementary organ-specific anatomic imaging offers the capacity to characterize sites of disease in greater anatomic detail. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03329274.
Subject(s)
Erdheim-Chester Disease , Fluorodeoxyglucose F18 , Adolescent , Adult , Aged , Erdheim-Chester Disease/diagnostic imaging , Humans , Middle Aged , Positron Emission Tomography Computed Tomography , Positron-Emission Tomography , Registries , Young AdultABSTRACT
BACKGROUND: The Relational and Item-Specific Encoding task (RISE) measures episodic memory subcomponents, including item-specific and relational encoding of to-be-remembered stimuli. These memory components are neurobiologically relevant because they may engage distinct subregions of the medial temporal lobe, perirhinal and entorhinal cortices, parahippocampus, and hippocampus. METHODS: A total of 125 participants, including 84 healthy controls (HC), 22 mild cognitive impairment-diagnosed and 19 Alzheimer disease (AD)-diagnosed participants, were administered the RISE and neuropsychological measures. Stepwise linear regressions assessed prediction of functional ability from RISE d' measures. ANOVAs and logistic regressions determined the ability of the RISE to discriminate between the diagnostic groups. In addition, the psychometric properties of the RISE were examined. RESULTS: RISE measures predicted diagnosis with pseudo R2 values in the range of 0.25-0.30. Receiver operating characteristic curves demonstrated adequate sensitivity and specificity with areas under the curve in the range of 0.78-0.98. Memory following relational encoding was a significant predictor of everyday functional competence. The RISE had acceptable psychometric properties, with the exception of floor effects in the AD group. CONCLUSION: The RISE measures significantly predicted diagnosis and predicted everyday functional competence. The RISE offers unique advantages in the assessment of HC and individuals with preclinical AD.
Subject(s)
Alzheimer Disease/psychology , Cognitive Dysfunction/psychology , Memory, Episodic , Adult , Aged , Aged, 80 and over , Case-Control Studies , Female , Humans , Linear Models , Logistic Models , Male , Memory , Middle Aged , Psychometrics , ROC CurveABSTRACT
PURPOSE: To overcome barriers to genomic testing for patients with rare cancers, we initiated a program to offer free clinical tumor genomic testing worldwide to patients with select rare cancer subtypes. EXPERIMENTAL DESIGN: Patients were recruited through social media outreach and engagement with disease-specific advocacy groups, with a focus on patients with histiocytosis, germ cell tumors (GCT), and pediatric cancers. Tumors were analyzed using the MSK-IMPACT next-generation sequencing assay with the return of results to patients and their local physicians. Whole-exome recapture was performed for female patients with GCTs to define the genomic landscape of this rare cancer subtype. RESULTS: A total of 333 patients were enrolled, and tumor tissue was received for 288 (86.4%), with 250 (86.8%) having tumor DNA of sufficient quality for MSK-IMPACT testing. Eighteen patients with histiocytosis have received genomically guided therapy to date, of whom 17 (94%) have had clinical benefit with a mean treatment duration of 21.7 months (range, 6-40+). Whole-exome sequencing of ovarian GCTs identified a subset with haploid genotypes, a phenotype rarely observed in other cancer types. Actionable genomic alterations were rare in ovarian GCT (28%); however, 2 patients with ovarian GCTs with squamous transformation had high tumor mutational burden, one of whom had a complete response to pembrolizumab. CONCLUSIONS: Direct-to-patient outreach can facilitate the assembly of cohorts of rare cancers of sufficient size to define their genomic landscape. By profiling tumors in a clinical laboratory, results could be reported to patients and their local physicians to guide treatment. See related commentary by Desai and Subbiah, p. 2339.
Subject(s)
Neoplasms, Germ Cell and Embryonal , Ovarian Neoplasms , Humans , Female , Mutation , Genomics , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , ExomeABSTRACT
Background and Objectives: Novel diagnostic techniques and neurologic biomarkers have greatly expanded clinical indications for CSF studies. CSF is most commonly obtained via lumbar puncture (LP). Although it is generally believed that LPs are well tolerated, there is a lack of supportive data for this claim, and patients anticipate LP to be painful. The objective of this study was to prospectively investigate discordance between patient perception and tolerability of LP. Methods: Adult patients were surveyed before and after LP regarding their perceptions and experience of LP. Physician perceptions were gathered through a web-based survey. Relative risk and Spearman correlation were used to assess the relationship between responses. Paired binomial and paired ordinal responses were compared by McNemar and paired Wilcoxon rank-sum tests. Results: A total of 178 patients completed the surveys. About half of the patients (58%) reported anxiety pre-LP, at median 3.0 of 10. Physicians overpredicted patients' pre-LP anxiety (median score 5.0, p < 0.001). Experienced pain was significantly less than predicted pain (median scores 0 and 3.0, respectively, p < 0.001). Patients who predicted pain were more likely to report pain from LP (relative risk [RR] 1.3). Predicting pain was also correlated with anxiety before LP (p < 0.001). Discussion: LP was generally well tolerated. The majority of patients experienced minimal pain. Anticipation of pain was correlated with both feeling anxious and experiencing pain. The results of this study can be used to reassure patients and providers that LP is indeed not as painful as imagined, which may both reduce pre-LP anxiety and improve LP tolerability.
ABSTRACT
Background: The importance of deriving benefit and meaning has been identified among cancer caregivers, but this has yet to be examined in the context of rare cancers. We sought to characterize unmet needs and experiences of caregivers of patients with Erdheim-Chester disease (ECD) and other histiocytic neoplasms (HN) and to identify factors associated with finding benefit and meaning-making in providing care for patients with rare cancers. Methods: Caregivers of patients with ECD and other HN completed quantitative surveys. Linear univariable regression modeling examined associations between unmet needs, social and family support, and intolerance of uncertainty with benefit finding and meaning-making. A subset participated in qualitative interviews assessing experiences of rare cancer caregiving that were analyzed with applied thematic analysis (NCT039900428). Findings: Of caregivers (N = 92, M = 54 years old, 68% female) of patients with ECD (75%) and other HN (25%), 78% reported moderately or severely unmet support needs, most frequently informational (58%) and psychological/emotional (66%) needs. Caregivers with unmet informational, psychological/emotional, and social support needs, difficulty tolerating uncertainty, a longer duration of the patient's illness, lower social support, more family conflict, and higher anxiety and depression symptoms demonstrated less benefit finding and meaning-making (ps <.05). Qualitative interviews (N = 19) underscored information and support needs and the capacity to derive meaning from caregiving. Interpretation: Rare cancer caregivers report numerous unmet information and support needs, needs that arise from disease rarity itself and which are associated with diminished capacity for deriving benefit and meaning from caregiving. Findings highlight targets for interventions to improve support for caregivers with HN and other rare cancers. Funding: NIH P30 CA008748 (PI: Craig Thompson, MD), NIH T32 CA009461 (H.M.; PI: Jamie Ostroff, PhD), Frame Family Fund (E.L.D.), Applebaum Foundation (E.L.D.).
ABSTRACT
Erdheim-Chester disease (ECD) is characterized by excessive production and accumulation of histiocytes within multiple tissues and organs. ECD patients harbor recurrent mutations of genes associated with the RAS/RAF/MEK/ERK signaling pathway, particularly, the BRAFV600E mutation. Following our previous finding that miR-15a-5p is the most prominently downregulated microRNA in ECD patients compared to healthy individuals, we elucidated its role in ECD pathogenesis. Bioinformatics analysis followed by a luciferase assay showed that chemokine ligand 10 (CXCL10) is a target gene regulated by miRNA-15a-5p. This was confirmed in 24/34 ECD patients that had low expression of miR-15a-5p concurrent with upregulated CXCL10. Overexpression of miR-15a-5p in cell lines harboring BRAF or RAS mutations (Ba/F3, KG-1a and OCI-AML3) resulted in CXCL10 downregulation, followed by LIN28a and p-ERK signaling downregulation and let-7 family upregulation. Overexpression of miR-15a-5p inhibited cell growth and induced apoptosis by decreasing Bcl-2 and Bcl-xl levels. Analysis of sequential samples from 7 ECD patients treated with MAPK inhibitors (vemurafenib/cobimetinib) for 4 months showed miR-15a-5p upregulation and CXCL10 downregulation. Our findings suggest that miR-15a-5p is a tumor suppressor in ECD through the CXCL10-ERK-LIN28a-let7 axis, highlighting another layer of post-transcriptional regulation in this disease. Upregulation of miR-15a-5p in ECD patients may have a potential therapeutic role.
Subject(s)
Erdheim-Chester Disease , MicroRNAs , Chemokine CXCL10/genetics , Chemokine CXCL10/metabolism , Down-Regulation , Genes, Tumor Suppressor , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , Up-RegulationABSTRACT
BACKGROUND: Management of patients with brain tumors can lead to ethical and decisional dilemmas. The aim of this study was to characterize ethical conflicts encountered in neuro-oncologic patients. METHODS: Retrospective review of ethics consultations performed upon patients with primary and metastatic brain tumors at a tertiary cancer center. An ethics consultation database was examined to characterize ethical conflicts, contextual factors, and interventions by the consultation team. RESULTS: Fifty consultations were reviewed; 28 (56%) patients were women, median age 54 (range 4-86); 27 (54%) patients had a primary central nervous system malignancy; 20 (40%) had brain metastasis. At the time of consultations, 41 (82%) patients lacked decisional capacity; 48 (96%) had a designated surrogate decision maker; 3 (6%) had an advance directive outlining wishes regarding medical treatment; 12 (24%) had a Do Not Attempt Resuscitation (DNAR) order. Ethical conflicts centered upon management of end-of-life (EOL) circumstances in 37 (72%) of cases; of these, 30 did not have decisional capacity. The most common ethical issues were DNAR status, surrogate decision making, and request for nonbeneficial treatment. Consultants resolved conflicts by facilitating decision making for incapacitated patients in 30 (60%) cases, communication between conflicting parties in 10 (20%), and re-articulation of patients' previously stated wishes in 6 (12%). CONCLUSIONS: Decisional capacity at EOL represents the primary ethical challenge in care of neuro-oncologic patients. Incomplete awareness among surrogate decision makers of patients' prognosis and preferences contributes to communication gaps and dilemmas. Early facilitation of communication between patients, caregivers, and medical providers may prevent or mitigate conflicts and allow the enactment of patients' goals and values.
ABSTRACT
Research examining the experience of informal caregivers (ICs) for patients with rare cancers is limited. This was a mixed-methods pilot study of 14 ICs for patients with Erdheim-Chester disease (ECD), an ultra-rare neoplasm. Participants were predominantly female and over half provided at least 60% of their loved one's care. Participants completed measures of the impact of caregiving, caregiver burden, unmet needs, quality of life, anxiety, and depression. Participants reported substantial impact of caregiving, including limiting (50%) or discontinuing (21%) paid employment, and exhausting financial savings (43%). ICs reported a moderate level of burden with five (38%) reporting risk for burnout. While participants reported anxiety (64%) and depression (14%), their overall quality of life was favorable. Semi-structured interviews highlighted factors related to the distress and isolation of navigating a rare cancer. ECD ICs report burden and distress shaped by the experience of providing care for a patient with a rare cancer.
Subject(s)
Erdheim-Chester Disease , Neoplasms , Caregivers , Female , Humans , Pilot Projects , Quality of LifeABSTRACT
The pathogenesis of histiocytic neoplasms is driven by mutations activating the MAPK/ERK pathway, but little is known about the transcriptional and post-transcriptional alterations involved in these neoplasms. We analyzed microRNA (miRNA) expression in plasma samples and tissue biopsies of Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) patients. In silico analysis revealed a potential role of miRNAs in regulating gene expression in these neoplasms as compared with healthy controls (HC). NanoString analysis revealed 101 differentially expressed plasma miRNAs in 16 ECD patients as compared with 11 HC, 95% of which were downregulated. MiRNAs-15a-5p, -15b-5p, -21-5p, -107, -221-3p, -320e, -630, and let-7 family miRNAs were further evaluated by qRT-PCR in an extended cohort of 32 ECD patients, seven LCH and 15 HC. Six miRNAs (let-7a, let-7c, miR-15a-5p, miR-15b-5p, miR-107 and miR-630) were highly expressed in LCH plasma and tissue samples as compared with ECD. Pathway enrichment analysis indicated the miRNA contribution to inflammatory and pro-survival signaling pathways. Moreover, the let-7 family members were downregulated in untreated ECD patients as compared with HC, while treatment with MAPK/ERK signaling inhibitors for 16 weeks resulted in their upregulation, which was in parallel with the radiologic response seen by PET-CT. The study highlights the potential contribution of miRNA to the inflammatory and neoplastic characteristics of ECD and LCH.
ABSTRACT
Erdheim-Chester disease (ECD) is an ultra-rare hematologic neoplasm characterized by somatic mutations of the MAPK pathway and by accumulation of lesional histiocytes within tissues. Clinical phenotypes and sites of disease involvement are heterogenous in ECD, and no tool exists for systematic and comprehensive assessment of ECD symptomatology. We describe a collaborative effort among ECD specialists, patient-reported outcome (PRO) methodologists, and ECD patients to develop the Erdheim-Chester Disease Symptom Scale (ECD-SS): a symptom inventory for clinical ECD care and evaluation of ECD therapies. Methodologically rigorous focus groups led to the identification of 63 ECD symptoms in 6 categories, incorporated into the ECD-SS with respect to both severity and frequency. Among 50 ECD patients participating in a prospective registry study completing the ECD-SS, 46 (92%) reported neurological/psychological symptoms, 29 (58%) reported pain, and at least one-half reported mood symptoms, memory problems, or fatigue. Symptoms were highly frequent or almost constant regardless of their severity. The ECD-SS is a rigorously developed, patient-centered tool that demonstrates the wide and previously unappreciated burden of symptomatology experienced by ECD patients. Further studies will refine the symptom inventory and define its psychometric properties and role in clinical care and investigation in the context of ECD.
Subject(s)
Erdheim-Chester Disease/diagnosis , Symptom Assessment/methods , Affect , Fatigue , Humans , Memory , Middle Aged , Pain , Patient Reported Outcome Measures , Severity of Illness IndexABSTRACT
BACKGROUND: Malignant glioma (MG) is a devastating neuro-oncologic disease with almost invariably poor prognosis. Prognostic awareness (PA) is the awareness of incurable disease and shortened life expectancy (LE). Accurate PA is associated with favorable psychological outcomes at the end of life (EoL) for patients with cancer; however, little is known about PA or prognostic communication in MG. Moreover, research has yet to evaluate the impact of cognitive impairment on PA and preferred forms of communication. METHODS: Fifty MG patients and 32 paired caregivers were evaluated in this exploratory study with a semi-structured PA assessment aimed to measure their awareness of MG incurability and LE. Full PA was defined as awareness of MG incurability and accurate estimate of LE. The assessment included a survey about preferences for prognostic communication (items from the Prognosis and Treatment Perceptions Questionnaire), neurocognitive assessment (Hopkins Verbal Learning Test-Revised, Trail Making Test Parts A and B, and the Controlled Oral Word Association Test), and measurements of mood (Hospital Anxiety and Depression Scale) and quality of life (Functional Assessment of Cancer Therapy-Brain [FACT-Br]). RESULTS: Twenty (40%) patients and 22 (69%) caregivers had full PA. Thirty (60%) patients and 23 (72%) caregivers reported that prognostic information was extremely or very important, and 21 (42%) patients and 16 (50%) caregivers desired more prognostic information. Patients with memory impairment more frequently believed that prognostic information was important (P = 0.04, P = 0.03) and desired more information (P = 0.05, P = 0.003) as compared with those without impairment. CONCLUSIONS: Most MG patients were unaware of their LE. Memory impairment may influence preferences for prognostic information.
Subject(s)
Caregivers/psychology , Cognition/physiology , Communication , Glioma/psychology , Health Knowledge, Attitudes, Practice , Quality of Life , Adolescent , Adult , Aged , Aged, 80 and over , Attitude to Health , Female , Follow-Up Studies , Glioma/physiopathology , Humans , Life Expectancy , Male , Middle Aged , Prognosis , Prospective Studies , Surveys and Questionnaires , Young AdultABSTRACT
BACKGROUND: Attention to existential needs is a component of comprehensive oncologic care, and understanding these needs among informal caregivers of patients with brain tumors is necessary to provide them with comprehensive psychosocial care. The purpose of this systematic review was to synthesize the literature on existential distress experienced by these informal caregivers to inform the development of psychotherapeutic interventions for this population. METHODS: A systematic review was conducted using electronic medical databases. Studies that examined any element of existential distress among informal caregivers of patients with brain tumors were included. A final sample of 35 articles was reviewed. RESULTS: Six existential themes emerged: identity; isolation; responsibility and guilt; death anxiety; deriving meaning and personal growth; and spirituality and religion. The unique existential experience of parenting a patient with a brain tumor also emerged. Existential distress in all areas was identified as experienced early in the cancer trajectory and as a critical, unmet need. CONCLUSIONS: Existential distress is well documented among informal caregivers of patients with brain tumors and is a significant driving force of burden. Awareness and acknowledgement of this distress, as well as interventions to ameliorate this suffering, are needed. More candid communication between health care providers and caregivers about brain tumor prognosis and caregivers' existential distress may improve their psychosocial outcomes.
ABSTRACT
BACKGROUND: Proton magnetic resonance spectroscopy ((1)H-MRS) studies on healthy aging have reported inconsistent findings and have not systematically taken into account the possible modulatory effect of APOE genotype. We aimed to quantify brain metabolite changes in healthy subjects in relation to age and the presence of the APOE E4 genetic risk factor for Alzheimer's disease. Additionally, we examined these measures in relation to cognition. METHODS: We studied a cohort of 112 normal adults between 50 and 86 years old who were genotyped for APOE genetic polymorphism. Measurements of (1)H-MRS metabolites were obtained in the posterior cingulate and precuneus region. Measures of general cognitive functioning, memory, executive function, semantic fluency, and speed of processing were also obtained. RESULTS: General linear model analysis demonstrated that older APOE E4 carriers had significantly higher choline/creatine and myo-inositol/creatine ratios than APOE E3 homozygotes. Structural equation modeling resulted in a model with an excellent goodness of fit and in which the APOE × age interaction and APOE status each had a significant effect on (1)H-MRS metabolites (choline/creatine and myo-inositol/creatine). Furthermore, the APOE × age variable modulation of cognition was mediated by (1)H-MRS metabolites. CONCLUSIONS: In a healthy aging normal population, choline/creatine and myo-inositol/creatine ratios were significantly increased in APOE E4 carriers, suggesting the presence of neuroinflammatory processes and greater membrane turnover in older carriers. Structural equation modeling analysis confirmed these possible neurodegenerative markers and also indicated the mediator role of these metabolites on cognitive performance among older APOE E4 carriers.
Subject(s)
Aging/genetics , Aging/metabolism , Apolipoproteins E/genetics , Brain/metabolism , Aged , Aged, 80 and over , Apolipoprotein E3/genetics , Apolipoprotein E4/genetics , Choline/metabolism , Creatine/metabolism , Female , Genotype , Humans , Inositol/metabolism , Magnetic Resonance Spectroscopy/methods , Male , Mental Processes/physiology , Middle Aged , Neuropsychological Tests , ProtonsABSTRACT
OBJECTIVE: The authors sought to directly examine compromises in the semantic system in mild cognitive impairment and their possible relationship to everyday functional competencies. METHOD: Study participants were 25 patients who met criteria for amnestic mild cognitive impairment, 27 patients with mild or moderate Alzheimer's disease, and 70 healthy comparison subjects. The authors administered a novel semantic distance task in which participants make decisions about word or image stimuli that correspond to real-world entities that differ in physical size. The authors also administered a performance-based measure of everyday functional competence. RESULTS: Participants in the mild cognitive impairment and Alzheimer's groups were consistently less accurate and slower than healthy comparison subjects in semantic decisions in which words were used as stimuli. When these participants had to make more fine-grained decisions about the semantic attribute of size, their performance in accuracy and reaction time disproportionately worsened relative to that of comparison subjects. In image-based conditions in which line drawings were used as stimuli, sensory-perceptual information (i.e., the size of the drawings themselves) had undue influence over semantic knowledge judgments in the mild cognitive impairment and Alzheimer's groups. Performance in the semantic distance task was a strong and significant predictor of everyday functional competence in the mild cognitive impairment and Alzheimer's groups. CONCLUSIONS: This study synthesized several distinct strands in the mild cognitive impairment literature by providing evidence for 1) compromises in the semantic system in mild cognitive impairment, not confounded by overt retrieval or refractory access; 2) intrusion of perceptual information on semantic processing; and 3) a robust relation between semantic corruption and difficulties in everyday functioning.