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1.  Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults 
Neurology  2011;76(16):1395-1402.
Objective:
Since Alzheimer disease (AD) neuropathology is thought to develop years before dementia, it may be possible to detect subtle AD-related atrophy in preclinical AD. Here we hypothesized that the “disease signature” of AD-related cortical thinning, previously identified in patients with mild AD dementia, would be useful as a biomarker to detect anatomic abnormalities consistent with AD in cognitively normal (CN) adults who develop AD dementia after longitudinal follow-up.
Methods:
We studied 2 independent samples of adults who were CN when scanned. In sample 1, 8 individuals developing AD dementia (CN-AD converters) after an average of 11.1 years were compared to 25 individuals who remained CN (CN-stable). In sample 2, 7 CN-AD converters (average follow-up 7.1 years) were compared to 25 CN-stable individuals.
Results:
AD-signature cortical thinning in CN-AD converters in both samples was remarkably similar, about 0.2 mm (p < 0.05). Despite this small absolute difference, Cohen d effect sizes for these differences were very large (>1). Of the 11 CN individuals with baseline low AD-signature thickness (≥1 SD below cohort mean), 55% developed AD dementia over nearly the next decade, while none of the 9 high AD-signature thickness individuals (≥1 SD above mean) developed dementia. This marker predicted time to diagnosis of dementia (hazard ratio = 3.4, p < 0.0005); 1 SD of thinning increased dementia risk by 3.4.
Conclusions:
By focusing on cortical regions known to be affected in AD dementia, subtle but reliable atrophy is identifiable in asymptomatic individuals nearly a decade before dementia, making this measure a potentially important imaging biomarker of early neurodegeneration.
doi:10.1212/WNL.0b013e3182166e96
PMCID: PMC3087406  PMID: 21490323
2.  Imaging amyloid deposition in Lewy body diseases 
Neurology  2008;71(12):903-910.
Background:
Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD).
Objectives:
To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features.
Methods:
Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio.
Results:
Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function.
Conclusions:
Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism.
GLOSSARY
= Automated Anatomic Labeling;
= Alzheimer disease;
= Alzheimer’s Disease Research Center;
= American version of the National Adult Reading Test;
= analysis of covariance;
= Blessed Dementia Scale;
= cerebral amyloid angiopathy;
= Clinical Dementia Rating;
= Clinical Dementia Rating Sum of Boxes;
= dementia with Lewy bodies;
= distribution volume ratio;
= Cued Selective Reminding Test;
= Free Selective Reminding Test;
= Hoehn and Yahr;
= Massachusetts General Hospital;
= Mini-Mental State Examination;
= normal control;
= neurofibrillary tangle;
= Neuropsychiatric Inventory Questionnaire;
= not significant;
= Parkinson disease;
= Parkinson disease dementia;
= Pittsburgh Compound B;
= region of interest;
= Statistical Parametric Mapping;
= UK Parkinson’s Disease Society Brain Bank Research Center;
= United Parkinson’s Disease Rating Scale;
= Wechsler Adult Intelligence Scale–Revised.
doi:10.1212/01.wnl.0000326146.60732.d6
PMCID: PMC2637553  PMID: 18794492
3.  Imaging amyloid deposition in Lewy body diseases 
Neurology  2008;71(12):903-910.
Background
Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD).
Objectives
To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features.
Methods
Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio.
Results
Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function.
Conclusions
Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism.
doi:10.1212/01.wnl.0000326146.60732.d6
PMCID: PMC2637553  PMID: 18794492
4.  MRI measures of temporoparietal regions show differential rates of atrophy during prodromal AD 
Neurology  2008;71(11):819-825.
Background
MRI studies have demonstrated differential rates of atrophy in the entorhinal cortex and hippocampus during the prodromal phase of Alzheimer disease (AD). The current study was designed to determine whether a broader set of temporoparietal regions show differential rates of atrophy during the evolution of AD.
Methods
Sixteen regions of interest (ROIs) were analyzed on MRI scans obtained at baseline and follow-up in 66 subjects comprising three groups: controls = individuals who were cognitively normal at both baseline and follow-up; nonconverters = subjects with mild cognitive impairment (MCI) at both baseline and follow-up; converters had MCI at baseline but had progressed to AD at follow-up.
Results
Annualized percent change was analyzed with multivariate analysis of variance (MANOVA), covaried for age. The MANOVA demonstrated an effect of group (p = 0.004). Post hoc comparisons demonstrated greater rates of atrophy for converters vs nonconverters for six ROIs: hippocampus, entorhinal cortex, temporal pole, middle temporal gyrus, fusiform gyrus, and inferior temporal gyrus. Converters showed differentially greater rates of atrophy than controls in five of the same ROIs (and inferior parietal lobule). Rates of change in clinical status were correlated with the atrophy rates in these regions. Comparisons between controls and nonconverters demonstrated no differences.
Conclusion
These results demonstrate that temporoparietal regions show differential rates of atrophy on MRI during prodromal Alzheimer disease (AD). MRI data correlate with measures of clinical severity and cognitive decline, suggesting the potential of these regions of interest as antemortem markers of prodromal AD.
doi:10.1212/01.wnl.0000320055.57329.34
PMCID: PMC2577003  PMID: 18672473
5.  Triflusal reduces dense-core plaque load, associated axonal alterations and inflammatory changes, and rescues cognition in a transgenic mouse model of Alzheimer’s disease 
Neurobiology of disease  2010;38(3):482-491.
Inflammation has been associated with the two classic lesions in the Alzheimer’s (AD) brain, amyloid deposits and neurofibrillary tangles. Recent data suggest that Triflusal, a compound with potent anti-inflammatory effects in the central nervous system in vivo, might delay the conversion from amnestic mild cognitive impairment to a fully established clinical picture of dementia. In the present study, we investigated the effect of Triflusal on brain Aβ accumulation, neuroinflammation, axonal curvature and cognition in an AD transgenic mouse model (Tg2576). Triflusal treatment did not alter the total brain Aβ accumulation but significantly reduced dense-cored plaque load and associated glial cell proliferation, proinflammatory cytokine levels and abnormal axonal curvature, and rescued cognitive deficits in Tg2576 mice. Behavioral benefit was found to involve increased expression of c-fos and BDNF, two of the genes regulated by CREB, as part of the signal transduction cascade underlying the molecular basis of long-term potentiation. These results add preclinical evidence of a potentially beneficial effect of Triflusal in AD.
doi:10.1016/j.nbd.2010.01.019
PMCID: PMC3707138  PMID: 20149872
Alzheimer’s disease; Transgenic mice; Triflusal; Amyloid; Neuroinflammation; Cytokines; Cognition; CREB; c-fos; BDNF
6.  Activation of glycogen synthase kinase-3 beta mediates β-amyloid induced neuritic damage in Alzheimer's disease☆,☆☆,★ 
Neurobiology of disease  2011;45(1):425-437.
β-Amyloid (Aβ) plaques in Alzheimer (AD) brains are surrounded by severe dendritic and axonal changes, including local spine loss, axonal swellings and distorted neurite trajectories. Whether and how plaques induce these neuropil abnormalities remains unknown. We tested the hypothesis that oligomeric assemblies of Aβ, seen in the periphery of plaques, mediate the neurodegenerative phenotype of AD by triggering activation of the enzyme GSK-3β, which in turn appears to inhibit a transcriptional program mediated by CREB. We detect increased activity of GSK-3β after exposure to oligomeric Aβ in neurons in culture, in the brain of double transgenic APP/tau mice and in AD brains. Activation of GSK-3β, even in the absence of Aβ, is sufficient to produce a phenocopy of Aβ-induced dendritic spine loss in neurons in culture, while pharmacological inhibition of GSK-3β prevents spine loss and increases expression of CREB-target genes like BDNF. Of note, in transgenic mice GSK-3β inhibition ameliorated plaque-related neuritic changes and increased CREB-mediated gene expression. Moreover, GSK-3β inhibition robustly decreased the oligomeric Aβ load in the mouse brain. All these findings support the idea that GSK3β is aberrantly activated by the presence of Aβ, and contributes, at least in part, to the neuronal anatomical derangement associated with Aβ plaques in AD brains and to Aβ pathology itself.
doi:10.1016/j.nbd.2011.09.002
PMCID: PMC3694284  PMID: 21945540
7.  Plasma Aβ, homocysteine, and cognition 
Neurology  2009;72(3):268-272.
Background:
Amyloid-beta protein (Aβ) plays a key role in Alzheimer disease (AD) and is also implicated in cerebral small vessel disease. Serum total homocysteine (tHcy) is a risk factor for small vessel disease and cognitive impairment and correlates with plasma Aβ levels. To determine whether this association results from a common pathophysiologic mechanism, we investigated whether vitamin supplementation–induced reduction of tHcy influences plasma Aβ levels in the Vitamin Intervention in Stroke Prevention (VISP) study.
Methods:
Two groups of 150 patients treated with either the high-dose or low-dose formulation of pyridoxine, cobalamin, and folic acid in a randomized, double-blind fashion were selected among the participants in the VISP study without recurrent stroke during follow-up and in the highest 10% of the distribution for baseline tHcy levels. Concentrations of plasma Aβ with 40 (Aβ40) and 42 (Aβ42) amino acids were measured at baseline and at the 2-year visit.
Results:
tHcy levels significantly decreased with vitamin supplementation in both groups. tHcy were strongly correlated with Aβ40 but not Aβ42 concentrations. There was no difference in the change in Aβ40, Aβ42 (p = 0.40, p = 0.35), or the Aβ42/Aβ40 ratio over time (p = 0.86) between treatment groups. Aβ measures were not associated with cognitive change.
Conclusions:
This double-blind randomized controlled trial of vitamin therapy demonstrates a strong correlation between serum tHcy and plasma Aβ40 concentrations in subjects with ischemic stroke. Treatment with high dose vitamins does not, however, influence plasma levels of Aβ, despite their effect on lowering tHcy. Our results suggest that although tHcy is associated with plasma Aβ40, they may be regulated by independent mechanisms.
GLOSSARY
= amyloid-beta;
= Alzheimer disease;
= body mass index;
= diastolic blood pressure;
= Mini-Mental State Examination;
= modified Rankin Scale;
= NIH Stroke Scale;
= systolic blood pressure;
= total homocysteine;
= Vitamin Intervention in Stroke Prevention study.
doi:10.1212/01.wnl.0000339486.63862.db
PMCID: PMC2677526  PMID: 19153374
8.  Serum cystatin C and the risk of Alzheimer disease in elderly men 
Neurology  2008;71(14):1072-1079.
Background:
Multiple lines of research suggest that increased cystatin C activity in the brain protects against the development of Alzheimer disease (AD).
Methods:
Serum cystatin C levels were analyzed at two examinations of the Uppsala Longitudinal Study of Adult Men, a longitudinal, community-based study of elderly men (age 70 years, n = 1,153 and age 77 years, n = 761, a subset of the age 70 examination). Cox regressions were used to examine associations between serum cystatin C and incident AD. AD cases were identified by cognitive screening and comprehensive medical chart review in all subjects.
Results:
On follow-up (median 11.3 years), 82 subjects developed AD. At age 70 years, lower cystatin C was associated with higher risk of AD independently of age, APOE4 genotype, glomerular filtration rate, diabetes, hypertension, stroke, cholesterol, body mass index, smoking, education level, and plasma amyloid-β protein 40 and 42 levels (hazard ratio [HR] for lowest [<1.12 μmol/L] vs highest [>1.30 μmol/L] tertile = 2.67, 95% CI 1.22–5.83, p < 0.02). The results were similar at age 77 years (43 participants developed AD during follow-up). Furthermore, a 0.1-μmol/L decrease of cystatin C between ages 70 and 77 years was associated with a 29% higher risk of incident AD (HR 1.29, 95% CI 1.03–1.63, p < 0.03).
Conclusions:
Low levels of serum cystatin C precede clinically manifest Alzheimer disease (AD) in elderly men free of dementia at baseline and may be a marker of future risk of AD. These findings strengthen the evidence for a role for cystatin C in the development of clinical AD.
GLOSSARY
= amyloid-β protein 40;
= amyloid-β protein 42;
= Alzheimer disease;
= body mass index;
= glomerular filtration rate;
= hazard ratio;
= International Classification of Diseases;
= Uppsala Longitudinal Study of Adult Men.
doi:10.1212/01.wnl.0000326894.40353.93
PMCID: PMC2676985  PMID: 18824671
9.  MRI measures of temporoparietal regions show differential rates of atrophy during prodromal AD 
Neurology  2008;71(11):819-825.
Background:
MRI studies have demonstrated differential rates of atrophy in the entorhinal cortex and hippocampus during the prodromal phase of Alzheimer disease (AD). The current study was designed to determine whether a broader set of temporoparietal regions show differential rates of atrophy during the evolution of AD.
Methods:
Sixteen regions of interest (ROIs) were analyzed on MRI scans obtained at baseline and follow-up in 66 subjects comprising three groups: controls = individuals who were cognitively normal at both baseline and follow-up; nonconverters = subjects with mild cognitive impairment (MCI) at both baseline and follow-up; converters had MCI at baseline but had progressed to AD at follow-up.
Results:
Annualized percent change was analyzed with multivariate analysis of variance (MANOVA), covaried for age. The MANOVA demonstrated an effect of group (p = 0.004). Post hoc comparisons demonstrated greater rates of atrophy for converters vs nonconverters for six ROIs: hippocampus, entorhinal cortex, temporal pole, middle temporal gyrus, fusiform gyrus, and inferior temporal gyrus. Converters showed differentially greater rates of atrophy than controls in five of the same ROIs (and inferior parietal lobule). Rates of change in clinical status were correlated with the atrophy rates in these regions. Comparisons between controls and nonconverters demonstrated no differences.
Conclusion:
These results demonstrate that temporoparietal regions show differential rates of atrophy on MRI during prodromal Alzheimer disease (AD). MRI data correlate with measures of clinical severity and cognitive decline, suggesting the potential of these regions of interest as antemortem markers of prodromal AD.
GLOSSARY
= Alzheimer disease;
= annualized percent change;
= Clinical Dementia Rating Sum of Boxes;
= California Verbal Learning Test;
= multivariate analysis of variance;
= mild cognitive impairment;
= region of interest;
= Selective Reminding Test.
doi:10.1212/01.wnl.0000320055.57329.34
PMCID: PMC2577003  PMID: 18672473
10.  Effect of Pretreatment Renal Function on Treatment and Clinical Outcomes in the Adjuvant Treatment of Older Women With Breast Cancer: Alliance A171201, an Ancillary Study of CALGB/CTSU 49907 
Journal of Clinical Oncology  2016;34(7):699-705.
Purpose
CALGB 49907 showed the superiority of standard therapy, which included either cyclophosphamide/doxorubicin (AC) or cyclophosphamide/methotrexate/fluorouracil over single-agent capecitabine in the treatment of patients age ≥ 65 with early-stage breast cancer. The treatment allowed dosing adjustments of methotrexate and capecitabine for pretreatment renal function. The purpose of the current analysis was to assess the relationship between pretreatment renal function and five end points: toxicity, dose modification, therapy completion, relapse-free survival, and overall survival.
Methods
Pretreatment renal function was defined as creatinine clearance (CrCl) using the Cockcroft-Gault equation. Multivariable logistic and proportional hazards regression were used to model separately for each regimen the relationship between CrCl and the first three binary end points and the last two time-to-event end points, respectively, after adjusting for variables of prognostic importance.
Results
Six hundred nineteen assessable patients were analyzed. The incidence of stage III (moderate) or stage IV (severe) renal dysfunction was 72%, 64%, and 75% for treatment with cyclophosphamide/methotrexate/fluorouracil, AC, and capecitabine, respectively. There was no relationship for any regimen between pretreatment renal function and the five end points. For AC, as CrCl increased, the odds of nonhematologic toxicity decreased (P = .008), whereas for capecitabine, as CrCl increased, the odds of experiencing toxicity of any type also increased (P = .035). Patients with renal insufficiency who received dose modifications were not at increased risk for complications compared with those who did not have renal insufficiency and received a full dose.
Conclusion
Excluding from clinical trials patients with renal insufficiency but good performance status on the basis of concern of excessive hematologic toxicity or poor outcomes may not be justified with appropriate dosing modifications. Results should be considered in the design of clinical trials for older patients.
doi:10.1200/JCO.2015.62.6341
PMCID: PMC4872024  PMID: 26755510
11.  Long‐term trajectories of self‐reported cognitive function in a cohort of older survivors of breast cancer: CALGB 369901 (Alliance) 
Cancer  2016;122(22):3555-3563.
BACKGROUND
The number of survivors of breast cancer aged ≥65 years (“older”) is growing, but to the authors' knowledge, little is known regarding the cognitive outcomes of these individuals.
METHODS
A cohort of cognitively intact older survivors with nonmetastatic, invasive breast cancer was recruited from 78 sites from 2004 through 2011; approximately 83.7% of the survivors (1280 survivors) completed baseline assessments. Follow‐up data were collected at 6 months and annually for up to 7 years (median, 4.1 years). Cognitive function was self‐reported using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ‐C30); scores ranged from 0 to 100, with a higher score indicating better function. Group‐based trajectory modeling determined trajectories; women were assigned to a trajectory group based on the highest predicted probability of membership. Multinomial logistic regression evaluated the association between receipt of chemotherapy (with or without hormonal treatment) and trajectory group.
RESULTS
Survivors were aged 65 to 91 years; approximately 41% received chemotherapy. There were 3 cognitive trajectories: “maintained high” (42.3% of survivors); “phase shift” (50.1% of survivors), with scores slightly below but parallel to maintained high; and “accelerated decline” (7.6% of survivors), with the lowest baseline scores and greatest decline (from 71.7 [standard deviation, 19.8] to 58.3 [standard deviation, 21.9]). The adjusted odds of being in the accelerated decline group (vs the maintained high group) were 2.1 times higher (95% confidence interval, 1.3‐3.5) for survivors who received chemotherapy (with or without hormonal therapy) versus those treated with hormonal therapy alone. Greater comorbidity and frailty also were found to be associated with accelerated decline.
CONCLUSIONS
Trajectory group analysis demonstrated that the majority of older survivors maintained good long‐term self‐reported cognitive function, and that only a small subset who were exposed to chemotherapy manifested accelerated cognitive decline. Future research is needed to determine factors that place some older survivors at risk of experiencing cognitive decline. Cancer 2016;122:3555–3563. © 2016 American Cancer Society
Among older survivors of breast cancer who were followed for up to 7 years, approximately 42% reported maintaining high cognitive function, but receipt of chemotherapy (with or without hormonal therapy) appeared to double the odds of being in the group that reported accelerated cognitive decline (vs maintaining high function), compared with receiving hormonal treatment alone. Further research is needed to determine factors that place some older survivors at risk of experiencing cognitive decline.
doi:10.1002/cncr.30208
PMCID: PMC5113662  PMID: 27447359
breast cancer; chemotherapy; cognition; older; survival; trajectory
12.  Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation 
Cell Death and Differentiation  2015;22(10):1676-1686.
Neuronal active Caspase-6 (Casp6) is associated with Alzheimer disease (AD), cognitive impairment, and axonal degeneration. Caspase-1 (Casp1) can activate Casp6 but the expression and functionality of Casp1-activating inflammasomes has not been well-defined in human neurons. Here, we show that primary cultures of human CNS neurons expressed functional Nod-like receptor protein 1 (NLRP1), absent in melanoma 2, and ICE protease activating factor, but not the NLRP3, inflammasome receptor components. NLRP1 neutralizing antibodies in a cell-free system, and NLRP1 siRNAs in neurons hampered stress-induced Casp1 activation. NLRP1 and Casp1 siRNAs also abolished stress-induced Casp6 activation in neurons. The functionality of the NLRP1 inflammasome in serum-deprived neurons was also demonstrated by NLRP1 siRNA-mediated inhibition of speck formation of the apoptosis-associated speck-like protein containing a caspase recruitment domain conjugated to green fluorescent protein. These results indicated a novel stress-induced intraneuronal NLRP1/Casp1/Casp6 pathway. Lipopolysaccharide induced Casp1 and Casp6 activation in wild-type mice brain cortex, but not in that of Nlrp1−/− and Casp1−/− mice. NLRP1 immunopositive neurons were increased 25- to 30-fold in AD brains compared with non-AD brains. NLRP1 immunoreactivity in these neurons co-localized with Casp6 activity. Furthermore, the NLRP1/Casp1/Casp6 pathway increased amyloid beta peptide 42 ratio in serum-deprived neurons. Therefore, CNS human neurons express functional NLRP1 inflammasomes, which activate Casp1 and subsequently Casp6, thus revealing a fundamental mechanism linking intraneuronal inflammasome activation to Casp1-generated interleukin-1-β-mediated neuroinflammation and Casp6-mediated axonal degeneration.
doi:10.1038/cdd.2015.16
PMCID: PMC4563782  PMID: 25744023
13.  Occupational Therapy for Adults With Cancer: Why It Matters 
The Oncologist  2016;21(3):314-319.
Adult cancer survivors are significantly more likely to report being in fair or poor health, have comorbidities, one or more limitations in activities of daily living, and poorer functional status when compared with similar age adults without a cancer diagnosis. Occupational therapy is specifically designed to evaluate and treat functional deficits, yet it remains underused in cancer care.
Adults with cancer may be at risk for limitations in functional status and quality of life (QOL). Occupational therapy is a supportive service with the specific mission to help people functionally engage in life as safely and independently as possible with the primary goal of improving QOL. Unfortunately, for people with cancer, occupational therapy remains underused. The overall purpose of this review is to provide an understanding of what occupational therapy is and its relevance to patients with cancer, highlight the reasons to refer, and, last, provide general advice on how to access services.
Implications for Practice:
Adults with cancer are at risk for functional decline, which can lead to increased hospitalization, poor tolerance of cancer treatment, and increased health-care costs. Occupational therapy is specifically designed to evaluate and treat functional deficits, yet it remains underused in cancer care. This article describes what occupational therapy is, how to identify those who may need it, and how to access services.
doi:10.1634/theoncologist.2015-0335
PMCID: PMC4786355  PMID: 26865588
Functional status; Occupational therapy; Activities of daily living; Quality of life
14.  Geriatric assessment as an aide to understanding falls in older adults with cancer 
Purpose
In older adults, falls are a common cause of functional decline, institutionalization, and reduced quality of life. This study (1) investigates the prevalence of falls in a large sample of community-dwelling older adults with a cancer diagnosis and (2) evaluates the association of falls with domains of comprehensive geriatric assessment (CGA) that pertain to falls risk.
Methods
Patients completed a CGA that includes a self-reported measure of number of falls in the past 6 months. Summary statistics are used to describe prevalence of falls and associations with hypothesized risk factors using Fisher’s exact tests and multivariable logistic regression.
Results
A total of 1172 patients were enrolled, mean age 73 (65–99), 74 % female, and 89 % Caucasian. Two hundred fifty-six (22 %) reported one or more falls within the last 6 months. Patients with at least one instrumental activities of daily living (IADL) or physical function deficit had more falls as compared those with no deficits identified (p≤0.001). The number of daily medications, comorbidities, Timed Up and Go score >14 s, and poor vision were also associated with increased falls (p≤0.001). Reduced physical function, poor vision, and low performance status had the highest adjusted odds ratio (3.6, 3.4, and 3.0, respectively) for falls.
Conclusions
There is a high prevalence of falls in community-dwelling older patients with a cancer diagnosis. Falls are significantly associated with several measures of geriatric assessment including IADL, physical function, comorbidities, medications, and vision. Timely identification and management of risk factors for falls are important considerations in the care of older cancer patients.
doi:10.1007/s00520-014-2598-0
PMCID: PMC4484313  PMID: 25576434
Falls; Cancer; Geriatric oncology; Geriatric assessment
15.  The Effect of Atorvastatin on Breast Cancer Biomarkers in High-Risk Women 
Statins have the potential to reduce breast cancer incidence and recurrence as shown in both epidemiologic and laboratory studies. The purpose of this study was to evaluate the effect of a lipophilic statin, atorvastatin, on breast cancer biomarkers of risk [mammographic density (MD) and insulin growth factor 1 (IGF-1)] in high-risk premenopausal women.
Premenopausal women at increased risk for breast cancer received either 40 mg of atorvastatin or placebo for 1 year. Biomarker assessment was performed prior to initiation and at completion of study medication. MD was determined using both Breast Imaging Reporting and Data System and the visual analogue scale. Serum IGF-1 was determined by ELISA assay at the end of the study.
Sixty-three women were enrolled between December 2005 and May 2010. Sixteen (25%) women withdrew. The mean age of participants was 43 (range, 35–50), 100% were white, and the average body mass index (BMI) was 26.4. The statin group demonstrated a significant decrease in cholesterol and low-density lipoprotein (LDL), suggesting compliance with study medication. After accounting for BMI, there was no difference in change in MD between groups. There was a significant increase in serum IGF-1 in the statin group.
In this multi-institutional randomized prospective clinical trial of premenopausal women at increased risk for breast cancer, we did not see an effect of atorvastatin on MD. Further investigation of statins may be warranted; however, design of prior trials and potential mechanism of action of the agent need to be considered in the design of future trials.
doi:10.1158/1940-6207.CAPR-15-0300
PMCID: PMC4965880  PMID: 26908565
16.  Geriatric Assessment of Older Adults With Cancer During Unplanned Hospitalizations: An Opportunity in Disguise 
The Oncologist  2015;20(7):767-772.
Geriatric assessment (GA) is an important tool in the management of older cancer patients. This study demonstrates that hospitalized older adults with cancer have high levels of functional deficits on GA. These deficits are under-recognized and poorly managed by hospital-based clinicians in a tertiary care setting. Incorporation of GA measures during a hospital stay is a way to improve outcomes in this population.
Background.
Geriatric assessment (GA) is an important tool for management of older cancer patients; however, GA research has been performed primarily in the outpatient setting. The primary objective of this study was to determine feasibility of GA during an unplanned hospital stay. Secondary objectives were to describe deficits found with GA, to assess whether clinicians recognized and addressed deficits, and to determine 30-day readmission rates.
Materials and Methods.
The study was designed as an extension of an existing registry, “Carolina Senior: Registry for Older Patients.” Inclusion criteria were age 70 and older and biopsy-proven solid tumor, myeloma, or lymphoma. Patients had to complete the GA within 7 days of nonelective admission to University of North Carolina Hospital.
Results.
A total of 142 patients were approached, and 90 (63%) consented to participation. All sections of GA had at least an 83% completion rate. Overall, 53% of patients reported problems with physical function, 63% had deficits in instrumental activities of daily living, 34% reported falls, 12% reported depression, 31% had ≥10% weight loss, and 12% had abnormalities in cognition. Physician documentation of each deficit ranged from 20% to 46%. Rates of referrals to allied health professionals were not significantly different between patients with and without deficits. The 30-day readmission rate was 29%.
Conclusion.
GA was feasible in this population. Hospitalized older cancer patients have high levels of functional and psychosocial deficits; however, clinician recognition and management of deficits were poor. The use of GA instruments to guide referrals to appropriate services is a way to potentially improve outcomes in this vulnerable population.
Implications for Practice:
Geriatric assessment (GA) is an important tool in the management of older cancer patients; however, its primary clinical use has been in the outpatient setting. During an unplanned hospitalization, patients are extremely frail and are most likely to benefit from GA. This study demonstrates that hospitalized older adults with cancer have high levels of functional deficits on GA. These deficits are under-recognized and poorly managed by hospital-based clinicians in a tertiary care setting. Incorporation of GA measures during a hospital stay is a way to improve outcomes in this population.
doi:10.1634/theoncologist.2015-0023
PMCID: PMC4492242  PMID: 26032136
Geriatric oncology; Inpatient; Readmission; Geriatric assessment
17.  Early detection of cryptic memory and glucose uptake deficits in pre-pathological APP mice 
Nature Communications  2016;7:11761.
Earlier diagnosis and treatment of Alzheimer's disease would greatly benefit from the identification of biomarkers at the prodromal stage. Using a prominent animal model of aspects of the disease, we here show using clinically relevant methodologies that very young, pre-pathological PDAPP mice, which overexpress mutant human amyloid precursor protein in the brain, exhibit two cryptic deficits that are normally undetected using standard methods of assessment. Despite learning a spatial memory task normally and displaying normal brain glucose uptake, they display faster forgetting after a long delay following performance to a criterion, together with a strong impairment of brain glucose uptake at the time of attempted memory retrieval. Preliminary observations suggest that these deficits, likely caused by an impairment in systems consolidation, could be rescued by immunotherapy with an anti-β-amyloid antibody. Our data suggest a biomarker strategy for the early detection of β-amyloid-related abnormalities.
Identifying early signs of Alzheimer's disease is important when it comes to diagnosis and treatment. Here, the authors identify subtle memory retrieval deficits and associated brain glucose uptake impairments in very young mouse models of Alzheimer's, prior to plaque development.
doi:10.1038/ncomms11761
PMCID: PMC4895343  PMID: 27249364
18.  Predicting participation in meaningful activity for older adults with cancer 
Purpose
Participation in activity that is personally meaningful leads to improved emotional and physical well-being and quality of life. However, little is known about what predicts participation in meaningful activity by older adults with cancer.
Methods
Seventy-one adults aged 65 years and older with a diagnosis of cancer were enrolled. All adults were evaluated with the following: a brief geriatric assessment, the meaningful activity participation assessment (MAPA), and the Possibilities for Activity Scale (PActS). The MAPA measures participation in meaningful activity, and the PActS measures what older adults believe they should and could be doing. A regression approach was used to assess the predictors of meaningful activity participation.
Results
The PActS (B = .56, p < .001) was the strongest predictor of meaningful activity participation.
Conclusions
What older adults with cancer feel they should and could do significantly predicted meaningful participation in activities above and beyond clinical and demographic factors. In future research, perceptions of possibilities for activity may be useful in the design of interventions targeted to improve meaningful participation in older adults with cancer.
doi:10.1007/s11136-014-0849-7
PMCID: PMC4405447  PMID: 25381123
Older adults; Cancer; Oncology; Occupational possibilities; Possibilities for activity; Meaningful activity; Participation; Occupational therapy; Functional status; Activity
19.  The Prevalence of Potentially Modifiable Functional Deficits and the Subsequent Use of Occupational and Physical Therapy by Older Adults with Cancer 
Journal of geriatric oncology  2015;6(3):194-201.
Background
Occupational and physical therapy (OT/PT) services seek to reduce morbidity, mortality, and improve the quality of life of individuals; however, little is known about the needs and use of OT/PT for older adults with cancer. The goal of this study was to describe the functional deficits and their associations with other factors, and to examine the use of OT/PT after a noted functional deficit.
Materials and Methods
This study analyzed data from an institution-based registry that included geriatric assessments of older adults with cancer linked to billing claims data. Logistic regression was used to model predictors of functional deficits. Use of OT/PT was determined and validated with medical chart review.
Results
529 patients with cancer, a median age of 71, 78% were female, 87% Caucasian, 57% married, 53% post-secondary education, 63% with breast cancer were included. In a multivariable model, the odds of having any functional deficits increased with age [5 year OR: 1.31, 95% CI: (1.10, 1.57)] were higher for those with a high school diploma versus those with advanced degrees [OR: 1.66, 95% CI: (1.00, 2.77)] and were higher for patients with comorbidities [OR: 1.15, 95% CI: (1.10, 1.21)]. Of patients with functional deficits only 9% (10/111) received OT/PT within 12 months of a noted deficit.
Discussion
The odds of having any potentially modifiable functional deficit were higher in patients with increasing age, comorbid conditions, and with less than a college degree. Few were referred for OT/PT services suggesting major underutilization of these potentially beneficial services.
doi:10.1016/j.jgo.2015.01.004
PMCID: PMC4459887  PMID: 25614296
20.  Geriatric Assessment-Identified Deficits in Older Cancer Patients With Normal Performance Status 
The Oncologist  2015;20(4):379-385.
This study shows that a brief, mostly patient-administered geriatric assessment (GA) can identify deficits that could affect treatment tolerance and outcomes in older cancer patients assessed as functionally normal by Karnofsky performance status. A brief GA should be incorporated into routine oncology practice for timely identification of patient deficits that may be remediable before or during treatment.
Background.
We investigated whether a brief geriatric assessment (GA) would identify important patient deficits that could affect treatment tolerance and care outcomes within a sample of older cancer patients rated as functionally normal (80%–100%) on the Karnofsky performance status (KPS) scale.
Methods.
Cancer patients aged ≥65 years were assessed using a brief GA that included both professionally and patient-scored KPS and measures of comorbidity, polypharmacy, cognition, function, nutrition, and psychosocial status. Data were analyzed using descriptive statistics and multivariable logistic regression.
Results.
The sample included 984 patients: mean age was 73 years (range: 65–99 years), 74% were female, and 89% were white. GA was conducted before (23%), during (41%), or after (36%) treatment. Overall, 54% had a breast cancer diagnosis (n = 528), and 46% (n = 456) had cancers at other sites. Moreover, 81% of participants (n = 796) had both professionally and self-rated KPS ≥80, defined as functionally normal, and those patients are the focus of analysis. In this subsample, 550 (69%) had at least 1 GA-identified deficit, 222 (28%) had 1 deficit, 140 (18%) had 2 deficits, and 188 (24%) had ≥3 deficits. Specifically, 43% reported taking ≥9 medications daily, 28% had decreased social activity, 25% had ≥4 comorbidities, 23% had ≥1 impairment in instrumental activities of daily living, 18% had a Timed Up and Go time ≥14 seconds, 18% had ≥5% unintentional weight loss, and 12% had a Mental Health Index score ≤76.
Conclusion.
Within this sample of older cancer patients who were rated as functionally normal by KPS, GA identified important deficits that could affect treatment tolerance and outcomes.
doi:10.1634/theoncologist.2014-0247
PMCID: PMC4391761  PMID: 25765876
Geriatric assessment; Performance status; Cancer; Older
21.  Elderly Patients With Squamous Cell Carcinoma of the Head and Neck and the Benefit of Multimodality Therapy 
The Oncologist  2015;20(2):159-165.
This study highlights the need for better understanding of the factors affecting head and neck cancer outcomes in elderly patients. Results showed older patients with early stage disease did as well as younger patients with cancer outcomes but had increased mortality from other causes, and at advanced stages, those treated with multimodality therapy had similar overall survival to younger patients. Information about life expectancy in these patients may help guide treatment decisions.
Background.
Limited data are available regarding outcomes in elderly head and neck cancer patients. This retrospective study was designed to characterize head and neck cancer in geriatric patients.
Patients and Methods.
This study included all patients in a large university-based tumor registry who were diagnosed with head and neck cancer from January 1, 1990, to December 31, 2005. Patients aged ≥70 years at the time of diagnosis were defined as older. Overall survival and progression-free survival were censored at 60 months. Survival differences were compared using the log-rank test. Hazard ratios were estimated using a Cox proportional hazards model, adjusting for potential confounders.
Results.
Of 1,598 patients identified, 1,166 patients were aged <70 years (i.e., younger) and 281 patients were aged ≥70 years (older). When controlling for possible confounders, older patients were nearly twice as likely to die within 5 years as their younger counterparts (hazard ratio: 1.92). The median life expectancy for older patients was nearly 5 years for stage I–II disease and <2 years for stage III–IV disease. Older patients with stage III–IV disease who received multimodality therapy had 5-year survival similar to that younger patients with stage III–IV disease who were treated similarly (33.2% vs. 44.0%). Older patients with stage III–IV disease who received single-modality therapy had extremely poor survival compared with all other patients (hazard ratio for progression-free survival: 1.5).
Conclusion.
This study highlights the need for better understanding of the factors affecting head and neck cancer outcomes in elderly patients. Information about life expectancy in elderly head and neck cancer patients may help guide treatment decisions.
doi:10.1634/theoncologist.2013-0325
PMCID: PMC4319622  PMID: 25582139
Head and neck neoplasms; Aged; Drug therapy; Surgical therapy; Radiotherapy
22.  Integrating Patient-Reported Outcome Measures into Routine Cancer Care: Cancer Patients’ and Clinicians’ Perceptions of Acceptability and Value 
eGEMs  2015;3(1):1169.
Introduction:
Despite growing interest in integrating patient-reported outcome (PRO) measures of symptoms and functional status into routine cancer care, little attention has been paid to patients’ and clinicians’ perceptions of acceptability and value.
Methods:
A two-phase qualitative study was conducted to develop a web-based PRO screening system with 21 items assessing symptoms (e.g., nausea) and functional status. Phase 1 involved cognitive interviews with 35 cancer outpatients (n=9 breast chemotherapy, radiation for prostate (n=8) or head and neck cancer (n=10), and n=8 bone marrow transplant [BMT]). In Phase 2, we evaluated the acceptability and perceived value of reviewing a PRO measure during real-time clinical encounters with 39 additional outpatients (n=10 breast, n=9 head and neck, n=10 prostate, n=10 BMT) and 12 clinicians (n=3 breast, n=2 head and neck, n=4 prostate, n=3 BMT). At least 20% of patients were ≥60 years, African American, or ≤ high school.
Results:
Patients felt that their PRO summary of symptoms and functional status was helpful in discussing health issues with clinicians (92%), wanted to review their results with clinicians during future visits (82%), and would recommend it to other patients (87%). Clinicians found the PRO summary to be easy to interpret (83%), most helpful for documenting the Review of Symptoms (92%), and would recommend it to future patients (92%). Over 90% of clinicians reported that consultation time did not increase.
Conclusion:
Both cancer patients and clinicians reported that discussing a PRO summary of symptoms and functional status during an outpatient visit was useful, acceptable, and feasible.
doi:10.13063/2327-9214.1169
PMCID: PMC4636110  PMID: 26557724
Health Information Technology; Patient Involvement; Standardized Data Collection
23.  Comorbidity, Chemotherapy Toxicity, and Outcomes Among Older Women Receiving Adjuvant Chemotherapy for Breast Cancer on a Clinical Trial: CALGB 49907 and CALGB 361004 (Alliance) 
Journal of Oncology Practice  2014;10(5):e285-e292.
Comorbidity was associated with shorter overall survival but not toxicity or relapse among older women with breast cancer with good functional status.
Purpose:
We evaluated associations among comorbidity, toxicity, time to relapse (TTR), and overall survival (OS) in older women with early-stage breast cancer receiving adjuvant chemotherapy.
Methods:
Cancer and Leukemia Group B 49907 (Alliance) randomly assigned women ≥ 65 years old with stages I-III breast cancer to standard adjuvant chemotherapy or capecitabine. We reviewed data from 329 women who participated in the quality of life companion study CALGB 70103 and completed the Physical Health Subscale of the Older American Resources and Services Questionnaire. This questionnaire captures data on 14 comorbid conditions and the degree to which each interferes with daily activities. A comorbidity burden score was computed by multiplying the total number of conditions by each condition's level of interference with function. Outcomes were grade 3 to 5 toxicity, TTR, and OS. Logistic regression was used to evaluate associations between comorbidity and toxicity, and Cox proportional hazards models for TTR and survival.
Results:
Number of comorbidities ranged from 0 to 10 (median 2); the comorbidity burden score ranged from 0 to 25 (median 3). The most common conditions were arthritis (58%) and hypertension (55%). Comorbidity was associated with shorter OS, but not with toxicity or TTR. The hazard of death increased by 18% for each comorbidity (hazard ratio [HR] = 1.18, 95% CI = 1.06 to 1.33) after adjusting for age, tumor size, treatment, node and receptor status. Comorbidity burden score was similarly associated with OS (HR = 1.08; 95% CI, 1.03 to 1.14).
Conclusions:
Among older women enrolled onto a clinical trial, comorbidity was associated with shorter OS, but not toxicity or relapse.
doi:10.1200/JOP.2014.001388
PMCID: PMC4161730  PMID: 25074878
24.  Designing Therapeutic Clinical Trials for Older and Frail Adults With Cancer: U13 Conference Recommendations 
Journal of Clinical Oncology  2014;32(24):2587-2594.
A majority of cancer diagnoses and deaths occur in patients age ≥ 65 years. With the aging of the US population, the number of older adults with cancer will grow. Although the coming wave of older patients with cancer was anticipated in the early 1980s, when the need for more research on the cancer-aging interface was recognized, many knowledge gaps remain when it comes to treating older and/or frailer patients with cancer. Relatively little is known about the best way to balance the risks and benefits of existing cancer therapies in older patients; however, these patients continue to be underrepresented in clinical trials. Furthermore, the available clinical trials often do not include end points pertinent to the older adult population, such as preservation of function, cognition, and independence. As part of its ongoing effort to advance research in the field of geriatric oncology, the Cancer and Aging Research Group held a conference in November 2012 in collaboration with the National Cancer Institute, the National Institute on Aging, and the Alliance for Clinical Trials in Oncology. The goal was to develop recommendations and establish research guidelines for the design and implementation of therapeutic clinical trials for older and/or frail adults. The conference sought to identify knowledge gaps in cancer clinical trials for older adults and propose clinical trial designs to fill these gaps. The ultimate goal of this conference series is to develop research that will lead to evidence-based care for older and/or frail adults with cancer.
doi:10.1200/JCO.2013.55.0418
PMCID: PMC4129504  PMID: 25071116
25.  Frailty and Adherence to Adjuvant Hormonal Therapy in Older Women With Breast Cancer: CALGB Protocol 369901 
Journal of Clinical Oncology  2014;32(22):2318-2327.
Purpose
Most patients with breast cancer age ≥ 65 years (ie, older patients) are eligible for adjuvant hormonal therapy, but use is not universal. We examined the influence of frailty on hormonal therapy noninitiation and discontinuation.
Patients and Methods
A prospective cohort of 1,288 older women diagnosed with invasive, nonmetastatic breast cancer recruited from 78 sites from 2004 to 2011 were included (1,062 had estrogen receptor–positive tumors). Interviews were conducted at baseline, 6 months, and annually for up to 7 years to collect sociodemographic, health care, and psychosocial data. Hormonal initiation was defined from records and discontinuation from self-report. Baseline frailty was measured using a previously validated 35-item scale and grouped as prefrail or frail versus robust. Logistic regression and proportional hazards models were used to assess factors associated with noninitiation and discontinuation, respectively.
Results
Most women (76.4%) were robust. Noninitiation of hormonal therapy was low (14%), but in prefrail or frail (v robust) women the odds of noninitiation were 1.63 times as high (95% CI, 1.11 to 2.40; P = .013) after covariate adjustment. Nonwhites (v whites) had higher odds of noninitiation (odds ratio, 1.71; 95% CI, 1.04 to 2.80; P = .033) after covariate adjustment. Among initiators, the 5-year continuation probability was 48.5%. After adjustment, the risk of discontinuation was higher with increasing age (P = .005) and lower for stage ≥ IIB (v stage I) disease (P = .003).
Conclusion
Frailty is associated with noninitiation of hormonal therapy, but it does not seem to be a major predictor of early discontinuation in older patients.
doi:10.1200/JCO.2013.51.7367
PMCID: PMC4105485  PMID: 24934786

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