Real-world outcomes in patients with ALK-positive non-small cell lung cancer treated with crizotinib.

BACKGROUND: Crizotinib has shown greater efficacy in clinical trials than chemotherapy in patients with anaplastic lymphoma kinase-positive (alk+) non-small cell lung cancer (nsclc), but little information is available on its use and outcomes in real-world settings. We therefore assessed treatment patterns and outcomes in alk+ nsclc patients treated with crizotinib in regular clinical practice. METHODS: A retrospective medical record review was conducted in North America for adults with alk+ nsclc treated with crizotinib as first- or later-line therapy for metastatic disease between 1 August 2011 and 31 March 2013 (for the United States) or 1 May 2012 and 31 March 2013 (for Canada). Crizotinib-related trial enrollees were excluded. Descriptive analyses were conducted to assess treatment patterns and objective response rate (orr). Progression-free survival (pfs) and overall survival (os) were descriptively analyzed using Kaplan-Meier methods. RESULTS: Data were extracted for 212 patients in the United States (n = 147) and Canada (n = 65). Mean (standard deviation [sd]) age was 58.9 (9.5) years, and 69% were male. Seventy-nine patients (37%) were deceased at record abstraction. Sixty-five percent (n = 137) initiated crizotinib as first-line therapy. Mean (sd) duration of crizotinib treatment was 8.7 (4.9) months. Objective response rate was 66% (69% for first-line recipients, 60% for second-/later-line). Median (95% ci) pfs and os from crizotinib initiation were 9.5 (8.7, 10.1) and 23.4 (19.5, -) months, respectively. One- and two-year survival probabilities were 82% and 49%, respectively. CONCLUSIONS: Outcomes for crizotinib recipients in this study align with previous trials, with orr appearing more favourable in first-line recipients. Our findings indicate that crizotinib outcomes in clinical studies may translate to regular clinical practice.

Characterizing the white matter hyperintensity penumbra with cerebral blood flow measures.

OBJECTIVE: White matter hyperintensities (WMHs) are common with age, grow over time, and are associated with cognitive and motor impairments. Mechanisms underlying WMH growth are unclear. We aimed to determine the presence and extent of decreased normal appearing white matter (NAWM) cerebral blood flow (CBF) surrounding WMHs to identify 'WM at risk', or the WMH CBF penumbra. We aimed to further validate cross-sectional finding by determining whether the baseline WMH penumbra CBF predicts the development of new WMHs at follow-up. METHODS: Sixty-one cognitively intact elderly subjects received 3 T MPRAGE, FLAIR, and pulsed arterial spin labeling (PASL). Twenty-four subjects returned for follow-up MRI. The inter-scan interval was 18 months. A NAWM layer mask, comprised of fifteen layers, 1 mm thick each surrounding WMHs, was generated for periventricular (PVWMH) and deep (DWMH) WMHs. Mean CBF for each layer was computed. New WMH and persistent NAWM voxels for each penumbra layer were defined from follow-up MRI. RESULTS: CBF in the area surrounding WMHs was significantly lower than the total brain NAWM, extending approximately 12 mm from both the established PVWMH and DWMH. Voxels with new WMH at follow-up had significantly lower baseline CBF than voxels that maintained NAWM, suggesting that baseline CBF can predict the development of new WMHs over time. CONCLUSIONS: A CBF penumbra exists surrounding WMHs, which is associated with future WMH expansion. ASL MRI can be used to monitor interventions to increase white matter blood flow for the prevention of further WM damage and its cognitive and motor consequences.

In-home walking speeds and variability trajectories associated with mild cognitive impairment.

OBJECTIVE: To determine whether unobtrusive long-term in-home assessment of walking speed and its variability can distinguish those with mild cognitive impairment (MCI) from those with intact cognition. METHODS: Walking speed was assessed using passive infrared sensors fixed in series on the ceiling of the homes of elderly individuals participating in the Intelligent Systems for Assessing Aging Change (ISAAC) cohort study. Latent trajectory models were used to analyze weekly mean speed and walking speed variability (coefficient of variation [COV]). RESULTS: ISAAC participants living alone included 54 participants with intact cognition, 31 participants with nonamnestic MCI (naMCI), and 8 participants with amnestic MCI at baseline, with a mean follow-up of 2.6 ± 1.0 years. Trajectory models identified 3 distinct trajectories (fast, moderate, and slow) of mean weekly walking speed. Participants with naMCI were more likely to be in the slow speed group than in the fast (p = 0.01) or moderate (p = 0.04) speed groups. For COV, 4 distinct trajectories were identified: group 1, the highest baseline and increasing COV followed by a sharply declining COV; groups 2 and 3, relatively stable COV; and group 4, the lowest baseline and decreasing COV. Participants with naMCI were more likely to be members of either highest or lowest baseline COV groups (groups 1 or 4), possibly representing the trajectory of walking speed variability for early- and late-stage MCI, respectively. CONCLUSION: Walking speed and its daily variability may be an early marker of the development of MCI. These and other real-time measures of function may offer novel ways of detecting transition phases leading to dementia.

Nutrient biomarker patterns, cognitive function, and MRI measures of brain aging.

OBJECTIVE: To examine the cross-sectional relationship between nutrient status and psychometric and imaging indices of brain health in dementia-free elders. METHODS: Thirty plasma biomarkers of diet were assayed in the Oregon Brain Aging Study cohort (n = 104). Principal component analysis constructed nutrient biomarker patterns (NBPs) and regression models assessed the relationship of these with cognitive and MRI outcomes. RESULTS: Mean age was 87 ± 10 years and 62% of subjects were female. Two NBPs associated with more favorable cognitive and MRI measures: one high in plasma vitamins B (B1, B2, B6, folate, and B12), C, D, and E, and another high in plasma marine ω-3 fatty acids. A third pattern characterized by high trans fat was associated with less favorable cognitive function and less total cerebral brain volume. Depression attenuated the relationship between the marine ω-3 pattern and white matter hyperintensity volume. CONCLUSION: Distinct nutrient biomarker patterns detected in plasma are interpretable and account for a significant degree of variance in both cognitive function and brain volume. Objective and multivariate approaches to the study of nutrition in brain health warrant further study. These findings should be confirmed in a separate population.

Amyloid precursor protein (APP) processing genes and cerebrospinal fluid APP cleavage product levels in Alzheimer's disease.

The aim of this exploratory investigation was to determine if genetic variation within amyloid precursor protein (APP) or its processing enzymes correlates with APP cleavage product levels: APPα, APPß or Aß42, in cerebrospinal fluid (CSF) of cognitively normal subjects or Alzheimer's disease (AD) patients. Cognitively normal control subjects (n = 170) and AD patients (n = 92) were genotyped for 19 putative regulatory tagging SNPs within 9 genes (APP, ADAM10, BACE1, BACE2, PSEN1, PSEN2, PEN2, NCSTN and APH1B) involved in the APP processing pathway. SNP genotypes were tested for their association with CSF APPα, APPß, and Aß42, AD risk and age-at-onset while taking into account age, gender, race and APOE ε4. After adjusting for multiple comparisons, a significant association was found between ADAM10 SNP rs514049 and APPα levels. In controls, the rs514049 CC genotype had higher APPα levels than the CA, AA collapsed genotype, whereas the opposite effect was seen in AD patients. These results suggest that genetic variation within ADAM10, an APP processing gene, influences CSF APPα levels in an AD specific manner.

Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease.

A number of distinct beta-amyloid (Abeta) variants or multimers have been implicated in Alzheimer's disease (AD), and antibodies recognizing such peptides are in clinical trials. Humans have natural Abeta-specific antibodies, but their diversity, abundance, and function in the general population remain largely unknown. Here, we demonstrate with peptide microarrays the presence of natural antibodies against known toxic Abeta and amyloidogenic non-Abeta species in plasma samples and cerebrospinal fluid of AD patients and healthy controls aged 21-89 years. Antibody reactivity was most prominent against oligomeric assemblies of Abeta and pyroglutamate or oxidized residues, and IgGs specific for oligomeric preparations of Abeta1-42 in particular declined with age and advancing AD. Most individuals showed unexpected antibody reactivities against peptides unique to autosomal dominant forms of dementia (mutant Abeta, ABri, ADan) and IgGs isolated from plasma of AD patients or healthy controls protected primary neurons from Abeta toxicity. Aged vervets showed similar patterns of plasma IgG antibodies against amyloid peptides, and after immunization with Abeta the monkeys developed high titers not only against Abeta peptides but also against ABri and ADan peptides. Our findings support the concept of conformation-specific, cross-reactive antibodies that may protect against amyloidogenic toxic peptides. If a therapeutic benefit of Abeta antibodies can be confirmed in AD patients, stimulating the production of such neuroprotective antibodies or passively administering them to the elderly population may provide a preventive measure toward AD.

Incidence of risk factors for myocardial infarction and other vascular diseases in patients with psoriasis.

BACKGROUND: Recent cross-sectional studies reported a higher prevalence of diabetes and other risk factors for cardiovascular disease in patients with psoriasis than in the general population. OBJECTIVES: To estimate the cumulative incidences of risk factors for myocardial infarction and other vascular diseases after a first recorded diagnosis of psoriasis and the hazard ratio (HR) for these conditions in patients with psoriasis compared with the general population. METHODS: We used the General Practice Research Database to conduct a cohort study of 44,164 patients with a first-time diagnosis of psoriasis and 219,784 nonpsoriasis comparison subjects psoriasis-matched on age, sex and index date. RESULTS: HRs were increased among patients with psoriasis vs. the comparison cohort for incident diabetes [HR 1.33; 95% confidence interval (CI) 1.25-1.42], hypertension (HR 1.09; 95% CI 1.05-1.14), obesity (HR 1.18; 95% CI 1.14-1.23) and hyperlipidaemia (HR 1.17; 95% CI 1.11-1.23). Patients with psoriasis also had higher risks of incident myocardial infarction (HR 1.21; 95% CI 1.10-1.32), angina (HR 1.20; 95% CI 1.12-1.29), atherosclerosis (HR 1.28; 95% CI 1.10-1.48), peripheral vascular disease (HR 1.29; 95% CI 1.13-1.47) and stroke (HR 1.12; 95% CI 1.00-1.25). CONCLUSIONS: Risk factors for cardiovascular disease as well as myocardial infarction and other vascular diseases occur with higher incidence in patients with psoriasis than in the general population. Further work is needed to investigate whether these associations involve causal factors related to psoriasis or its treatment.

Impact of white matter hyperintensity volume progression on rate of cognitive and motor decline.

BACKGROUND: White matter hyperintensity (WMH) change on brain MRI is observed with increased frequency in the elderly and has been independently associated with neurologic decline. The degree to which the location and rate of volume increase in WMH affects other structural brain changes along with cognitive and motor performance over time may determine subsequent degrees of risk for dementia and other syndromes of aging. METHODS: One hundred four cognitively intact men and women followed longitudinally for up to 13 years underwent at least three MRIs with corresponding annual cognitive and neurologic assessments. Brain volume, ventricular CSF (vCSF), and total periventricular (PV) and subcortical WMH volumes were measured. Progression of MRI volumes was examined in relation to rates of cognitive, motor, and cerebral volume change based on slopes of outcomes. RESULTS: Higher initial total and PV WMH volume was associated with total WMH, PV WMH, and vCSF progression, and with increased time and number of steps to walk 30 feet. Progression of PV WMH volume was associated with increased time to walk 30 feet. Progression of subcortical WMH volume was associated with decreased performance on logical memory testing and increased rate of vCSF volume change. CONCLUSION: Increased total and periventricular (PV) white matter hyperintensity (WMH) burden and progression of PV WMH burden are associated with decreased gait performance over time, while progression of subcortical WMH volume is associated with memory decline in cognitively intact elderly. Greater progression of WMH burden is associated with an increased risk of memory and gait dysfunction, and thus should not be considered a benign process.

Trajectories of brain loss in aging and the development of cognitive impairment.

BACKGROUND: The use of volumetric MRI as a biomarker for assessing transitions to dementia presumes that more rapid brain loss marks the clinical transition from benign aging to mild cognitive impairment (MCI). The trajectory of this volume loss relative to the timing of the clinical transition to dementia has not been established. METHODS: The authors annually evaluated 79 healthy elderly subjects for up to 15 consecutive years with standardized clinical examinations and volumetric brain MRI assessments of ventricular volume. During the study period, 37 subjects developed MCI. A mixed effects model with a change point modeled the pattern of brain volume loss in healthy aging compared with subjects diagnosed with MCI. RESULTS: The brain loss trajectory of subjects developing MCI during follow-up differed from healthy aging in a two-phase process. First, the annual rate of expansion of ventricular volume decreased with age; however, the annual rates of expansion were greater in those who developed cognitive impairment during follow-up compared with those who did not. Further, subjects who developed MCI had an acceleration of ventricular volume expansion approximately 2.3 years prior to clinical diagnosis of MCI. CONCLUSIONS: Ventricular expansion is faster in those developing mild cognitive impairment years prior to clinical symptoms, and eventually a more rapid expansion occurs approximately 24 months prior to the emergence of clinical symptoms. These differential rates of preclinical atrophy suggest that there are specific windows for optimal timing of introduction of dementia prevention therapies in the future.

CSF tau/Abeta42 ratio for increased risk of mild cognitive impairment: a follow-up study.

BACKGROUND: Processes of Alzheimer disease (AD) likely begin years prior to the onset of cognitive impairment (latent AD), progress though a prodromal phase of mild cognitive impairment (MCI), and culminate in dementia. While many studies have evaluated CSF tau and Abeta(42) as biomarkers of the dementia or prodromal stages of AD, we are unaware of any study to evaluate these potential CSF biomarkers of latent AD. METHODS: We determined the ratio of CSF tau/Abeta(42) (T/Abeta) using Luminex reagents in 129 control individuals that spanned from 21 to 100 years of age; for comparison we included patients with MCI (n = 12), probable AD (n = 21), or other neurodegenerative diseases (n = 12). RESULTS: We identified 16% of the control group with abnormally elevated CSF T/Abeta; all were 53 years or older. Using age-matched controls with normal CSF T/Abeta we showed that the high CSF T/Abeta subgroup of controls had significantly increased frequency of the epsilon4 allele of the apolipoprotein E gene and significantly increased risk of conversion to MCI during follow-up of up to 42 months suggesting that they had latent AD at the time of lumbar puncture. CONCLUSIONS: These generally applicable methods establish cutoff values to identify control individuals at increased risk of conversion to mild cognitive impairment which may be useful to people weighing the risk-benefit ratio of new preventive therapeutics and to researchers striving to enrich clinical trial populations with people with latent Alzheimer disease.

Brain volumes in Guam dementia vs Parkinson dementia complex vs aging Chamorro adults.

We sought to determine if Chamorro individuals with a family history of Guam dementia (GD) or Parkinson dementia complex (PDC) exhibit presymptomatic brain MRI changes. Sixty-six Chamorro subjects had neurocognitive assessment and volumetric MRI. MRI brain volumes differed between diagnostic groups (GD, PDC, control) and according to family history. Chamorros with a family history of PDC or dementia may have increased brain atrophy, suggesting a hereditary susceptibility to neurodegenerative disorders.

Blood-brain barrier impairment in Alzheimer disease: stability and functional significance.

OBJECTIVE: To determine the stability and functional significance of blood-brain barrier (BBB) integrity in patients with mild to moderate Alzheimer disease (AD). METHODS: Thirty-six patients (mean age 71 +/- 7 years) with mild to moderate AD (Mini-Mental State Examination [MMSE] 19 +/- 5) participated in a biomarker study involving clinical assessments, brain imaging, and CSF and plasma collection over 1 year. BBB integrity was assessed with the CSF-albumin index (CSF-AI). RESULTS: BBB disruption was present in an important subgroup of patients (n = 8/36, 22%) at all time points measured. CSF-AI was highly reproducible over 1 year with an intraclass correlation of 0.96. Age, sex, and APOE status did not correlate with CSF-AI. Vascular factors (blood pressure, Hachinski ischemia score, MR-derived white matter hyperintensity, body mass index) were not strongly associated with CSF-AI levels (p = 0.066). CSF/plasma IgG ratio correlated with CSF-AI in a manner indicating that peripheral IgG has greater access to the CNS in patients with an impaired BBB. Further evidence for the physiologic significance of the CSF-AI was noted in the form of correlations with rates of disease progression, including annual change on MMSE (r(2) = 0.11, p = 0.023), annual Clinical Dementia Rating sum-of-boxes change (r(2) = 0.29, p = 0.001), and annual ventricular volume change (r(2) = 0.17, p = 0.007). CONCLUSIONS: Blood-brain barrier (BBB) impairment is a stable characteristic over 1 year and present in an important subgroup of patients with Alzheimer disease. Age, gender, APOE status, vascular risk factors, and baseline Mini-Mental State Examination score did not explain the variability in BBB integrity. A role for BBB impairment as a modifier of disease progression is suggested by correlations between CSF-albumin index and measures of disease progression over 1 year.

Cortical excitability and age-related volumetric MRI changes.

OBJECTIVE: Normative data on transcranial magnetic stimulation (TMS)-derived measures of cortical excitability in the elderly is sparse. Nevertheless, elderly subjects are included as controls in studies utilizing TMS to investigate disease states. Age-associated increased ventricular cerebrospinal fluid CSF (vCSF) and white matter hyperintensity (WMH) MRI volumes have uncertain significance in non-demented elderly. Information regarding cortical excitability in neurologically intact elderly would augment our understanding of the pathophysiology of aging and assist in the interpretation of TMS studies involving elderly subjects. METHODS: Twenty-four healthy elderly subjects underwent TMS testing to determine outcomes of resting motor threshold (RMT) cortical silent period (cSP) and central motor conduction time for examination in relation to WMH, vCSF, and CNS volumes. RESULTS: Increased vCSF and WMH volumes were associated with decreased right and left hemisphere RMT. Smaller CNS volumes were associated with decreased right hemisphere RMT and shorted cSP. CONCLUSIONS: Commonly observed age-associated MRI changes are associated with findings consistent with increased cortical excitability. SIGNIFICANCE: Age-related MRI findings likely reflect changes at a cellular level, and may influence cognitive and motor integrity in the elderly. Future TMS studies investigating cortical excitability may wish to consider neuroimaging markers of neurodegeneration prior to enrolling elderly subjects as controls.

Asynchronous regional brain volume losses in presymptomatic to moderate AD.

To determine if rates and locations of brain volume loss associated with AD are phase-specific, occurring prior to clinical onset and at later stages, we performed longitudinal volumetric MRI analysis on 155 subjects enrolled in a prospective study of aging and dementia. Subjects were divided by Clinical Dementia Rating (CDR) scale into stages of Normal (CDR 0 --> 0), Very Mild (CDR 0 --> 0.5 and 0.5 --> 0.5), Mild (CDR 0.5 --> 1.0 and 1.0 --> 1.0) and Moderate (CDR 1.0 --> 2.0 and 2.0 --> 2.0) dementia. Rates of volume change in CSF spaces, lobar and medial temporal lobe regions were analyzed for group differences across stages. Annual rates of ventricular volume change differed between non-demented and very mild group (p<0.01). In later severity stages, ventricular, temporal, basal ganglia-thalamic region and total volumes show change. Rates of volume loss increase as dementia progresses, but not uniformly in all regions. These regional and phase-specific volume changes form targets for monitoring disease-modifying therapies at clinically relevant, defined stages of dementia.

Epidemiology of lower limb fractures in general practice in the United Kingdom.

STUDY OBJECTIVE: To estimate the incidence of lower limb fractures in the United Kingdom and assess the relative importance of various risk factors for lower limb fractures. DESIGN: Cohort analysis and matched case-control study. SETTING: General practices contributing information to the General Practice Research Database. SUBJECTS: Individuals registered with these general practices who were at risk for a first time lower limb fracture from 1 January 1990 to 31 December 2001. MAIN OUTCOME MEASURES: Age, sex, and fracture site specific incidence rates; relative risks and population attributable risks for various medical risk factors. RESULTS: Overall, the risk of lower limb fracture was 17% higher in women then in men. Within age groups, men and women had generally similar proportions of fractures at specific sites in the lower limb. Among the risk factors evaluated, road collisions were associated with the highest relative risk for lower limb fracture, but only accounted for 3.1% or less of the population attributable risk for specific fracture types in any age group. The relative risk for lower limb fracture associated with a diagnosis of dementia was 2.3 (95% confidence interval 2.0 to 2.6), while relative risk estimates for other medical diagnoses were less than 2. Fracture risk was increased among current users of corticosteroids, antipsychotics, antidepressants, and hypnotic/sedatives, but the population attributable risks for each of these drug classes within fracture and age specific strata were only 3.0% or less. CONCLUSIONS: Many risk factors for lower limb fracture have been identified, but population attributable risk estimates for various risk factors are small. These findings suggest that multifactorial prevention programs are needed to decrease the incidence of lower limb fractures in the general population.

Predicting the rate of cognitive decline in aging and early Alzheimer disease.

OBJECTIVES: To determine prognostic factors affecting the course of Alzheimer disease (AD) and to determine the role of region-specific brain volumes as predictors of cognitive decline. METHODS: Longitudinal data from 166 normal elderly individuals and 59 early AD patients were analyzed. Brain volumes were extracted from MRI scans using semiautomated recursive segmentation methods. Prognostic factors were considered significant if they had a significant effect on the rate of cognitive decline. RESULTS: In multivariate analysis, higher Clinical Dementia Rating Scale (CDR) score at entry was a significant prognostic factor for an increased rate of cognitive decline. Significant prognostic factors within the baseline CDR = 0 group were base rate of progression and percent total high signal intensity (HSI), percent ventricular, and percent CSF volumes. Base rate of progression, family history, and percent ventricular volume were significant prognostic factors within the CDR = 0.5 group and APOE had a marginally significant effect on the rate of cognitive decline in the CDR = 1 group. CONCLUSIONS: Percent total HSI, ventricular, and total CSF volume measures can independently predict the rate of cognitive decline and improve the predictive power of statistical models that use only clinical data. Brain volumetric measures from MRI can be used to estimate the rate of cognitive decline even among normal elderly individuals and thus may aid in the prediction of time of onset of disease.

Statin use and cancer risk in the General Practice Research Database.

In a matched case-control study using the General Practice Research Database, current statin use was not associated with a significantly altered risk of any of 13 studied cancers. Untreated hyperlipidaemia was associated with slightly increased risks of colon cancer (relative risk 1.8; 95% confidence interval 1.2-2.8), prostate cancer (1.5; 1.1-2.0), and bladder cancer (1.9; 1.2-3.1).

An unobtrusive in-home monitoring system for detection of key motor changes preceding cognitive decline.

The existing paradigm of ongoing or posttreatment monitoring of patients through periodic but infrequent office visits has many limitations. Relying on self-report by the patient or their family is equally unreliable. We propose an alternative paradigm in which continuous, unobtrusive monitoring is used to observe changes in physical behavior over time. We highlight the use of this technique for monitoring motor activity that may be predictive of early cognitive changes in the elderly. Initial results using a system of low-cost wireless sensors are presented, together with a discussion of appropriate analyses and interpretation of such data. Using low-cost wireless sensor network coupled with algorithms to detect changes in relevant patterns of behavior, we are able to detect both acute and gradual changes that may indicate a need for medical intervention.