Neuroepidemiology of cancer and treatment-related neurocognitive dysfunction in adult-onset cancer patients and survivors.

Cancer and treatment-related neurocognitive dysfunction (CRND) - impairments in aspects of cognition commonly including attention and memory, information-processing speed, and executive functioning - can negatively affect patients' and survivors' participation in routine activities of daily living and overall quality of life. CRND can be enduring, and varies in severity level. The epidemiology of CRND is not yet clearly established; reported incidence has ranged from 17% to 75% among patients and survivors of noncentral nervous system malignancies, including breast, prostate, cervical, and colorectal cancers. Progress in the development of strategies for assessing and treating CRND has been delayed by limitations in the knowledge of the precise etiology of this adverse condition, as well as the lack of sufficiently sensitive and reliable methods to determine its presence and quantify its severity. In this chapter, we present a brief description of the concept of CRND and its clinical presentation, and discuss the descriptive epidemiology, pathophysiology, risk factors, and availability of treatment interventions. This neuroepidemiologic perspective provides a framework for characterizing CRND, determining its etiology, and understanding its negative effects on routine activities of daily living, to help support the development and testing of reliable interventions to treat this deleterious condition for patients and survivors.

FASTKD2 is associated with memory and hippocampal structure in older adults.

Memory impairment is the cardinal early feature of Alzheimer's disease, a highly prevalent disorder whose causes remain only partially understood. To identify novel genetic predictors, we used an integrative genomics approach to perform the largest study to date of human memory (n=14 781). Using a genome-wide screen, we discovered a novel association of a polymorphism in the pro-apoptotic gene FASTKD2 (fas-activated serine/threonine kinase domains 2; rs7594645-G) with better memory performance and replicated this finding in independent samples. Consistent with a neuroprotective effect, rs7594645-G carriers exhibited increased hippocampal volume and gray matter density and decreased cerebrospinal fluid levels of apoptotic mediators. The MTOR (mechanistic target of rapamycin) gene and pathways related to endocytosis, cholinergic neurotransmission, epidermal growth factor receptor signaling and immune regulation, among others, also displayed association with memory. These findings nominate FASTKD2 as a target for modulating neurodegeneration and suggest potential mechanisms for therapies to combat memory loss in normal cognitive aging and dementia.

Integrating imaging findings in evaluating the post-chemotherapy brain.

Cognitive complaints following cancer and cancer therapy are common. Many studies have investigated the effects of chemotherapy on the brain. However, the mechanisms for the associated cognitive impairment are not well understood. Some studies have also included brain imaging to investigate potential neurological substrates of cognitive changes. This review examines recent neuroimaging studies on cancer- and chemotherapy-related cognitive dysfunction in non-central nervous system cancers and compares findings across imaging modalities. Grey matter volume reductions and decreases in white matter integrity are seen after exposure to adjuvant chemotherapy for breast cancer, and functional studies have illuminated both hypo- and hyperactivations in many of the same regions months to years following therapy. These comparisons can assist in further characterizing the dysfunction reported by patients and contribute to a better understanding of the mechanisms involved.

Whole-exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment.

Whole-exome sequencing of individuals with mild cognitive impairment, combined with genotype imputation, was used to identify coding variants other than the apolipoprotein E (APOE) ε4 allele associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE ε3 homozygous male Caucasian participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were selected at the extremes of the 2-year longitudinal change distribution of hippocampal volume (eight subjects with rapid rates of atrophy and eight with slow/stable rates of atrophy). We identified 57 non-synonymous single nucleotide variants (SNVs) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group, but not in any of the 8 subjects in the slow atrophy group. Among these SNVs, the variants that accounted for the greatest group difference and were predicted in silico as 'probably damaging' missense variants were rs9610775 (CARD10) and rs1136410 (PARP1). To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis including whole-brain search in the remaining ADNI APOE ε3/ε3 group (N=315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE ε3/ε3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE ε3/ε3 individuals (N=923). Larger sequencing studies and longitudinal follow-up are needed for confirmation. The combination of next-generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration.

Retrievable Gunther Tulip inferior vena cava filter: experience in 317 patients.

The aim of our study was to assess our experience with the retrievable Gunther Tulip (GT) inferior vena cava (IVC) filter, with regard to its insertion, efficacy, ease of placement and retrieval, and associated complications. Between November 2001 and October 2005, 322 GT filters were placed in 317 patients. Insertion indications included the following: pulmonary embolus (PE) prophylaxis in trauma patients (n = 232), PE prophylaxis in perioperative patients (n = 27), PE prophylaxis in moribund intensive care unit patients (n = 22), recent PE (n = 48), extensive deep venous thrombosis (n = 66), contraindication to anticoagulation (n = 63), anticoagulation complication (n = 8) and deep venous thrombosis with failed anticoagulation (n = 8). Some patients had more than one indication for caval filter placement. Two hundred and five attempted retrievals have been carried out, with 15 failures. Our successful retrieval rate is 92%. Nineteen filters were originally inserted permanently. There have been three minor complications associated with insertion and five with retrieval. The mean time from filter insertion to attempted retrieval was 76.95 days. The ideal filter implantation time gives the patient the benefit of PE protection, while avoiding the long-term risks associated with caval filters. Although GT retrieval times have lengthened considerably, our data suggest that this is at the expense of successful retrieval rates.

Regional brain atrophy in cognitively intact adults with a single APOE epsilon4 allele.

OBJECTIVE: To determine whether cognitively intact adults with the APOE epsilon3/epsilon4 genotype show reduced gray matter density on voxel-based morphometry (VBM) vs those homozygous for the epsilon3 allele. METHODS: Participants were healthy, cognitively intact, right-handed adults, age 19 to 80, who completed genotyping, neuropsychological testing, and MRI. Forty-nine participants had the epsilon3/epsilon3 genotype and 27 had the epsilon3/epsilon4 genotype. Gray matter data were analyzed using the general linear model as implemented in the Statistical Parametric Mapping package, adjusting for age and sex. RESULTS: The epsilon3/epsilon4 participants showed lower gray matter density than the epsilon3/epsilon3 participants in right medial temporal and bilateral frontotemporal regions as well as other areas. There were no regions in which epsilon3/epsilon4 participants showed higher gray matter density than epsilon3/epsilon3 participants. CONCLUSIONS: Regionally reduced gray matter density is detectable in cognitively intact adults with a single copy of the APOE epsilon4 allele.

Brain activation patterns associated with working memory in relapsing-remitting MS.

BACKGROUND: Patients with multiple sclerosis (MS) show changes in brain activation patterns during visual and motor tasks that include decreases in the typical local network for a function and increases in other brain regions. OBJECTIVE: To determine whether brain activation patterns associated with working memory are affected by MS. METHODS: Activation of working memory circuitry was examined using an fMRI n-back task in adults with mild relapsing-remitting MS (RRMS; n = 10) and demographically matched healthy controls (n = 10). RESULTS: Group differences in brain activation emerged during both low- and high-demand conditions (p < 0.001). Overall, patients showed less activation than controls in core prefrontal and parietal regions of working memory circuitry, and greater activation in other regions within and beyond typical working memory circuitry, including bilateral medial frontal, cingulate, parietal, bilateral middle temporal, and occipital regions. CONCLUSIONS: Relative to controls, patients with mild RRMS showed shifts in brain activation patterns within and beyond typical components of working memory circuitry.

Chronic deep brain stimulation for the treatment of tremor in multiple sclerosis: review and case reports.

BACKGROUND: Deep brain stimulation (DBS) offers a non-ablative alternative to thalamotomy for the surgical treatment of medically refractory tremor in multiple sclerosis. However, relatively few outcomes have been reported. OBJECTIVE: To provide a systematic review of the published cases of DBS use in multiple sclerosis and to present four additional patients. METHODS: Quantitative and qualitative review of the published reports and description of a case series from one centre. RESULTS: In the majority of reported cases (n=75), the surgical target for DBS implantation was the ventrointeromedial nucleus of the thalamus. Tremor reduction and improvement in daily functioning were achieved in most patients, with 87.7% experiencing at least some sustained improvement in tremor control postsurgery. Effects on daily functioning were less consistently assessed across studies; in papers reporting relevant data, 76.0% of patients experienced improvement in daily functioning. Adverse effects were similar to those reported for DBS in other patient populations. CONCLUSIONS: Few of the studies reviewed used highly standardised quantitative outcome measures, and follow up periods were generally one year or less. Nonetheless, the data suggest that chronic DBS often produces improved tremor control in multiple sclerosis. Complete cessation of tremor is not necessarily achieved, there are cases in which tremor control decreases over time, and frequent reprogramming appears to be necessary.

Prenatal alcohol exposure influences the effects of neuroactive steroids on separation-induced ultrasonic vocalizations in rat pups.

Fetal alcohol exposure has been reported to be associated with hyper-responsiveness to stress. Using a maternal separation paradigm, this study examined whether prenatal alcohol exposure affected sensitivity to neurosteroid modulation of stress. We have shown that the neuroactive steroid allopregnanolone reduces ultrasonic vocalizations (USVs) after brief maternal separation in week-old rat pups. Prenatal alcohol exposure, however, resulted in reduced sensitivity to this neurosteroid. In this study's first experiment, the behavioral effects of pregnenolone sulfate, a neurosteroid with reportedly opposite modulatory effects on the GABAA receptor, were characterized. Pregnenolone sulfate had a triphasic effect on the production of ultrasonic vocalizations and on open field activity. Blockade of conversion of pregnenolone sulfate to allopregnanolone via the 5 alpha-reductase inhibitor 4-MA also blocked the drug-related reduction in USVs, but not the higher-dose augmentation. The enzyme inhibitor alone had no significant effects on USV production, nor did progesterone. These results suggest that the neuroactive steroid pregnenolone sulfate may play an independent role in the stress response after maternal separation as well as being a precursor for the anxiolytic neurosteroid allopregnanolone. In the second experiment, prenatal alcohol exposure was found to eliminate both the low dose USV-reducing effect and the higher dose USV-increasing effect. These results support previous results demonstrating that prenatal alcohol exposure may cause an altered sensitivity to the neuromodulatory effects of neurosteroids.