Optimizing Spatial Biopsy Sampling for the Detection of Prostate Cancer.

PURPOSE: The appropriate number of systematic biopsy cores to retrieve during magnetic resonance imaging (MRI)-targeted prostate biopsy is not well defined. We aimed to demonstrate a biopsy sampling approach that reduces required core count while maintaining diagnostic performance. MATERIALS AND METHODS: We collected data from a cohort of 971 men who underwent MRI-ultrasound fusion targeted biopsy for suspected prostate cancer. A regional targeted biopsy (RTB) was evaluated retrospectively; only cores within 2 cm of the margin of a radiologist-defined region of interest were considered part of the RTB. We compared detection rates for clinically significant prostate cancer (csPCa) and cancer upgrading rate on final whole mount pathology after prostatectomy between RTB, combined, MRI-targeted, and systematic biopsy. RESULTS: A total of 16,459 total cores from 971 men were included in the study data sets, of which 1,535 (9%) contained csPCa. The csPCa detection rates for systematic, MRI-targeted, combined, and RTB were 27.0% (262/971), 38.3% (372/971), 44.8% (435/971), and 44.0% (427/971), respectively. Combined biopsy detected significantly more csPCa than systematic and MRI-targeted biopsy (p <0.001 and p=0.004, respectively) but was similar to RTB (p=0.71), which used on average 3.8 (22%) fewer cores per patient. In 102 patients who underwent prostatectomy, there was no significant difference in upgrading rates between RTB and combined biopsy (p=0.84). CONCLUSIONS: A RTB approach can maintain state-of-the-art detection rates while requiring fewer retrieved cores. This result informs decision making about biopsy site selection and total retrieved core count.

Increased structural connectivity of thalamic stimulation sites to motor cortex relates to tremor suppression.

Deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM-DBS) is a highly successful treatment for medication-refractory essential tremor (ET). Clinical outcomes are dependent on accurate targeting. Here, we aim to develop a framework for connectivity-guided DBS targeting by evaluating probabilistic tractography and clinical response at both initial programming (IP) and clinical follow-up (CF). Magnetic resonance imaging and clinical outcomes were evaluated in 23 ET patients who were treated by VIM-DBS at the University of California Los Angeles (20 at IP, 18 at CF, 14 at both). Lead-DBS was used to model the volume of tissue activated tissue (VTA) based on programming configurations at both IP and CF. Probabilistic tractography, calculated in FSL, was used to evaluate 1) clinically weighted whole brain connectivity of VTA; 2) connectivity between VTA and freesurfer-derived target regions of interest (ROI) including primary motor, premotor, and prefrontal cortices, and cerebellum; and 3) volume of intersection between VTA and probabilistic tractography-based segmentation of the thalamus. At IP, individual contacts were scored as high or low efficacy based on acute tremor improvement. At CF, clinical response was measured by percent of change of the Clinical Rating Scale for Tremor (CRST) compared to preoperative scores. Contributions from each target ROI to clinical response was measured using logistic regression for IP and linear regression for CF. The clinically weighted map of whole brain connectivity of VTA shows preferential connectivity to precentral gyrus and brainstem/cerebellum. The volume of intersection between VTA and thalamic segmentation map based on probabilistic connectivity to primary motor cortex was a significant predictor of contact efficacy at IP (OR = 2.26 per 100 mm3 of overlap, p = .04) and percent change in CRST at CF (ß = 14.67 per 100 mm3 of overlap, p = .003). Targeting DBS to the area of thalamus most connected to primary motor cortex based on probabilistic tractography is associated with superior outcomes, providing a potential guide not only for lead targeting but also therapeutic programming.

Impulsivity Relates to Relative Preservation of Mesolimbic Connectivity in Patients with Parkinson Disease.

INTRODUCTION: The relationship between Parkinson Disease (PD) pathology, dopamine replacement therapy (DRT), and impulse control disorder (ICD) development is still incompletely understood. Given the sensorimotor-lateral substantia nigra (SN) selective degeneration associated with PD, we posit that a relative sparing of the limbic-medial SN in the context of DRT drives impulsive, reward-seeking behavior in PD patients with recent history of severe impulsivity. METHODS: Impulsive and control participants were selected from a consecutive list of PD patients receiving pre-operative deep brain stimulation (DBS) planning scans including 3T structural MRI and 64 direction diffusion tensor imaging (DTI). Using previously identified substantia nigra (SN) subsegment network connectivity profiles to develop classification targets, split-hemisphere target-based SN segmentation with probabilistic tractography was performed. The relative subsegment volumes and strength of connectivity between the SN and the limbic, associative, and motor network targets were compared. RESULTS: Our results show that there is greater probability of connectivity between the SN and limbic network targets relative to motor and associative network targets in PD patients with recent history of severe impulsivity as compared to PD patients without impulsivity (P = 0.0075). We did not observe relative volumetric subsegment differences across groups. CONCLUSION: Firstly, our results suggest that fine-grained, atlas-derived classification targets may be used in PD to parcellate and classify functionally distinct subsegments of the SN, with the apparent preservation of previously reported topographical limbic-medial SN, associative-ventral SN, and sensorimotor-lateral SN orientation. We suggest that relative, as opposed to absolute, degeneration amongst SN-associated dopaminergic networks relates to the impulsivity phenotype in PD.

Impact of Health-related Quality of Life and Prediagnosis Risk of Major Depressive Disorder on Treatment Choice in Low- and Intermediate-Risk Prostate Cancer.

BACKGROUND: Treatment for low-risk (LR), favorable intermediate-risk (FIR), and unfavorable intermediate-risk (UIR) prostate cancer (PC) is complicated by clinical equipoise between multiple options. It is unknown how prediagnosis health-related quality of life (HRQoL) and major depressive disorder (MDD) risk impact treatment decisions. OBJECTIVE: To analyze associations of patient-reported HRQoL and MDD risk with treatment for LR, FIR, and UIR PC patients. DESIGN SETTING AND PARTICIPANTS: Using the Surveillance, Epidemiology and End Results and Medicare Health Outcomes Survey-linked database, we identified 1678 PC patients (498 with LR, 685 with FIR, and 495 with UIR) aged ≥65 yr and diagnosed between 2004 and 2015, who completed the health outcomes survey ≤24 mo before diagnosis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: HRQoL was measured by physical (PCS) and mental (MCS) component summaries of the Medical Outcomes Study Short Form 36 (SF-36) and Veterans RAND 12-item (VR-12) health survey instruments. MDD risk was derived from survey items screening for depressive symptoms. Associations with treatment choice were assessed by multivariable multinomial logistic regression. RESULTS AND LIMITATIONS: LR patients with higher PCS scores were more likely to receive radiation than surgery (adjusted odds ratio [AOR] 1.5 [95% confidence interval {CI}: 1.1-2.1; p = 0.02]). FIR patients with MDD risk were more likely to receive neither treatment than surgery or radiation (surgery: AOR 2.6 [95% CI: 1.1-6.2; p = 0.03]; radiation: AOR 2.2 [95% CI: 1.2-4.2; p = 0.01]). UIR patients with MDD risk were more likely to undergo radiation than surgery (AOR 2.3 [95% CI: 1.0-4.9; p =0.04]). Additionally, higher PCS scores were associated with receipt of surgery compared with neither treatment (AOR 1.5 [95% CI: 1.1-2.0; p =0.01]). This study is limited by its retrospective design. CONCLUSIONS: Older PC patients with MDD risk received less invasive treatments in the FIR and UIR groups. Higher PCS scores were associated with treatment modality in LR and UIR patients. HRQoL and MDD risk impact treatment choice, warranting additional study. PATIENT SUMMARY: Treatment of prostate cancer requires thoughtful decision-making processes. This study shows that both pretreatment mental status and pretreatment physical status affect treatment decisions, and should be considered during counseling.

Alterations to task positive and task negative networks during executive functioning in Mild Cognitive Impairment.

Poor executive functioning increases risk of decline in Mild Cognitive Impairment (MCI). Executive functioning can be conceptualized within the framework of working memory. While some components are responsible for maintaining representations in working memory, the central executive is involved in the manipulation of information and creation of new representations. We aimed to examine the neural correlates of these components of working memory using a maintenance working memory and visuospatial reasoning task. Twenty-five patients with amnestic MCI and 19 elderly controls (EC) completed functional MRI during reasoning and maintenance working memory tasks. In MCI, maintenance working memory was associated with hypoactivation of right frontoparietal regions and hyperactivation of left prefrontal cortex, coupled with attenuation of default mode network (DMN) relative to EC. During reasoning, MCI showed hypoactivation of parietal regions, coupled with attenuation of anterior DMN and increased deactivation of posterior DMN relative to EC. Comparing the reasoning task to the maintenance working memory task yields the central executive. In MCI, the central executive showed hypoactivation of right parietal lobe and increased deactivation of posterior DMN compared to EC. Consistent with prior work on executive functioning, MCI show different neural circuitry during visuospatial reasoning, including changes to both task positive frontoparietal regions, as well as to deactivation patterns within the DMN. Both hyperactivation of task positive networks and increased deactivation of DMN may be compensatory.

Cholinergic Receptor Binding in Alzheimer Disease and Healthy Aging: Assessment In Vivo with Positron Emission Tomography Imaging.

OBJECTIVE: To compare regional nicotinic cholinergic receptor binding in older adults with Alzheimer disease (AD) and healthy older adults in vivo and to assess relationships between receptor binding and clinical symptoms. METHODS: Using cross-sectional positron emission tomography (PET) neuroimaging and structured clinical assessment, outpatients with mild to moderate AD (N = 24) and healthy older adults without cognitive complaints (C group; N = 22) were studied. PET imaging of α4ß2* nicotinic cholinergic receptor binding using 2-[18F]fluoro-3-(2(S)azetidinylmethoxy)pyridine (2FA) and clinical measures of global cognition, attention/processing speed, verbal memory, visuospatial memory, and neuropsychiatric symptoms were used. RESULTS: 2FA binding was lower in the AD group compared with the C group in the medial thalamus, medial temporal cortex, anterior cingulate, insula/opercula, inferior caudate, and brainstem (p < 0.05, corrected cluster), but binding was not associated with cognition. The C group had significant inverse correlations between 2FA binding in the thalamus (left: rs = -0.55, p = 0.008; right: rs = -0.50, p = 0.02; N = 22) and hippocampus (left: rs = -0.65, p = 0.001; right: rs = -0.55, p = 0.009; N = 22) and the Trails A score. The AD group had inverse correlation between 2FA binding in anterior cingulate (left: rs = -0.50, p = 0.01; right: rs = -0.50, p = 0.01; N = 24) and Neurobehavioral Rating Scale agitation/disinhibition factor score. CONCLUSION: Cholinergic receptor binding is reduced in specific brain regions in mild to moderate AD and is related to neuropsychiatric symptoms. Among healthy older adults, lower receptor binding may be associated with slower processing speed. Cholinergic receptor binding in vivo may reveal links to other key brain changes associated with aging and AD and may provide a potential molecular treatment target.

The functional neuroanatomy of verbal memory in Alzheimer's disease: [18F]-Fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) correlates of recency and recognition memory.

INTRODUCTION: The objective of this study was to distinguish the functional neuroanatomy of verbal learning and recognition in Alzheimer's disease (AD) using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word Learning task. METHOD: In 81 Veterans diagnosed with dementia due to AD, we conducted a cluster-based correlation analysis to assess the relationships between recency and recognition memory scores from the CERAD Word Learning Task and cortical metabolic activity measured using [18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET). RESULTS: AD patients (Mini-Mental State Examination, MMSE mean = 20.2) performed significantly better on the recall of recency items during learning trials than of primacy and middle items. Recency memory was associated with cerebral metabolism in the left middle and inferior temporal gyri and left fusiform gyrus (p < .05 at the corrected cluster level). In contrast, recognition memory was correlated with metabolic activity in two clusters: (a) a large cluster that included the left hippocampus, parahippocampal gyrus, entorhinal cortex, anterior temporal lobe, and inferior and middle temporal gyri; (b) the bilateral orbitofrontal cortices (OFC). CONCLUSIONS: The present study further informs our understanding of the disparate functional neuroanatomy of recency memory and recognition memory in AD. We anticipated that the recency effect would be relatively preserved and associated with temporoparietal brain regions implicated in short-term verbal memory, while recognition memory would be associated with the medial temporal lobe and possibly the OFC. Consistent with our a priori hypotheses, list learning in our AD sample was characterized by a reduced primacy effect and a relatively spared recency effect; however, recency memory was associated with cerebral metabolism in inferior and lateral temporal regions associated with the semantic memory network, rather than regions associated with short-term verbal memory. The correlates of recognition memory included the medial temporal lobe and OFC, replicating prior studies.

An FMRI-compatible Symbol Search task.

Our objective was to determine whether a Symbol Search paradigm developed for functional magnetic resonance imaging (FMRI) is a reliable and valid measure of cognitive processing speed (CPS) in healthy older adults. As all older adults are expected to experience cognitive declines due to aging, and CPS is one of the domains most affected by age, establishing a reliable and valid measure of CPS that can be administered inside an MR scanner may prove invaluable in future clinical and research settings. We evaluated the reliability and construct validity of a newly developed FMRI Symbol Search task by comparing participants' performance in and outside of the scanner and to the widely used and standardized Symbol Search subtest of the Wechsler Adult Intelligence Scale (WAIS). A brief battery of neuropsychological measures was also administered to assess the convergent and discriminant validity of the FMRI Symbol Search task. The FMRI Symbol Search task demonstrated high test-retest reliability when compared to performance on the same task administered out of the scanner (r=.791; p<.001). The criterion validity of the new task was supported, as it exhibited a strong positive correlation with the WAIS Symbol Search (r=.717; p<.001). Predicted convergent and discriminant validity patterns of the FMRI Symbol Search task were also observed. The FMRI Symbol Search task is a reliable and valid measure of CPS in healthy older adults and exhibits expected sensitivity to the effects of age on CPS performance.

The impact of hypertension on cerebral perfusion and cortical thickness in older adults.

Hypertension may increase risk for dementia possibly because of its association with decreased cortical thickness. Disturbed cerebral autoregulation is one plausible mechanism by which hypertension impacts the cerebral structure, but the associations among hypertension, brain perfusion, and cortical thickness are poorly understood. The current sample consisted of 58 older adults with varying levels of vascular disease. Diagnostic history of hypertension and antihypertensive medication status was ascertained through self-report, and when available, confirmed by medical record review. All participants underwent arterial spin labeling and T1-weighted magnetic resonance imaging to quantify total and regional cortical perfusion and thickness. Analysis of covariance adjusting for medical variables showed that participants with hypertension exhibited reduced temporal and occipital brain perfusion and total and regional cortical thickness relative to those without hypertension. The effects of hypertension on total brain perfusion remained unchanged even after adjustment for age, although no such pattern emerged for cortical thickness. Decreased total brain perfusion predicted reduced thickness of the total brain and of the frontal, temporal, and parietal lobe cortices. Antihypertensive treatment was not associated with total cerebral perfusion or cortical thickness. This study provides initial evidence for the adverse effects of a diagnostic history of hypertension on brain hypoperfusion and reduced cortical thickness. Longitudinal studies are needed to investigate the role of hypertension and its interaction with other contributing factors (e.g., age) in the manifestation of cerebral hypoperfusion and reduced cortical thickness.