Long-Term Clinical and Neuronuclear Imaging Sequelae of Cancer Therapy, Trauma, and Brain Injury.

Neuronuclear imaging has been used for several decades in the study of primary neurodegenerative conditions, such as dementia and parkinsonian syndromes, both for research and for clinical purposes. There has been a relative paucity of applications of neuronuclear imaging to evaluate nonneurodegenerative conditions that can also have long-term effects on cognition and function. This article summarizes clinical and imaging aspects of 3 such conditions that have garnered considerable attention in recent years: cancer- and chemotherapy-related cognitive impairment, posttraumatic stress disorder, and traumatic brain injury. Further, we describe current research using neuroimaging tools aimed to better understand the relationships between the clinical presentations and brain structure and function in these conditions.

Deficits in physiological and self-conscious emotional response to errors in hoarding disorder.

Hoarding disorder (HD) has been hypothesized to arise from deficits in error monitoring and abnormalities in emotional processing, but the relationship between error monitoring and emotional processing has not been examined. We examined measures of self-report, as well as behavioral, physiological, and facial responses to errors during a Stop-Change Task. 25 participants with HD and 32 healthy controls (HC) were recruited. Participants reported on number of errors committed and pre/post emotional response to errors. Skin conductance response (SCR) during correct and error commission trials was examined. Facial expression during task performance was coded for self-conscious and negative emotions. HD and HC participants had significantly different error rates but comparable error correction and post-error slowing. SCR was significantly lower for HD during error commission than for HC. During error trials, HD participants showed a significant deficit in displays of self-conscious emotions compared to HC. Self-reported emotions were increased in HD, with more negative and self-conscious emotion reported than was reported for HC participants. These findings suggest that hypoactive emotional responding at a physiological level may play a role in how errors are processed in individuals with HD.

Mistakes, Too Few to Mention? Impaired Self-conscious Emotional Processing of Errors in the Behavioral Variant of Frontotemporal Dementia.

Anosognosia, or lack of awareness of one's deficits, is a core feature of the behavioral variant of frontotemporal dementia (bvFTD). We hypothesized that this deficit has its origins in failed emotional processing of errors. We studied autonomic and facial emotional reactivity to errors in patients with bvFTD (n = 17), Alzheimer's disease (AD, n = 20), and healthy controls (HC, n = 35) during performance of a timed two-alternative-choice button press task. Performance-related behavioral responses to errors were quantified using rates of error correction and post-error slowing of reaction times. Facial emotional responses were measured by monitoring facial reactivity via video and subsequently coding the type, duration and intensity of all emotional reactions. Skin conductance response (SCR) was measured via noninvasive sensors. SCR and total score for each facial emotion expression were quantified for each trial. Facial emotions were grouped into self-conscious (amusement, embarrassment) and negative (fear, sadness, anger, disgust, contempt) emotions. HCs corrected 99.4% of their errors. BvFTD patients corrected 94% (not statistically different compared with HC) and AD corrected 74.8% of their errors (p < 0.05 compared with HC and bvFTD). All groups showed similar post-error slowing. Errors in HCs were associated with greater facial reactivity and SCRs compared with non-error trials, including both negative and self-conscious emotions. BvFTD patients failed to produce self-conscious emotions or an increase in SCR for errors, although they did produce negative emotional responses to a similar degree as HCs. AD showed no deficit in facial reactivity to errors. Although, SCR was generally reduced in AD during error trials, they showed a preserved increase in SCR for errors relative to correct trials. These results demonstrate a specific deficit in emotional responses to errors in bvFTD, encompassing both physiological response and a specific deficit in self-conscious emotions, despite intact awareness and correction of errors. The findings provide a potential mechanism for anosognosia and possibly other behavioral abnormalities in bvFTD and highlight the importance of studying multiple channels of reactivity to errors, including performance related responses and emotional responses, in order to understand how impaired error processing could influence behavior.

Decreased Self-Appraisal Accuracy on Cognitive Tests of Executive Functioning Is a Predictor of Decline in Mild Cognitive Impairment.

OBJECTIVE: Mild cognitive impairment (MCI) in older individuals is associated with increased risk of progression to dementia. The factors predicting progression are not yet well established, yet cognitive performance, particularly for memory, is known to be important. Anosognosia, meaning lack of awareness of one's impaired function, is commonly reported in dementia and is often also a feature of MCI, but its association with risk of progression is not well understood. In particular, self-appraisal measures provide an autonomous measure of insight abilities, without the need of an informant. METHODS: The present study examined the utility of self-appraisal accuracy at baseline for predicting cognitive decline in 51 patients using an informant-free assessment method. Baseline task performance scores were compared to self-assessments of performance to yield a discrimination score (DS) for tasks tapping into memory and executive functions. RESULTS: Linear regression revealed that a larger DS for executive function tasks in MCI predicted functional decline, independent of age, education, and baseline memory and executive task scores. CONCLUSION: These findings indicate that objective estimates of self-appraisal can be used to quantify anosognosia and increase predictive accuracy for decline in MCI.

Divergent CSF τ alterations in two common tauopathies: Alzheimer's disease and progressive supranuclear palsy.

BACKGROUND: Elevated CSF τ is considered a biomarker of neuronal injury in newly developed Alzheimer's disease (AD) and mild cognitive impairment (MCI) criteria. However, previous studies have failed to detect alterations of τ species in other primary tauopathies. We assessed CSF τ protein abnormalities in AD, a tauopathy with prominent Aß pathology, and progressive supranuclear palsy (PSP), a primary tauopathy characterised by deposition of four microtubule-binding repeat (4R) τ with minimal Aß pathology. METHODS: 26 normal control (NC), 37 AD, and 24 patients with PSP participated in the study. AD and PSP were matched for severity using the clinical dementia rating sum of boxes (CDR-sb) scores. The INNO BIA AlzBio3 multiplex immunoassay was used to measure CSF Aß, total τ, and ptau181. Additional, novel ELISAs targeting different N-terminal and central τ epitopes were developed to examine CSF τ components and to investigate interactions between diagnostic group, demographics and genetic variables. RESULTS: PSP had lower CSF N-terminal and C-terminal τ concentrations than NC and AD measured with the novel τ ELISAs and the standard AlzBio3 τ and ptau assays. AD had higher total τ and ptau levels than NC and PSP. There was a gender by diagnosis interaction in AD and PSP for most τ species, with lower concentrations for male compared to female patients. CONCLUSIONS: CSF τ fragment concentrations are different in PSP compared with AD despite the presence of severe τ pathology and neuronal injury in both disorders. CSF τ concentration likely reflects multiple factors in addition to the degree of neuronal injury.

Regional functional connectivity predicts distinct cognitive impairments in Alzheimer's disease spectrum.

Understanding neural network dysfunction in neurodegenerative disease is imperative to effectively develop network-modulating therapies. In Alzheimer's disease (AD), cognitive decline associates with deficits in resting-state functional connectivity of diffuse brain networks. The goal of the current study was to test whether specific cognitive impairments in AD spectrum correlate with reduced functional connectivity of distinct brain regions. We recorded resting-state functional connectivity of alpha-band activity in 27 patients with AD spectrum--22 patients with probable AD (5 logopenic variant primary progressive aphasia, 7 posterior cortical atrophy, and 10 early-onset amnestic/dysexecutive AD) and 5 patients with mild cognitive impairment due to AD. We used magnetoencephalographic imaging (MEGI) to perform an unbiased search for regions where patterns of functional connectivity correlated with disease severity and cognitive performance. Functional connectivity measured the strength of coherence between a given region and the rest of the brain. Decreased neural connectivity of multiple brain regions including the right posterior perisylvian region and left middle frontal cortex correlated with a higher degree of disease severity. Deficits in executive control and episodic memory correlated with reduced functional connectivity of the left frontal cortex, whereas visuospatial impairments correlated with reduced functional connectivity of the left inferior parietal cortex. Our findings indicate that reductions in region-specific alpha-band resting-state functional connectivity are strongly correlated with, and might contribute to, specific cognitive deficits in AD spectrum. In the future, MEGI functional connectivity could be an important biomarker to map and follow defective networks in the early stages of AD.

A prospective study of grey matter and cognitive function alterations in chemotherapy-treated breast cancer patients.

PURPOSE: Subsequent to chemotherapy treatment, breast cancer patients often report a decline in cognitive functioning that can adversely impact many aspects of their lives. Evidence has mounted in recent years indicating that a portion of breast cancer survivors who have undergone chemotherapy display reduced performance on objective measures of cognitive functioning relative to comparison groups. Neurophysiological support for chemotherapy-related cognitive impairment has been accumulating due to an increase in neuroimaging studies in this field; however, longitudinal studies are limited and have not examined the relationship between structural grey matter alterations and neuropsychological performance. The aim of this study was to extend the cancer-cognition literature by investigating the association between grey matter attenuation and objectively measured cognitive functioning in chemotherapy-treated breast cancer patients. METHODS: Female breast cancer patients (n = 19) underwent magnetic resonance imaging after surgery but before commencing chemotherapy, one month following treatment, and one year after treatment completion. Individually matched controls (n = 19) underwent imaging at similar intervals. All participants underwent a comprehensive neuropsychological battery comprising four cognitive domains at these same time points. Longitudinal grey matter changes were investigated using voxel-based morphometry. RESULTS: One month following chemotherapy, patients had distributed grey matter volume reductions. One year after treatment, a partial recovery was observed with alterations persisting predominantly in frontal and temporal regions. This course was not observed in the healthy comparison group. Processing speed followed a similar trajectory within the patient group, with poorest scores obtained one month following treatment and some improvement evident one year post-treatment. CONCLUSION: This study provides further credence to patient claims of altered cognitive functioning subsequent to chemotherapy treatment.

Persistent cognitive changes in breast cancer patients 1 year following completion of chemotherapy.

Numerous studies have shown that there are acute cognitive side-effects of chemotherapy for breast cancer. Presumably, patients are more concerned about chronic treatment effects. This report from a prospective longitudinal study compares cognitive functioning in 56 breast cancer patients 1 year after chemotherapy to that of 56 healthy individuals. Neuropsychological test scores were combined into verbal memory, visual memory, working memory, and processing speed scores, as well as an overall summary score, and analyzed using multi-level growth modeling. Frequency of cognitive decline was assessed using regression-based change scores. There was significant rebound in the overall summary score from end of treatment to 1-year follow-up as well as a substantial reduction in the frequency of cognitive decline. However, more than one-third of the breast cancer patients who showed cognitive decline immediately following completion of chemotherapy showed persistent cognitive decline 1 year later. Furthermore, recovery was not seen in all cognitive domains. In fact, the rebound was significant only for working memory. Longer multi-site studies are recommended to explore the risk factors for and the permanence of these longer-term cognitive effects.

Cerebrospinal fluid neurofilament concentration reflects disease severity in frontotemporal degeneration.

OBJECTIVE: Cerebrospinal fluid (CSF) neurofilament light chain (NfL) concentration is elevated in neurological disorders, including frontotemporal degeneration (FTD). We investigated the clinical correlates of elevated CSF NfL levels in FTD. METHODS: CSF NfL, amyloid-ß1-42 (Aß42), tau, and phosphorylated tau concentrations were compared in 47 normal controls (NC), 8 asymptomatic gene carriers (NC2) of FTD-causing mutations, and 79 FTD (45 behavioral variant frontotemporal dementia [bvFTD], 18 progressive nonfluent aphasia [PNFA], 16 semantic dementia [SD]), 22 progressive supranuclear palsy, 50 Alzheimer disease, 6 Parkinson disease, and 17 corticobasal syndrome patients. Correlations between CSF analyte levels were performed with neuropsychological measures and the Clinical Dementia Rating scale sum of boxes (CDRsb). Voxel-based morphometry of structural magnetic resonance images determined the relationship between brain volume and CSF NfL. RESULTS: Mean CSF NfL concentrations were higher in bvFTD, SD, and PNFA than other groups. NfL in NC2 was similar to NC. CSF NfL, but not other CSF measures, correlated with CDRsb and neuropsychological measures in FTD, but not in other diagnostic groups. Analyses in 2 independent FTD cohorts and a group of autopsy-verified or biomarker-enriched cases confirmed the larger group analysis. In FTD, gray and white matter volume negatively correlated with CSF NfL concentration, such that individuals with the highest NfL levels exhibited the most atrophy. INTERPRETATION: CSF NfL is elevated in symptomatic FTD and correlates with disease severity. This measurement may be a useful surrogate endpoint of disease severity in FTD clinical trials. Longitudinal studies of CSF NfL in FTD are warranted.

Opening up the window into "chemobrain": a neuroimaging review.

As more chemotherapy-treated cancer patients are reaching survivorship, side-effects such as cognitive impairment warrant research attention. The advent of neuroimaging has helped uncover a neural basis for these deficits. This paper offers a review of neuroimaging investigations in chemotherapy-treated adult cancer patients, discussing the benefits and limitations of each technique and study design. Additionally, despite the assumption given by the chemobrain label that chemotherapy is the only causative agent of these deficits, other factors will be considered. Suggestions are made on how to more comprehensively study these cognitive changes using imaging techniques, thereby promoting generalizability of the results to clinical applications. Continued investigations may yield better long-term quality of life outcomes by supporting patients' self-reports, and revealing brain regions being affected by chemotherapy.

Differences in verbal memory retrieval in breast cancer chemotherapy patients compared to healthy controls: a prospective fMRI study.

Cognitive complaints by breast cancer survivors receiving chemotherapy have led to an increasing interest in elucidating the possible causes of such impairment. Although a number of neuroimaging studies have been conducted, only a handful of them have taken into account cognitive status pre-chemotherapy. The current study included pre-chemotherapy and post-chemotherapy assessment. In addition, various factors such as depression, anxiety, fatigue and days since surgery were considered during analyses. Breast cancer patients performed an fMRI verbal recall task before and an average of 1 month after chemotherapy. Well matched controls also performed the task with a similar timeline. Pre-chemotherapy analyses revealed that patients activated the anterior cingulate less than controls during memory retrieval when anxiety and fatigue scores were added as covariates during group comparisons. In addition, there were also changes in brain activation from pre- to post-chemotherapy in patients but not in controls. Post-chemotherapy, patients had less activation in the bilateral insula, the left inferior orbitofrontal cortex and the left middle temporal gyrus. Finally, patients also showed significantly less activation when compared to controls. Brain regions included: the right middle and superior temporal gyrus, the right medial frontal gyrus, the right inferior orbitofrontal cortex, the left insula and left superior temporal pole. Importantly, depression, anxiety, and particularly fatigue accounted for some of brain activation differences. Our results suggest that chemotherapy in part plays a role in brain activation differences and it also highlights the importance of rigorously controlling for confounding variables. Only by controlling such factors can we understand the role that chemotherapy may play on cognition.

Cognitive effects of chemotherapy in breast cancer patients: a dose-response study.

OBJECTIVE: The purpose of this study was to determine if cognition progressively worsens with cumulative chemotherapy exposure. We reasoned that the demonstration of such a 'dose-response' relationship would help to establish whether cognitive changes are caused by neurotoxic effects of chemotherapy or whether they are due to other confounding factors such as mood and pre-treatment differences in cognition. METHODS: Sixty women with early stage breast cancer, aged 65 years or younger with no previous history of cancer or chemotherapy, were matched to 60 healthy women on age and education. Neuropsychological assessment was conducted after surgery but prior to commencing chemotherapy and then again following each chemotherapy cycle in patients and at yoked intervals in healthy controls. We used multilevel modeling to assess change over time in an overall cognitive summary score as well as domain-specific cognitive scores. RESULTS: After controlling for baseline performance, age, education, and mood, the chemotherapy group showed a significant progressive decline over time relative to a matched healthy control group in an overall cognitive summary score, as well as in working memory, processing speed, verbal memory, and visual memory scores. A linear model best fit the trajectory of cognitive change over the course of treatment in the chemotherapy group supporting a dose-response hypothesis. CONCLUSIONS: These results are in keeping with a dose-response relationship and provide the most compelling clinical evidence to date that cognitive decline is caused by chemotherapy exposure.

Prechemotherapy differences in response inhibition in breast cancer patients compared to controls: a functional magnetic resonance imaging study.

Prechemotherapy neuroimaging data are lacking in posttreatment cognitive impairment studies. Breast cancer patients and noncancer controls were scanned prior to chemotherapy during a response inhibition task. Task reaction times and error rates, as well as neuropsychological tests, hospital records, and salivary biomarkers, were investigated, yielding no significant group differences. Significant group differences observed for the functional magnetic resonance imaging (fMRI) data depended on the type of analysis performed, most consistently implicating widespread attenuated activations in patients. The patient group also revealed considerable variability in task-related brain activity. These pretreatment differences highlight the need to understand the effects of confounding variables before considering posttreatment effects. Role of the funding source: The Canadian Breast Cancer Foundation has funded this project. Their contribution was solely financial support.

Pre-chemotherapy differences in visuospatial working memory in breast cancer patients compared to controls: an FMRI study.

INTRODUCTION: Cognitive deficits are a side-effect of chemotherapy, however pre-treatment research is limited. This study examines neurofunctional differences during working memory between breast cancer (BC) patients and controls, prior to chemotherapy. METHODS: Early stage BC females (23), scanned after surgery but before chemotherapy, were individually matched to non-cancer controls. Participants underwent functional magnetic resonance imaging (fMRI) while performing a Visuospatial N-back task and data was analyzed by multiple group comparisons. fMRI task performance, neuropsychological tests, hospital records, and salivary biomarkers were also collected. RESULTS: There were no significant group differences on neuropsychological tests, estrogen, or cortisol. Patients made significantly fewer commission errors but had less overall correct responses and were slower than controls during the task. Significant group differences were observed for the fMRI data, yet results depended on the type of analysis. BC patients presented with increased activations during working memory compared to controls in areas such as the inferior frontal gyrus, insula, thalamus, and midbrain. Individual group regressions revealed a reverse relationship between brain activity and commission errors. CONCLUSION: This is the first fMRI investigation to reveal neurophysiological differences during visuospatial working memory between BC patients pre-chemotherapy and controls. These results also increase the knowledge about the effects of BC and related factors on the working memory network. SIGNIFICANCE: This highlights the need to better understand the pre-chemotherapy BC patient and the effects of associated confounding variables.

Neural correlates of processing stressful information: an event-related fMRI study.

Recent neuroimaging studies investigating neural correlates of psychological stress employ cognitive paradigms that induce a significant hormonal stress response in the scanner. The Montreal Imaging Stress Task (MIST) is one such task that combines challenging mental arithmetic with negative social evaluative feedback. Due to the block design nature of the MIST, it has not been possible thus far to investigate which brain areas respond specifically to the key components of the MIST (mental arithmetic, failure, negative social evaluation). In the current study, we developed an event-related MIST (eventMIST) in order to investigate which neural activation patterns are associated with performing mental arithmetic vs. processing of social evaluative threat. Data was available from twenty healthy university students. The eventMIST induced a significant stress response in a subsample of subjects, called the responders (n=7). Direct comparison between brain activity changes in responders vs. non-responders, in response to challenging math, revealed increased activity bilaterally in dorsomedial prefrontal cortex (PFC), left temporal pole, and right dorsolateral PFC. In response to negative social evaluation, responders showed reduction of brain activity in limbic system regions (medial orbitofrontal cortex and hippocampus), which was largely lacking in non-responders. Direct comparison between the groups for this contrast did not reveal any significant difference, probably due to small number of events available. This is the first study to use an event-related paradigm to investigate brain activity patterns in relation to challenging math and social evaluative threat separately.

Acute nicotine fails to alter event-related potential or behavioral performance indices of auditory distraction in cigarette smokers.

Behavioral studies have shown that nicotine enhances performance in sustained attention tasks, but they have not shown convincing support for the effects of nicotine on tasks requiring selective attention or attentional control under conditions of distraction. We investigated distractibility in 14 smokers (7 females) with event-related brain potentials (ERPs) and behavioral performance measures extracted from an auditory discrimination task requiring a choice reaction time response to short- and long-duration tones, both with and without embedded deviants. Nicotine gum (4 mg), administered in a randomized, double-blind, placebo-controlled crossover design, failed to counter deviant-elicited behavioral distraction (i.e., slower reaction times and increased response errors), and it did not influence the distracter-elicited mismatch negativity, the P300a, or the reorienting negativity ERP components reflecting acoustic change detection, involuntary attentional switching, and attentional reorienting, respectively. Results are discussed in relation to a stimulus-filter model of smoking and in relation to future research directions.

Neural effects of nicotine during auditory selective attention in smokers: an event-related potential study.

Acute nicotine has been found to improve task performance in smokers after smoking abstinence, but the attentional processes mediating these improvements are unclear. Since scalp-recorded event-related potentials (ERPs) have been shown to be sensitive indicators of selective attention, the effects of acutely administered nicotine were examined on ERPs and concomitant behavioural performance measures in an auditory selective attention task. Ten (6 males) overnight smoking-abstinent cigarette smokers received nicotine gum (4 mg) in a randomized, double-blind, placebo-controlled, crossover design. In a dichotic listening task [which required participants to attend and detect (target) deviant stimuli in one ear and to ignore similar stimuli in the other ear] which included ERP recordings and assessment of response speed and accuracy measures, nicotine gum failed to alter behavioural performance or amplitudes of ERP components sensitive to selective attention [reflected in the N100 and negative difference (Nd) component] or to pre-attentive detection of acoustic change [reflected in the mismatch negativity (MMN) component]. However, nicotine did influence the speed of these voluntary selective processes, as reflected by shortened latencies of the early Nd component. The findings are discussed in relation to the stimulus filter theory of smoking, and with respect to nicotine's actions on involuntary and controlled aspects of selective attention processes.