Carole Scherling

Cerebrospinal fluid neurofilament concentration reflects disease severity in frontotemporal degeneration

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.

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 Alzheimers 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 Aβ pathology, and progressive supranuclear palsy (PSP), a primary tauopathy characterised by deposition of four microtubule-binding repeat (4R) τ with minimal Aβ 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 Aβ, 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.

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

PurposeSubsequent 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.MethodsFemale 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.ResultsOne 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.ConclusionThis study provides further credence to patient claims of altered cognitive functioning subsequent to chemotherapy treatment.

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.

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.

CSF neurofilament concentration reflects disease severity in frontotemporal degeneration

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.

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 ones 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), Alzheimers 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.

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.

Cerebrospinal fluid neurofilament concentration reflects disease severity in frontotemporal degeneration: Neurofilament in FTD

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.