Graph lesion-deficit mapping of fluid intelligence.

Fluid intelligence is arguably the defining feature of human cognition. Yet the nature of its relationship with the brain remains a contentious topic. Influential proposals drawing primarily on functional imaging data have implicated 'multiple demand' frontoparietal and more widely distributed cortical networks, but extant lesion-deficit studies with greater causal power are almost all small, methodologically constrained, and inconclusive. The task demands large samples of patients, comprehensive investigation of performance, fine-grained anatomical mapping, and robust lesion-deficit inference, yet to be brought to bear on it. We assessed 165 healthy controls and 227 frontal or non-frontal patients with unilateral brain lesions on the best-established test of fluid intelligence, Raven's Advanced Progressive Matrices, employing an array of lesion-deficit inferential models responsive to the potentially distributed nature of fluid intelligence. Non-parametric Bayesian stochastic block models were used to reveal the community structure of lesion deficit networks, disentangling functional from confounding pathological distributed effects. Impaired performance was confined to patients with frontal lesions [F(2,387) = 18.491; P < 0.001; frontal worse than non-frontal and healthy participants P < 0.01, P <0.001], more marked on the right than left [F(4,385) = 12.237; P < 0.001; right worse than left and healthy participants P < 0.01, P < 0.001]. Patients with non-frontal lesions were indistinguishable from controls and showed no modulation by laterality. Neither the presence nor the extent of multiple demand network involvement affected performance. Both conventional network-based statistics and non-parametric Bayesian stochastic block modelling heavily implicated the right frontal lobe. Crucially, this localization was confirmed on explicitly disentangling functional from pathology-driven effects within a layered stochastic block model, prominently highlighting a right frontal network involving middle and inferior frontal gyrus, pre- and post-central gyri, with a weak contribution from right superior parietal lobule. Similar results were obtained with standard lesion-deficit analyses. Our study represents the first large-scale investigation of the distributed neural substrates of fluid intelligence in the focally injured brain. Combining novel graph-based lesion-deficit mapping with detailed investigation of cognitive performance in a large sample of patients provides crucial information about the neural basis of intelligence. Our findings indicate that a set of predominantly right frontal regions, rather than a more widely distributed network, is critical to the high-level functions involved in fluid intelligence. Further they suggest that Raven's Advanced Progressive Matrices is a useful clinical index of fluid intelligence and a sensitive marker of right frontal lobe dysfunction.

Long-term study of the cognitive profile of Moyamoya Disease in adults.

Moyamoya Disease (MMD) is a rare cerebrovascular disorder which can have significant cognitive consequences. The aim of the current study was to describe comprehensively the domain-specific cognitive profile of adult patients with MMD and to assess whether this changes in the absence of recurrent stroke over long-term follow-up. Comprehensive neuropsychological assessment covering seven cognitive domains was conducted on 61 adult patients with MMD at baseline and then at up to 3 further time points during follow up (median=2.31, 4.87 and 7.12 years). Although 27 patients had had prior surgical revasculariation, none had surgery between neuropsychological assessments. Cognitive impairment was common. At baseline, impairment in executive functions was most frequent (57%), followed by performance IQ (36%), speed of information processing (31%) and visual memory (30%). We found that the neuropsychological profile remains broadly stable over long-term follow-up with no clear indication of improvement or significant decline. The pattern of impairment also did not differ depending on age of onset or whether there was a history of either prior stroke at presentation or revascularisation surgery at presentation.

Cognitive dysfunction and white matter hyperintensities in Fabry disease.

Fabry disease (FD) is an X-linked lysosomal storage disorder with multi-system involvement including cerebrovascular disease. Patients with FD also have a high risk of ischaemic stroke and TIA. White matter hyperintensities are common, but their clinical impact on cognition remains uncertain. Previous studies have examined the neuropsychological profile of FD, but have been inconclusive in part due to methodological limitations including small sample sizes. We sought to address these limitations in a case-control study of 26 patients with Fabry disease with mild to moderate disease symptoms matched with 18 healthy controls for age and premorbid intellectual level. We obtained detailed neuropsychological data and MRI neuroimaging data on the severity of white matter changes. Mood was accounted for as a possible confounder. Our results showed significant compromise of executive functions and information processing speed for the FD group. Error analyses suggested that the compromise of executive functions could not be entirely accounted for by slowed information processing speed. We demonstrated significant correlations between cognitive decline and the overall volume of white matter hyperintensities in the FD group. Our results point to significant compromise of cognition in FD even without stroke or mood difficulties. This suggests that neuropsychological assessment and rehabilitation should be routinely offered to patients with FD.

Classical infratentorial superficial siderosis of the central nervous system: pathophysiology, clinical features and management.

The term superficial siderosis (SS) is derived from the Greek word 'sideros', meaning iron. It includes two subtypes, distinguished by their anatomical distribution, causes and clinical features: 'classical' infratentorial SS (iSS, which sometimes also affects supratentorial regions) and cortical SS (cSS, which affects only supratentorial regions). This paper considers iSS, a potentially disabling disorder usually associated with very slow persistent or intermittent subarachnoid bleeding from a dural defect, and characterised by progressive hearing and vestibular impairment, ataxia, myelopathy and cognitive dysfunction. The causal dural defect-most often spinal but sometimes in the posterior fossa-typically follows trauma or neurosurgery occurring decades before diagnosis. Increasing recognition of iSS with paramagnetic-sensitive MRI is leading to an unmet clinical need. Given the diagnostic challenges and complex neurological impairments in iSS, we have developed a multidisciplinary approach involving key teams. We discuss pathophysiology, diagnosis and management of iSS, including a proposed clinical care pathway.

Is the Weigl Colour-Form Sorting Test Specific to Frontal Lobe Damage?

OBJECTIVE: The Weigl Colour-Form Sorting Test is a brief, widely used test of executive function. So far, it is unknown whether this test is specific to frontal lobe damage. Our aim was to investigate Weigl performance in patients with focal, unilateral, left or right, frontal, or non-frontal lesions. METHOD: We retrospectively analysed data from patients with focal, unilateral, left or right, frontal (n = 37), or non-frontal (n = 46) lesions who had completed the Weigl. Pass/failure (two correct solutions/less than two correct solutions) and errors were analysed. RESULTS: A greater proportion of frontal patients failed the Weigl than non-frontal patients, which was highly significant (p < 0.001). In patients who failed the test, a significantly greater proportion of frontal patients provided the same solution twice. No significant differences in Weigl performance were found between patients with left versus right hemisphere lesions or left versus right frontal lesions. There was no significant correlation between performance on the Weigl and tests tapping fluid intelligence. CONCLUSIONS: The Weigl is specific to frontal lobe lesions and not underpinned by fluid intelligence. Both pass/failure on this test and error types are informative. Hence, the Weigl is suitable for assessing frontal lobe dysfunction.

White matter integrity correlates with cognition and disease severity in Fabry disease.

Cerebral white matter pathology is a common CNS manifestation of Fabry disease, visualized as white matter hyperintensities on MRI in 42-81% of patients. Diffusion tensor imaging (DTI) MRI is a sensitive technique to quantify microstructural damage within the white matter with potential value as a disease biomarker. We evaluated the pattern of DTI abnormalities in Fabry disease, and their correlations with cognitive impairment, mood, anxiety, disease severity and plasma lyso-Gb3 levels in 31 patients with genetically proven Fabry disease and 19 age-matched healthy control subjects. We obtained average values of fractional anisotropy and mean diffusivity within the white matter and performed voxelwise analysis with tract-based spatial statistics. Using a standardized neuropsychological test battery, we assessed processing speed, executive function, anxiety, depression and disease severity. The mean age (% male) was 44.1 (45%) for patients with Fabry disease and 37.4 (53%) for the healthy control group. In patients with Fabry disease, compared to healthy controls the mean average white matter fractional anisotropy was lower in [0.423 (standard deviation, SD 0.023) versus 0.446 (SD 0.016), P = 0.002] while mean average white matter mean diffusivity was higher (749 × 10-6 mm2/s (SD 32 × 10-6) versus 720 × 10-6 mm2/s (SD 21 × 10-6), P = 0.004]. Voxelwise statistics showed that the diffusion abnormalities for both fractional anisotropy and mean diffusivity were anatomically widespread. A lesion probability map showed that white matter hyperintensities also had a wide anatomical distribution with a predilection for the posterior centrum semiovale. However, diffusion abnormalities in Fabry disease were not restricted to lesional tissue; compared to healthy controls, the normal appearing white matter in patients with Fabry disease had reduced fractional anisotropy [0.422 (SD 0.022) versus 0.443 (SD 0.017) P = 0.003] and increased mean diffusivity [747 × 10-6 mm2/s (SD 26 × 10-6) versus 723 × 10-6 mm2/s (SD 22 × 10-6), P = 0.008]. Within patients, average white matter fractional anisotropy and white matter lesion volume showed statistically significant correlations with Digit Symbol Coding Test score (r = 0.558, P = 0.001; and r = -0.633, P ≤ 0.001, respectively). Average white matter fractional anisotropy correlated with the overall Mainz Severity Score Index (r = -0.661, P ≤ 0.001), while average white matter mean diffusivity showed a strong correlation with plasma lyso-Gb3 levels (r = 0.559, P = 0.001). Our findings using DTI confirm widespread areas of microstructural white matter disruption in Fabry disease, extending beyond white matter hyperintensities seen on conventional MRI. Moreover, diffusion measures show strong correlations with cognition (processing speed), clinical disease severity and a putative plasma biomarker of disease activity, making them promising quantitative biomarkers for monitoring Fabry disease severity and progression.

Cognitive Reserve Proxies Do Not Differentially Account for Cognitive Performance in Patients with Focal Frontal and Non-Frontal Lesions.

OBJECTIVE: Cognitive reserve (CR) suggests that premorbid efficacy, aptitude, and flexibility of cognitive processing can aid the brain's ability to cope with change or damage. Our previous work has shown that age and literacy attainment predict the cognitive performance of frontal patients on frontal-executive tests. However, it remains unknown whether CR also predicts the cognitive performance of non-frontal patients. METHOD: We investigated the independent effect of a CR proxy, National Adult Reading Test (NART) IQ, as well as age and lesion group (frontal vs. non-frontal) on measures of executive function, intelligence, processing speed, and naming in 166 patients with focal, unilateral frontal lesions; 91 patients with focal, unilateral non-frontal lesions; and 136 healthy controls. RESULTS: Fitting multiple linear regression models for each cognitive measure revealed that NART IQ predicted executive, intelligence, and naming performance. Age also significantly predicted performance on the executive and processing speed tests. Finally, belonging to the frontal group predicted executive and naming performance, while membership of the non-frontal group predicted intelligence. CONCLUSIONS: These findings suggest that age, lesion group, and literacy attainment play independent roles in predicting cognitive performance following stroke or brain tumour. However, the relationship between CR and focal brain damage does not differ in the context of frontal and non-frontal lesions.

Limitations of the trail making test part-B in assessing frontal executive dysfunction.

Part B of the Trail Making Test (TMT-B) is one of the most widely used neuropsychological tests of "executive" function. A commonly held assumption is that the TMT-B can be used to detect frontal executive dysfunction. However, so far, research evidence has been limited and somewhat inconclusive. In this retrospective study, performance on the TMT-B of 55 patients with known focal frontal lesions, 27 patients with focal non-frontal lesions and 70 healthy controls was compared. Completion time and the number of errors made were examined. Patients with frontal and non-frontal lesions performed significantly worse than healthy controls for both completion time and the number of errors. However, there was no significant difference for both completion time and the number of errors when patients with frontal and non-frontal lesions were compared. Performance was also not significantly different between patients with focal lesions within different regions of the frontal lobe (orbital, left lateral, right lateral, medial). Our findings suggest that the TMT-B is a robust test for detection of brain dysfunction. However, its capacity for detecting frontal executive dysfunction appears rather limited. Clinicians should be cautious when drawing conclusions from performance on the TMT-B alone.

Negative emotional experiences during navigation enhance parahippocampal activity during recall of place information.

It is known that the parahippocampal cortex is involved in object-place associations in spatial learning, but it remains unknown whether activity within this region is modulated by affective signals during navigation. Here we used fMRI to measure the neural consequences of emotional experiences on place memory during navigation. A day before scanning, participants undertook an active object location memory task within a virtual house in which each room was associated with a different schedule of task-irrelevant emotional events. The events varied in valence (positive, negative, or neutral) and in their rate of occurrence (intermittent vs. constant). On a subsequent day, we measured neural activity while participants were shown static images of the previously learned virtual environment, now in the absence of any affective stimuli. Our results showed that parahippocampal activity was significantly enhanced bilaterally when participants viewed images of a room in which they had previously encountered negatively arousing events. We conclude that such automatic enhancement of place representations by aversive emotional events serves as an important adaptive mechanism for avoiding future threats.

Characterizing phonemic fluency by transfer learning with deep language models.

Though phonemic fluency tasks are traditionally indexed by the number of correct responses, the underlying disorder may shape the specific choice of words-both correct and erroneous. We report the first comprehensive qualitative analysis of incorrect and correct words generated on the phonemic ('S') fluency test, in a large sample of patients (n = 239) with focal, unilateral frontal or posterior lesions and healthy controls (n = 136). We conducted detailed qualitative analyses of the single words generated in the phonemic fluency task using categorical descriptions for different types of errors, low-frequency words and clustering/switching. We further analysed patients' and healthy controls' entire sequences of words by employing stochastic block modelling of Generative Pretrained Transformer 3-based deep language representations. We conducted predictive modelling to investigate whether deep language representations of word sequences improved the accuracy of detecting the presence of frontal lesions using the phonemic fluency test. Our qualitative analyses of the single words generated revealed several novel findings. For the different types of errors analysed, we found a non-lateralized frontal effect for profanities, left frontal effects for proper nouns and permutations and a left posterior effect for perseverations. For correct words, we found a left frontal effect for low-frequency words. Our novel large language model-based approach found five distinct communities whose varied word selection patterns reflected characteristic demographic and clinical features. Predictive modelling showed that a model based on Generative Pretrained Transformer 3-derived word sequence representations predicted the presence of frontal lesions with greater fidelity than models of native features. Our study reveals a characteristic pattern of phonemic fluency responses produced by patients with frontal lesions. These findings demonstrate the significant inferential and diagnostic value of characterizing qualitative features of phonemic fluency performance with large language models and stochastic block modelling.

Domain-specific neuropsychological investigation of CAA with and without intracerebral haemorrhage.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is associated with cognitive impairment, but the contributions of lobar intracerebral haemorrhage (ICH), underlying diffuse vasculopathy, and neurodegeneration, remain uncertain. We investigated the domain-specific neuropsychological profile of CAA with and without ICH, and their associations with structural neuroimaging features. METHODS: Data were collected from patients with possible or probable CAA attending a specialist outpatient clinic. Patients completed standardised neuropsychological assessment covering seven domains. MRI scans were scored for markers of cerebral small vessel disease and neurodegeneration. Patients were grouped into those with and without a macro-haemorrhage (CAA-ICH and CAA-non-ICH). RESULTS: We included 77 participants (mean age 72, 65% male). 26/32 (81%) CAA-non-ICH patients and 41/45 (91%) CAA-ICH patients were impaired in at least one cognitive domain. Verbal IQ and non-verbal IQ were the most frequently impaired, followed by executive functions and processing speed. We found no significant differences in the frequency of impairment across domains between the two groups. Medial temporal atrophy was the imaging feature most consistently associated with cognitive impairment (both overall and in individual domains) in both univariable and multivariable analyses. DISCUSSION: Cognitive impairment is common in CAA, even in the absence of ICH, suggesting a key role for diffuse processes related to small vessel disease and/or neurodegeneration. Our findings indicate that neurodegeneration, possibly due to co-existing Alzheimer's disease pathology, may be the most important contributor. The observation that general intelligence is the most frequently affected domain suggests that CAA has a generalised rather than focal cognitive impact.

Distinct neural networks underlie encoding of categorical versus coordinate spatial relations during active navigation.

It has been proposed that spatial relations are encoded either categorically, such that the relative positions of objects are defined in prepositional terms; or in terms of visual coordinates, such that the precise distances between objects are represented. In humans, it has been assumed that a left hemisphere neural network subserves categorical representations, and that coordinate representations are right lateralised. However, evidence in support of this distinction has been garnered exclusively from tasks that involved static, two-dimensional (2D) arrays. We used functional magnetic resonance imaging (fMRI) to identify neural circuits underlying categorical and coordinate representations during active spatial navigation. Activity in the categorical condition was significantly greater in the parietal cortex, whereas the coordinate condition revealed greater activity in medial temporal cortex and dorsal striatum. In addition, activity in the categorical condition was greater in parietal cortex within the left hemisphere than within the right. Our findings are consistent with analogous studies in rodents, and support the suggestion of distinct neural circuits underlying categorical and coordinate representations during active spatial navigation. The findings also support the claim of a left hemispheric preponderance for the processing of categorical spatial relations.

The impact of the UK COVID-19 pandemic on patient-reported health outcomes after stroke: a retrospective sequential comparison.

BACKGROUND AND PURPOSE: The COVID-19 pandemic and related social isolation measures are likely to have adverse consequences on community healthcare provision and outcome after acute illnesses treated in hospital, including stroke. We aimed to evaluate the impact of the COVID-19 pandemic on patient-reported health outcomes after hospital admission for acute stroke. METHODS: This retrospective study included adults with acute stroke admitted to the University College Hospital NHS Foundation Trust Hyperacute Stroke Unit. We included two separate cohorts of consecutively enrolled patients from the same geographical population at two time points: 16th March-16th May 2018 (pre-COVID-19 pandemic); and 16th March-16th May 2020 (during the COVID-19 pandemic). Patients in both cohorts completed the validated Patient Reported Outcomes Measurement Information System-29 (PROMIS-29 version 2.0) at 30 days after stroke. RESULTS: We included 205 patients who were alive at 30 days (106 admitted before and 99 admitted during the COVID-19 pandemic), of whom 201/205 (98%) provided patient-reported health outcomes. After adjustment for confounding factors, admission with acute stroke during the COVID-19 pandemic was independently associated with increased anxiety (ß = 28.0, p < 0.001), fatigue (ß = 9.3, p < 0.001), depression (ß = 4.5, p = 0.002), sleep disturbance (ß = 2.3, p = 0.018), pain interference (ß = 10.8, p < 0.001); and reduced physical function (ß = 5.2, p < 0.001) and participation in social roles and activities (ß = 6.9, p < 0.001). CONCLUSION: Compared with the pre-pandemic cohort, patients admitted with acute stroke during the first wave of the COVID-19 pandemic reported poorer health outcomes at 30 day follow-up in all domains. Stroke service planning for any future pandemic should include measures to mitigate this major adverse impact on patient health.

Factors contributing to the distress, concerns, and needs of UK Neuroscience health care workers during the COVID-19 pandemic.

COVID-19 research from China suggests health care workers are at risk of distress, have specific concerns, and need support. It remains unknown whether findings are applicable to UK health care staff and whether psychological support based on generic approaches is effective. We administered an online survey at a leading neuroscience hospital in the UK to examine how individual staff characteristics contribute to distress, concerns, and interventions most valued during the COVID-19 pandemic. We found a high incidence of distress, particularly in females and staff with previous mental health history. Concerns fell into three factors: 'risk of infection', 'work challenges', and 'social change', and were affected by professional role and contact with COVID-19 patients. These three factors predicted distress. Psychological support and clear updates were deemed most useful, with specific needs affected by age, professional role, and contact with COVID-19 patients. This is the first documentation of a high incidence of psychological distress predicted by three types of concerns in health care workers of a neuroscience hospital. Distress, concerns, and interventions most valued were all affected by individual staff characteristics. These findings highlight the importance of providing stratified, one to one support interventions, tailored to professional group, and background, rather than more generic approaches. PRACTITIONER POINTS: The COVID-19 pandemic has resulted in a high incidence of psychological distress in UK health care staff. Distress, concerns, and interventions most valued are influenced by individual staff characteristics. Stratified, one-to-one support interventions, tailored to professional group, and background, rather than more generic approaches for stress reduction and resilience, are crucial.

Multi-model mapping of phonemic fluency.

The voluntary generation of non-overlearned responses is usually assessed with phonemic fluency. Like most frontal tasks, it draws upon different complex processes and systems whose precise nature is still incompletely understood. Many claimed aspects regarding the pattern of phonemic fluency performance and its underlying anatomy remain controversial. Major limitations of past investigations include small sample size, scant analysis of phonemic output and methodologically insufficient lesion analysis approaches. We investigated a large number of patients with focal unilateral right or left frontal (n = 110) or posterior (n = 100) or subcortical (n = 65) lesions imaged with magnetic resonance or computed tomography and compared their performance on the number of overall responses, words produced over time, extremely infrequent/unknown words and inappropriate words generated. We also employed, for the first time parcel-based lesion-symptom mapping, tract-wise statistical analysis as well as Bayesian multi-variate analysis based on meta-analytically defined functional region of interest, including their interactions. We found that left frontal damage was associated with greater impairment than right frontal or posterior damage on overall fluency performance, suggesting that phonemic fluency shows specificity to frontal lesions. We also found that subcorticals, similar to frontals, performed significantly worse than posteriors on overall performance suggesting that subcortical regions are also involved. However, only frontal effects were found for words produced over time, extremely infrequent/unknown and inappropriate words. Parcel-based lesion-symptom mapping analysis found that worse fluency performance was associated with damage to the posterior segment of the left frontal middle and superior gyrus, the left dorsal anterior cingulate gyrus and caudate nucleus. Tract-wise statistical analysis revealed that disconnections of left frontal tracts are critical. Bayesian multi-variate models of lesions and disconnectome maps implicated left middle and inferior frontal and left dorsomedial frontal regions. Our study suggests that a set of well localized left frontal areas together with subcortical regions and several left frontal tracts are critical for word generation. We speculate that a left lateralized network exists. It involves medial, frontal regions supporting the process of 'energization', which sustains activation for the duration of the task and middle and inferior frontal regions concerned with 'selection', required due to the competition produced by associated stored words, respectively. The methodology adopted represents a promising and empirically robust approach in furthering our understanding of the neurocognitive architecture underpinning executive processes.

The neuropsychology needs of a hyper-acute stroke unit.

BACKGROUND AND AIM: Guidelines recommend routine assessment and management of mood and cognition after stroke, but little is known about the value or feasibility of providing neuropsychology input during the hyper-acute period. We aimed to identify and describe the extent and nature of neuropsychological needs and to investigate the feasibility of providing direct neuropsychology input within a hyper-acute setting. METHODS: Over a 7-month period, Multidisciplinary Team (MDT) members of a central London Hyper-Acute Stroke Unit (HASU) identified stroke patients who they believed would benefit from neuropsychology input, and categorised the nature of neuropsychology intervention required. We examined the demographic and clinical characteristics of the patients identified and the type of intervention required. RESULTS: 23% of patients (101/448) were identified as requiring neuropsychology input. Patients deemed to require input were younger, more likely to be male and more functionally disabled than those not requiring input. Cognitive assessment was the main identified need (93%) followed by mood (29%) and family support (9%). 30% of patients required two types of intervention. During a pilot of neuropsychology provision, 17 patients were seen; 15 completed a full cognitive assessment. All patients assessed presented with cognitive impairment despite three being deemed cognitively intact (> standardised cut-off) using a cognitive screening tool. CONCLUSION: We showed that direct neuropsychology input on a HASU is necessary for complex and varied interventions involving cognition, mood and family support. Furthermore, input is feasible and useful in detecting cognitive impairment not revealed by screening instruments.

Neuropsychological and neuroimaging characteristics of classical superficial siderosis.

OBJECTIVE: To define the neuropsychological and neuroimaging characteristics of classical infratentorial superficial siderosis (iSS), a rare but disabling disorder defined by hemosiderin deposition affecting the superficial layers of the cerebellum, brainstem and spinal cord, usually associated with a slowly progressive neurological syndrome of deafness, ataxia and myelopathy. METHODS: We present the detailed neuropsychological and neuroimaging findings in 16 patients with iSS (mean age 57 years; 6 female). RESULTS: Cognitive impairment was present in 8/16 (50%) of patients: executive dysfunction was the most prevalent (44%), followed by impairment of visual recognition memory (27%); other cognitive domains were largely spared. Disease symptom duration was significantly correlated with the number of cognitive domains impaired (r = 0.59, p = 0.011). Mood disorders were also common (anxiety 62%, depression 38%, both 69%) but not associated with disease symptom duration. MRI findings revealed siderosis was not only in infratentorial brain regions, but also in characteristic widespread symmetrical supratentorial brain regions, independent of disease duration and degree of cognitive impairment. The presence of small vessel disease markers was very low and did not account for the cognitive impairment observed. CONCLUSION: Neuropsychological disturbances are common in iSS and need to be routinely investigated. The lack of association between the anatomical extent of hemosiderin and cognitive impairment or disease duration suggests that hemosiderin itself is not directly neurotoxic. Additional biomarkers of iSS disease severity and progression are needed for future research and clinical trials.

Dissociable neural circuits for encoding and retrieval of object locations during active navigation in humans.

Several cortical and subcortical circuits have been implicated in object location memory and navigation. Uncertainty remains, however, about which neural circuits are involved in the distinct processes of encoding and retrieval during active navigation through three-dimensional space. We used functional magnetic resonance imaging (fMRI) to measure neural responses as participants learned the location of a single target object relative to a small set of landmarks. Following a delay, the target was removed and participants were required to navigate back to its original position. The relative and absolute locations of landmarks and the target object were changed on every trial, so that participants had to learn a novel arrangement for each spatial scene. At encoding, greater activity within the right hippocampus and the parahippocampal gyrus bilaterally predicted more accurate navigation to the hidden target object in the retrieval phase. By contrast, during the retrieval phase, more accurate performance was associated with increased activity in the left hippocampus and the striatum bilaterally. Dividing participants into good and poor navigators, based upon behavioural performance, revealed greater striatal activity in good navigators during retrieval, perhaps reflecting superior procedural learning in these individuals. By contrast, the poor navigators showed stronger left hippocampal activity, suggesting reliance on a less effective verbal or symbolic code by this group. Our findings suggest separate neural substrates for the encoding and retrieval stages of object location memory during active navigation, which are further modulated by participants' overall navigational ability.

A new revised Graded Naming Test and new normative data including older adults (80-97 years).

The Graded Naming Test (GNT) is commonly used in clinical and research settings to assess nominal functions. However, normative data for the GNT is over 20 years old and norms for the older adult population are rather limited. Hence, confounding factors such as generational familiarity due to cultural changes need to be considered when applying the currently available norms. Moreover, normative data for the older population (80-97) are virtually absent. Such factors can be powerful confounds that can lead to incorrect interpretation of test scores. We gathered data for the GNT from 326 healthy controls aged between 18 and 97 years. Surprisingly, we found no decline in performance for older adults, even for the cohort aged 80-97 years (N = 40). In contrast, the youngest cohort (aged 18-29 years) performed unexpectedly below the whole sample mean. An item-by-item analysis revealed that five test items were unfamiliar to the youngest age cohort. To account for this generational familiarity effect, we created a revised 25-item GNT. The performance of the youngest cohort on the 25-item GNT was no longer below the whole sample mean. The performance of the oldest cohort (80-97 years old) on the revised GNT was characterized by a significant decline in performance for the oldest cohort with an average NART IQ. By contrast, those with a NART IQ above the average range did not show a decline. This suggests that factors such cognitive reserve arrested the decline in performance in the oldest age cohort with higher premorbid IQ.