Peter Watson

The nature and staging of attention dysfunction in early (minimal and mild) Alzheimer’s disease: relationship to episodic and semantic memory impairment

The development of cholinergic therapies for Alzheimers disease (AD) has highlighted the importance of understanding the role of attentional deficits and the relationship between attention and memory in the earliest stages of the disease. Variability in the tasks used to examine aspects of attention, and in the disease severity, between studies makes it difficult to determine which aspects of attention are affected earliest in AD, and how attentional impairment is related to other cognitive modules. We tested 27 patients in the early stages of the disease on the basis of the MMSE (minimal 24-30 corresponding to minimal cognitive impairment, very mild or possible AD in other classifications; and mild 18-23) on a battery of attentional tests aimed to assess sustained, divided, and selective attention, plus tests of episodic memory, semantic memory, visuoperceptual and visuospatial function, and verbal short-term memory. Although the mildly demented group were impaired on all attentional tests, the minimally impaired group showed a preserved ability to sustain attention, and to divide attention based on a dual-task paradigm. The minimally demented group had particular problems with response inhibition and speed of attentional switching. Examination of the relationship between attention and other cognitive domains showed impaired episodic memory in all patients. Deficits in attention were more prevalent than deficits in semantic memory suggesting that they occur at an earlier stage and the two were partially independent. Impairment in visuoperceptual and visuospatial functions and verbal short-term memory were the least common. Although attention is impaired early in AD, 40% of our patients showed deficits in episodic memory alone, confirming that amnesia may be the only cognitive deficit in the earliest stages of sporadic AD.

Social reasoning, emotion and empathy in frontotemporal dementia

INTRODUCTION Social cognition is crucial for human interaction, and is markedly impaired in the frontal variant of frontotemporal dementia (fvFTD). The relationship of various aspects of social functioning, however, remains controversial in this group. METHODS Patients with fvFTD (n = 18), and matched controls (n = 13), were tested using tasks designed to assess their Theory of Mind (ToM), moral reasoning, emotion recognition and executive function. Caregivers documented changes in empathy compared to premorbid functioning. RESULTS We found marked impairments in the abilities of fvFTD patients, relative to controls, in ability to mentalise (ToM), which was evident on a cartoon test, but not on a story-based ToM task. Knowledge of social rules was intact, but moral reasoning was defective, and was due, in part, to an inability to rate the seriousness of moral and conventional transgressions appropriately. Executive function was impaired in this group, and compromised aspects of moral reasoning, but ToM performance was independent of this. Emotion recognition was globally impaired in fvFTD, but was particularly so for anger and disgust which may partly explain the difficulty these patients have with identifying social violations. Empathy, as rated by carers, was also shown to be abnormal. CONCLUSION It appears that social reasoning is disrupted in a number of ways in fvFTD, and the findings provide a basis for the understanding and further study of abnormal behaviour in this disease. The results are discussed in light of neuroimaging findings in studies of social cognition and the locus of pathology in fvFTD.

Sirolimus Therapy for Angiomyolipoma in Tuberous Sclerosis and Sporadic Lymphangioleiomyomatosis: A Phase 2 trial

Purpose: Renal angiomyolipomas are a frequent manifestation of tuberous sclerosis and sporadic lymphangioleiomyomatosis (LAM). These disorders are associated with mutations of TSC1 or TSC2 that lead to overactivation of mTOR complex 1 (mTORC1), suggesting an opportunity for targeted therapy by using mTORC1 inhibitors. This study investigated the efficacy and safety of the mTORC1 inhibitor sirolimus for treatment of renal angiomyolipomas in patients with these disorders. Experimental Design: In this multicenter phase 2 nonrandomized open label trial, 16 patients with tuberous sclerosis or sporadic LAM and renal angiomyolipoma(s) were treated with oral sirolimus for up to 2 years. Steady-state blood levels were 3 to 10 ng/mL. The primary outcome was change in size of renal angiomyolipomas measured by MRI and assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Secondary outcomes included safety, neurocognitive function, and pulmonary function. Results: The response rate, by RECIST criteria, was 50%. Summated angiomyolipoma diameters were reduced in all 16 patients and by 30% or more in eight (all from the per protocol group of 10). Forty-one of 48 angiomyolipomas were smaller at the last measurement than at baseline. Most shrinkage occurred during the first year of treatment. There was little change in pulmonary function. Recall memory improved in seven of eight patients with tuberous sclerosis. Adverse events were consistent with the known toxicities of sirolimus. Conclusions: This study showed sustained regression of renal angiomyolipomas in patients with tuberous sclerosis or sporadic LAM receiving 2 years of sirolimus treatment. Possible effects on pulmonary function and neurocognition require further investigation. Clin Cancer Res; 17(12); 4071–81. ©2011 AACR.

The use of a wearable camera, SenseCam, as a pictorial diary to improve autobiographical memory in a patient with limbic encephalitis: A preliminary report

This case study describes the use of a wearable camera, SenseCam, which automatically captures several hundred images per day, to aid autobiographical memory in a patient, Mrs B, with severe memory impairment following limbic encephalitis. By using SenseCam to record personally experienced events we intended that SenseCam pictures would form a pictorial diary to cue and consolidate autobiographical memories. After wearing SenseCam, Mrs B plugged the camera into a PC which uploaded the recorded images and allowed them to be viewed at speed, like watching a movie. In the control condition, a written diary was used to record and remind her of autobiographical events. After viewing SenseCam images, Mrs B was able to recall approximately 80% of recent, personally experienced events. Retention of events was maintained in the long-term, 11 months afterwards, and without viewing SenseCam images for three months. After using the written diary, Mrs B was able to remember around 49% of an event; after one month with no diary readings she had no recall of the same events. We suggest that factors relating to rehearsal/re-consolidation may have enabled SenseCam images to improve Mrs Bs autobiographical recollection.

Prospective memory functioning in people with and without brain injury

Prospective remembering has been relatively underinvestigated in neurological patients. This paper describes a group study in which the prospective memory performance of 36 people with brain injury and 28 control participants is compared. We used a new instrument, the Cambridge Behaviour Prospective Memory Test (CBPMT) to assess prospective memory. This comprises 4 time-based and 4 event-based tasks. Participants were allowed to take notes to help them remember the tasks. The relationships between CBPMT scores, scores on formal tests and subjective reports on memory, attention and executive functioning were analyzed. The key findings were that (1) note-taking significantly benefited prospective memory performance, (2) significant relationships were found between scores on the prospective memory test and scores on tests of memory and executive functions, and (3) participants had more difficulty with the time-based than with the event-based prospective memory tasks. The results suggest that compensatory strategies improve prospective memory functioning; memory for content as well as attention and executive functioning processes are involved in prospective memory; and that time-based tasks are more difficult than event-based tasks because they place higher demands on inhibitory control mechanisms. Discussion focuses on the implications of these results for neuropsychological assessment and rehabilitation.

Focal posterior cingulate atrophy in incipient Alzheimer's disease

Severe posterior cingulate cortex hypometabolism is a feature of incipient, sporadic Alzheimers disease (AD). The aim was to test the hypothesis that this region is focally atrophic in very early disease by studying AD patients at the mild cognitive impairment (MCI) stage, and, if so, to determine whether the amount of atrophy was comparable to that of the hippocampus. Twenty-four patients meeting criteria for amnestic MCI, who all subsequently progressed to fulfil AD criteria, and 28 age-matched controls, were imaged with volumetric MRI. Four regions of interest were manually traced in each hemisphere: two posterior cingulate regions (BA 23 and BA 29/30), the hippocampus (as a positive control) and the anterior cingulate (as a negative control). BA 23 and BA 29/30 were both significantly atrophic and this atrophy was comparable to that found in the hippocampus, in the absence of anterior cingulate cortex (ACC) atrophy. Contrary to previous reports, there was no evidence that posterior cingulate atrophy is specifically associated with early-onset AD. The results indicate that posterior cingulate cortex atrophy is present from the earliest clinical stage of sporadic AD and that this region is as vulnerable to neurodegeneration as the hippocampus.

Measuring autistic traits in the general population: a systematic review of the Autism-Spectrum Quotient (AQ) in a nonclinical population sample of 6,900 typical adult males and females

[This corrects the article DOI: 10.1186/2040-2392-6-2.].

Longitudinal Profiles of Semantic Impairment for Living and Nonliving Concepts in Dementia of Alzheimer's Type

Two types of theoretical account have been proposed to explain the phenomenon of category-specific impairment in tests of semantic memory: One stresses the importance of different cortical regions to the representation of living and nonliving categories, while the other emphasize the importance of statistical relationships among features of concepts belonging to these two broad semantic domains. Theories of the latter kind predict that the direction of a domain advantage will be determined in large part by the overall damage to the semantic system, and that the profiles of patients with progressive impairments of semantic memory are likely to include a point at which an advantage for one domain changes to an advantage for the other. The present series of three studies employed semantic test data from two separate cohorts of patients with probable dementia of Alzheimers type (DAT) to look for evidence of such a crossover. In the first study, longitudinal test scores from a cohort of 58 patients were examined to confirm the presence of progressive semantic deterioration in this group. In the second study, Kaplan-Meier survival curves based on serial naming responses and plotted separately for items belonging to living and nonliving domains indicated that the representations of living concepts (as measured by naming) deteriorated at a consistently and significantly faster rate than those of nonliving concepts. A third study, carried out to look in detail at the performance of mildly affected patients, employed an additional cross-sectional cohort of 20 patients with mild DAT and utilized a graded naming assessment. This study also revealed no evidence for a crossover in the advantage of one domain over the other as a function of disease severity. Taken together with the model of anatomical progression in DAT based on the work of Braak and Braak (1991), these findings are interpreted as evidence for the importance of regional cerebral anatomy to the genesis of semantic domain effects in DAT.

A randomized control trial to evaluate a paging system for people with traumatic brain injury

Although memory problems following acquired brain damage are common, some people are able to compensate for these problems through external aids. It was recently demonstrated that a paging system could reduce the everyday memory and planning problems for people with non-progressive brain injury. The 143 patients who participated in the study comprised several diagnostic groups. This paper reports on the sub-group of people with TBI (n = 63). This sub-group was part of the larger sample of 143 already published in the 2001 study. A randomized control cross-over design randomly allocated people to group A (pager first) or group B (waiting list first). Each participant chose their own tasks for which they needed reminders. During a 2 week baseline, successful task achievement was documented. Group A achieved 47.14% of tasks and group B 47.88%. People in group A then received a pager for 7 weeks. During the last 2 weeks of this 7 week period, task achievement was documented again. Group A now achieved 71.80% of tasks and group B (on the waiting list) achieved 49.05% (no different from baseline). Group A then returned their pagers and group B received pagers. During the last 2 weeks of this stage participants were monitored once more. At this point, people in group A had dropped back slightly but were still statistically significantly better than during the baseline (67.23%). Group B, meanwhile, were now achieving 73.62% of tasks. This was statistically significantly better than baseline and significantly better than group A, now in the post-pager phase. It is concluded that this paging system significantly reduces the everyday memory and planning problems of people with TBI.

Improvement or simply practice? The effects of twenty repeated assessments on people with and without brain injury

Measuring recovery of function may mean testing the same individual many times, a procedure that is inevitably open to improvement due to learning on the specific tests rather than recovery per se. This is particularly likely to be an issue with measures of memory performance. We therefore studied the performance of normal and brain-injured people across 20 successive test sessions on measures of orientation, simple reaction time, forward and backward digit span, visual and verbal recognition, word list learning and forgetting, and on three semantic memory measures, namely, letter and category fluency and speed of semantic processing. Differences in overall performances between the two groups occurred for all tests other than orientation, digit span forward, and simple reaction time, although the tests differed in their degree of sensitivity. The tests varied in the presence or absence of practice effects and in the extent to which these differed between the two groups. Data are presented that should allow investigators to select measures that are likely to optimize sensitivity while minimizing possible confounding due to practice effects.