Can you detect early dementia from an email? A proof of principle study of daily computer use to detect cognitive and functional decline.

OBJECTIVE: To determine whether multiple computer use behaviours can distinguish between cognitively healthy older adults and those in the early stages of cognitive decline, and to investigate whether these behaviours are associated with cognitive and functional ability. METHODS: Older adults with cognitive impairment (n = 20) and healthy controls (n = 24) completed assessments of cognitive and functional abilities and a series of semi-directed computer tasks. Computer use behaviours were captured passively using bespoke software. RESULTS: The profile of computer use behaviours was significantly different in cognitively impaired compared with cognitively healthy control participants including more frequent pauses, slower typing, and a higher proportion of mouse clicks. These behaviours were significantly associated with performance on cognitive and functional assessments, in particular, those related to memory. CONCLUSION: Unobtrusively capturing computer use behaviours offers the potential for early detection of neurodegeneration in non-clinical settings, which could enable timely interventions to ultimately improve long-term outcomes.

The frequency and extent of mammillary body atrophy associated with surgical removal of a colloid cyst.

BACKGROUND AND PURPOSE: Patients who have had a colloid cyst removed from the third ventricle sometimes experience some difficulty with day-to-day memory. This study provided quantitative MR imaging volume measures of 1 structure potentially responsible for mnemonic problems, the mammillary bodies. Additional volume estimates in structures connected to the mammillary bodies sought to determine the specificity of any atrophy. MATERIALS AND METHODS: Volume estimates of the mammillary bodies were performed on 38 patients after surgical removal of colloid cysts and 20 control subjects by the application of stereologic volume-estimation techniques. For the mammillary body measures, 2 groups of MR images were assessed (0.8- and 1.0-mm section thickness) to compare the sensitivity of each imaging sequence for detecting any atrophy. Other structures associated with memory processes, such as the hippocampus and fornix, were also assessed quantitatively to determine whether there was a correlation between mammillary body damage and atrophy in connecting structures. RESULTS: Our investigations established the superiority of 0.8-mm-volume scans over standard isotropic 1.0-mm-thick-volume scans for mammillary body assessments. Comparisons with 20 age-matched controls revealed that patients with colloid cysts frequently showed significant mammillary body atrophy (mean volume of colloid cysts, 0.037 cm(3) right and 0.038 cm(3) left; control subjects, 0.069 cm(3) right and 0.067 cm(3) left). In fact, every patient had a mammillary body volume below the control mean, and the majority of patients had a volume decrease of >1 SD (82% right, 74% left). Mammillary body volumes correlated with fornix volumes in the same patient group. CONCLUSIONS: Our results reveal the frequent presence of mammillary body atrophy in patients with surgical removal of colloid cysts and indicate that this atrophy is partly due to a loss of temporal lobe projections in the fornix.

Two case studies illustrating how relatively selective hippocampal lesions in humans can have quite different effects on memory.

Two patients, with magnetic resonance imaging (MRI)-confirmed relatively selective hippocampal damage, showed distinct patterns of performance on tests of recall, item recognition, and associative recognition. Patient AC showed a mean bilateral volume reduction of the hippocampus of 28%, but displayed no memory deficit. Both recall and recognition memory were unimpaired. In contrast, patient PR, who showed a mean bilateral hippocampal volume reduction of 59%, was more consistently impaired on recall than recognition tests, although his recognition scores were highly variable. Patients AC and PR illustrate how variable the memory deficit following seemingly selective hippocampal damage can be in humans. They highlight the need for more sophisticated imaging in future studies if the human hippocampus' role in memory is to be fully identified.

Associative recognition in a patient with selective hippocampal lesions and relatively normal item recognition.

Previous work (Mayes et al., Hippocampus 12:325-340, 2002) found that patient YR, who suffered a selective bilateral lesion to the hippocampus in 1986, showed relatively preserved verbal and visual item recognition memory in the face of clearly impaired verbal and visual recall. In this study, we found that YR's Yes/No as well as forced-choice recognition of both intra-item associations and associations between items of the same kind was as well preserved as her item recognition memory. In contrast, YR was clearly impaired, and more so than she was on the above kinds of recognition, at recognition of associations between different kinds of information. Thus, her recognition memory for associations between objects and their locations, words and their temporal positions, abstract visual items or words and their temporal order, animal pictures and names of professions, faces and voices, faces and spoken names, words and definitions, and pictures and sounds, was clearly impaired. Several of the different information associative recognition tests at which YR was impaired could be compared with related item or inter-item association recognition tests of similar difficulty that she performed relatively normally around the same time. It is suggested that YR's familiarity memory for items, intra-item associations, and associations between items of the same kind was mediated by her intact medial temporal lobe cortices and was preserved, whereas her hippocampally mediated recall/recollection of these kinds of information was impaired. It is also suggested that the components of associations between different kinds of information are represented in distinct neocortical regions and that initially they only converge for memory processing within the hippocampus. No familiarity memory may exist in normal subjects for such associations, and, if so, YR's often chance recognition occurred because of her severe recall/recollection deficit. Conflicting data and views are discussed, and the way in which recall as well as item and associative recognition need to be systematically explored in patients with apparently selective hippocampal lesions, in order to resolve existing conflicts, is outlined.

Exploring the neural bases of episodic and semantic memory: the role of structural and functional neuroimaging.

Exploration of the neural bases of episodic and semantic memory is best pursued through the combined examination of the effects of identified lesions on memory and functional neuroimaging of both normal people and patients when they engage in memory processing of various kinds. Both structural and functional neuroimaging acquisition and analysis techniques have developed rapidly and will continue to do so. This review briefly outlines the history of neuroimaging as it impacts on memory research. Next, what has been learned so far from lesion-based research is outlined with emphasis on areas of disagreement as well as agreement. What has been learned from functional neuroimaging, particularly emission tomography and functional magnetic resonance imaging, is then discussed, and some stress is placed on topics where the interpretation of imaging studies has so far been unclear. Finally, how functional and structural imaging techniques can be optimally used to help resolve three areas of disagreement in the lesion literature will be discussed. These disagreements concern what the hippocampus and perirhinal cortex contribute to memory; whether any form of priming depends on the medial temporal lobes; and whether remote episodic as well as semantic memories cease to depend on the medial temporal lobes. Although the discussion will show the value of imaging techniques, it will also emphasize some of the limitations of current neuroimaging studies.

Effects of level of retrieval success on recall-related frontal and medial temporal lobe activations.

Brain dedicated single photon emission computed tomography (SPECT) was used to compare the neuroactivation produced by the cued recall of response words in a set of studied word pairs with that produced by the cued retrieval of words semantically related to unstudied stimulus words. Six of the 12 subjects scanned were extensively trained so as to have good memory of the studied pairs and the remaining six were minimally trained so as to have poor memory. When comparing episodic with semantic retrieval, the well-trained subjects showed significant left medial temporal lobe activation, which was also significantly greater than that shown by the poorly trained subjects, who failed to show significant medial temporal lobe activation. In contrast, the poorly trained subjects showed significant bilateral frontal lobe activation, which was significantly greater than that shown by the well-trained subjects who failed to show significant frontal lobe activation. The frontal activations occurred mainly in the dorsolateral region, but extended into the ventrolateral and, to a lesser extent, the frontal polar regions. It is argued that whereas the medial temporal lobe activation increased as the proportion of response words successfully recalled increased, the bilateral frontal lobe activation increased in proportion to retrieval effort, which was greater when learning had been less good.

Memory for single items, word pairs, and temporal order of different kinds in a patient with selective hippocampal lesions.

One kind of between-list and two kinds of within-list temporal order memory were examined in a patient with selective bilateral hippocampal lesions. This damage disrupted memory for all three kinds of temporal order memory, but left item and word pair recognition relatively intact. These findings are inconsistent with claims that (1) hippocampal lesions, like those of the medial temporal lobe (MTL) cortex, disrupt item and word pair recognition, and that (2) hippocampal lesions disrupt temporal order memory and item recognition to the same degree. Not only was word pair recognition intact in the patient, but further evidence indicates that her recognition of other associations between items of the same kind is also spared so retrieval of such associations cannot be sufficient to support within-list temporal order recognition. Rather, as other evidence indicates that the patient is impaired at recognition of associations between different kinds of information, within-list (and possibly between-list) temporal order memory may be impaired by hippocampal lesions because it critically depends on retrieving associations between different kinds of information.

Wernicke-Korsakoff syndrome and the use of brain imaging.

The proportion of patients with Korsakoff psychosis (KP) who have a history of Wernicke's encephalopathy is smaller in recent studies compared to previous studies. Neuropsychological tests, magnetic resonance imaging (MRI), and single photon emission computed tomography were conducted in eight patients with KP, only four of whom had had a documented Wernicke episode. All subjects showed amnesia without intellectual deterioration. MRI abnormalities were seen in each group to the same extent (atrophy of mammillary bodies, to a less extent thalamus and some generalized gyral atrophy). No MRI measure differentiated the groups. Cerebral blood flow showed reduction of flow to the anterior temporal regions bilaterally, extending to the parietal lobes, to the same degree in each group. Despite the small number of patients examined, the study supports the belief that patients with an insidious onset of KP have the same pathology as those with classical Wernicke-Korsakoff syndrome. This raises the question of whether episodes of alcohol withdrawal without adequate thiamine protection result in occasionally subclinical Wernicke's events, followed by a subsequently diagnosable KP.

The neuroactivation of cognitive processes investigated with SPECT.

The last ten years have seen the development and expansion of an exciting new field of neuroscientific research; functional mapping of the human brain. Whilst many of the questions addressed by this area of research could be answered using SPECT, relatively few SPECT activation studies of this kind have been carried out. The present paper combines an evaluation of SPECT procedures used for neuroactivation studies, and their comparison with other imaging modalities (i.e., PET and fMRI), with a review of SPECT neuroactivation studies that yield information concerning normal brain function with a particular emphasis on the brain activations produced by memory processing. The paper aims to describe and counter common misunderstandings regarding potential limitations of the SPECT technique, to explain and illustrate which SPECT procedures best fulfill the requirements of a neuroactivation study, and how best to obtain information about normal brain function (whether using normal healthy subjects or patients) and finally to highlight SPECT's potential future role in the functional mapping of the human brain.

The neuroimaging of long-term memory encoding processes.

There needs to be more crosstalk between the lesion and functional neuroimaging memory literatures. This is illustrated by a discussion of episode and fact encoding. The lesion literature suggests several hypotheses about which brain regions underlie the storage of episode and fact information, which can be explored by functional neuroimaging. These hypotheses have been underexplored because neuroimaging studies of encoding have been insufficiently hypothesis-driven and have not controlled encoding-related processes sufficiently well to allow clear interpretations of results to be made. Nevertheless, there is good evidence that certain kinds of associative encoding and/or consolidation are sufficient to activate the medial temporal lobes, and preliminary evidence that some kinds of associative priming may reduce activation of this region. It remains to be proved that attentional orienting to certain kinds of novel information activates the medial temporal lobes. Evidence is growing that the HERA model, developed from neuroimaging rather than lesion data, requires modification and that frontal cortex encoding activations are probably caused by executive processes that are important in effortful memory processing. Neuroimaging studies allow the detection of encoding-related activations in previously unexpected brain regions (e.g. parietal lobes) and, in turn, these findings can be explored with lesion studies.

Associative encoding of pictures activates the medial temporal lobes.

It remains unresolved whether the medial temporal lobe activations found in recent neuroimaging studies are mediated by novelty detection alone, by specific kinds of encoding or consolidation operations, or both. This study attempted to see whether associative encoding or consolidation is sufficient to cause such activation by matching for novelty across conditions. Using single-photon emission computer tomography (SPECT) (with TC99mHMPAO), we compared the activation patterns produced by the associative encoding and the perceptual matching of novel complex scenes in 10 normal subjects using both statistical parametric mapping (SPM) and a regions-of-interest (ROI) approach. During the encoding condition, significant activations were detected in the left hippocampal/parahippocampal region, the left cingulate cortex, and the right prefrontal cortex, using both statistical techniques. Additionally, activation was found in the right cingulate cortex, and a trend towards activation was found in the right hippocampal/parahippocampal region using the ROI approach. In contrast, no medial temporal activations were found during the matching condition, which produced bilateral occipito-parietal and right posterior inferior parietal (supramarginal gyrus) activations. These results no only confirm that the associative encoding and/or consolidation of complex scenes is partially mediated by medial temporal lobe structures, but also demonstrate, for the first time, that associative encoding/consolidation is sufficient to produce such an activation. The implications of the high degree of consistency revealed by the results of the SPM and ROI comparison are discussed.

Face processing impairments after encephalitis: amygdala damage and recognition of fear.

Face processing and facial emotion recognition were investigated in five post-encephalitic people of average or above-average intelligence. Four of these people (JC, YW, RB and SE) had extensive damage in the region of the amygdala. A fifth post-encephalitic person with predominantly hippocampal damage and relative sparing of the amygdala (RS) participated, allowing us to contrast the effects of temporal lobe damage including and excluding the amygdala region. The findings showed impaired recognition of fear following bilateral temporal lobe damage when this included the amygdala. For JC, this was part of a constellation of deficits on face processing tasks, with impaired recognition of several emotions. SE, YW and RB, however, showed relatively circumscribed deficits. Although they all had some problems in recognizing or naming famous faces, and had poor memory for faces on the Warrington Recognition Memory Test, none showed a significant impairment on the Benton Test of Facial Recognition, indicating relatively good perception of the face's physical structure. In a test of recognition of basic emotions (happiness, surprise, fear, sadness, disgust and anger), SE, YW and RB achieved normal levels of performance in comparison to our control group for all emotions except fear. Their results contrast with those of RS, with relative sparing of the amygdala region and unimpaired recognition of emotion, pointing clearly toward the importance of the amygdala in the recognition of fear.

The relation between MRI neuroactivation changes and response rate on a word-fluency task.

This study investigated the functional magnetic resonance imaging response of the left premotor cortex activated during a word-fluency task. We hypothesized that a cortical region crossing the boundary between Brodmann's areas 44 and 6 would show bias toward output during word generation (i.e., the more words generated the greater the activation), supporting the view that this region is involved in the motor planning of speech rather than the search component of word generation. Ten participants were shown letters with different word-generational frequencies, and these were correlated with magnetic resonance signal changes over the region. Significant differences (p = .05) were found in the neuroactivation changes between groups of letters associated with high and low overt frequencies. This finding supports our hypothesis concerning the role of areas 44 and 6 in word-generation tasks.

Image quality versus statistical power.

We investigated whether SPET studies of neuroactivation might benefit from a similar approach used in PET; that is, increase the number of scans per task and accept poorer individual scan quality. Different study paradigms were simulated by varying the scanning parameters: (1) administered radiation activity per scan, (2) number of scans per task and (3) scan acquisition time. The maximum total dose received by each simulated subject remained the same. Areas of activation of varying signal strength were added to the scans using a customized graphics package. To establish the statistical benefits of a replication paradigm versus a non-replication paradigm, the datasets were analysed using SPM95 statistics software. This simulation was able to show that, when an SPM investigation is used for data analysis, study replication is more important than the individual image quality typically available from a high-performance SPET system.

Longitudinal changes in cognitive function and regional cerebral function in Alzheimer's disease: a SPECT blood flow study.

In Alzheimer's disease (AD), SPECT imagining of regional cerebral blood flow (rCBF) has emphasized deficits in the posterior association cortex. Previous studies have shown an association between these deficits and cognitive performance, both on overall cognitive tests and more specific tests such as praxis and language. Frontal deficits have been reported in more severe patients. This has led to the conclusion that the deficit in AD, at least with functional neuroimaging, starts in the posterior association cortex, and later in the disease process "spreads" to involve the frontal cortex. This study set out to measure, in a group of AD patients, the change over time of cognitive performance and the pattern of functional deficit measured by neuroimaging. Change in function was measured using 99TCm-HMPAO and SPECT and change in cognitive function using the CAMCOG. Two time points were used, 0 and 2 years. Twenty-four patients satisfying the DSM-III R criteria for probable AD were studied, nine of whom were subsequently diagnosed as having AD at post-mortem. The most striking finding was the effect that decreases in frontal lobe function had on cognitive function. A similar study by the same group, using the same techniques and many of the same patients but at only one time point, showed a correlation between cognitive function and rCBF in the parietal and posterior temporal lobes. This suggests that as AD patients deteriorate from unaffected to mild or moderately affected, the posterior association cortex exerts the greatest effect on cognitive deficit. In this longitudinal study, we found, using a MANOVA, that there were significant decreases over time for all the cortical regions studied, but that no region decreased significantly more than any other. In addition we found a correlation between change in frontal rCBF and change in cognitive function (both overall cognitive function and the CAMCOG sub tests of language and praxis). These data suggest, in contrast to the previous study, that as the disease progresses from mild or moderate to moderate or severe, the frontal cortex exerts the greatest effect on cognitive decline. These data support the concept of the deficit in functional imaging spreading from posterior to anterior as the disease progresses. However, both the initial pattern of deficit and the change over time were very heterogeneous when examined qualitatively. A posterior to anterior spread is the predominant pattern for the group as a whole, but individual patients, and possibly groups of patients, may well show alternative patterns.

Abnormalities in rCBF and computed tomography in patients with Alzheimer's disease and in controls.

The pattern of abnormal distribution of the single photon emission computed tomography (SPECT) cerebral blood flow tracer 99m-technetium-hexamethylpropyleneamine oxime (99Tcm-HMPAO) was investigated in 14 patients with clinically diagnosed Alzheimer's disease (AD) who subsequently had post-mortem confirmation of the disease and also in 14 elderly control subjects. These abnormalities were compared with computed tomography (CT) scans to investigate the degree to which the focal SPECT deficits were due to atrophy. The results show that SPECT imaging with 99Tcm-HMPAO and CT scanning both have a higher incidence of abnormality in AD patients than in controls and that the difference between patients and controls is greater with SPECT than with CT. Frontal SPECT and CT abnormalities in moderate/severe Alzheimer's disease occur as frequently as temporal/occipital abnormalities but the latter are rare in control subjects. Around 50% of the SPECT deficits occur in CT normal brain regions, showing that atrophy is not the sole cause of SPECT deficits.

Contextual cueing effects in the remote memory of alcoholic Korsakoff patients and normal subjects.

This study examines the effects of contextual cueing on the remote memory of alcoholic Korsakoff patients and normal subjects. Naming of personalities who became famous in each of the five decades beginning 1935 was tested under two conditions: "no-context", in which minimal extraneous cues to identification were provided, and "context", where clear extraneous cues were available. Normal subjects performed better than Korsakoff patients, showed no evidence of a temporal gradient, and exhibited a contextual cueing advantage across all decades. In contrast, Korsakoff patients demonstrated a marked temporal gradient, and the contextual cueing advantage declined systematically as more recent decades were sampled. Further analyses demonstrated that the differential pattern of deficits shown by Korsakoffs and controls was not attributable to absolute differences in performance level. Theoretical implications of these data for explanations of Korsakoff retrograde amnesia are discussed.

Measurements of regional cerebral blood flow and cognitive performance in Alzheimer's disease.

Single photon emission computed tomography (SPECT) with 99mTc-HMPAO was used to image 26 patients with dementia of the Alzheimer type (DAT) and 10 healthy controls. Regional cerebral blood flow (rCBF) data indicated a relative sparing of the occipital regions in DAT. Normalisation to occipital flow illustrated highly significant CBF deficits in a number of cortical regions, particularly in the left and right posterior--temporal cortex in DAT compared to controls. The cognitive performance of DAT patients was measured using a clinical cognitive assessment procedure (CAMCOG) and numerous correlations between these scores and rCBF were obtained. The implications and value of this investigative technique are discussed.