Established donepezil treatment modulates task relevant regional brain activation in early Alzheimer's disease.

Neuroimaging studies of cholinesterase inhibitor (ChEI) treatment in Alzheimer's disease (AD) have shown the different short and long term actions of ChEIs. fMRI studies of the ChEI donepezil have focused on its short to medium term action without exploring the effects of established treatment. In this exploratory study the effect of 20 weeks donepezil treatment on regional brain activity was measured with fMRI in patients with mild AD. Twelve patients with probable AD and nine age-matched controls were assessed with a Pyramids and Palm Trees semantic association fMRI paradigm and an n-back working memory fMRI paradigm. In the patient group only, the assessment was repeated after 20 weeks of treatment. After treatment, differences from normal healthy elderly became more pronounced. There was also a spread of deactivation which at retest was detectable in task relevant areas. Behaviourally, however, there were no significant differences between group baseline and retest scores, with a range of performance probably reflecting variation in drug efficacy across patients. Parametric analyses established that increased behavioural scores at retest correlated significantly with higher activation levels in non task relevant areas. Behavioural stability with donepezil treatment was not paralleled by the pattern of improved task specific brain activation reported in similar studies of other ChEIs. This is arguably related to the different mechanisms of action of the ChEIs and might be a clinical correlate of the reported synaptic upregulation following long term donepezil treatment.

Short-term longitudinal evaluation of cerebral blood flow in mild Alzheimer's disease.

The aim of this study was to estabilish whether subtle changes in regional cerebral blood flow (rCBF) can be detected in patients with mild Alzheimer's disease (AD) over a period as short as three months. Aprospective evaluation of rCBF changes with HMPAO SPECT at baseline and after 3 and 6 months was carried out. Standard clinical dementia tests were performed in parallel. The study enrolled 13 patients with mild probable AD from an outpatient memory clinic. SPECT data collected at baseline and after three months were compared using Statistical Parametric Mapping (SPM). Significant clusters of rCBF decrement in the medial part of the temporal lobe in both hemispheres, in the orbital part of the right frontal lobe and in the inferior part of the right parietal lobe were observed. No significant differences were found using a region of interest (ROI) analysis. After six months SPM analysis showed larger clusters of significant decrement in the same areas. ROI analysis was now sensitive to the rCBF changes and significant differences were shown in all brain regions except the temporal lobes. SPM analysis of SPECT data can detect significant changes in rCBF in mild AD over a short time interval. This method might be of potential advantage for the early diagnosis of AD and for its differentiation from stable cognitive impairments.

Preservation of golf skills in a case of severe left lobar frontotemporal degeneration.

The authors report the longitudinal study of a 53-year-old man with severe lobar atrophy confined to the left frontal and temporal lobes, including the left hippocampus, but sparing other cortical regions. He experienced profound cognitive deterioration, sparing only visuospatial memory. Despite these deficits, he could play golf at a high level of competence, following rules and etiquette as well as monitoring the ongoing game. The patient's golf performance may have been supported by residual visuospatial declarative memory and complex flexible implicit memory programs.

Quality of spelling breakdown in Alzheimer's disease is independent of disease progression.

There is a convergence of evidence from recent studies that spelling is impaired in Alzheimer's Disease (AD) relative to normal aging. However, the literature is more divided over whether there is a logical pattern in spelling deterioration with disease progression. The present study reviewed performance of participants with mild AD, moderate AD, and control participants on a written and oral spelling task. Results suggest that spelling in individuals with AD is impaired relative to controls. Comparison between those with mild AD and moderate AD failed to find evidence of a logical pattern of deterioration. We further examined the effects of word characteristics on spelling performance. Although increasing in quantity with disease progression, analysis of quality of spelling errors reveal a multi-componential disruption of spelling ability, which is independent of disease progression.

HMPAO SPECT imaging of Alzheimer's disease patients with similar content-specific autobiographic delusion: comparison using statistical parametric mapping.

UNLABELLED: Delusional behavior and thinking are common symptoms in Alzheimer's disease (AD). In the past, these delusions have been considered to be psychotic complications of global neurologic dysfunction. Recently, authors have suggested that content-specific delusions in AD are associated with discrete regional abnormalities of the right hemisphere. METHOD: This study compared 99mTc-hexamethyl propyleneamine oxime (HMPAO) SPECT images of a group of AD patients with a similar autobiographic delusion with a group of AD patients without delusions and a group of AD patients with a range of delusions but without autobiographic content. The reconstructed SPECT data were compared using a statistical parametric mapping technique. RESULTS: The autobiographic AD group had a significant area of hypoperfusion in the right frontal lobe when compared with the 2 other groups. The area of hypoperfusion included parts of Brodmann's areas 9 and 10. Region 9 has been identified previously as having a role in episodic memory retrieval. CONCLUSION: This result suggests that autobiographic delusions in AD may have an identifiable neuropsychologic mechanism and that it may be possible to identify an organic cause in some patients using 99mTc-HMPAO SPECT.

Changes in the rCBF images of patients with Alzheimer's disease receiving Donepezil therapy.

Alzheimer's disease is associated with a loss in presynaptic cholinergic function. It has been suggested that cholinergic inhibitors such as donepezil hydrochloride (Donepezil) could restore this function and improve some of the symptoms of Alzheimer's disease. Previous work has shown that Donepezil improves cognitive and global function in patients with mild to moderate Alzheimer's disease. This study reviewed retrospectively 12 patients who had previously had a 99Tcm-hexamethylpropylene amine oxime (99Tcm-HMPAO) single photon emission tomography (SPET) regional cerebral blood flow (rCBF) examination and had gone on to receive Donepezil therapy. These patients were recalled for a further 99Tcm-HMPAO SPET rCBF examination and the image data sets were compared. The results showed an overall increase in global cerebral blood flow (P = 0.04) averaged over the group with a percentage change in blood flow ranging from -1.8% to 6.4%. However, some patients showed a slight decrease in blood flow. When the data were analysed in terms of regional cerebral blood flow, we found that the most significant increase in blood flow occurred in the frontal lobes (P = 0.02).

Nurturing syndrome: a form of pathological bereavement with delusions in Alzheimer's disease.

We report the history and neuroimaging profile of two patients, CS and KC who developed an unusual bereavement reaction with delusions following the deaths of their husbands. Their neuropsychological profiles met criteria for dementia of Alzheimer type. The delusions about their husbands' existence were persistent despite a considerable passage of time after their deaths. SPECT investigation showed reduction of blood flow in the frontal area in both patients when compared with demented controls and in particular a significant reduction in perfusion was observed in the right frontal regions. We argue that this significant reduction of blood flow in the right frontal area, in the context of severe cognitive deterioration, might be responsible for their delusional reaction to bereavement which we interpret as result of reality monitoring and episodic memory failure.

Delusions in Alzheimer's disease: spet evidence of right hemispheric dysfunction.

Delusional thinking and related behaviours are common symptoms in Alzheimer's disease (AD). The aim of the study was to determine if any consistent cerebral image pattern can be identified using Tc99m-hexamethylpropyleneamine (HMPAO) SPET in AD patients with and without delusions. 18 AD patients with delusion and 15 AD patients without delusion underwent neuropsychological testing and regional cerebral blood flow imaging using Tc99m-HMPAO SPET. The reconstructed data was compared using regions of interest drawn over each cerebral lobe and a statistical parametric mapping (SPM) approach. The neuropsychological testing showed that there was no difference in the profiles of the deluded and non deluded AD patients. The imaging results showed a significant degree of image asymmetry. This took the form of a right hemisphere hypoperfusion mainly in the right frontal and limbic regions. The results do not indicate a specific focal site of hypoperfusion in the patients with delusion. They do, however, indicate that delusions in AD may be associated with areas of hypoperfusion in the right anterior hemisphere.

A clinical study of chronic fatigue syndrome.

BACKGROUND: This study examines the hypothesis that more recently ill patients with chronic fatigue syndrome (CFS) might have different characteristics from more chronic patients in tertiary referral centres. METHOD: Sixty-four patients who fulfilled strict diagnostic criteria for CFS had detailed medical, viral, immunological and psychiatric assessment. Patients were advised to remain within their energy limits. Patient and doctor monitored progress using a scoring system. RESULTS: Using the Schedule for Affective Disorders and Schizophrenia, patients were placed into four groups: group A (no psychiatric disorder, 35 patients), group B (psychiatric disorder before onset of CFS, 7 patients), group C (coincident psychiatric disorder and CFS, 11 patients), and group D (psychiatric disorder after onset of CFS, 11 patients). There were no viral or immunological differences between the groups. Patients in groups B, C and D had more severe illness than those in group A (P < 0.05), but patients in group A had more muscle pain (P < 0.05) than patients in group C. Counselling resulted in 52 patients becoming better; nine remained the same and three became worse. CONCLUSIONS: A lower incidence of psychiatric disorder may characterise patients who are more recently ill, as may the type of associated emotional disorder and better outcome.

The callosal connexions of the primary somatic sensory cortex in the monkey.

The callosal connexions of the primary somatic sensory cortex, SI, of the monkey have been studied with axonal degeneration methods after the placement of lesions of varying size in the cortex of one hemisphere and after section of the corpus callosum. For the correlation of the distribution of the degeneration with the cytoarchitectonic subdivisions of SI and with their boundaries, planar reconstructions of the extents of the subdivisions and of area 5 were made. The extent of area 5 is surprisingly large, being about the same as SI, and area 3a can be recognized as a distinct subdivision along the entire medio-lateral extent of SI. The callosal fibres end in narrow, irregular bands aligned in the medio-lateral dimension and there are accentuations at the boundaries of the cytoarchitectural subdivisions. In the representations of the trunk and face, the bands of degeneration are present across the entire antero-posterior extent of SI and with increases at the boundaries, while in the limb regions the degeneration becomes restricted to the boundaries. It is suggested that the callosal connexions of the somatic sensory cortex, like those in the visual and auditory areas, are connecting those parts of the cortex in the two hemispheres that are concurrently activated by a peripheral stimulus. The parts of SI that are devoid of callosal connexions are related to the distal limbs. The callosal connexions are homo- and heterotopical; an architectonic subdivision within the callosally connected regions projects to the same and other architectonic subdivisions at the same medio-lateral level in the opposite hemisphere; the cortex containing the representation of the caudal trunk near the post-central dimple is connected with the same region in the other hemisphere and with that of the separate representation of the caudal trunk in the posterior part of the cingulate sulcus, while the representation of the occipital region at the post-central dimple is connected both with the homotopical site in the other hemisphere and with the other representation of this part of the periphery at the level of the lower end of the intraparietal sulcus.

The ipsilateral cortico-cortical connexions between the cytoarchitectonic subdivisions of the primary somatic sensory cortex in the monkey.

The ipsilateral cortico-cortical connexions passing between the architectonic subdivisions of the primary somatic sensory cortex, S1, of the monkey have been studied with axonal degeneration methods after the placement of small lesions. All architectonic subdivisions except area 3a, and all the topographic representations, have been involved by the lesions. The degeneration of local intracortical fibres has the same features that have been described in other cortical areas: dense terminal degeneration for about 200 micron immediately around the lesion and moderate degeneration extending for a few millimetres with that in layers I, IV and the deep part of V being the most marked and reaching furthest; the degeneration extends further in the antero-posterior than in the medio-lateral dimension, and further posteriorly than anteriorly. The arrangement of the intercortical fibre connexions varies with the architectonic subdivision and with the topographic representation, and as in other sensory areas these fibres may be considered as either feed-forward or feed-back. The feed-forward projections are heavy, terminate in all layers of the cortex but mainly in layer IV and the deep part of layer III, whereas the feed-back connexions are lighter and end in layers I, II, the superficial part of layer III and in layers V and VI. In the antero-posterior dimension, feed-forward fibres from area 3b go to areas 3a, 1 and 2; area 1 sends feed-forward connexions to areas 3a and 2 and feed-back to area 3b; area 2 sends a feed-forward projection to area 3a and feed-back to areas 3b and 1; all areas also send fibres to area 5. A lesion in one of the architectonic subdivisions in the trunk and face representations results in degeneration throughout the antero-posterior extent of S1, but after damage within an architectonic area in the distal limb regions, there are foci of degeneration in the middle of the antero-posterior extents of the other areas but with little or none at the boundaries. The cortico-cortical fibres also extend medially or laterally for a few millimetres, in bands a few hundred micron wide. After damage of the trunk, occiput or proximal limb representations, the degenerating fibres pass predominantly along the boundaries; the separate representations of the caudal trunk, at the postcentral dimple and cingulate sulcus, are connected by continuous bands along the boundaries of area 3a and at the 2/5 boundary, and those of the occiput region at the levels of the postcentral dimple and lower end of the intraparietal sulcus are similarly linked.(ABSTRACT TRUNCATED AT 400 WORDS)

An electron microscopic study of the termination of thalamocortical fibres in areas 3b, 1 and 2 of the somatic sensory cortex in the monkey.

The degeneration of the terminals of thalamocortical fibres has been studied in areas 2b, 1 and 2 of the first somatic sensory area of the monkey 4 and 5 days after large electrolytic lesions in the ventral posterior nucleus of the thalamus. The number of degenerating terminals is much greater and the rate of their degeneration faster in area 3b than in areas 1 and 2, and in all areas they are concentrated in a band occupying the deep part of layer III and the upper half of layer IV. Two examples of dendrodendritic synapses were found in the deep part of the somatic sensory cortex, one in area 3b and the other in area 1.

A study of 24-hour profiles of plasma met-enkephalin in man.

Met-enkephalin has recently been demonstrated to circulate in human plasma and using this highly specific extracted radioimmunoassay the fluctuations of plasma Met-enkephalin in man were studied over 24 h. The subjects were 6 healthy volunteers. Following a 24 h adaptation period in the metabolic ward and sleep laboratory, an i.v. catheter was inserted. Blood samples were taken at hourly intervals through the day and at 30 min intervals between 23.00 h and 07.00 h. Sleep was monitored polygraphically. There was no regular rhythm discernible in plasma Met-enkephalin levels throughout the 24 h, nor was there any relationship with sleep or food intake. In a further 3 subjects beta-LPH and beta-endorphin levels as estimated by N- and C-terminal beta-LPH radioimmunoassay were elevated on waking compared with 01.00 h, suggesting a nyctohemeral rhythm. In contrast to the correlated circadian fluctuations in beta-LPH, ACTH and beta-endorphin levels therefore, the lack of circadian rhythmicity and dissociation of plasma Met-enkephalin from plasma levels of the former group of peptides suggests control mechanisms for the secretion of Met-enkephalin are quite different and adds support to the concept of separate Met-enkephalin precursors.