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Clinical referral patterns and cognitive profile in mild cognitive impairment.
BACKGROUND: There is current interest in exploring the different subtypes of mild cognitive impairment (MCI), in terms of both their epidemiology and their cognitive profile. AIMS: To examine the frequency of MCI subtypes presenting to a memory clinic and to document detailed neuropsychological profiles of patients with the amnestic subtype. METHOD: Consecutive tertiary referrals (n=187) were psychiatrically evaluated; 45 patients met criteria for amnestic mild cognitive impairment (aMCI). A subgroup of 33 patients with aMCI as well as 21 healthy controls took part in a thorough neuropsychological examination. RESULTS: Of the patients who were examined in greater neuropsychological detail, ten had pure aMCI (none with visual memory impairment only). Fifteen met criteria for non-amnestic MCI. Fifteen had normal neuropsychological profiles. Using more than one test increased sensitivity to detect episodic memory impairment. CONCLUSIONS: Amnestic MCI is an important diagnosis in secondary and tertiary memory clinics. There is scope to improve the efficacy and sensitivity of the clinical assessment of this impairment.
Predicting schizophrenia: findings from the Edinburgh High-Risk Study.
BACKGROUND: The hypothesis that schizophrenia is neurodevelopmental was investigated in a prospective study of young people with a postulated 10-15% risk for the development of schizophrenia. AIMS: To determine premorbid variables distinguishing high-risk people who will go on to develop schizophrenia from those who will not. METHOD: A high-risk sample of 163 young adults with two relatives with schizophrenia was recruited. They and 36 controls were serially examined. Baseline measures were compared between those who did develop schizophrenia, a well control group, a well high-risk group and high-risk participants with partial or isolated psychotic symptoms. RESULTS: Of those at high risk, 20 developed schizophrenia within 2(1/2) years. More experienced isolated or partial psychotic symptoms. Those who developed schizophrenia differed from those who did not on social anxiety, withdrawal and other schizotypal features. The whole high-risk sample differed from the control group on developmental and neuropsychological variables. CONCLUSIONS: The genetic component of schizophrenia affects many more individuals than will develop the illness, and partial impairment can be found in them. Highly significant predictors of the development of schizophrenia are detectable years before onset.
Direct comparison of spatially normalized PET and SPECT scans in Alzheimer's disease.
UNLABELLED: Hexamethylpropyleneamine oxime (HMPAO) SPECT and 18F-FDG PET depict similar aspects of perfusion and metabolic abnormalities in Alzheimer's disease (AD), but the correspondence between them is not known in detail. We therefore used statistical parametric mapping to detect and compare abnormal brain areas objectively and quantitatively. METHODS: Twenty-six patients with probable AD (mean age +/- SD, 66 +/- 9 y; mean Mini-Mental State Examination score, 22.5 +/- 4.2) and 6 nondemented healthy volunteers (mean age, 63 +/- 11 y) were studied with HMPAO SPECT and 18F-FDG PET. All images underwent the same processing steps, including 12-mm gaussian smoothing, spatial normalization, and z transformation with respect to normal average and SD. Thresholding of z maps was used to detect abnormal voxels. RESULTS: The overall correlation between PET and SPECT across the entire brain was significant but not close (average r = 0.43). The best correspondence was found in the temporoparietal and posterior cingulate association cortices. There, the number of abnormal voxels for PET correlated strongly with the number for SPECT (r = 0.90 at a z threshold of -2.25), but tracer uptake reductions were significantly more pronounced for PET than for SPECT. Discordant findings were most frequently seen in the temporobasal and orbitofrontal areas (PET low, SPECT high) and in the cerebellum, parahippocampal cortex, and midcingulate cortex (PET high, SPECT low). The correlation between dementia severity and the number of abnormal voxels was closer for PET than for SPECT. Separation of patients from healthy volunteers by counting the number of abnormal voxels was possible over a much wider range of z thresholds with PET than with SPECT. CONCLUSION: Correspondence between 18F-FDG PET and HMPAO SPECT is limited to the main finding of temporoparietal and posterior cingulate functional impairment in mild to moderate AD. The distinction between healthy volunteers and patients is less sensitive to threshold selection with PET than with SPECT, and findings in the frontal, temporobasal, and temporomesial cortices and in the cerebellum may differ between the 2 techniques.
The effects of noradrenergic re-uptake inhibition on memory encoding in man.
RATIONALE: Animal and human evidence implicate the central noradrenergic system in the process of memory modulation for emotional material. Blockade of the beta-adrenergic system in humans has been shown to result in decreased recall and recognition memory performance, relative to placebo, for the emotional elements of a series of slides accompanied by a narrative. Stimulation of the noradrenergic system with yohimbine has also been shown to result in increased recall and recognition performance relative to placebo for the same stimulus materials. OBJECTIVES: The present study tested the hypothesis that stimulating the central noradrenergic system using the new noradrenaline re-uptake inhibitor reboxetine would result in a dose-dependent enhancement of memory for emotional material in man. METHODS: The central noradrenergic system was manipulated using reboxetine in a double-blind, randomised between-group, placebo-controlled design with 36 healthy adult subjects in each of three groups (placebo, 4 and 8 mg reboxetine). Free recall and recognition memory performance were assessed in a 'surprise' memory test following a 7-day interval. RESULTS: We found no memory enhancing effect of reboxetine. In contrast we observed a dose-dependent effect on memory opposite to the predicted direction. There were no significant differences between groups in self-rated stress and arousal scores or self-rated emotional reactions to the stimuli. All groups showed the expected increased memory performance for the middle 'emotive' phase of the story. CONCLUSION: Selective stimulation of the central noradrenergic system at encoding did not result in enhanced long-term memory for emotional material in man.
Abnormal response to negative feedback in depression.
BACKGROUND: Recent studies have suggested that subjects with depression suffer a diagnosis-specific motivational deficit, characterized by an abnormal response to negative feedback that endures beyond clinical recovery. Furthermore, it has been suggested that negative feedback may motivate non-depressed controls, but not depressed patients, to improve their performance in neuropsychological tests. METHODS: We describe two studies. The first compared performance on the simultaneous and delayed match to sample (SDMS) task from the CANTAB neuropsychological test battery, in 20 patients with severe depression with 20 with acute schizophrenia, 40 with chronic schizophrenia and 40 healthy controls. The second examined the performance of depressed patients with diurnal variation in symptoms and cognitive function. RESULTS: All patients groups showed impairments on the simultaneous and delayed match to sample task compared to controls. Depressed patients did not show an abnormal response to negative feedback. Controls did not show a motivational effect of negative feedback. Depressed patients with diurnal variation showed no variation in their response to perceived failure. There was no evidence of abnormal response to negative feedback in any patient group using the 'runs test' or of a motivational effect in controls. Conditional probability analysis was not independent of the total number of errors made in the SDMS task. CONCLUSIONS: Further studies are suggested to examine whether an abnormal response to negative feedback characterizes particular subgroups of patients suffering from depression.
A double-blind, placebo-controlled study of tacrine in patients with Alzheimer's disease using SPET.
BACKGROUND: the effect of single-dose and long-term cholinergic enhancement with tacrine on regional cerebral perfusion was examined in patients with Alzheimer's disease using single-photon emission tomography (SPET). METHOD: 23 patients with probable Alzheimer's disease (DSM-III-R and NINCDS-ADRDA criteria) were scanned before and after a single oral dose of tacrine at the start of the study and again after 12 weeks of randomized, double-blind treatment with tacrine or placebo, using high resolution (99m)Tc-Exametazime SPET. Patients also underwent neuropsychological testing with the CAMCOG, the Mini-Mental State Examination and the Rivermead Behavioural Memory Test before and after 12 weeks of treatment. RESULTS: occipital count ratios in all regions of interest declined by 3% over 12 weeks, indicating a progression of the disease. Acute tacrine challenge resulted in a 16% increase in the superior frontal and a 11% decrease in the anterior temporal cortex. The acute effects of tacrine were modified by 12 weeks of treatment, particularly in the medial frontal (cingulate) cortex where active treatment was associated with a reduced acute tacrine response. There were no changes in cognitive function associated with active treatment. CONCLUSION: the study demonstrates the sensitivity of cerebral perfusion measures to changes during acute and medium-term tacrine treatment.
Short-term effects of electroconvulsive treatment on the uptake of 99mTc-exametazime into brain in major depression shown with single photon emission tomography.
Fifteen patients with major depression who were being treated with bilateral electroconvulsive treatment (ECT) were investigated before and 45 min after a single ECT using split-dose Single Photon Emission Tomography (SPET or SPECT) with 99mTc-Exametazime. All patients suffered from unipolar depressive illness and were rated on the Newcastle scale and with the 17-item Hamilton scale. They completed tests of orientation and verbal memory on the day of ECT. For comparison, verbal memory was also tested on the preceding day. The uptake of 99mTc-Exametazime was expressed relative to calcarine/occipital cortex. Significant decreases in tracer uptake were confined to the inferior anterior cingulate cortex. The changes were correlated with the severity of depressive symptoms and more weakly with decrements of memory function produced by ECT; there was no significant correlation with stimulus intensity or electroencephalographic measures of seizure duration.
The clinical manifestation of mental disorder in Huntington's disease: a retrospective case record study of disease progression.
All cases (86) of Huntington's Disease presenting between 1970 and 1987 in the Grampian Health Board region were identified and a case note analysis of neurological and psychiatric syndromes carried out--the latter using the PSE syndrome check-list. The commonest syndromes were organic impairment, irritability, loss of interest and concentration and simple depression and these were often the presenting psychiatric syndromes. General anxiety, worrying and social unease occurred early, commonly before movement disorder and were associated with longer survival.
MRI correlates of episodic memory in Alzheimer's disease, mild cognitive impairment, and healthy aging.
Episodic memory is a core feature of Alzheimer's disease (AD) and mild cognitive impairment (MCI). Impaired episodic memory in AD results from the dysfunction of an integrated network and involves both gray and white matter pathologies. We explored the neural correlates of episodic memory in AD, MCI and healthy aging by correlating a measure of episodic memory with hippocampal volume and fractional anisotropy (FA) and mean diffusivity (MD) of the cingulum and fornix. Episodic memory was associated with hippocampal volume and MD of the cingulum and fornix. In contrast, there were fewer significant associations between episodic memory and FA. These findings support a relationship between episodic memory and hippocampal circuitry, and suggest that MD is a more sensitive marker of decreased white matter integrity in the study of AD and MCI than FA. Furthermore, MD was significantly associated with hippocampal volume, indicating that white matter pathology is not completely independent of gray matter pathology. However, the pattern of diffusivity differences in AD and MCI implies a more complex pathology than simply Wallerian degeneration.
Predicting the accuracy of a diagnosis of Alzheimer's disease with 99mTc HMPAO single photon emission computed tomography.
The current clinical practice of reporting images obtained with single photon emission computed tomography (SPECT) with 99mTc-d,l-hexamethylpropylene amine oxime (99mTc HMPAO) images was examined by having 16 experts evaluate the appearance of SPECT images in patients with probable Alzheimer type dementia (ATD), patients with major depressive episode (DSM-IV), and healthy volunteers. The experts rated diagnostic criteria of scan appearance in respect of importance for their individual diagnostic practice. Experts were nuclear medicine specialists, psychiatrists and physicists taking part in a European multi-centre collaborative project. They examined 158 perfusion scans and then the same perfusion scans together with statistical parametric maps (SPMs). The sensitivity of experts' diagnostic judgments was significantly and negatively correlated with the importance they attributed to reduced regional perfusion in the parietal lobes. A corresponding positive correlation was observed for diagnostic specificity against depressed and healthy volunteers. Similar results were observed with SPMs, where in addition area under the receiver operating characteristic (ROC) curve was significantly reduced with raters' increased diagnostic reliance on frontal lobe perfusion deficits. Sensitivity was greater with SPM for patients younger than 70 years and with dementia severity. The more importance experts placed on parietal (symmetrical) perfusion deficits, the less sensitive and the more specific their diagnostic judgment was. Using multiple raters in large patient samples may provide a way of identifying successful explicit diagnostic strategies for clinical image analysis.
Transcranial magnetic stimulation for auditory hallucinations in schizophrenia.
It has been suggested that low frequency transcranial magnetic stimulation (TMS) over left temporo-parietal cortex may reduce the frequency and intensity of auditory hallucinations in schizophrenia. Sixteen patients with hallucinations, treatment-resistant for at least 2 months, were randomised into a placebo-controlled crossover study of TMS at 1 Hz and 80% of motor threshold over left temporo-parietal cortex. Treatment periods lasted for 4 days, with daily duration escalating from 4 to 8, 12 and 16 min on subsequent days. Each minute of stimulation was followed by 15 s of rest to check coil position and allow the patient to move, if necessary. Both patients and symptom raters were unaware of the treatment condition. Patients' hallucination scores improved from baseline with both real and sham TMS, and there was no significant difference between real and sham treatments. There was a trend for second treatments, whether sham or real, to be more effective than first treatments. Other psychopathology scales (apart from positive symptoms) and verbal memory were not affected by real or sham TMS. Previous positive studies could not be replicated with these parameters. TMS is safe if applied within the protocol used.
A Systematic Review and Meta-Analysis of Magnetic Resonance Imaging Studies in Late-Life Depression.
Gray matter abnormalities within frontal-subcortical and limbic networks are hypothesized to play a key role in the pathophysiology of late-life depression. In this work, gray matter abnormalities in late-life depression are examined in a systematic review and meta-analysis of magnetic resonance imaging studies. In the systematic review, 27 articles were identified that compared participants with late-life depression with comparison group participants, and 17 studies were suitable for inclusion in meta-analyses of volumes of the whole brain, orbitofrontal cortex, caudate, hippocampus, putamen, and thalamus. Volume reductions were detected in 7 of 15 comparisons of the hippocampus and a meta-analysis revealed a significant, but small, effect size. Although examined by fewer studies, meta-analyses also revealed significant volume reductions in the orbitofrontal cortex, putamen, and thalamus. A more systematic and comprehensive analysis of the global distribution of gray matter abnormalities, and an examination of subcortical abnormalities were identified as key areas for future research.
Physical Treatments in Bipolar Disorder
Practical guide covering pharmacological and psychosocial treatments, management of bipolar disorder with a clinical perspective and insights from 'lived ...
Regional cerebral blood flow and cognitive function in patients with chronic liver disease.
Subtle impairments of cognitive function may be an important cause of occupational and psychosocial morbidity in patients with chronic liver disease. Correlation of structural brain abnormalities with cognitive deficits has yielded inconsistent results. 10 patients with cirrhotic liver disease were compared with 10 age, education, and intelligence matched control subjects. Neuropsychological assessment revealed significant overall cognitive impairments in cirrhotic patients compared with controls (p = 0.02). Regional cerebral blood flow was measured by single photon emission computed tomography (SPET or SPECT) and showed increased uptake of radiotracer in the right and left posterior parts of the basal ganglia and right occipital lobe, together with reduced uptake in the right anterior cingulate region. The degree of cognitive impairment was directly correlated with functional abnormalities in the basal ganglia and limbic cortex (p less than 0.05). Our results suggest that impaired cognitive status may be associated with abnormalities of regional brain function in patients with chronic liver disease. Since these deficits are clinically inapparent, our findings have important implications for identification and management of patients with chronic liver disease.
Does the Framingham Stroke Risk Profile predict white-matter changes in late-life depression?
BACKGROUND: Cardiovascular risk factors and diseases are important etiological factors in depression, particularly late-life depression. Brain changes associated with vascular disease and depression can be detected using magnetic resonance imaging. Using diffusion tensor imaging (DTI), we investigated whether the Framingham Stroke Risk Profile (FSRP), a well-validated risk prediction algorithm, is associated with changes in white-matter connectivity. We hypothesized that depressed participants would show reduced white-matter integrity with higher FSRP, and non-depressed controls (matched for mean vascular risk) would show minimal co-variance with white-matter changes. METHODS: Thirty-six participants with major depression (age 71.8 ± 7.7 years, mean FSRP 10.3 ± 7.6) and 25 controls (age 71.8 ± 7.3 years, mean FSRP 10.1 ± 7.7) were clinically interviewed and examined, followed by 60-direction DTI on a 3.0 Tesla scanner. Image analysis was performed using FSL tools (www.fmrib.ox.ac.uk/fsl) to assess the correlation between FSRP and fractional anisotropy (FA). Voxelwise statistical analysis of the FA data was carried out using Tract Based Spatial Statistics. The significance threshold for correlations was set at p < 0.05 using threshold-free cluster-enhancement. Partial correlation analysis investigated significant correlations in each group. RESULTS: Participants in the depressed group showed highly significant correlations between FSRP and FA within the body of corpus callosum (r = -0.520, p = 0.002), genu of corpus callosum (r = -0.468, p = 0.005), splenium of corpus callosum (r = -0.536, p = 0.001), and cortico-spinal tract (r = -0.473, p = 0.005). In controls, there was only one significant correlation in the body of corpus callosum (r = -0.473, p = 0.023). CONCLUSIONS: FSRP is associated with impairment in white-matter integrity in participants with depression; these results suggest support for the vascular depression hypothesis.
Depressive illness.
WHO estimate that by the beginning of the next century major unipolar depression will be one of the most important causes of ill health overall. Whereas the cause of depression is still obscure, it is becoming clear that a number of diverse factors are likely to be implicated, both genetic and environmental. Effective treatment of depression similarly involves a variety of methods, from electro-convulsive therapy to inter-personal psychotherapy. The pathophysiology of depression is gradually becoming accessible through research strategies, such as functional neuroimaging paired with mood altering interventions.