Applying generalizability theory to examine assessments of subjective cognitive complaints: whose reports should we rely on - participant versus informant?

OBJECTIVES: This study aimed to apply the generalizability theory (G-theory) to investigate dynamic and enduring patterns of subjective cognitive complaints (SCC), and reliability of two widely used SCC assessment tools. DESIGN: G-theory was applied to assessment scales using longitudinal measurement design with five assessments spanning 10 years of follow-up. SETTING: Community-dwelling older adults aged 70-90 years and their informants, living in Sydney, Australia, participated in the longitudinal Sydney Memory and Ageing Study. PARTICIPANTS: The sample included 232 participants aged 70 years and older, and 232 associated informants. Participants were predominantly White Europeans (97.8%). The sample of informants included 76 males (32.8%), 153 females (65.9%), and their age ranged from 27 to 86 years, with a mean age of 61.3 years (SD = 14.38). MEASUREMENTS: The Memory Complaint Questionnaire (MAC-Q) and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). RESULTS: The IQCODE demonstrated strong reliability in measuring enduring patterns of SCC with G = 0.86. Marginally acceptable reliability of the 6-item MAC-Q (G = 0.77-0.80) was optimized by removing one item resulting in G = 0.80-0.81. Most items of both assessments were measuring enduring SCC with exception of one dynamic MAC-Q item. The IQCODE significantly predicted global cognition scores and risk of dementia incident across all occasions, while MAC-Q scores were only significant predictors on some occasions. CONCLUSIONS: While both informants' (IQCODE) and self-reported (MAC-Q) SCC scores were generalizable across sample population and occasions, self-reported (MAC-Q) scores may be less accurate in predicting cognitive ability and diagnosis of each individual.

The Vascular Behavioral and Cognitive Disorders criteria for vascular cognitive disorders: a validation study.

BACKGROUND AND PURPOSE: The Vascular Behavioral and Cognitive Disorders (VASCOG) criteria for vascular cognitive disorders were published in 2014, but their concurrent and predictive validity have not been examined. METHODS: Participants (N = 165, aged 49-86 years) were from Sydney Stroke Study, a longitudinal study of post-stroke cognitive impairment and dementia. Diagnoses using the National Institute of Neurological Disorders and Stroke - Association Internationale pour la Recherché et l'Enseignement en Neurosciences (NINDS-AIREN), the Alzheimer's Disease Diagnostic and Treatment Centers (ADDTC) and the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), criteria for vascular dementia (VaD) were made by consensus at multidisciplinary case conferences. Diagnoses for mild vascular cognitive disorder (mVCD) and VaD using VASCOG, DSM-5 and the Vascular Impairment of Cognition Classification Consensus Study (VICCCS) criteria were made by two study authors. Agreement levels between criteria sets were examined using Cohen's kappa (κ). The ability of VaD diagnoses to predict mortality over 10 years and of mVCD to predict dementia over 5 years was investigated. RESULTS: The VASCOG criteria yielded rates of mVCD slightly lower than for DSM-5 and VICCCS. VaD rates were similar for all criteria, although slightly lower for DSM-IV. Agreement between the VASCOG, VICCCS and DSM-5 criteria was excellent for VaD and mVCD (κ = 0.83-1.0), but lower for VaD between VASCOG and the other criteria (κ = 0.47-0.63). VaD-based mortality predictions were similar for the VASCOG, VICCCS and DSM-5 criteria, and higher than those for other criteria. The prediction of incident dementia within 5 years from mVCD was slightly lower with VASCOG criteria than with DSM-5 and VICCCS criteria. CONCLUSIONS: The VASCOG criteria have greater sensitivity, modest concurrent validity and better predictive validity than older criteria for VaD, but are comparable to DSM-5 and VICCCS criteria. Their operationalization and inclusion of a mild VCD category make them useful for clinical and research applications.

Body mass index is associated with cortical thinning with different patterns in mid- and late-life.

OBJECTIVE: High BMI at midlife is associated with increased risk of dementia as well as faster decline in cognitive function. In late-life, however, high BMI has been found to be associated with both increased and decreased dementia risk. The objective of this study was to investigate the neural substrates of this age-related change in body mass index (BMI) risk. METHODS: We measured longitudinal cortical thinning over the whole brain, based on magnetic resonance imaging scans for 910 individuals aged 44-66 years at baseline. Subjects were sampled from a large population study (PATH, Personality and Total Health through Life). After attrition and exclusions, the final analysis was based on 792 individuals, including 387 individuals aged 60-66 years and 405 individuals aged 44-49 years. A mixed-effects model was used to test the association between cortical thinning and baseline BMI, as well as percentage change in BMI. RESULTS: Increasing BMI was associated with increased cortical thinning in posterior cingulate at midlife (0.014 mm kg-1 m-2, confidence interval; CI=0.005, 0.023, P<0.05 false discovery rate (FDR) corrected). In late-life, increasing BMI was associated with reduced cortical thickness, most prominently in the right supramarginal cortex (0.010 mm kg-1 m-2, CI=0.005-0.016, P<0.05 FDR corrected), as well as frontal regions. In late-life, decreasing BMI was also associated with increased cortical thinning, including right caudal middle frontal cortex (0.014 mm kg-1 m-2 (CI=0.006-0.023, P<0.05 FDR corrected). CONCLUSIONS: The pattern of cortical thinning-in association with increasing BMI at both midlife and late-life-is consistent with known obesity-related dementia risk. Increased cortical thinning in association with decreasing BMI at late-life may help explain the 'obesity paradox', where high BMI in midlife appears to be a risk factor for dementia, but high BMI in late-life appears, at times, to be protective.

Genetic and Environmental Influences on Language Ability in Older Adults: Findings from the Older Australian Twins Study.

We used a sub-sample from the Older Australian Twins Study to estimate the heritability of performance on three tests of language ability: Boston Naming Test (BNT), Letter/Phonemic Fluency (FAS) and Category/Semantic Fluency (CFT) Tests. After adjusting for age, sex, education, mood, and global cognition (GC), heritability estimates obtained for the three tests were 0.35, 0.59, and 0.20, respectively. Multivariate analyses showed that the genetic correlation were high for BNT and CFT (0.61), but low for BNT and FAS (0.17), and for FAS and CFT (0.28). Genetic modelling with Cholesky decomposition indicated that the covariation between the three measures could be explained by a common genetic factor. Environmental correlations between the language ability measures were low, and there were considerable specific environmental influences for each measure. Future longitudinal studies with language performance and neuroimaging data can further our understanding of genetic and environmental factors involved in the process of cognitive aging.

Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: evidence from voxel-based meta-analysis.

Finding robust brain substrates of mood disorders is an important target for research. The degree to which major depression (MDD) and bipolar disorder (BD) are associated with common and/or distinct patterns of volumetric changes is nevertheless unclear. Furthermore, the extant literature is heterogeneous with respect to the nature of these changes. We report a meta-analysis of voxel-based morphometry (VBM) studies in MDD and BD. We identified studies published up to January 2015 that compared grey matter in MDD (50 data sets including 4101 individuals) and BD (36 data sets including 2407 individuals) using whole-brain VBM. We used statistical maps from the studies included where available and reported peak coordinates otherwise. Group comparisons and conjunction analyses identified regions in which the disorders showed common and distinct patterns of volumetric alteration. Both disorders were associated with lower grey-matter volume relative to healthy individuals in a number of areas. Conjunction analysis showed smaller volumes in both disorders in clusters in the dorsomedial and ventromedial prefrontal cortex, including the anterior cingulate cortex and bilateral insula. Group comparisons indicated that findings of smaller grey-matter volumes relative to controls in the right dorsolateral prefrontal cortex and left hippocampus, along with cerebellar, temporal and parietal regions were more substantial in major depression. These results suggest that MDD and BD are characterised by both common and distinct patterns of grey-matter volume changes. This combination of differences and similarities has the potential to inform the development of diagnostic biomarkers for these conditions.

Strength measures are better than muscle mass measures in predicting health-related outcomes in older people: time to abandon the term sarcopenia?

There is no clear consensus on definition, cut-points or standardised assessments of sarcopenia. We found a lower limb strength assessment was at least as effective in predicting balance, mobility and falls in 419 older people as muscle mass-based measures of sarcopenia. INTRODUCTION: There is currently no consensus on the definition, cut-points or standardised assessments of sarcopenia. This study aimed to investigate whether several published definitions of sarcopenia differentiate between older people with respect to important functional and health outcomes. METHODS: Four hundred nineteen community-living older adults (mean age 81.2 ± 4.5, 49 % female) completed assessments of body composition (dual-energy X-ray absorptiometry), strength, balance, mobility and disability. Falls were recorded prospectively for a year using monthly calendars. Sarcopenia was defined according to four skeletal mass-based definitions, two strength-based definitions (handgrip or knee extensor force) and a consensus algorithm (low mass and low strength or slow gait speed). Obesity was defined according to percentage fat mass or waist circumference. RESULTS: The four skeletal mass-based definitions varied considerably with respect to the percentage of participants classified as sarcopenic and their predictive accuracy for functional and health outcomes. The knee extension strength-based definition was equivalent to or better than the mass-based and consensus algorithm definitions; i.e. weaker participants performed poorly in tests of leaning balance, stepping reaction time, gait speed and mobility. They also had higher physiological fall risk scores and were 43 % more likely to fall at home than their stronger counterparts. Adding obesity to sarcopenia definitions identified participants with greater self-reported disability. CONCLUSIONS: A simple lower limb strength assessment was at least as effective in predicting balance, functional mobility and falls in older people as more expensive and time-consuming muscle mass-based measures. These findings imply that functional terms such as muscle weakness or motor impairment are preferable to sarcopenia.

Impairment in instrumental activities of daily living with high cognitive demand is an early marker of mild cognitive impairment: the Sydney memory and ageing study.

BACKGROUND: Criteria for mild cognitive impairment (MCI) consider impairment in instrumental activities of daily living (IADL) as exclusionary, but cross-sectional studies suggest that some high-level functional deficits are present in MCI. This longitudinal study examines informant-rated IADL in MCI, compared with cognitively normal (CN) older individuals, and explores whether functional abilities, particularly those with high cognitive demand, are predictors of MCI and dementia over a 2-year period in individuals who were CN at baseline. METHOD: A sample of 602 non-demented community dwelling individuals (375 CN and 227 with MCI) aged 70-90 years underwent baseline and 24-month assessments that included cognitive and medical assessments and an interview with a knowledgeable informant on functional abilities with the Bayer Activities of Daily Living Scale. RESULTS: Significantly more deficits in informant-reported IADL with high cognitive demand were present in MCI compared with CN individuals at baseline and 2-year follow-up. Functional ability in CN individuals at baseline, particularly in activities with high cognitive demand, predicted MCI and dementia at follow-up. Difficulties with highly cognitively demanding activities specifically predicted amnestic MCI but not non-amnestic MCI whereas those with low cognitive demand did not predict MCI or dementia. Age, depressive symptoms, cardiovascular risk factors and the sex of the informant did not contribute to the prediction. CONCLUSIONS: IADL are affected in individuals with MCI, and IADL with a high cognitive demand show impairment predating the diagnosis of MCI. Subtle cognitive impairment is therefore likely to be a major hidden burden in society.

Prevalence and characteristics of depression in mild cognitive impairment: the Sydney Memory and Ageing Study.

OBJECTIVE: Depression might be a risk factor for dementia. However, little is known about the prevalence of depressive symptoms in mild cognitive impairment (MCI) and whether mood or motivation-related symptoms are predominant. METHOD: A total of 767 non-demented community-dwelling adults aged 70-90 years completed a comprehensive assessment, including neuropsychological testing, and a past psychiatric/medical history interview. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS) and Kessler Psychological Distress Scale (K10). Exploratory factor analysis was performed on the GDS and K10 to derive 'mood' and 'motivation' subscales. RESULTS: A total of 290 participants were classified as having MCI and 468 as cognitively normal (CN). Participants with MCI reported more depressive symptoms, and more MCI participants met the cut-off for clinically significant symptoms, relative to CN participants. Those with amnestic MCI (aMCI), but not non-amnestic MCI, had more depressive symptoms and were more likely to meet the cut-off for clinically significant depressive symptoms, relative to CN participants. Participants with MCI reported more mood-related symptoms than CN participants, while there were no differences between groups on motivation-related symptoms. CONCLUSION: Individuals with MCI, especially aMCI, endorse more depressive symptoms when compared with cognitively intact individuals. These findings highlight the importance of assessing and treating depressive symptoms in MCI.

Relationships between serum vitamin D levels, neuromuscular and neuropsychological function and falls in older men and women.

UNLABELLED: Among 463 community dwellers aged 70-90 years, those with vitamin D insufficiency showed reduced neuromuscular function, balance control and stepping ability and performed worse in tests of cognitive function. In men, vitamin D insufficiency was associated with an increased risk of falling. INTRODUCTION: The purpose of this study was to investigate the relationship between serum 25-hydroxy vitamin D (serum 25OHD) levels, physiological and neuropsychological function in older people, and to examine the relationship between serum 25OHD and prospective falls. METHODS: Four hundred sixty-three community-dwelling people aged 70-90 years underwent an assessment of physiological and neuropsychological performance and structured interviews relating to comorbidity and disability. Fall frequency during the 12 months follow-up was monitored with monthly falls diaries. RESULTS: Twenty-one percent of the men and 44% of the women were vitamin D insufficient (serum 25OHD ≤ 50 nmol/L). Participants with vitamin D insufficiency had weaker upper and lower limb strength, slower simple finger press and choice stepping reaction time, poorer leaning balance and slower gait speed, after controlling for age and body mass index, and, poorer executive function and visuospatial ability, after controlling for age and education. Vitamin D insufficiency significantly increased the rate of falls in men (IRR = 1.94, 95% CI = 1.19-3.15, p = 0.008) but not in women. CONCLUSIONS: These findings highlight the associations between vitamin D insufficiency and impairments in physiological and neuropsychological function that predispose older people to fall. The significant relationship between vitamin D insufficiency and falls found in the men may relate to the stronger association found between serum 25OHD levels and dynamic balance measures evident in this male population.

Dietary Patterns and Cognitive Health in Older Adults: Findings from the Sydney Memory and Ageing Study.

OBJECTIVES: Systematic reviews report dietary patterns may be associated with cognitive health in older adults. However, inconsistent findings have been reported and relevant research lacks large scale studies. This study aims to examine the associations of dietary patterns and cognitive function among older adults in an Australian ageing cohort. DESIGN: A population-based, cross-sectional analysis of the baseline phase of the Sydney Memory and Ageing Study, a well-characterised Australian ageing study. SETTING: The Sydney Memory and Ageing Study was initiated in 2005 to examine the clinical characteristics and prevalence of mild cognitive impairment (MCI). PARTICIPANTS: Non-demented community-dwelling individuals from English-speaking background (N = 819) aged 70-90 recruited from two areas of Sydney, following a random approach to 8914 individuals on the electoral roll in the Sydney Memory and Ageing study. MEASUREMENTS: The Cancer Council of Victoria Food Frequency Questionnaire was used to assess dietary intake. Scores for Mediterranean diet, Dietary Approaches to Stop Hypertension (DASH) diet and the Dietary Guidelines Index (DGI 2013) were generated. Two patterns - a Prudent healthy and a Western dietary pattern - were derived using principal components analysis (PCA). Neuropsychological tests were used to assess global cognition and six cognitive domains. Multivariate linear modelling assessed the relationship between dietary patterns and cognitive domain scores. RESULTS: Mediterranean diet and DASH diet were both positively linked to visuospatial cognition (P=0.002 and P=0.001 respectively). Higher intake of legumes and nuts was related to better performance in global cognition (ß=0.117; 95% CI:0.052, 0.181; P<0.001) and language and visuospatial cognitive domains. The Prudent healthy diet was associated with better global cognition (ß=0.307; 95% CI: 0.053, 0.562; P=0.019) in women and a Western diet was related to poorer global function (ß=-0.242; 95% CI: -0.451,-0.034; P=0.023) and executive function (ß=-0.325; 95% CI: -0.552,-0.099; P=0.005) in men. CONCLUSION: In this analysis, higher adherence to the Mediterranean diet, DASH diet, Prudent healthy diet and greater consumption of legumes and nuts were associated with better cognition among older adults.

A sham-controlled trial of left and right temporal rTMS for the treatment of auditory hallucinations.

BACKGROUND: Several studies have reported reduction of auditory hallucinations (AH) after repetitive transcranial magnetic stimulation (rTMS) to the left temporal cortex. This study explored the effects of rTMS to the left and right temporal cortex. METHOD: Eighteen subjects with schizophrenia and frequent AH were enrolled in a double-blind, cross-over trial of 3 days of active rTMS to the left or right temporal cortex, or sham rTMS to the vertex (control condition), followed by an open treatment phase. The effects on AH were assessed by a blinded rater, using the Auditory Hallucination Rating Scale (AHRS). RESULTS: During the double-blind phase, active temporal rTMS did not result in significantly greater improvement in hallucination scores than sham rTMS to the vertex, apart from a reduction in distress scores. Hallucination scores improved during the open continued treatment phase. CONCLUSIONS: This study did not demonstrate an advantage for left temporal rTMS compared to right temporal and sham stimulation, over a 3-day stimulation period, but found modest improvement in hallucinations during continued open label treatment.

Functional alterations in brain activation and deactivation in mild cognitive impairment in response to a graded working memory challenge.

AIM: To investigate dynamic changes in functional brain activity in mild cognitive impairment (MCI) in response to a graded working memory (WM) challenge with increasing memory load. METHODS: In an event-related functional magnetic resonance imaging (fMRI) study, 35 MCI and 22 cognitively normal subjects performed a visuospatial associative WM task with 3 load levels. Potential performance differences were controlled for by individually calibrating the number of items presented at each load. RESULTS: An interaction between group and WM load was observed during stimulus encoding. At lower loads, greater activity in the right anterior cingulate and right precuneus was observed in MCI subjects. As the load increased to higher levels, reduced activation in these regions and greater deactivation in the posterior cingulate-medial precuneus were observed in MCI compared to control subjects. Stronger expression of load-related patterns of activation and deactivation in MCI subjects was associated with greater clinical severity and a more abnormal pattern of performance variability. CONCLUSION: Patterns of overactivation, underactivation and deactivation during successful encoding in MCI subjects were dependent on WM load. This type of graded cognitive challenge may operate like a 'memory stress test' in MCI and may be a useful biomarker of disease at the pre-dementia stage.

Parity and the risk of incident dementia: a COSMIC study.

AIMS: To investigate the association between parity and the risk of incident dementia in women. METHODS: We pooled baseline and follow-up data for community-dwelling women aged 60 or older from six population-based, prospective cohort studies from four European and two Asian countries. We investigated the association between parity and incident dementia using Cox proportional hazards regression models adjusted for age, educational level, hypertension, diabetes mellitus and cohort, with additional analysis by dementia subtype (Alzheimer dementia (AD) and non-Alzheimer dementia (NAD)). RESULTS: Of 9756 women dementia-free at baseline, 7010 completed one or more follow-up assessments. The mean follow-up duration was 5.4 ± 3.1 years and dementia developed in 550 participants. The number of parities was associated with the risk of incident dementia (hazard ratio (HR) = 1.07, 95% confidence interval (CI) = 1.02-1.13). Grand multiparity (five or more parities) increased the risk of dementia by 30% compared to 1-4 parities (HR = 1.30, 95% CI = 1.02-1.67). The risk of NAD increased by 12% for every parity (HR = 1.12, 95% CI = 1.02-1.23) and by 60% for grand multiparity (HR = 1.60, 95% CI = 1.00-2.55), but the risk of AD was not significantly associated with parity. CONCLUSIONS: Grand multiparity is a significant risk factor for dementia in women. This may have particularly important implications for women in low and middle-income countries where the fertility rate and prevalence of grand multiparity are high.

Hippocampal size and dementia in stroke patients: the Sydney stroke study.

BACKGROUND: Hippocampal atrophy is an early feature of Alzheimer's disease (AD) but it has also been reported in vascular dementia (VaD). It is uncertain whether hippocampal size can help differentiate the two disorders. METHODS: We assessed 90 stroke/TIA patients 3-6 months after the event, and 75 control subjects, with neuropsychological tests, medical and psychiatric examination and brain MRI scans. A diagnosis of VaD, vascular mild cognitive impairment (VaMCI) or no cognitive impairment (NCI) was reached by consensus on agreed criteria. T1-weighted MRI was used to obtain total intracranial volume (TICV), gray and white matter volume, CSF volume, hippocampus and amygdala volumes, and T2-weighted scans for white matter hyperintensity (WMH) ratings. RESULTS: Stroke/TIA patients had more white matter hyperintensities (WMHs), larger ventricle-to-brain ratios and smaller amygdalae than controls, but hippocampus size and gray and white matter volumes were not different. WMHs and amygdala but not hippocampal volume distinguished stroke/TIA patients with VaD and VaMCI and without NCI and amygdala volumes. Right hippocampus volume significantly correlated with new visual learning. CONCLUSIONS: Stroke/TIA patients and patients with post-stroke VaMCI or mild VaD do not have hippocampal atrophy. The amygdala is smaller in stroke/TIA patients, especially in those with cognitive impairment, and this may be accounted for by white matter lesions. The hippocampus volume relates to episodic memory, especially right hippocampus and new visual learning. A longitudinal study of these subjects will determine whether hippocampal atrophy is a late development in VaD.

1H MRS in stroke patients with and without cognitive impairment.

The pathophysiological basis of cognitive impairment in patients with cerebrovascular disease (CVD) is not well understood, particularly in relation to the role of non-infarction ischemic change and associated Alzheimer-type pathology. We used single voxel 1H MRS to determine the differences in brain neurometabolites in non-infarcted frontal white matter and occipito-parietal gray matter of 48 stroke patients with or without cognitive impairment and 60 elderly controls. The results showed that there were no significant neurometabolite differences between the stroke cohort and healthy elderly controls, but there was a difference in NAA/H2O between the stroke patients that had cognitive impairment (vascular dementia (VaD) and vascular cognitive impairment (VCI)) compared with those patients with no impairment. This was significant in the occipito-parietal gray matter, but not in the frontal white matter, although the results were in the same direction for the latter. This suggests that cognitive impairment in stroke patients may be related to cortical neuronal dysfunction rather than purely subcortical change. Moreover, cortical regions not obviously infarcted may have dysfunctional neurons, the pathophysiological basis for which needs further study.

A continuing survey of drug-resistant tuberculosis, New York City, April 1994.

BACKGROUND: A 1991 survey showed high levels of drug resistance among tuberculosis patients in New York, NY. As a result, the tuberculosis control program was strengthened, including expanded use of directly observed therapy and improved infection control. METHODS: We collected isolates from every patient in New York City with a positive culture for Mycobacterium tuberculosis during April 1994; results were compared with those in the April 1991 survey. RESULTS: From 1991 to 1994, the number of patients decreased from 466 to 332 patients. The percentage with isolates resistant to 1 or more antituberculosis drugs decreased from 33% to 24% (P < .01); with isolates resistant to at least isoniazid decreased from 26% to 18% (P < .05); and with isolates resistant to both isoniazid and rifampin decreased from 19% to 13% (P < .05). The number of patients with isolates resistant to both isoniazid and rifampin decreased by more than 50%. Among never previously treated patients, the percentage with resistance to 1 or more drugs decreased from 22% in 1991 to 13% in 1994 (P < .05). The number of patients with consistently positive culture results for more than 4 months decreased from 130 to 44. A history of antituberculosis treatment was the strongest predictor of drug resistance (odds ratio = 3.1; P < .001). Human immunodeficiency virus infection was associated with drug resistance among patients who never had been treated for tuberculosis. CONCLUSIONS: Drug-resistant tuberculosis declined significantly in New York City from 1991 to 1994. Measures to control and prevent tuberculosis were associated with a 29% decrease in the proportion of drug resistance and a 52% decrease in the number of patients with multidrug-resistant tuberculosis.

Animal models of acute drug-induced akathisia - a review.

Akathisia is a complex neurobehavioural side effect of neuroleptics and some other drugs which is characterised by subjective report and objective manifestations of restlessness. Its pathophysiology is poorly understood and there are many limitations to its investigation in humans. This paper reviews the various attempts that have been made in modelling acute akathisia in animals. Homologous as well as isomorphic models have been attempted, but most models are partial as they reproduce either the subjective or the objective features of the syndrome. None of the available models has been fully validated. Neuroleptic-induced defecation in the rat, even though constrained by a lack of symptom similarity and thereby face validity, has been most studied as a model of subjective akathisia. Rat models of restlessness, in particular those involving the use of serotonergic drugs or lesions of the ventral tegmentum or medial prefrontal cortex, are interesting partial models that should be further investigated. Neuroleptic-induced akathisia is observed in primates and has been modelled in dogs, and these should be studied further for their validation. It is also necessary to consider the subtypes of akathisia in the attempts to develop these models.

The audiogenic startle reflex in Tourette's syndrome.

The motor response pattern of the audiogenic startle reflex was studied in 15 Tourette's syndrome (TS) patients and 15 normal, age-matched control subjects, using auditory stimuli at 88 and 114 dB. The louder stimuli readily elicited responses in the orbicularis oculi (in all subjects), masseter, sternomastoid, trapezius, deltoid, and biceps (in most subjects) muscles, with a few subjects having responses in the forearm flexors and quadriceps. The TS subjects did not differ from controls in the onset latency, amplitude, and first peak latency of the reflex response in any of the muscles. Rates of habituation in the orbicularis oculi muscle were widely variable across the subjects, and the two groups did not differ overall in the habituation rates. Our study does not support the reports of an abnormal audiogenic startle reflex in TS.

Transcranial magnetic stimulation (TMS) in controlled treatment studies: are some "sham" forms active?

BACKGROUND: Carefully designed controlled studies are essential in further evaluating the therapeutic efficacy of transcranial magnetic stimulation (TMS) in psychiatric disorders. A major methodological concern is the design of the "sham" control for TMS. An ideal sham would produce negligible cortical stimulation in conjunction with a scalp sensation akin to real treatment. Strategies employed so far include alterations in the position of the stimulating coil, but there has been little systematic study of their validity. In this study, we investigated the effects of different coil positions on cortical activation and scalp sensation. METHODS: In nine normal subjects, single TMS pulses were administered at a range of intensities with a "figure eight" coil held in various positions over the left primary motor cortex. Responses were measured as motor-evoked potentials in the right first dorsal interosseus muscle. Scalp sensation to TMS with the coil in various positions over the prefrontal area was also assessed. RESULTS: None of the coil positions studied met the criteria for an ideal sham. Arrangements associated with a higher likelihood of scalp sensation were also more likely to stimulate the cortex. CONCLUSIONS: The choice of a sham for TMS involves a trade-off between effective blinding and truly inactive "stimulation." Further research is needed to develop the best sham condition for a range of applications.

Differentiation of vascular dementia from AD on neuropsychological tests.

BACKGROUND: The concept of vascular dementia (VaD) is currently in a state of evolution. Memory impairment is emphasized as a primary criterion, reflecting the influence of AD on the concept of dementia. We have systematically reviewed whether the nature of neuropsychological dysfunction is distinct in AD and VaD, and whether similar defining criteria for the concept of dementia in both disorders can be supported. METHODS: We searched five bibliographic databases (Medline, Biological Abstracts, EMBASE, PsychINFO, PsychLIT) for research articles in which VaD and AD had been compared using neuropsychological tests and that met criteria for scientific merit. RESULTS: Of the 45 studies, 18 were excluded because of inadequacies, and the remaining 27 were analyzed. There were a number of similarities of dysfunction between VaD and AD. However, when matched for age, education, and severity of dementia, VaD patients had relatively superior function in verbal long-term memory and more impairment in frontal executive functioning compared with AD patients. Interpretation of the results is limited by uncertainty in diagnostic criteria for VaD, possible inclusion bias due to use of clinical diagnosis alone, possible overlap of AD and VaD, and the methodologic shortcomings of some studies. CONCLUSIONS: The neuropsychological differentiation of VaD from AD was consistent with the different neuroimaging findings in the two disorders, and argues for differential criteria for the definition of the syndromes. The simple application of Alzheimer's dementia criteria to VaD, with the inclusion of cerebrovascular disease etiology, may not be sufficient to capture the uniqueness of VaD.