Coated-platelet levels and progression from mild cognitive impairment to Alzheimer disease.

OBJECTIVES: Coated-platelets are a subset of platelets produced by dual-agonist activation with collagen and thrombin. These platelets retain full-length amyloid precursor protein on their surface, are elevated in patients with amnestic as compared to nonamnestic mild cognitive impairment (MCI), and correlate with disease progression in Alzheimer disease (AD). Prompted by these findings, we investigated the association between coated-platelet production in amnestic MCI and rate of progression to AD. METHODS: Coated-platelet levels were assayed in 74 patients with amnestic MCI who were subsequently followed longitudinally for up to 36 months in an outpatient dementia clinic. Levels are reported as percent of cells converted into coated-platelets. Subjects were categorized into tertiles of coated-platelet levels. The distributions of time to progression to AD were estimated for each tertile using cumulative incidence curves and compared statistically using a log-rank test. Cox proportional hazards regression was used to adjust for potential confounders. RESULTS: The 24-month cumulative incidence of progression to AD was different among tertiles: 4% for the first tertile (lowest coated-platelet levels), 13% for the second tertile, and 37% for the third tertile (overall log-rank test, p = 0.02). The hazard rate of progression to AD for patients in the highest coated-platelet tertile was 5.1 times that for patients in the lowest tertile (p = 0.04), whereas the hazard rate for the middle tertile was similar to that for the lowest tertile (hazard rate ratio = 1.5, p = 0.7). CONCLUSIONS: Elevated coated-platelet levels in patients with amnestic MCI are associated with increased risk for progression to AD.

Cumulative incidence of vitamin B12 deficiency in patients with Alzheimer disease.

BACKGROUND: Although vitamin B12 is routinely measured in patients with Alzheimer disease (AD) at the time of the initial diagnosis, it is not known if repeat vitamin B12 measurements are indicated to detect new deficiency cases. We aimed to determine the incidence of de-novo vitamin B12 deficiency over a period of 3 years in a cohort of AD patients without a prior diagnosis of vitamin B12 deficiency and with initial vitamin B12 levels greater than 350 ng/L. METHODS: Vitamin B12 levels were measured at the time of AD diagnosis and repeated 3 years later in 102 consecutive patients, unless a diagnosis of B12 deficiency was made in the interim. RESULTS: Vitamin B12 deficiency was diagnosed in 7 patients, corresponding to a cumulative incidence in the cohort studied of 7.6% after 3 years of follow-up. Statistical comparison of initial and repeat vitamin B12 measurements in patients that completed follow-up showed a significant reduction in levels (p=0.003). Among the 79 subjects with follow-up, 17 patients (22%, 95% CI, 13%-32%) had a repeat level less than 350 ng/L. No significant correlates of deficiency incidence were identified. CONCLUSION: Our pilot data indicate that vitamin B12 levels decreased in this cohort of AD patients putting a substantial percentage at risk of deficiency and reaching deficiency state in a meaningful number of patients. Repeat screening for B12 deficiency after approximately 2 years of follow-up seems warranted in order to prevent hematological and neurological manifestations that may significantly alter their quality of life.

Hemispheric differences in recognizing upper and lower facial displays of emotion.

OBJECTIVE: To determine if there are hemispheric differences in processing upper versus lower facial displays of emotion. BACKGROUND: Recent evidence suggests that there are two broad classes of emotions with differential hemispheric lateralization. Primary emotions (e.g. anger, fear) and associated displays are innate, are recognized across all cultures, and are thought to be modulated by the right hemisphere. Social emotions (e.g., guilt, jealousy) and associated "display rules" are learned during early child development, vary across cultures, and are thought to be modulated by the left hemisphere. Display rules are used by persons to alter, suppress or enhance primary emotional displays for social purposes. During deceitful behaviors, a subject's true emotional state is often leaked through upper rather than lower facial displays, giving rise to facial blends of emotion. We hypothesized that upper facial displays are processed preferentially by the right hemisphere, as part of the primary emotional system, while lower facial displays are processed preferentially by the left hemisphere, as part of the social emotional system. METHOD: 30 strongly right-handed adult volunteers were tested tachistoscopically by randomly flashing facial displays of emotion to the right and left visual fields. The stimuli were line drawings of facial blends with different emotions displayed on the upper versus lower face. The subjects were tested under two conditions: 1) without instructions and 2) with instructions to attend to the upper face. RESULTS: Without instructions, the subjects robustly identified the emotion displayed on the lower face, regardless of visual field presentation. With instructions to attend to the upper face, for the left visual field they robustly identified the emotion displayed on the upper face. For the right visual field, they continued to identify the emotion displayed on the lower face, but to a lesser degree. CONCLUSIONS: Our results support the hypothesis that hemispheric differences exist in the ability to process upper versus lower facial displays of emotion. Attention appears to enhance the ability to explore these hemispheric differences under experimental conditions. Our data also support the recent observation that the right hemisphere has a greater ability to recognize deceitful behaviors compared with the left hemisphere. This may be attributable to the different roles the hemispheres play in modulating social versus primary emotions and related behaviors.

Impaired affective prosody in AD: relationship to aphasic deficits and emotional behaviors.

OBJECTIVE: To assess the ability of patients with AD to produce, repeat, and comprehend affective prosody in relationship to severity of dementia, aphasic deficits, and changes in emotional behaviors. METHODS: An Aprosodia Battery was used to assess affective-prosodic performance and to identify patterns of deficits in affective communication. In addition, the presence and severity of aberrant behaviors, depression, and aphasia were assessed using standardized assessment tools. RESULTS: Patients with AD had significant impairments in their ability to repeat, comprehend, and discriminate affective aspects of speech, but maintained normal spontaneous affective-prosodic performances. As dementia severity increased, performance on the comprehension tasks and, to a lesser degree, on the repetition tasks became more impaired; spontaneous affective prosody remained normal. In the current study, affective-prosodic comprehension impairments were present in patients with all stages of AD; comparable aphasic deficits were not observed until patients were severely demented. The majority of aphasic deficits involved anomia without loss of comprehension. Patients with AD with sensory aprosodia had increased frequency and severity of behavioral changes whereas patients with AD with normal affective-prosodic performance were significantly less demented, had normal linguistic ability, and displayed fewer aberrant psychiatric behaviors. CONCLUSION: Patients with mild AD are at considerable risk for affective-prosodic comprehension deficits. As patients become more demented and develop sensory aprosodia, they are at greater risk for disturbances in behavior and mood.

HMG proteins and DNA flexibility in transcription activation.

The relative stiffness of naked DNA is evident from measured values of longitudinal persistence length (approximately 150 bp) and torsional persistence length (approximately 180 bp). These parameters predict that certain arrangements of eukaryotic transcription activator proteins in gene promoters should be much more effective than others in fostering protein-protein interactions with the basal RNA polymerase II transcription apparatus. Thus, if such interactions require some kind of DNA looping, DNA loop energies should depend sensitively on helical phasing of protein binding sites, loop size, and intrinsic DNA curvature within the loop. Using families of artificial transcription templates where these parameters were varied, we were surprised to find that the degree of transcription activation by arrays of Gal4-VP1 transcription activators in HeLa cell nuclear extract was sensitive only to the linear distance separating a basal promoter from an array of bound activators on DNA templates. We now examine the hypothesis that this unexpected result is due to factors in the extract that act to enhance apparent DNA flexibility. We demonstrate that HeLa cell nuclear extract is rich in a heat-resistant activity that dramatically enhances apparent DNA longitudinal and torsional flexibility. Recombinant mammalian high-mobility group 2 (HMG-2) protein can substitute for this activity. We propose that the abundance of HMG proteins in eukaryotic nuclei provides an environment in which DNA is made sufficiently flexible to remove many constraints on protein binding site arrangements that would otherwise limit efficient transcription activation to certain promoter geometries.

Affective-prosodic deficits in schizophrenia: comparison to patients with brain damage and relation to schizophrenic symptoms [corrected].

OBJECTIVE: Although affective prosody seems to be a dominant and lateralised communication function of the right hemisphere, focal lesions of either hemisphere may cause problems with its modulation. When impairment occurs after brain damage, the profiles of affective-prosodic disturbances differ depending on the hemisphere injured. Patients with left brain damage (LBD) improve their performance whereas patients with right brain damage (RBD) do not when the verbal-articulatory demands of the test stimuli are reduced systematically. One of the major arguments for a right hemispheric contribution to schizophrenia has been the documentation of affective prosodic deficits under the assumption that these abnormalities reflect right hemispheric dysfunction. Thus, an essential question to resolve is whether the profile of affective prosodic disturbances in schizophrenia is similar to LBD or RBD, or represents a unique variation. METHODS: Data were collected from four subject groups: 45 chronic, medication-stabilised, schizophrenic patients, 10 patients with focal LBD, nine patients with focal RBD, and 19 controls. All groups were tested on the aprosodia battery, which uses stimuli having incrementally reduced verbal-articulatory demands. Schizophrenic and aphasic symptoms were evaluated using standard assessment tools. RESULTS: For patients with impaired performance on the aprosodia battery, schizophrenic patients were statistically identical to patients with RBD and robustly different from those with LBD. Thirty eight schizophrenic patients (84.4%) were found to have some type of affective prosodic deficit with the predominant pattern indicating, at minimum, right posterior sylvian dysfunction (57.8%). When schizophrenic symptoms and aprosodic deficits were examined using a principal component analysis, affective comprehension and repetition loaded uniquely as separate factors. CONCLUSIONS: The profile of affective-prosodic deficits found in impaired schizophrenic patients is characteristic of RBD, supporting the concept that schizophrenia is a bihemispheric disease process. These deficits may also represent cardinal symptoms of schizophrenia as they are highly prevalent and, except for spontaneous affective prosody, are not associated statistically with traditional clusters of schizophrenic symptoms.

Relating independent measures of DNA curvature: electrophoretic anomaly and cyclization efficiency.

Electrophoretic methods are often used to measure DNA curvature and protein-induced DNA bending. Though convenient and widely-applied, quantitative analyses are generally limited to assays for which empirical calibration standards have been developed. Alternatively, solution-based cyclization of short DNA duplexes allows analysis of DNA curvature and bending from first principles, but a detailed understanding of this assay is still lacking. In this work, we demonstrate that calibration with an independent electrophoretic assay of DNA curvature permits interpretation of cyclization assay results in a quantitatively meaningful way. We systematically measure intrinsic DNA curvature in short duplexes using a well-established empirical ligation ladder assay. We then compare the results to those obtained from the analysis of the distribution of circular products obtained in simple enzymatic cyclization assays of the same duplexes when polymerized. A strong correlation between DNA curvature estimates from these two assays is obtained for DNA fragments between 150-300 bp in length. We discuss how this result might be used to improve quantitative analysis of protein-mediated bending events evaluated by cyclization methods. Our results suggest that measurements of DNA curvature obtained under similar conditions, in solution and in an acrylamide gel matrix, can be compared directly. The ability to correlate results of these simple assays may prove convenient in monitoring DNA curvature and flexibility.

DNA constraints on transcription activation in vitro.

Activators of eukaryotic transcription often function over a range of distances. It is commonly hypothesized that the intervening DNA between the transcription start site and the activator binding sites forms a loop in order to allow the activators to interact with the basal transcription apparatus, either directly or through mediators. If this hypothesis is correct, activation should be sensitive to the presence of intrinsic bends in the intervening DNA. Similarly, the precise helical phasing of such DNA bends and of the activator binding sites relative to the basal promoter should affect the degree of transcription activation. To explore these considerations, we designed transcription templates based on the adenovirus E4 promoter supplemented with upstream Gal4 activator binding sites. Surprisingly, we found that neither insertion of intrinsically curved DNA sequences between the activator binding sites and the basal promoter, nor alteration of the relative helical alignment of the activator binding sites and the basal promoter significantly affected in vitro transcription activation in HeLa cell nuclear extract. In all cases, the degree of transcription activation was a simple inverse function of the length of intervening DNA. Possible implications of these unexpected results are discussed.

Improved quantitation of DNA curvature using ligation ladders.

It is often desirable to estimate accurately the local shape of DNA molecules. Such measurements are useful in understanding the intrinsic contribution of DNA sequence to curvature, as well as in assessing the effects of chemical modifications. We have been investigating the effects of asymmetric phosphate neutralization on DNA shape using the well-characterized ligation ladder approach developed by Crothers and co-workers [D.M. Crothers and J.Drak (1992) Meth. Enzymol.,212, 46-71]. This technique is remarkably sensitive to differences in DNA shape. We now report a general quantitative assay of DNA curvature that we have validated using a set of phased A(5)tract standards. This approach allows simultaneous estimation of helix axis deflection magnitude and direction when a test sequence is monitored in at least three phasings relative to a reference A(5-6)tract in short DNA duplexes. Analysis using this improved approach confirms our published data on DNA curvature due to electrostatic effects.

Hop modulates Hsp70/Hsp90 interactions in protein folding.

Hop is a 60-kDa protein characterized by its ability to bind the two chaperones, hsp70 and hsp90. We have tested the function of Hop using an assay for the refolding of denatured firefly luciferase. We show that Hop is involved in the process of refolding thermally denatured firefly luciferase in rabbit reticulocyte lysate. Hop also stimulates refolding by hsp70 and Ydj-1 in a purified refolding system. Hsp90 can also stimulate refolding, and optimal refolding is observed in the presence of both Hop and hsp90. Similar stimulation was observed when Hop was replaced by its yeast homolog Sti1. In assays of the binding of Hop to hsp70 and hsp90, Hop preferentially forms a complex with ADP-bound hsp70, and this process is unaffected by the presence of hsp90. Hop does not alter the ATPase activity or the rate of ADP dissociation of hsp70. Hop also appears to bind to the ADP-bound form of hsp90, blocking the ATP-dependent conversion of hsp90 to a form capable of interacting with p23. Conversely, once p23 is bound to hsp90, Hop binding is diminished. These results confirm that Hop provides a physical link between hsp70 and hsp90 and also indicate that Hop modulates the activities of both of these chaperone proteins.

Alien hand syndrome: influence of neglect on the clinical presentation of frontal and callosal variants.

Three patients with mesial frontal and extensive callosal lesions due to anterior cerebral artery infarction manifested an alien hand syndrome (AHS) with varied features. Patient 1 with left hemispheric lesion showed right hand's impulsive reaching and grasping and left hand's antagonistic movements to the right (intermanual conflict; IMC). Patients 2 and 3 with right hemispheric lesion manifested a left hemihypokinesia which was thought to have suppressed the frequency and amplitude or even the occurrence of left hand's reaching and grasping. IMC and other left hand's non-antagonistic, irrelevant movements to the right remained. Because the term "IMC" is often misused and not strictly defined, its association with right hand's reaching and grasping is quite uncommon, its significance as a sign of callosal disconnection is not well validated, and because left hand's reaching and grasping tend to be suppressed by motor neglect, a trend may then develop for the right hand to be the sole focus of pathological behaviour in patients with the so-called frontal AHS (Feinberg, Schindler, Flanagan et al., 1992).

Lateralization of affective prosody in brain and the callosal integration of hemispheric language functions.

Although affective prosody appears to be a dominant function of the right hemisphere, its degre of lateralization has not yet been established since various publications have reported affective-prosodic deficits following left brain damage in association with aphasia. This paper explores the mechanisms underlying affective-prosodic deficits following left and right brain damage by testing the ability of subjects to repeat and comprehend affective prosody under progressively reduced verbal-articulatory conditions. The results demonstrate that reducing verbal-articulatory conditions robustly improves the performance of left but not right brain damaged patients, a finding that supports the supposition that affective prosody is strongly lateralized to the right hemisphere. However, the performance of left brain damaged patients was not correlated to the presence, severity, or type of aphasic deficit(s). Based on functional-anatomic correlations for spontaneous affective prosody and affective-prosodic repetition, deep white matter lesions located below the supplementary motor area that disrupt interhemispheric connections coursing through the mid-rostral corpus callosum may contribute to affective-prosodic deficits that are both additive and independent of any aphasic deficits. In light of these and other findings, various anatomical, functional, and maturational hierarchic relationships between the affective-prosodic and verbal-linguistic aspects of language are posited in order to help further explain discrepancies that exist in the literature regarding the neurology of affective prosody.

Dexamethasone suppression test and onset of poststroke depression in patients with ischemic infarction.

BACKGROUND: Studies documenting abnormal results in the 1.0-mg dexamethasone suppression test (DST) and the prevalence of depression in stroke patients are usually accomplished between 1 and 6 months poststroke. One study, however, reported that 27% of patients met DSM-III criteria for major depression and 20% for minor depression 1 to 3 weeks poststroke even though previous research has indicated that the prevalence of poststroke depression was greatest at approximately 6 months. Therefore, we decided to assess DST abnormalities and depression within the first month of stroke. METHOD: Twelve patients with single, computed tomography (CT)-verified, ischemic infarctions were administered the DST at 1 and 3 weeks poststroke. Each patient also received a complete psychiatric evaluation, including a special clinical interview and the 17-item Hamilton Rating Scale for Depression (HAM-D). 3 to 4 weeks poststroke. RESULTS: DST results were abnormal in 75% of the patients at 1 week poststroke and 50% of the patients at 3 weeks poststroke. Those patients whose HAM-D scores revealed more depressive symptoms at 3 to 4 weeks were more likely to evidence abnormal DST results (cortisol nonsuppression). None of the patients, however, met either DSM-III or modified criteria for clinical depression at 3 to 4 weeks. CONCLUSION: Poststroke depression appears to have a delayed clinical onset. Abnormal DST results at 3 weeks poststroke may serve as a potential marker for those patients at risk for developing poststroke depression.

Nonverbal aspects of language.

This article describes the recently discovered language functions of the right hemisphere that involve the (nonverbal) modulation of affective prosody and gestures. The organization of these functions, at a syndomic level, appears to be analogous to the organization of verbal language in the left hemisphere. The relationship of the affective aspects of language and communication with general emotions and the neurology of poststroke depression are discussed also.

Acquired aprosodia in children.

In adults, the affective components of language, including certain aspects of prosody and gesturing, appear to be a dominant function of the right hemisphere. The various combinations of affective processing deficits associated with focal right brain damage are called aprosodias and have functional and anatomical correlates similar to the propositional language deficits associated with aphasias secondary to focal left brain damage. Developmental affective-prosodic deficits have been reported recently in children with congenital or very early right hemisphere injury. We now report two school-aged children with acquired motor-type aprosodias following acute right focal brain injury. Their affective prosody and singing were also analyzed acoustically during the acute and recovery phases of illness. Based on these cases, we propose the term children aprosodia to describe affective-prosodic deficits that result from acquired lesions of the right hemisphere in children.

Crossed aprosodia in strongly dextral patients.

Two strongly right-handed patients with aprosodia following left hemisphere strokes are described. These patients appear to represent the aprosodia analogue of crossed aphasia--crossed aprosodia--and provide further evidence that the organization of the effective components of language is functionally and anatomically similar to the organization of the propositional components of language in the brain. In addition, both patients evidenced "double-crossed" agraphia involving the left hand.