Brain structure and verbal function across adulthood while controlling for cerebrovascular risks.

The development and decline of brain structure and function throughout adulthood is a complex issue, with cognitive aging trajectories influenced by a host of factors including cerebrovascular risk. Neuroimaging studies of age-related cognitive decline typically reveal a linear decrease in gray matter (GM) volume/density in frontal regions across adulthood. However, white matter (WM) tracts mature later than GM, particularly in regions necessary for executive functions and memory. Therefore, it was predicted that a middle-aged group (MC: 35-45 years) would perform best on a verbal working memory task and reveal greater regional WM integrity, compared with both young (YC: 18-25 years) and elder groups (EC: 60+ years). Diffusion tensor imaging (DTI) and magnetoencephalography (MEG) were obtained from 80 healthy participants. Objective measures of cerebrovascular risk and cognition were also obtained. As predicted, MC revealed best verbal working memory accuracy overall indicating some maturation of brain function between YC and MC. However, contrary to the prediction fractional anisotropy values (FA), a measure of WM integrity, were not greater in MC (i.e., there were no significant differences in FA between YC and MC but both groups showed greater FA than EC). An overall multivariate model for MEG ROIs showed greater peak amplitudes for MC and YC, compared with EC. Subclinical cerebrovascular risk factors (systolic blood pressure and blood glucose) were negatively associated with FA in frontal callosal, limbic, and thalamic radiation regions which correlated with executive dysfunction and slower processing speed, suggesting their contribution to age-related cognitive decline. Hum Brain Mapp 38:3472-3490, 2017. © 2017 Wiley Periodicals, Inc.

Characterization of a normal control group: are they healthy?

We examined the health of a control group (18-81years) in our aging study, which is similar to control groups used in other neuroimaging studies. The current study was motivated by our previous results showing that one third of the elder control group had moderate to severe white matter hyperintensities and/or cortical volume loss which correlated with poor performance on memory tasks. Therefore, we predicted that cardiovascular risk factors (e.g., hypertension, high cholesterol) within the control group would account for significant variance on working memory task performance. Fifty-five participants completed 4 verbal and spatial working memory tasks, neuropsychological exams, diffusion tensor imaging (DTI), and blood tests to assess vascular risk. In addition to using a repeated measures ANOVA design, a cluster analysis was applied to the vascular risk measures as a data reduction step to characterize relationships between conjoint risk factors. The cluster groupings were used to predict working memory performance. The results show that higher levels of systolic blood pressure were associated with: 1) poor spatial working memory accuracy; and 2) lower fractional anisotropy (FA) values in multiple brain regions. In contrast, higher levels of total cholesterol corresponded with increased accuracy in verbal working memory. An association between lower FA values and higher cholesterol levels were identified in different brain regions from those associated with systolic blood pressure. The conjoint risk analysis revealed that Risk Cluster Group 3 (the group with the greatest number of risk factors) displayed: 1) the poorest performance on the spatial working memory tasks; 2) the longest reaction times across both spatial and verbal memory tasks; and 3) the lowest FA values across widespread brain regions. Our results confirm that a considerable range of vascular risk factors are present in a typical control group, even in younger individuals, which have robust effects on brain anatomy and function. These results present a new challenge to neuroimaging studies both for defining a cohort from which to characterize 'normative' brain circuitry and for establishing a control group to compare with other clinical populations.

Development and decline of memory functions in normal, pathological and healthy successful aging.

Many neuroimaging studies of age-related memory decline interpret resultant differences in brain activation patterns in the elderly as reflecting a type of compensatory response or regression to a simpler state of brain organization. Here we review a series of our own studies which lead us to an alternative interpretation, and highlights a couple of potential confounds in the aging literature that may act to increase the variability of results within age groups and across laboratories. From our perspective, level of cognitive functioning achieved by a group of elderly is largely determined by the health of individuals within this group. Individuals with a history of hypertension, for example, are likely to have multiple white matter insults which compromise cognitive functioning, independent of aging processes. The health of the elderly group has not been well-documented in most previous studies and elderly participants are rarely excluded, or placed into a separate group, due to health-related problems. In addition, recent results show that white matter tracts within the frontal and temporal lobes, regions critical for higher cognitive functions, continue to mature well into the 4th decade of life. This suggests that a young age group may not be the best control group for understanding aging effects on the brain since development is ongoing within this age range. Therefore, we have added a middle-age group to our studies in order to better understand normal development across the lifespan as well as effects of pathology on cognitive functioning in the aging brain.

Different strategies for auditory word recognition in healthy versus normal aging.

To explore the effects of commonly encountered pathology on auditory recognition strategies in elderly participants, magnetoencephalographic (MEG) brain activation patterns and performance were examined in 30 elderly [18 controls and 12 elderly with mild cognitive impairment (MCI) or probable Alzheimer's disease (AD)]. It was predicted that participants with known pathology would reveal different networks of brain activation, compared to healthy elderly, which should correlate with poorer performance. Participants heard a list of words representing common objects, twice. After 20 minutes a list of new and old words was presented and participants judged whether each word was heard earlier. MEG responses were analyzed using a semiautomated source modeling procedure. A cluster analysis using all subjects' MEG sources revealed three dominant patterns of activity which correlated with IQ and task performance. The highest performing group revealed activity in premotor, anterior temporal, and superior parietal lobes with little contribution from prefrontal cortex. Performance and brain activation patterns were also compared for individuals with or without abnormalities such as white matter hyperintensities and/or volume reduction evidenced on their MRIs. Memory performance and activation patterns for individuals with white matter hyperintensities resembled the group of MCI/AD patients. These results emphasize the following: (1) general pathology correlates with cognitive decline and (2) full characterization of the health of elderly participants is important in studies of normal aging since random samples from the elderly population are apt to include individuals with subclinical pathology that can affect cognitive performance.

Nocardial cerebral abscess in the acquired immunodeficiency syndrome.

Nocardial cerebral abscess is an unusual neurologic manifestation of the acquired immunodeficiency syndrome. A 20-year-old woman with the acquired immunodeficiency syndrome presented with headache and fever. Nocardia asteroides was cultured from a stereotaxic brain biopsy specimen. Despite antibiotic therapy to which the pathogen was sensitive, resolution of the abscess followed only after complete surgical excision.

Diffusion-weighted magnetic resonance imaging in probable Creutzfeldt-Jakob disease: a clinical-anatomic correlation.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a rare transmissible disease that typically causes a rapidly progressive dementia and leads to death in less than 1 year. Although a few anecdotal reports suggest that diffusion-weighted magnetic resonance imaging may help substantiate premortem diagnosis of CJD, detailed correlation between radiographic data and clinical, electrophysiologic, and metabolic parameters is not available. METHODS: Signal abnormalities on diffusion-weighted images in 3 consecutive patients with probable CJD were correlated with psychometric features, electroencephalographic findings, and functional images with either positron emission tomography or single photon emission computed tomography. RESULTS: Focality of abnormalities on diffusion-weighted image, not apparent on routine magnetic resonance images, correlated closely with clinical manifestations of CJD. The topographic distribution of signal abnormality on diffusion-weighted image corresponded with abnormal metabolism or perfusion on positron emission and single photon emission computed tomographic scans. In 2 cases, the laterality of diffusion abnormalities correlated with periodic sharp wave activity on electroencephalograms. CONCLUSION: These findings extend previous observations that suggested a diagnostic and localizing utility of diffusion-weighted imaging in CJD.

Controlled trial of N-acetylcysteine for patients with probable Alzheimer's disease.

The antioxidant N-acetylcysteine (NAC) or placebo was administered in a double-blind fashion to patients who met National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable AD. Testing for efficacy occurred after 3 and 6 months of treatment. Comparison of interval change favored NAC treatment on nearly every outcome measure, although significant differences were obtained only for a subset of cognitive tasks.

Anosognosia for hemiplegia: an electrophysiologic investigation of the feed-forward hypothesis.

The cause of anosognosia for hemiplegia (AHP) remains unclear. Weakness is detected when there is a mismatch between the expectancy of movement and the sensory perception of movement. The feed-forward hypothesis of AHP posits that there is a failure of detection because there is a loss of motor intention and expectancy of movement. We tested motor intention by measuring the activation of proximal muscles (pectoralis majoris) while subjects squeezed a dynamometer with each hand. We tested a group of normal controls, a group of patients with hemiparesis, a patient with neglect, a patient with resolved AHP, and a patient with persistent AHP. The patient with AHP did not contract either of his pectoralis muscles when asked to squeeze with his contralesional, paretic hand, yet he contracted both of them when squeezing the dynamometer with his ipsilesional hand. Normal controls, hemiparetic controls, and the patient with hemispatial neglect contracted both pectorales when asked to squeeze with each hand. The pattern of activation seen in the patients with persistent AHP and resolved AHP demonstrates a loss of motor intention and lends support to the feed-forward hypothesis of AHP.

Anosognosia during intracarotid barbiturate anesthesia: unawareness or amnesia for weakness.

Previous studies have demonstrated asymmetric hemispheric contributions to deficit awareness during hemisphere inactivation with intracarotid barbiturate infusion (Wada studies). These observations provide insight into the neuropsychological basis of anosognosia for hemiparesis (AHP), arguing against earlier explanations based upon psychological denial, global cognitive disturbance, or emotional indifference. Although prior Wada studies equated AHP after the procedure with AHP during the period of deficit, a selective memory failure could also account for these findings. We, therefore, assessed the occurrence of AHP during and after right-hemisphere inactivation in a group of epilepsy patients undergoing preoperative Wada testing. Because aphasia obscures assessment of deficit awareness during left carotid studies, we compared the frequency of AHP between right- and left-hemisphere inactivation only after recovery. As noted in earlier reports, AHP was present significantly more often after right- than left-hemisphere inactivation. The proportions of subjects with AHP during right-hemisphere anesthesia compared with the proportion of subjects with AHP after the procedure were statistically equivalent, suggesting that the AHP observed after right-hemisphere anesthesia results from true failure of deficit awareness rather than inability to recall the deficit.

Ventral tegmental area injury and frontal lobe disorder.

A patient developed acute behavioral changes implicating frontal-executive dysfunction. His clinical signs suggested mesencephalic injury, and a cranial MRI scan showed an abnormality restricted to a small region of the ventral midbrain. We suggest that the patient's behavioral disorder originated from disruption of the ventral tegmental area or it projections, structures that influence frontal brain processes via the mesocortical dopamine tract.

Aseptic meningitis following cardiac transplantation: clinical characteristics and relationship to immunosuppressive regimen.

Neurologic disorders are uncommon but alarming complications of cardiac transplantation. Of 29 patients from the Utah Cardiac Transplant Program (UCTP) who had lumbar puncture because of change in neurologic function, or to assess fever of uncertain etiology, CSF pleocytosis was present in 14 patients, 4 of whom had an active infectious process involving the nervous system. In 10 other patients, CSF pleocytosis with negative cultures appeared following treatment with OKT3 monoclonal antibody. The most prominent clinical signs of this aseptic meningitis syndrome are fever and transient cognitive dysfunction.

Cerebrovascular syndromes following cardiac transplantation.

Between 1985 and 1990, there were 275 orthotopic cardiac transplantations performed on 263 patients. To determine the frequency and define the clinical spectrum of cerebrovascular disease among these patients, we followed them over an average period of 18.5 months (range, 1 to 59 months). Cerebrovascular disorders developed in 24 of 263 patients. We established and classified stroke etiology directly related to transplant procedures or therapies in 13 cases. Nine of 11 cases not directly attributable to transplantation had presumed thromboembolic ischemic events. While stroke most commonly results from conditions unique to heart transplant patients, some disorders may develop from vascular conditions that antedate transplantation.

Spatial bias: attentional and intentional influence in normal subjects.

Normal subjects often demonstrate a spatial bias on line bisection (LB) and cancellation (CA) tasks. We wanted to learn if horizontal spatial bias found in normal subjects may be dissociable into sensory-attentional (ATT) and motor-intentional (INT) subgroups similar to those described in brain-injured patients with spatial neglect. We studied the influence of ATT and INT factors on the spatial bias observed in normal subjects using a new technique that uncouples the direction of action from the direction of attention. This technique also allowed us to test both LB and CA tasks on the same individuals. Our results show that ATT bias significantly influenced performance on an LB task, whereas performance on a CA task was influenced by biases in both the ATT and INT systems. In addition, the overall bias on these two tasks reflects an interaction between the biases induced by the ATT and INT systems that may be in the same or different directions.

Dissociation of anosognosia for hemiplegia and aphasia during left-hemisphere anesthesia.

The stroke literature indicates that the explicit denial of hemiplegia, a form of anosognosia, is associated more commonly with right- than left-hemisphere lesions. Some investigators have suggested that this asymmetry may be an artifact and that the aphasia that often accompanies left-hemisphere dysfunction may mask some instances of anosognosia. Mechanisms suggested for anosognosia have been either "global" or "modular" in nature. Mechanisms posited in global explanations include psychological denial and general mental deterioration; modular explanations include feedback and feedforward theories. Videotapes of 54 patients with medically intractable seizures who had selective barbiturate anesthesia (Wada test) as part of their evaluation for seizure surgery were assessed for anosognosia of hemiplegia and aphasia after hemispheric anesthesia had worn off. The results suggest that, although aphasia may confound the reported rate of anosognosia for hemiplegia following left-hemisphere dysfunction, the frequency of anosognosia for hemiplegia is still higher with right- than left-side dysfunction. Anosognosia for hemiplegia and aphasia were dissociable, providing support for the postulate that awareness of dysfunction is mediated by a modular system.

Anosognosia for hemiplegia: test of the personal neglect hypothesis.

OBJECTIVE: To test the personal neglect hypothesis of anosognosia for hemiplegia (AHP) using selective anesthesia of the right hemisphere. BACKGROUND: Although AHP most commonly follows right-hemisphere injury, the mechanism responsible for this hemispheric asymmetry has not been entirely elucidated. Because denial of ownership of parts on the contralesional side of one's body (personal neglect) also more commonly follows right-hemisphere damage, personal neglect might account for AHP. DESIGN/METHODS: AHP and personal neglect were assessed in 20 patients during right intracarotid barbiturate infusion. With vision restricted to the central field, patients were randomly presented with either their own hands or those of examiners matched for size, gender, and race. Patients were asked to read numbers placed on the hands to establish that hemianopia did not confound hand recognition. RESULTS: All subjects correctly read the numbers on all trials. Only 4 of 20 subjects misidentified their hands and denied awareness of left hemiplegia. All errors occurred for the left hand, indicating personal neglect. However, the 16 subjects without personal neglect also demonstrated AHP. CONCLUSION: Because AHP and personal neglect are dissociable, personal neglect cannot completely account for AHP.

Diffusion-weighted MRI in vascular dementia.

OBJECTIVE: To examine the ability of diffusion-weighted MRI (DWI) to detect ongoing cerebral ischemia in patients with vascular dementia (VaD). BACKGROUND: VaD due to small-vessel disease results from the cumulative impact of recurrent cerebral ischemia. Cerebral ischemia may produce clinical manifestations, producing the "stepwise" decline characteristic of VaD. Conventional MRI can detect small regions of ischemic damage but cannot determine when injury developed. In contrast, DWI shows sensitivity in detecting ischemia of recent onset. DESIGN/METHODS: Patients with VaD (n = 30) underwent DWI in addition to standard MRI sequences. Patients were divided into two groups according to the presence of new focal deficits or mental change within 10 days before MRI. In 10 patients of positive group, symptomatic neurologic decline occurred an average of 4.2 days before the imaging procedure. RESULTS: Seven (70%) of 10 patients with a recent neurologic event showed 15 new regions of signal abnormality on DWI. The anatomic distribution of signal change could account for the patients' new symptoms or signs in all but one patient. Similar signal abnormality was detected in 4 (20%) of 20 patients without a recent neurologic event. New foci of altered signal intensity were distinguishable from prior injuries only with DWI. No significant difference was found between patients with and without DWI abnormalities in gender, age, Mini-Mental State Examination score, Hachinski Ischemic Score, vascular risk factors, or severity of increased signal on T2-weighted MRI scans. CONCLUSION: Small foci of abnormal signal on diffusion-weighted MRI (DWI), presumably representing recent small infarcts, occur often in vascular dementia (VaD) from small-vessel disease, even in patients without a recent "stepwise decline." The results suggest that DWI might be used to monitor VaD progression in future observational and interventional studies of this disorder.

Motor perseverative behavior on a line cancellation task.

OBJECTIVES: To study the behavioral and neuroanatomic characteristics of perseverative behavior encountered on a target cancellation task in patients with neglect. METHODS: Motor perseverative behavior during line cancellation task was evaluated retrospectively in 60 patients with left hemispatial neglect from right hemispheric stroke. RESULTS: More than 30% of the patients (21 of 60) showed perseveration, manifested as either repetitive cancellation of the same target (18/21) or cancelling extra lines created by the patients themselves (3/21). Neglect severity correlated positively with the frequency of perseverative errors. Perseveration was most prominent in the rightmost portion of the array. Anterior lesions or massive lesions involving anterior and posterior regions were more likely to be associated with motor perseveration than were lesions restricted to posterior areas. CONCLUSIONS: Although the mechanism of motor perseveration remains to be elucidated, our findings suggest that the combination of aberrant approach behaviors associated with frontal lobe injury and an attentional or intentional bias toward the rightsided targets might explain the behavior.

Ipsilateral neglect during intracarotid amobarbital test.

Neglect usually occurs in the space contralateral to brain injury. Recent studies describe ipsilateral neglect (IN) whereby patients with right hemisphere injury misbisect lines to the left of midpoint. IN usually develops after contralateral neglect (CN) resolves. We observed whether IN occurs during intracarotid amobarbital infusion. After clinical testing but before resolution of barbiturate effect, 20 right-handed subjects bisected lines until baseline performance returned. More than half (12 of 20) showed transient CN. IN occurred in 40% (8 of 20) of patients, always during the recovery stage of anesthesia, and most frequently followed initial CN.

Ideomotor limb apraxia in Huntington's disease: implications for corticostriate involvement.

Ideomotor limb apraxia, a disorder of goal-directed movement, has been attributed to lesions in the frontal and parietal lobes, but the role of subcortical structures is less certain. In order to determine its prevalence in a disorder affecting the basal ganglia and corticostriatal connections, we examined imitation of hand gestures in Huntington's disease (HD) patients. We also assessed the relationship between apraxia and cognitive and motor dysfunction in an effort to better understand the neural underpinnings of apraxia in HD. If damage restricted to the basal ganglia produces ideomotor limb apraxia, then we would expect to find evidence of apraxia in patients who were early in the disease course when selective striatal damage is most common. Such a pattern, however, was not found in our sample. Instead, patients with greater neurological impairment and with a longer duration of disease were more likely than less affected patients to demonstrate apraxia. Apraxia was not related to severity of chorea, but was associated with greater impairment in eye movements, voluntary movements, and verbal fluency. These findings suggest that apraxia in HD results from damage to the corticostriate pathways and the basal ganglia rather than from damage restricted to the basal ganglia.

Attentional bias in normal subjects performing visual and tactile radial line bisections.

Misbisection of lines is thought to represent an attentional bias. When radial lines (intersection of the midsagittal and transverse planes) are presented below eye level, normal subjects are biased toward far peripersonal space in the visual modality and to near peripersonal space in the tactile modality. These errors may be related to a body centered, a retinotopic, or an object centered attentional bias. The purpose of this study was to contrast the body centered and retinotopic-objective centered hypotheses by having 12 normal subjects perform visual and tactile bisections of radial lines that are above and below eye level. The top of the page, which may be defined by retinotopic or object centered coordinates, contains the portion of the line that is most distant from our bodies when the page is below eye level. However, above eye level, the top of a radial line would be the portion of the page that is most proximal to our bodies. We observed that when stimuli are presented below eye level, normal subjects have a visual bias toward far peripersonal space or the top of the page or both, and have a tactile bias in the opposite direction. In the above eye position we found no overall bias in either modality. Because above eye level the body centered bias should have remained the same but the retinotopic or object centered bias should have reversed, our results suggest that the body and object centered or retinotopic biases, which are oriented in opposite directions, nullified each other.