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.

Education research: neurology residency training in the new millennium.

OBJECTIVE: To survey adult neurology program directors (ANPD) to identify their most pressing needs at a time of dramatic change in neurology resident education. METHODS: All US ANPD were surveyed in 2007 using an instrument adjusted from a 1999 survey instrument. The goal was to characterize current program content, the institution and evaluation of the core competencies, program director characteristics, program director support, the institution of work duty hour requirements, resident support, and the curriculum needs of program directors and programs. RESULTS: A response rate of 82.9% was obtained. There is a significant disconnect between administration time spent by ANPD and departmental/institutional support of this, with ANPD spending approximately 35% of a 50-hour week on administration with only 16.7% salary support. Rearrangement of rotations or services has been the most common mode for ANPD to deal with work duty hour requirements, with few programs employing mid level providers. Most ANPD do not feel work duty hour reform has improved resident education. More residents are entering fellowships following graduation than documented in the past. Curriculum deficiencies still exist for ANPD to meet all Neurology Program Requirements, especially for nontraditional neurology topics outside the conventional bounds of clinical neurology (e.g., practice management). Nearly one quarter of neurology residency programs do not have a meeting or book fund for every resident in the program. CONCLUSIONS: Adult neurology program directors (ANPDs) face multiple important financial and organizational hurdles. At a time of increasing complexity in medical education, ANPDs need more institutional support.

Dominant limb motor impersistence associated with callosal disconnection.

Motor impersistence occurs more frequently after right than left hemispheric lesions. Following a callosal lesion, motor impersistence may thus occur more frequently in the right (dominant) than left limb. After an infarction involving the right medial frontal lobe and corpus callosum, a 66-year-old right-handed man demonstrated right limb motor impersistence on bedside evaluation, which was substantiated experimentally. Results demonstrated hemispatial effects with greater impersistence in the neglected (right) space.

Survey of training programs' means for promoting neurology and attracting trainees.

OBJECTIVE: To determine neurology training opportunities available to medical students and to define factors that influence program choice. METHODS: All neurology residency program directors and a random sample of residents were surveyed. Resident questions related to application, interview, and training experience. Directors' questions focused on ways their department generated interest in clinical neurosciences. RESULTS: Medical schools introduce students to clinical neurology primarily through required clerkships. Contact time averages less than 4 weeks and emphasizes inpatient encounters. Preceptorships with neurology faculty do not exist at almost 40% of schools and only 14% have neuroscience tracks. Nearly all residency applicants matched their first or second choice. The majority declined at least one interview and 39% failed to rank at least one site they visited. When choosing where to apply, the programs' reputation and geographic considerations were paramount. When making a rank list, interactions with faculty and residents at interview were most important. Residents generally reported satisfaction with their programs and attribute morale to supportive relationships with faculty and residents. CONCLUSIONS: Neurology programs may be able to enhance students' impression of neurology through changes in their clinical experience and development of venues for more meaningful relationships with faculty. Attention to the residents' personal needs may increase the likelihood of matching the best available candidates and ensuring their satisfaction.

The Character-line Bisection Task: a new test for hemispatial neglect.

A failure to report or respond to stimuli presented in a portion of space is termed hemispatial neglect. Line bisection and line cancellation are two of the tests used most commonly to assess for neglect. Perhaps, because neglect can be induced by a variety of deficits, neither of these tests used alone is as sensitive as both used together. Hence, the primary purpose of this study was to assess the sensitivity, reliability and validity of a new test called the Character-line Bisection Task (CLBT) that combines features of both the bisection and cancellation tests. Since local attention and language are primarily mediated by and activate the left hemisphere, our second goal was to learn if the CLBT and especially the letter version induce a greater rightward bias than the solid-line bisection task. Eighty patients with acute right hemisphere stroke and 81 controls performed the CLBT that consists of two subtests, the Letter-line and Star-line Bisection tasks. All subjects also completed four conventional tests for neglect (Standard solid-line bisection, line cancellation, Star Cancellation, and figure copying). In the bisection tasks both patients and controls bisected to the right with the CLBT than with the solid-line bisection task, suggesting the CLBT induces asymmetrical hemispheric activation. This enhanced rightward deviation with the CLBT was the same for the Letter-line and Star-line Bisection tasks. In regard to sensitivity, we defined the presence of neglect syndrome based on a total score derived from performance of controls on all six tests. This total score detected 55 (68.8%) patients with neglect. Within this group, the Letter-line and Star-line tasks diagnosed neglect in 50 and 48 patients, respectively, resulting in the highest sensitivities (90.9, 87.3%) of the six tests. Thus, the CLBTs demonstrated higher sensitivities than the other commonly used neglect tests and these new tests can be useful for the detection and quantification of unilateral neglect.

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.

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.

Sneddon's syndrome: a cause of cognitive decline in young adults.

OBJECTIVE: To review the clinical, psychometric, laboratory, and radiologic findings of 6 patients with Sneddon's syndrome (SS) who presented with cognitive dysfunction rather than stroke. DESIGN AND METHODS: Case series. All patients fulfilled were diagnosed as SS based on the co-occurrence of livedo racemosa and neurologic disease. Patients presenting with clinical stroke were excluded. RESULTS: Patients presented with cognitive complaints at an early age and all noted skin lesions from 6 months to 10 years before onset of cognitive symptoms. Associated systemic disorders included hypertension and seizures. Laboratory evidence of a hypercoagulable condition was identified in 4 of 6 cases. Brain MRI scans demonstrated atrophy, especially in parieto-occipital regions and cerebral blood flow on brain SPECT scan was reduced in a similar distribution. CONCLUSION: Patients with SS can develop dementia without antecedent clinical stroke. While the specific pathogenic mechanism of dementia in SS remains speculative, the disease predominantly injures brain tissue in vascular "watershed" territories.

Contralesional directional hypermetria associated with line bisection-specific ipsilesional neglect.

Patients with contralesional neglect from right hemisphere injuries often fail to be aware of or respond to visual stimuli in the left hemispace. In contrast, other patients with right hemisphere damage rarely demonstrate behavior consistent with task-specific ipsilesional neglect (IN). We performed a series of experiments in a patient with IN on a line bisection task after a right frontal infarct. When asked to perform horizontal limb movements without visual feedback, the patient showed a leftward directional hypermetria. Similar performance was also observed during a representational production of a given distance without sensory input. These results suggest that IN is induced by a directional hypermetria resulting from disruption of the motor-intentional system.

Effects of bromocriptine in a patient with crossed nonfluent aphasia: a case report.

OBJECTIVE: Because studies have shown some positive effects of the dopaminergic agent bromocriptine for improving verbal production in patients with nonfluent aphasia, we examined its effect in a patient with an atypical form of crossed nonfluent aphasia from a right hemisphere lesion. DESIGN: Open-label single-subject experimental ABAB withdrawal design. PATIENT: A right-handed man who, after a right frontal stroke, developed nonfluent aphasia, emotional aprosodia, and limb apraxia. INTERVENTION: Escalating doses up to 20mg of bromocriptine in 2 separate phases. MAIN OUTCOME MEASURES: We measured verbal fluency (words/min in discourse, Thurstone letter fluency), expression of emotional prosody, and gesture production. RESULTS: The patient showed substantial improvement in both verbal fluency measures and no significant improvement in gesture or emotional prosody. Verbal fluency improvements continued in withdrawal phases. CONCLUSIONS: Our results are less likely caused by practice or spontaneous recovery because we observed little improvement in emotional prosody and gesture tasks. Verbal fluency improvements during treatment and withdrawal phases suggest that the effects of bromocriptine may be long-lasting in its influence on the neural networks subserving verbal initiation.

Line quadrisection errors in normal subjects.

Many studies have investigated line bisection behaviors in normal individuals and patients with hemispatial neglect. However, little is known about what happens when subjects attempt to fractionate line into more than two equal components (e.g., line quadrisection). Thirty right handed normal subjects were asked to place a mark either 25% (left quadrisection) or 75% (right quadrisection) of the distance along on a 240 mm line. On average, they placed the left quadrisection mark significantly to the left (- 4.2+/-6.7 mm) from the true quadrisection point but they were relatively accurate on the right quadrisection task (1.0+/-6.7 mm). However, comparison of actual quadrisection performances with those of expected performance based on subjective midpoint disclosed that both right and left quadrisection marks deviate toward each end of the line. Individual data analysis also support this trend because majority of subjects showed the lateral deviation in either or both quadrisection tasks. Therefore, in the left quadrisection task the pseudoneglect (leftward bias) in bisection and the lateral bias are additive, resulting in a robust left lateral deviation, whereas in the right quadrisection, these two biases nullify each other, resulting in accurate performance.

Ipsilesional versus contralesional neglect depends on attentional demands.

Right hemisphere injuries often produce contralesional hemispatial neglect (CN). In contrast to CN, some patients with right hemisphere damage can also show so-called ipsilesional neglect (IN). Previous reports found that patients tend to show IN on line bisection tasks but CN on other tasks such as target cancellation. To learn why these two tasks induce different spatial biases in patients with right hemisphere injury, conventional (i.e. solid) line bisection was compared with two novel bisection tasks consisting of horizontally aligned strings of characters. The subjects' task was to mark a target character that was at or closest to the true midpoint of the simulated line. Four of the 5 patients showed a dissociation whereby IN occurred for solid lines while CN was observed on character lines. The two patients assessed with an antisaccade paradigm showed a "visual grasp" for leftward stimuli. The present results suggest that neglect on line bisection may reflect two opposing forces, an approach behavior or "visual grasp" toward left hemispace and an attentional bias toward right hemispace.

Conceptual apraxia in probable Alzheimer's disease as demonstrated by the Florida Action Recall Test.

Patients with probable Alzheimer's disease (AD) often have difficulties associated with semantic knowledge. Therefore, conceptual apraxia, a defect of action semantics and mechanical knowledge, may be an early sign of this disease. The Florida Action Recall Test (FLART), developed to assess conceptual apraxia, consists of 45 line drawings of objects or scenes. The subject must imagine the proper tool to apply to each pictured object or scene and then pantomime its use. Twelve participants with Alzheimer's disease (NINCDS-ADRDA criteria) and 21 age- and education-matched controls were tested. Nine Alzheimer's disease participants scored below a 2-standard-deviation cutoff on conceptual accuracy, and the three who scored above the cutoff were beyond a 2-standard-deviation cutoff on completion time. The FLART appears to be a sensitive measure of conceptual apraxia in the early stages of Alzheimer's disease.

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.

Alterations in the functional anatomy of reading induced by rehabilitation of an alexic patient.

OBJECTIVE: The goal of the study was to measure regional cerebral blood flow (CBF) in a stroke patient with acquired phonologic alexia before and after therapy using the Auditory Discrimination in Depth (ADD) program. BACKGROUND: After rehabilitation of acquired language disorders, functional imaging can detect activity in brain structures that do not mediate language during normal conditions. However, the anatomic correlates of recovery or rehabilitation from acquired reading disorders are largely undescribed. METHODS: Cerebral SPECT scans were obtained before and after the intervention with Auditory Discrimination in Depth. The first and last activation tasks necessitated that the patient read nonwords during radionuclide uptake. Another (control) scan was acquired during performance of a nonlinguistic task shortly before the end of the ADD program. RESULTS: Before therapy, the right hemisphere was inactive during nonword reading relative to the nonlinguistic task. After treatment, nonword reading increased cerebral blood flow in the posterior right perisylvian cortices homologous to the dominant hemisphere areas engaged by reading. Brain activity also increased in Broca's area of both hemispheres. CONCLUSIONS: Dyslexia rehabilitation may facilitate right-hemisphere cortical networks in the reading process and increase engagement of phonologic articulatory motor representations in Broca's area.

Cognitive impairment in elderly who are not yet demented.

Patients with neuropathological changes of Alzheimer disease may not be demented during initial evaluation of memory disturbance. Understanding current issues regarding the patient with incipient degenerative dementia should help identify those at greatest risk for progression and may help delay onset of symptoms.