Neuropsychiatric assessment of patients with hyperkinetic and hypokinetic movement disorders.

BACKGROUND: The role of the basal ganglia in neuropsychiatric behaviors is not well known. Anatomical, neurophysiological, and neurochemical evidence supports the notion of parallel direct and indirect basal ganglia thalamocortical motor systems, the differential involvement of which accounts for the hypokinesia or hyperkinesia observed in basal ganglia disorders. OBJECTIVES: To evaluate the neuropsychiatric manifestations of patients with a hyperkinetic movement disorder, such as Huntington disease (HD), vs a hypokinetic disease, such as progressive supranuclear palsy (PSP). To verify if patients with HD show a greater frequency of hyperactive behaviors (eg, agitation, irritation, euphoria, or anxiety), while those with PSP exhibit hypoactive behaviors (eg, apathy). PATIENTS AND METHODS: The Neuropsychiatric Inventory, a tool with established validity and reliability, was administered to 29 patients with HD (mean +/- SD age, 43.8 +/- 2 years) and 34 with PSP (mean +/- SD age, 66.6 +/- 1.2 years), matched for education, symptom duration, and overall degree of dementia. RESULTS: There was no difference between the groups in the total Neuropsychiatric Inventory scores. However, there was a double dissociation in behaviors: patients with HD exhibited significantly more agitation (45%), irritability (38%), and anxiety (34%), whereas patients with PSP exhibited more apathy (82%) (P < .01). Euphoria was present only in patients with HD. CONCLUSIONS: We found that patients with HD manifested predominantly hyperactive behaviors, while those with PSP manifested hypoactive behaviors. Based on our findings and the anatomical lesions known to occur in these disorders, we suggest that the hyperactive behaviors in HD are secondary to an excitatory subcortical output through the medial and orbitofrontal cortical circuits, while in PSP the hypoactive behaviors are secondary to hypostimulation.

The spectrum of behavioral responses to cholinesterase inhibitor therapy in Alzheimer disease.

BACKGROUND: Behavioral abnormalities are common in Alzheimer disease (AD); cholinergic treatment reduces the behavioral disturbances of some patients with AD. Characterizing the pretreatment profile of patients who are likely to respond to cholinergic therapy will aid the efficient use of clinical resources. OBJECTIVE: To determine the baseline behavioral profile for 86 patients with AD treated with the cholinesterase inhibitor donepezil hydrochloride. METHODS: Open-label retrospective study of treatment-related behavioral assessments. Based on previous double-blind placebo-controlled experience using the Neuropsychiatric Inventory (NPI), patients were divided into responder (> or =4-point total NPI score decrease, indicating improvement), unchanged (+/-3-point total NPI score change), or nonresponder (> or =4-point total NPI score increase, indicating worsening) groups. The Mini-Mental State Examination assessed cognitive response. RESULTS: Behavioral improvement was seen in 35 patients (41%), worsening in 24 (28%), and no change in 27 (31%). Comparison of profiles in behavioral responders vs nonresponders revealed significantly worse delusions (P = .04), agitation (P = .04), depression (P = .006), anxiety (P = .02), apathy (P = .003), disinhibition (P = .02), and irritability (P<.001) at baseline in responders. Five behaviors changed significantly from baseline, improving for the responders and worsening for the nonresponders: delusions (P = .003 for nonresponders, P = .004 for responders), agitation (P = .01), anxiety (P = .006 for nonresponders, P = .004 for responders), disinhibition (P = .02 for nonresponders, P = .05 for responders), and irritability (P = .003 for nonresponders, P = .001 for responders). The behavioral changes were dose dependent. Cognition did not change significantly with donepezil treatment within any group. CONCLUSIONS: Donepezil has psychotropic properties, and pretreatment behaviors help predict patients' responses to treatment.

Left frontotemporal hypoperfusion is associated with aggression in patients with dementia.

BACKGROUND: Aggressive behavior is common in patients with dementia. Temporolimbic and prefrontal cortical lesions can produce pathological aggression; however, involvement of these structures has not been established in aggressive patients with dementia. OBJECTIVE: To study the relation between regional brain perfusion and aggressive behavior in patients with dementia. METHODS: We compared the pattern of regional cerebral perfusion determined with technetium Tc 99m-labeled hexamethylpropelene amineoxime single photon emission computed tomography in 2 groups of 10 patients with dementia with and without aggression, that were comparable for demographic factors, severity of cognitive impairments, and other behavioral symptoms as measured by the Neuropsychiatric Inventory. RESULTS: Patients with aggression revealed significant (P<.001) hypoperfusion in the left anterior temporal cortex; additional bilateral dorsofrontal and right parietal cortex were also found to be significantly hypoperfused. CONCLUSION: These results indicated an association between aggression and decreased perfusion in the left anterior temporal cortex. Arch Neurol. 2000.

Behavioral disorders in Alzheimer disease: a transcultural perspective.

OBJECTIVES: To compare 2 samples of patients with Alzheimer disease (AD), from Italy and the United States, in order to determine transcultural differences in the manifestation of noncognitive symptoms. To analyze the concurrent validity, internal consistency reliability, between-rater reliability, and test-retest reliability of the Neuropsychiatric Inventory Scale (NPI). METHODS: The NPI was given to 50 Italian and 50 US patients with AD. To demonstrate the validity and reliability of the Italian version of the instrument, several different methods of analysis were used. The total score on the NPI and the score of single items in the different stages of the disease were compared in the 2 samples of patients. RESULTS: A high level of internal consistency reliability was confirmed, the between-rater reliability was very high, and the test-retest reliability was significantly correlated. Apathy was the most frequently recorded behavior in the Italian sample. Five of 10 NPI item scores showed a significant relation with the Mini-Mental State Examination scores in both samples. The Italian patients showed an increasing and significantly higher mean NPI total score at all levels of dementia severity when compared with the US patients. The scores on some NPI subscales, such as apathy, aberrant motor behavior, disinhibition, and agitation, were significant higher in Italian patients at different levels of severity covarying with educational level. CONCLUSIONS: These results indicate that NPI is a reliable instrument with which to study transcultural differences in the presentation of neuropsychiatric disturbances in patients with AD. The described similar pattern of behaviors between Italians and US patients with AD suggests a biological origin of the disorders. However, cultural influences must be taken in account when the focus of the study is on psychopathological aspects of dementia.

Subcortical aphasia: the core profile of capsulostriatal infarction.

There has been disagreement about the precise characteristics of "subcortical aphasia." We evaluated 14 patients with aphasia after subcortical lesions and controlled for duration, general anatomic site of lesions (capsulostriatal only), and etiology. The clinical profiles of the patients were quite similar, varying in severity in rough proportion to lesion size and varying in quality in proportion to anterior paraventricular extent. Large lesions were associated with impaired "executive" and "generative" language functions. Similar aphasia profiles in patients with deep frontal and paraventricular white matter lesions suggest that damage to a frontal-caudate functional system underlies a "core" aphasia profile in these patients.

The spectrum of behavioral changes in Alzheimer's disease.

We investigated the range of behavioral abnormalities in patients with Alzheimer's disease (AD) compared with normal age-matched control subjects. The range of behavioral disturbances manifested and the relationship between specific abnormalities with the level of cognitive impairment have not been established. Fifty consecutive outpatients with mild (n = 17), moderate (n = 20), and severe (n = 13) AD and 40 age-matched normal controls were evaluated for behavioral abnormalities occurring in the month preceding the interview. The caregivers of the patients and the spouses of the control subjects were interviewed with the Neuropsychiatric Inventory (NPI). The frequency and severity of the following 10 behaviors were assessed: delusions, hallucinations, agitation, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability, and aberrant motor behavior. Correlations among these 10 behaviors and their relationship with cognitive impairment were also investigated. Eighty-eight percent of AD patients had measurable behavioral changes. All 10 behaviors were significantly increased in the AD patients compared with normal subjects. The most common behavior was apathy, which was exhibited by 72% of patients, followed by agitation (60%), anxiety (48%), irritability (42%), dysphoria and aberrant motor behavior (both 38%), disinhibition (36%), delusions (22%), and hallucinations (10%). Agitation, dysphoria, apathy, and aberrant motor behavior were significantly correlated wit cognitive impairment.

Neuropsychiatric aspects of progressive supranuclear palsy.

Administering the Neuropsychiatric Inventory (NPI), we examined the behavioral symptoms of 22 patients with progressive supranuclear palsy (PSP), 50 patients with Alzheimer's disease, and 40 controls. PSP patients exhibited apathy (91%), disinhibition (36%), dysphoria (18%) and anxiety (18%), but rarely (< 9%) irritability, abnormal motor behaviors, or agitation. Apathy in PSP was significantly associated with executive dysfunction. The presence of high apathy and low agitation and anxiety scale scores correctly identified the PSP patients 85% of the time. Evaluating the behavioral abnormalities of patients with neurodegenerative disorders will aid diagnosis and facilitate management.

Alien hand syndrome: interhemispheric motor disconnection due to a lesion in the midbody of the corpus callosum.

The neuroanatomic substrate of the alien hand syndrome has remained controversial due to the noncircumscribed nature of cerebral injuries present in most cases. There have been few cases studied in which damage was restricted to portions of the body of the callosum, and most of those involved surgical callosotomy for tumors or epilepsy. We report the case of a woman with a transient alien hand syndrome caused by a stroke limited to the middle and posterior portions of the body of the corpus callosum. This case provides supportive evidence for damage to the midbody of the corpus callosum as the anatomic basis of nondominant alien hand syndrome and conforms to a model of interhemispheric motor disconnection as the essential component of this unusual behavioral syndrome. This disconnection can occur with injuries involving interhemispheric premotor and motor fibers traveling in the midportion of the callosum in individuals with left hemisphere dominance for motor activities.

Sulcal variability in the Alzheimer's brain: correlations with cognition.

We mapped the three dimensional (3D) extents and variability of selected sulci in the Alzheimer's brain and explored the relationship between sulcal pattern and patient's cognitive performance. High-resolution MRIs of 10 patients with probable Alzheimer's disease (AD) were linearly transformed into a standard "normalized" 3D atlas (known as the Talairach coordinate system) and, on each relevant slice, contours of the left and right Sylvian fissure, anterior and posterior calcarine, callosal, parietooccipital, and cingulate sulci and the floor of the temporal horn of the lateral ventricle were traced. These landmarks were chosen because of their relative invariant location across individuals and because they demarcate functional boundaries relevant in AD. The sulcal contours were resolved into two-dimensional surfaces that cut through a brain volume. All 10 patients' sulcal surfaces were averaged to determine their mean spatial locations in the Talairach coordinate system. The 3D spatial extents of each patient's sulci were compared with their disease severity based on neuropsychological performance. The 3D sulcal variability, within the "normalized" atlas space, ranged from 4.0 mm for the left callosal sulcus to 9.1 mm for the left Sylvian fissure. Significant correlations were found among the spatial extents for the posterior floor of the right temporal horn of the lateral ventricle (r = -0.89, p < 0.001 for vertical extent) and right anterior calcarine sulcus (r = -0.75, p < 0.01 for anterior-posterior extent) with copying ability of the Rey-Osterrieth Complex Figure; the right anterior calcarine also had a significant relationship (r = -0.72, p = 0.02 for anterior-posterior extent) with performance on the Block Design subtest from the Wechsler Adult Intelligence Scale-Revised. Verbal fluency performance measured by the Controlled Oral Word Association Test was significantly related to the left cingulate (r = 0.91, p < 0.001 for anterior-posterior extent, and r = -0.82, p < 0.01 for vertical extent) and right cingulate (r = -0.72, p < or = 0.02 for vertical extent) sulci. This exploratory study is the first to evaluate the relationship between 3D sulcal variability and cognition; our preliminary findings suggest that the 3D pattern of sulci in the AD brain is related to the severity of the disease as reflected by cognitive performance. In the Talairach brain atlas, sulcal variability, within an AD population, approaches 1 cm. This large variability requires correction when functional imaging data are transformed into the Talairach atlas space to "normalize" individual morphologic differences.

Dementia with Lewy bodies: reliability and validity of clinical and pathologic criteria.

Clinical criteria for dementia with Lewy bodies (DLB) have been proposed, but their formulation, reliability, and validity require further study. Pathologic criteria for DLB are also undergoing evolution. Two studies were conducted with the goal of identifying the components of these evolving criteria that may benefit from further refinement; one study evaluated the components of the clinical criteria and another study operationalized the pathologic criteria for DLB. Twenty-four patients with a premorbid diagnosis of probable or possible Alzheimer's disease (AD) (n = 18), Parkinson's disease (PD) (n = 5), or progressive supranuclear palsy (PSP) (n = 1) were studied. Inter-rater reliability and validity of the clinical criteria were determined by a retrospective chart review, done by five neurologists, and a blinded pathologic evaluation. The Consortium on dementia with Lewy bodies (CDLB) pathologic criteria were operationalized to compare past criteria and test the validity of the evolving clinical criteria on the dementia patients. Three or more cortical fields (at 250 x magnification) with many (four or more) Lewy bodies (LBs) on ubiquitin immunoreactive sections were required to meet the CDLB neocortical score of > 6. Fifteen of the AD patients had at least one LB in a cortical section, four had many LBs, while three had no LBs; all patients with movement disorder had at least one LB in a cortical section. The sensitivity/specificity ratio of the CDLB probable DLB clinical criteria based upon many LBs being present was 75%/79%. Reformulated clinical criteria that require the presence of extrapyramidal signs significantly predicted those patients with many LBs versus those with few or no LBs (chi 2 = 5.48, p = 0.02) and increased clinical specificity to 100%. This preliminary study identifies components of the evolving clinical and pathologic criteria for DLB that require further refinement.

Mapping biochemistry to metabolism: FDG-PET and amyloid burden in Alzheimer's disease.

We evaluated the relationship between amyloid-beta protein (A beta) concentration and the metabolic abnormality in an Alzheimer's disease (AD) patient as measured by [18F]fluorodeoxyglucose positron emission tomography (FDG-PET). Across most regions there were significant inverse correlations among FDG-PET intensity values and both insoluble. The temporal lobe samples showed no significant correlation between FDG-PET values and A beta deposition. Findings support A beta as contributing to the hypometabolism in regions of the AD brain that are still relatively viable metabolically; those regions with chronic pathologic damage, such as temporal cortex, may have other factors that contribute to metabolic deficits.

A transcultural study of agitation in dementia.

Agitation is one of the most troublesome behaviors in demented patients. It is etiologically heterogeneous and has varied associated behaviors. To explore the transcultural differences in the manifestation of agitation, we evaluated 50 consecutive Alzheimer's disease (AD) patients in three countries (Taiwan, Italy, and the United States) using the Neuropsychiatric Inventory (NPI) and the Mini-Mental State Examination (MMSE). In a focused analysis, only patients with composite NPI scores > 2 for agitation were selected, with similar levels of disease severity as measured by the MMSE, from the three groups (n = 15 per group) to evaluate culturally specific correlates of agitation. Agitated Taiwanese had significantly more hallucinations than either Italian or American patients. Agitated Italian patients had significantly more apathy than both Taiwanese and American patients. Cultural factors may influence the manifestation of agitation more than a common underlying neuropathology. Management strategies targeting unique behavioral instigators of agitation may be specific for different ethnic groups.

Probabilistic approaches for atlasing normal and disease-specific brain variability.

The extreme variability in the structural conformation of the human brain poses significant challenges for the creation of population-based atlases. The ability to statistically and visually compare and contrast brain image data from multiple individuals is essential to understanding normal variability within a particular population as well as differentiating normal from diseased populations. This paper introduces the application of probabilistic atlases that describe specific subpopulations, measures their variability and characterizes the structural differences between them. Utilizing data from structural MRI, we have built atlases with defined coordinate systems creating a framework for mapping data from functional, histological and other studies of the same population. This paper describes the basic approach and a brief description of the underlying mathematical constructs that enable the calculation of probabilistic atlases and examples of their results from several different normal and diseased populations.

Differential diagnosis of dementia: clinical examination and laboratory assessment.

Recent breakthroughs in putative disease-modifying interventions for Alzheimer's disease (AD) underscore the urgency of making the earliest possible diagnosis. In the absence of a convenient and reliable laboratory test for AD, the clinical assessment is still the cornerstone of the diagnostic approach. This article provides a basis for conducting an assessment within the realities of a busy clinical practice for patients complaining of cognitive decline. The assessment will enable the clinician to diagnose the earliest manifestation of AD.

Frontal-subcortical circuits and neuropsychiatric disorders.

Five parallel anatomic circuits link regions of the frontal cortex to the striatum, globus pallidus/substantia nigra, and thalamus. The circuits originate in the supplementary motor area, frontal eye fields, dorsolateral prefrontal region, lateral orbito-frontal area, and anterior cingulate cortex. Open loop structures that provide input to or receive output from specific circuits share functions, cytoarchitectural features, and phylogenetic histories with the relevant circuits. The circuits mediate motor and oculomotor function as well as executive functions, socially responsive behavior, and motivation. Neuropsychiatric disorders of frontal-subcortical circuits include impaired executive function, disinhibition, and apathy; indicative mood disorders include depression, mania, and lability. Transmitters, modulators, receptor subtypes, and second messengers within the circuits provide a chemoarchitecture that can inform pharmacotherapy.

Akinetic mutism: disconnection of frontal-subcortical circuits.

Akinetic mutism may result from anterior cingulate lesions or a disconnection of the limbic connections projecting from the cingulate through subcortical circuits. Based on nonhuman primate primate tracer studies, ventral pallidal lesions should disrupt the anterior cingulate frontal-subcortical circuit. A patient developed a rigid akinetic mute state caused by bilateral lesions of the globus pallidus interna with ventral extension. The anatomic basis of the patient's clinical findings support a similarity in frontal-subcortical anatomy between humans and nonhuman primates. Isolated pallidal lesions are rare. Future studies should document whether ventral extension below the anterior commissure is associated with a loss of motivation.

The limbic system: an anatomic, phylogenetic, and clinical perspective.

The limbic system is the border zone where psychiatry meets neurology. The authors provide a model of limbic function that combines phylogenetic, anatomic, functional, and clinical data to interpret diseases relevant to neuropsychiatry. They provide evidence supporting two major divisions in the limbic system: a paleocortical division with the amygdala and orbitofrontal cortex at its center, and an archicortical division with the hippocampus and cingulate cortex at its center. The implicit integration of affect, drives, and object associations is the function of the paleocortical limbic division; explicit sensory processing, encoding, and attentional control is the function of the archicortical limbic division. The two work in concert to integrate thought, feeling, and action. Understanding their development and organization informs us about how best to care for our patients.

Mathematical/computational challenges in creating deformable and probabilistic atlases of the human brain.

Striking variations in brain structure, especially in the gyral patterns of the human cortex, present fundamental challenges in human brain mapping. Probabilistic brain atlases, which encode information on structural and functional variability in large human populations, are powerful research tools with broad applications. Knowledge-based imaging algorithms can also leverage atlased information on anatomic variation. Applications include automated image labeling, pathology detection in individuals or groups, and investigating how regional anatomy is altered in disease, and with age, gender, handedness and other clinical or genetic factors. In this report, we illustrate some of the mathematical challenges involved in constructing population-based brain atlases. A disease-specific atlas is constructed to represent the human brain in Alzheimer's disease (AD). Specialized strategies are developed for population-based averaging of anatomy. Sets of high-dimensional elastic mappings, based on the principles of continuum mechanics, reconfigure the anatomy of a large number of subjects in an anatomic image database. These mappings generate a local encoding of anatomic variability and are used to create a crisp anatomical image template with highly resolved structures in their mean spatial location. Specialized approaches are also developed to average cortical topography. Since cortical patterns are altered in a variety of diseases, gyral pattern matching is used to encode the magnitude and principal directions of local cortical variation. In the resulting cortical templates, subtle features emerge. Regional asymmetries appear that are not apparent in individual anatomies. Population-based maps of cortical variation reveal a mosaic of variability patterns that segregate sharply according to functional specialization and cytoarchitectonic boundaries.

Detection and mapping of abnormal brain structure with a probabilistic atlas of cortical surfaces.

PURPOSE: We have devised, implemented, and tested a technique for creating a comprehensive probabilistic atlas of the human cerebral cortex, based on high-dimensional fluid transformations. The goal of the atlas is to detect and quantify subtle and distributed patterns of deviation from normal cortical anatomy, in a 3D brain image from any given subject. METHOD: Given a 3D MR image of a new subject, a high-resolution surface representation of the cerebral cortex is automatically extracted. The algorithm then calculates a set of high-dimensional volumetric maps, fluidly deforming this surface into structural correspondence with other cortical surfaces, selected one by one from an anatomic image database. The family of volumetric warps so constructed encodes statistical properties of local anatomical variation across the cortical surface. Additional strategies are developed to fluidly deform the sulcal patterns of different subjects into structural correspondence. A probability space of random transformations, based on the theory of anisotropic Gaussian random fields, is then used to encode information on complex variations in gyral and sulcal topography from one individual to another. A complete system of 256(2) probability density functions is computed to reflect the observed variability in stereotaxic space of the points whose correspondences are found by the warping algorithm. Confidence limits in stereotaxic space are determined for cortical surface points in the new subject's brain. RESULTS: Color-coded probability maps are generated, which highlight and quantify regional patterns of deformity in the anatomy of new subjects. These maps indicate locally the probability of each anatomic point being as unusually situated, given the distributions of corresponding points in the scans of normal subjects. 3D MRI volumes are analyzed, from subjects with clinically determined Alzheimer disease and age-matched normal subjects. CONCLUSION: Applications of the random fluid-based probabilistic atlas include the transfer of multisubject 3D functional, vascular, and histologic maps onto a single anatomic template, the mapping of 3D atlases onto the scans of new subjects, and the rapid detection, quantification, and mapping of local shape changes in 3D medical images in disease and during normal or abnormal growth and development.

Neuropsychiatric aspects of Huntington's disease.

OBJECTIVE: Neuropsychiatric symptoms are common in Huntington's disease and have been considered its presenting manifestation. Research characterising these symptoms in Huntington's disease is variable, however, encumbered by limitations within and across studies. Gaining a better understanding of neuropsychiatric symptoms is essential, as these symptoms have implications for disease management, prognosis, and quality of life for patients and caregivers. METHOD: Fifty two patients with Huntington's disease were administered standardised measures of cognition, psychiatric symptoms, and motor abnormalities. Patient caregivers were administered the neuropsychiatric inventory. RESULTS: Ninety eight per cent of the patients exhibited neuropsychiatric symptoms, the most prevalent being dysphoria, agitation, irritability, apathy, and anxiety. Symptoms ranged from mild to severe and were unrelated to dementia and chorea. CONCLUSIONS: Neuropsychiatric symptoms are prevalent in Huntington's disease and are relatively independent of cognitive and motor aspects of the disease. Hypothesised links between neuropsychiatric symptoms of Huntington's disease and frontal-striatal circuitry were explored. Findings indicate that dimensional measures of neuropsychiatric symptoms are essential to capture the full range of pathology in Huntington's disease and are vital to include in a comprehensive assessment of the disease.