Michael S. Mega

The Neuropsychiatric Inventory Comprehensive assessment of psychopathology in dementia

We developed a new instrument, the Neuropsychiatric Inventory (NPI), to assess 10 behavioral disturbances occurring in dementia patients: delusions, hallucinations, dysphoria, anxiety, agitation/aggression, euphoria, disinhibition, irritability/lability, apathy, and aberrant motor activity. The NPI uses a screening strategy to minimize administration time, examining and scoring only those behavioral domains with positive responses to screening questions. Both the frequency and the severity of each behavior are determined. Information for the NPI is obtained from a caregiver familiar with the patients behavior. Studies reported here demonstrate the content and concurrent validity as well as between-rater, test-retest, and internal consistency reliability; the instrument is both valid and reliable. The NPI has the advantages of evaluating a wider range of psychopathology than existing instruments, soliciting information that may distinguish among different etiologies of dementia, differentiating between severity and frequency of behavioral changes, and minimizing administration time.

The spectrum of behavioral changes in Alzheimer's disease

Article abstract-We investigated the range of behavioral abnormalities in patients with Alzheimers 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 with cognitive impairment. NEUROLOGY 1996;46: 130-135

Neuropsychiatric aspects of Huntington's disease

OBJECTIVE Neuropsychiatric symptoms are common in Huntingtons disease and have been considered its presenting manifestation. Research characterising these symptoms in Huntingtons 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 Huntingtons 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 Huntingtons disease and are relatively independent of cognitive and motor aspects of the disease. Hypothesised links between neuropsychiatric symptoms of Huntingtons 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 Huntingtons disease and are vital to include in a comprehensive assessment of the disease.

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 Alzheimers 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. Hum. Brain Mapping 9:81–92, 2000.

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 subjects 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.

Orbitofrontal and anterior cingulate cortex neurofibrillary tangle burden is associated with agitation in Alzheimer disease

Few studies evaluate neuropathological correlates of behavioral changes in Alzheimer disease (AD). We identified 31 autopsy patients with a diagnosis of definite AD. Behavioral changes were assessed with the Neuropsychiatric Inventory. Brain sections were collected from bilateral orbitofrontal and left anterior cingulate, superior temporal, inferior parietal, occipital, and hippocampal cortices for quantification of neurofibrillary tangles (NFTs) and diffuse and neuritic plaques. Sections from frontal, cingulate, and hippocampal cortices were reviewed for the presence of Lewy bodies (LBs). Hypothesis‐driven correlational analyses were performed by the bootstrap method. Subgroup analyses contrasted a group with high scores of one specific behavior to a group with low scores after equating groups for other behaviors. NFT burden in the left orbitofrontal cortex across all 31 patients significantly correlated with agitation scores (r = 0.41, p < 0.015) and NFTs correlated significantly (r = 0.66, p = 0.004) with higher agitation scores in the subgroup analysis. Left anterior cingulate NFTs, although not within our hypotheses, also showed a significant relationship to agitation within the subgroups (r = 0.76, p = 0.0003; Bonferroni p = 0.02). Seven patients, including three in the agitation subgroup, had cortical LBs. Aberrant motor behavior and NFT density in the left orbitofrontal cortex showed a significant relationship for the entire group (r = 0.38, p < 0.03) and for subgroups (r = 0.49, p = 0.04), whereas apathy and left anterior cingulate NFTs showed a significant relationship only for the entire group (r = 0.25, p ≤ 0.01). These observations suggest that agitation and aberrant motor behavior are correlates of greater NFT pathology in the orbitofrontal cortex in AD, whereas increasing apathy may relate to greater NFT burden in the anterior cingulate. Ann Neurol 2001;49:355–361

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 Alzheimers disease (AD) (n = 18), Parkinsons 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 250x 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 squared = 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. NEUROLOGY 1996;47: 1403-1409

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 Alzheimers 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. NEUROLOGY 1996;47: 1184-1189

Cerebral correlates of psychotic symptoms in Alzheimer's disease

BACKGROUND Psychotic symptoms are produced by distributed neuronal dysfunction. Abnormalities of reality testing and false inference implicate frontal lobe abnormalities. OBJECTIVES To identify the functional imaging profile of patients with Alzheimers disease manifesting psychotic symptoms as measured by single photon emission computed tomography (SPECT). METHODS Twenty patients with Alzheimers disease who had SPECT and clinical evaluations were divided into two equal groups with similar mini mental status examination (MMSE), age, sex, and the range of behaviours documented by the neuropsychiatric inventory (NPI), except delusions and hallucinations. SPECT studies, registered to a probabilistic anatomical atlas, were normalised across the combined group mean intensity level, and subjected to a voxel by voxel subtraction of the non-psychotic minus psychotic groups. Subvolume thresholding (SVT) corrected random lobar noise to produce a three dimensional functional significance map. RESULTS The significance map showed lower regional perfusion in the right and left dorsolateral frontal, left anterior cingulate, and left ventral striatal regions along with the left pulvinar and dorsolateral parietal cortex, in the psychotic versus non-psychotic group. CONCLUSION Patients with Alzheimers disease who manifest psychosis may have disproportionate dysfunction of frontal lobes and related subcortical and parietal structures.

Mapping histology to metabolism: coregistration of stained whole-brain sections to premortem PET in Alzheimer's disease.

The association between [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) counts obtained 8 h before death and neurofibrillary tangle (NFT) staining density in a patient with Alzheimers disease (AD) was evaluated. In our patient FDG-PET counts were globally decreased with a greater focal deficit in the left medial temporal region independent of volume loss. After death, whole-brain sections derived from cryomacrotome sectioning were stained for NFTs by the Gallyas method and elastically warped into their native space enabling registration with premortem FDG-PET data. Gallyas staining density was localized to the paralimbic cortex of the basal forebrain, medial temporal, and orbital frontal regions. The poor correlation between NFT staining density and hypometabolism on FDG-PET implicates alternate mechanisms underlying the metabolic defect in AD.