Entrapment and social problem-solving in suicidal behavior across the adult lifespan.

BACKGROUND: Feelings of entrapment and deficits in social problem-solving skills have been associated with risk for suicidal behavior in the context of depression. However, few studies have examined the effect of age on the association between these risk factors and suicidal behavior across most of the adult lifespan. METHODS: In a three-site study, we tested interactions of age with feelings of entrapment and social problem-solving style in 105 depressed patients with a recent suicide attempt, 95 depressed patients with no history of suicide attempt, and 97 demographically similar non-psychiatric participants (age 16-80). Attempter/non-attempter differences, age interactions, and the relative contribution of entrapment and social problem-solving style to past attempter were examined. RESULTS: Entrapment significantly interacted with age such that it discriminated past attempters from depressed non-attempters better at older ages. Social Problem-Solving Inventory (SPSI) total score and most subscales did not distinguish past attempters, but the SPSI Impulsive Style Problem-Solving was an effective discriminator of past suicide attempts across the full adult lifespan and did not interact with age. In a multipredictor model, both the entrapment by age interaction and SPSI Impulsive Style Problem-Solving score were significant predictors for the classification of attempters. LIMITATIONS: The cross-sectional nature of our research design limited conclusions that may be drawn about individual change over time or cohort effects. CONCLUSIONS: Entrapment did not distinguish past attempters at younger ages but became a better discriminator in middle to late adulthood. An impulsive problem-solving style was associated with past suicide attempts across the full adult lifespan.

A pilot in vivo proton magnetic resonance spectroscopy study of amino acid neurotransmitter response to ketamine treatment of major depressive disorder.

The N-methyl-D-aspartate receptor antagonist ketamine can improve major depressive disorder (MDD) within hours. To evaluate the putative role of glutamatergic and GABAergic systems in ketamine's antidepressant action, medial prefrontal cortical (mPFC) levels of glutamate+glutamine (Glx) and γ-aminobutyric acid (GABA) were measured before, during, and after ketamine administration using proton magnetic resonance spectroscopy. Ketamine (0.5 mg kg(-1) intravenously) was administered to 11 depressed patients with MDD. Glx and GABA mPFC responses were measured as ratios relative to unsuppressed voxel tissue water (W) successfully in 8/11 patients. Ten of 11 patients remitted (50% reduction in 24-item Hamilton Depression Rating Scale and total score ⩽10) within 230 min of commencing ketamine. mPFC Glx/W and GABA/W peaked at 37.8%±7.5% and 38.0%±9.1% above baseline in ~26 min. Mean areas under the curve for Glx/W (P=0.025) and GABA/W (P=0.005) increased and correlated (r=0.796; P=0.018). Clinical improvement correlated with 90-min norketamine concentration (df=6, r=-0.78, P=0.023), but no other measures.

Emotion recognition deficits as predictors of transition in individuals at clinical high risk for schizophrenia: a neurodevelopmental perspective.

BACKGROUND: Schizophrenia is characterized by profound and disabling deficits in the ability to recognize emotion in facial expression and tone of voice. Although these deficits are well documented in established schizophrenia using recently validated tasks, their predictive utility in at-risk populations has not been formally evaluated. METHOD: The Penn Emotion Recognition and Discrimination tasks, and recently developed measures of auditory emotion recognition, were administered to 49 clinical high-risk subjects prospectively followed for 2 years for schizophrenia outcome, and 31 healthy controls, and a developmental cohort of 43 individuals aged 7-26 years. Deficit in emotion recognition in at-risk subjects was compared with deficit in established schizophrenia, and with normal neurocognitive growth curves from childhood to early adulthood. RESULTS: Deficits in emotion recognition significantly distinguished at-risk patients who transitioned to schizophrenia. By contrast, more general neurocognitive measures, such as attention vigilance or processing speed, were non-predictive. The best classification model for schizophrenia onset included both face emotion processing and negative symptoms, with accuracy of 96%, and area under the receiver-operating characteristic curve of 0.99. In a parallel developmental study, emotion recognition abilities were found to reach maturity prior to traditional age of risk for schizophrenia, suggesting they may serve as objective markers of early developmental insult. CONCLUSIONS: Profound deficits in emotion recognition exist in at-risk patients prior to schizophrenia onset. They may serve as an index of early developmental insult, and represent an effective target for early identification and remediation. Future studies investigating emotion recognition deficits at both mechanistic and predictive levels are strongly encouraged.

Neuropsychological deficits in past suicide attempters with varying levels of depression severity.

BACKGROUND: Our previous work identified deficits in interference processing and learning/memory in past suicide attempters who were currently depressed and medication-free. In this study, we extend this work to an independent sample studied at various stages of illness and treatment (mild symptoms, on average) to determine if these deficits in past suicide attempters are evident during a less severe clinical state. METHOD: A total of 80 individuals with a past history of major depression and suicide attempt were compared with 81 individuals with a history of major depression and no lifetime suicide attempts on a battery of neurocognitive measures assessing attention, memory, abstract/contingent learning, working memory, language fluency and impulse control. RESULTS: Past attempters performed more poorly in attention, memory and working memory domains, but also in an estimate of pre-morbid intelligence. After correction for this estimate, tests that had previously distinguished past attempters - a computerized Stroop task and the Buschke Selective Reminding Test - remained significantly worse in attempters. In a secondary analysis, similar differences were found among those with the lowest levels of depression (Hamilton Depression Rating Scale score <10), suggesting that these deficits may be trait markers independent of current symptomatology. CONCLUSIONS: Deficits in interference processing and learning/memory constitute an enduring defect in information processing that may contribute to poor adaptation, other higher-order cognitive impairments and risk for suicidal behavior.

Neuropsychological function and suicidal behavior: attention control, memory and executive dysfunction in suicide attempt.

BACKGROUND: Executive dysfunction, distinct from other cognitive deficits in depression, has been associated with suicidal behavior. However, this dysfunction is not found consistently across samples. METHOD: Medication-free subjects with DSM-IV major depressive episode (major depressive disorder and bipolar type I disorder) and a past history of suicidal behavior (n = 72) were compared to medication-free depressed subjects with no history of suicidal behavior (n = 80) and healthy volunteers (n = 56) on a battery of tests assessing neuropsychological functions typically affected by depression (motor and psychomotor speed, attention, memory) and executive functions reportedly impaired in suicide attempters (abstract/contingent learning, working memory, language fluency, impulse control). RESULTS: All of the depressed subjects performed worse than healthy volunteers on motor, psychomotor and language fluency tasks. Past suicide attempters, in turn, performed worse than depressed non-attempters on attention and memory/working memory tasks [a computerized Stroop task, the Buschke Selective Reminding Task (SRT), the Benton Visual Retention Test (VRT) and an N-back task] but not on other executive function measures, including a task associated with ventral prefrontal function (Object Alternation). Deficits were not accounted for by current suicidal ideation or the lethality of past attempts. A small subsample of those using a violent method in their most lethal attempt showed a pattern of poor executive performance. CONCLUSIONS: Deficits in specific components of attention control, memory and working memory were associated with suicidal behavior in a sample where non-violent attempt predominated. Broader executive dysfunction in depression may be associated with specific forms of suicidal behavior, rather than suicidal behavior per se.

A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy.

BACKGROUND: Optimal treatment remains uncertain for patients with cognitive impairment that persists or returns after standard IV antibiotic therapy for Lyme disease. METHODS: Patients had well-documented Lyme disease, with at least 3 weeks of prior IV antibiotics, current positive IgG Western blot, and objective memory impairment. Healthy individuals served as controls for practice effects. Patients were randomly assigned to 10 weeks of double-masked treatment with IV ceftriaxone or IV placebo and then no antibiotic therapy. The primary outcome was neurocognitive performance at week 12-specifically, memory. Durability of benefit was evaluated at week 24. Group differences were estimated according to longitudinal mixed-effects models. RESULTS: After screening 3368 patients and 305 volunteers, 37 patients and 20 healthy individuals enrolled. Enrolled patients had mild to moderate cognitive impairment and marked levels of fatigue, pain, and impaired physical functioning. Across six cognitive domains, a significant treatment-by-time interaction favored the antibiotic-treated group at week 12. The improvement was generalized (not specific to domain) and moderate in magnitude, but it was not sustained to week 24. On secondary outcome, patients with more severe fatigue, pain, and impaired physical functioning who received antibiotics were improved at week 12, and this was sustained to week 24 for pain and physical functioning. Adverse events from either the study medication or the PICC line were noted among 6 of 23 (26.1%) patients given IV ceftriaxone and among 1 of 14 (7.1%) patients given IV placebo; these resolved without permanent injury. CONCLUSION: IV ceftriaxone therapy results in short-term cognitive improvement for patients with posttreatment Lyme encephalopathy, but relapse in cognition occurs after the antibiotic is discontinued. Treatment strategies that result in sustained cognitive improvement are needed.

Selective cognitive deficits in obsessive-compulsive disorder compared to panic disorder with agoraphobia.

OBJECTIVE: Visual-spatial and executive functions deficits have been reported in obsessive-compulsive disorder (OCD). We investigated their specificity comparing cognitive function in OCD, panic disorder with agoraphobia (PD/A) and controls by a comprehensive neuropsychological battery. METHOD: Fifty-five subjects (25 OCD, 15 PD/A, 15 controls) without current depressive episode underwent structured clinical interview for DSM-IV, Yale-Brown Obsessive Compulsive Scale, Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale. Neuropsychological battery assessed: executive functions, visual discrimination, spatial memory and learning, verbal memory, general intellectual functioning. RESULTS: OCD showed controlled fluency, visual-spatial construction, learning and memory deficits; PD/A spatial learning impairment. OCD was discriminated from PD/A and controls by three tests scores, predicting group membership for 76.4% of the cases. CONCLUSION: Visual-constructive and controlled fluency deficits seem specific in OCD, while the spatial learning deficit, shared with PD patients, may not be disorder-specific, but anxiety-related. Results support the proposed ventral frontal-striatal circuit involvement in OCD.

A controlled study of cognitive deficits in children with chronic Lyme disease.

Although neurologic Lyme disease is known to cause cognitive dysfunction in adults, little is known about its long-term sequelae in children. Twenty children with a history of new-onset cognitive complaints after Lyme disease were compared with 20 matched healthy control subjects. Each child was assessed with measures of cognition and psychopathology. Children with Lyme disease had significantly more cognitive and psychiatric disturbances. Cognitive deficits were still found after controlling for anxiety, depression, and fatigue. Lyme disease in children may be accompanied by long-term neuropsychiatric disturbances, resulting in psychosocial and academic impairments. Areas for further study are discussed.

Neuropsychological dysfunction in depressed suicide attempters.

OBJECTIVE: Neuropsychological deficits in the context of psychiatric disease may be associated with suicide risk. In this study, neuropsychological performance was compared among depressed patients with at least one prior suicide attempt of high lethality, depressed patients with low-lethality prior attempts, depressed patients with no prior suicide attempts, and nonpatients. METHOD: Fifty unmedicated patients in a major depressive episode (21 with no history of suicide attempts and 14 and 15 patients with previous attempts of low and high lethality, respectively) and 22 nonpatients were assessed. Groups were comparable in age, education, occupational level, and estimated premorbid intelligence. The neuropsychological battery produced scores within five composite domains: general intellectual functioning (current), motor functioning, attention, memory, and executive functioning. RESULTS: Patients whose prior suicide attempts were of high lethality performed significantly worse than all groups on tests of executive functioning and were the only group to perform significantly worse than nonpatients on tests of general intellectual functioning, attention, and memory. A discriminant function analysis revealed two prominent dimensions in the data: one that discriminated high-lethality suicide attempters from all other groups (primarily associated with performance on tests of executive functioning) and another that discriminated all depressed patient groups from nonpatients (associated with performance on measures of attention and memory). For the patients with high-lethality prior suicide attempts, deficits did not appear to reflect diffuse brain damage from past attempts, since the results of tests commonly affected by diffuse injury were not selectively impaired. CONCLUSIONS: Neuropsychological deficits in depressed patients with high-lethality prior suicide attempts suggest impairment of executive functioning beyond that typically found in major depression. This more extensive neuropsychological impairment in the context of depression may be a risk factor for severe suicide attempts.

The effects of vagus nerve stimulation on cognitive performance in patients with treatment-resistant depression.

BACKGROUND: Chronic vagus nerve stimulation (VNS) is effective in the management of treatment-resistant epilepsy. Open-trial evidence suggests that VNS has clinically significant antidepressant effects in some individuals who experience treatment-resistant major depressive episodes. However, limited information regarding the effects of VNS on neurocognitive performance exists. OBJECTIVE: The primary aim of this study was to determine whether VNS leads to neurocognitive deterioration. METHOD: A neuropsychological battery was administered to 27 patients with treatment-resistant depression before and after 10 weeks of VNS. Thirteen neurocognitive tests sampled the domains of motor speed, psychomotor function, language, attention, memory, and executive function. RESULTS: No evidence of deterioration in any neurocognitive measure was detected. Relative to baseline, improvement in motor speed (finger tapping), psychomotor function (digit-symbol test), language (verbal fluency), and executive functions (logical reasoning, working memory, response inhibition, or impulsiveness) was found. For some measures, improved neurocognitive performance correlated with the extent of reduction in depressive symptoms, but VNS output current was not related to changes in cognitive performance. CONCLUSIONS: Vagus nerve stimulation in treatment-resistant depression may result in enhanced neurocognitive function, primarily among patients who show clinical improvement. Controlled investigation is needed to rule out the contribution of practice effects.

Structural abnormalities of subicular dendrites in subjects with schizophrenia and mood disorders: preliminary findings.

BACKGROUND: Postmortem studies of the subiculum from subjects with schizophrenia have detected smaller pyramidal cell bodies and diminished immunoreactivity for the dendritic protein, microtubule-associated protein 2. While these findings suggest that subicular pyramidal cell dendrites may be structurally altered in subjects with schizophrenia, this possibility had not been tested directly. METHODS: Rapid Golgi impregnation of archival brain specimens was used to compare the morphologic characteristics of subicular dendrites in subjects with schizophrenia (n = 13) and mood disorders (n = 6) with subjects without psychiatric disease (n = 8). The specimens were processed and analyzed by physicians blind to diagnosis. The extent of dendritic trees in the subiculum and fusiform gyrus was examined by Sholl analysis. Spine density on apical dendrites of subicular pyramidal cells was determined at a fixed distance from the cell body. RESULTS: Spine density and arborization of subicular apical dendrites were significantly related to diagnostic group. Spine density was significantly lower in the schizophrenia and mood disorder groups than in the nonpsychiatric group. Among the mood disorder cases, diminished spine density was apparently related to a strong family history of major psychiatric diseases. There were no significant effects of diagnostic group on Sholl analysis of nonapical subicular dendrites nor on Sholl analysis of dendrites of neocortical pyramidal cells in the fusiform gyrus. CONCLUSIONS: We have observed an association between schizophrenia and major mood disorders and structural abnormalities of subicular apical dendrites. Further studies are needed to test this association in a larger sample and to evaluate the potential role of family history and of confounding factors, such as medications and chronic institutionalization.

Cerebral blood flow patterns underlying the differential impairment in category vs letter fluency in Alzheimer's disease.

Verbal fluency tasks are used to assess language functioning in Alzheimer's disease (AD), and performance typically declines as the disease progresses. However, several studies have shown that Category Fluency performance (produce words from a category) declines faster than Letter Fluency performance (produce words beginning with a certain letter), which is not the case for other dementias. The purpose of this study was to determine if each of these two types of fluency tasks was associated with different patterns of cerebral blood flow abnormality in AD. A resting, Xenon-inhalation regional cerebral blood flow measurement (133Xe rCBF) and neuropsychological evaluation was administered to 25 patients with probable AD and 24 healthy elderly controls. Stepwise regression using rCBF measures as predictor variables was used to predict Category and Letter Fluency performance, in both a combined group of patients and controls, and in the patient group alone. Correlations were also computed between rCBF variables and the difference between normatively corrected scores on each task for each subject, which characterized the extent of the discrepancy between them. In full sample regressions, both Category and Letter Fluency were predicted by education and the decline in left inferior parietal flow, a focal AD-related deficit. Additional variance in Category fluency, however, was predicted by global mean flow, while additional variance in Letter Fluency was predicted by frontal flow. Within the patient sample, in turn, the primary predictor of Category Fluency was mean flow; the primary predictor of Letter Fluency was left-sided frontal flow. Analysis of the fluency difference score revealed that relatively greater impairment of Category Fluency was associated with more typical, AD-related deficits in posterior temporal and parietal perfusion. When the two were equivalently impaired, typical AD-related deficits were accompanied by marked deficits in frontal perfusion. These findings are consistent with the underlying neuropsychology of these tasks, and suggest that Category Fluency's stronger association to the most typical CBF deficits of AD account for its greater sensitivity to this disease. Letter Fluency deficits, on the other hand, carry significant information about the degree to which perfusion deficits have spread to frontal cortex.

Application of cognitive scales to medical records of schizophrenia inpatients.

The Scales of Cognitive Impairment Rated From Institutional Records (SCIRFIR), a battery based on commonly used dementia rating instruments, was tested on the records of 26 chronically institutionalized, elderly schizophrenia patients, for the purpose of retrospectively evaluating the long-term course of cognitive change in schizophrenia and relating it to available autopsy materials. The inter-rater reliability of the component scales was high (Intraclass Correlations = 0.78-0.96), the final item scores were comparable to ratings on living subjects, and Alzheimer-type neuropathological changes were associated with a markedly deteriorating course. The substantial potential of this method is discussed.

Senile degeneration and cognitive impairment in chronic schizophrenia.

OBJECTIVE: This study was an investigation of the role of Alzheimer-type senile degenerative abnormalities in the cognitive impairment of chronic schizophrenia. METHOD: The study group comprised 145 deceased elderly institutionalized psychiatric patients: 66 with schizophrenia, 26 with mood disorders, 36 with dementia, and 17 with other psychiatric diagnoses. The comparison group included 16 deceased elderly individuals without neurologic or psychiatric disease. Psychiatric diagnoses and cognitive status were established by standardized review of medical records. Neuritic senile plaques and neurofibrillary tangles were identified immunohistochemically and counted, by investigators blind to clinical information, in standardized regions of each brain. RESULTS: Of the subjects with schizophrenia, 68% had definite cognitive impairment, but only 8% satisfied neuropathological criteria for Alzheimer's disease. Among the schizophrenia subjects without Alzheimer's disease, definite cognitive impairment was associated with higher levels of plaques and tangles. The schizophrenia subjects without definite cognitive impairment had fewer plaques and tangles than the unimpaired nonpsychiatric subjects. CONCLUSIONS: Most cases of cognitive impairment in schizophrenia could not be attributed to Alzheimer's disease. An association of mild Alzheimer-type pathology with definite cognitive impairment was unique to schizophrenia. Enhanced sensitivity to the effects of aging on the brain may be a manifestation of diminished cognitive reserve in schizophrenia.

A brain imaging (single photon emission computerized tomography) study of semantic and affective processing in psychopaths.

Psychopaths have been described as human predators who use charm, intimidation, and violence to control others and to satisfy their own needs. Underlying their propensity to violate social norms and expectations is a profound lack of empathy, guilt, or remorse, affective processes that have long resisted scientific investigation. Using brain imaging technology we found that psychopaths differed from nonpsychopaths in the pattern of relative cerebral blood flow during processing of emotional words. The results were consistent with the hypothesis that there are anomalies in the way psychopaths process semantic and affective information.

The continuous performance test, identical pairs version (CPT-IP): III. Brain functioning during performance of numbers and shapes subtasks.

The numbers and shapes subtasks of the CPT-IP are difficulty-matched measures of independent aspects of attentional skill that have been used to differentiate the impairments of schizophrenics and major depressives. Previous studies suggest that they tap into lateralized aspects of attentional performance. To investigate this hypothesis, seven subjects free of psychiatric illness were presented with these CPT-IP subtasks during a SPECT procedure. Subtasks--4-digit number strings and nonsense shapes--were administered on successive weeks, in counterbalanced order, simultaneous with administration of 10 mCi 99mTc HMPAO. Scanning took place after 10 min of test performance. Quantitative data were extracted from each scan via a semi-automated region of interest (ROI) analysis which defined eight cortical and four subcortical ROI on each of five transverse slices. Data for each ROI were normalized and compared between task conditions. Results indicate that the two tasks produce different patterns of functioning within two general areas of the brain. First, during Numbers task performance, left-sided activity was increased on multiple transverse slices in an anterior subcortical region that incorporated the anterior cingulate, frontal white matter, and much of the basal ganglia. Left-sided activity was also increased in a posterior subcortical region including the left side of the thalamus. Lateralization of function, defined as relative activity on the left and right sides, changed within these regions across tasks, but primarily as a result of the contribution of increased or decreased activity on the left side alone. Second, relative perfusion to occipital regions, bilaterally, was more extensive during the Shapes task. These results suggest that subtle alterations in stimulus parameters can affect activation patterns in regions that are critically associated with task performance. They also suggest that the Numbers task may provide more robust activation of anterior attention systems, that may better discriminate the functioning of these systems in normal and psychopathological groups.

Inferior parietal perfusion, lateralization, and neuropsychological dysfunction in Alzheimer's disease.

The severity of inferior parietal perfusion deficits in Alzheimer's disease (AD) is strongly associated with global intellectual decline. The relationship to specific losses of neuropsychological functioning, however, is less clear, as is the relative importance of the side (left vs. right) of hemispheric deficit. In this study, 53 patients with probable AD and 35 elderly controls received both a resting 133Xe rCBF measurement and neuropsychological examination. AD patients demonstrated the expected bilateral deficits in inferior parietal perfusion, as well as impairment on measures of mental status, intelligence verbal and visual memory, attention, language, and construction abilities. The severity of this bilateral parietal deficit, in turn, was associated with virtually all of these AD-related neuropsychological impairments, most strongly with declining Performance IQ. Left-sided deficits correlated better with overall declines in IQ, as well as with declining attention and language fluency. Right-sided deficits, on the other hand, correlated best with declines in mental status and--paradoxically--verbal memory and contributed independently to declines in Full Scale and Performance IQ. In terms of the number and strength of their association to neuropsychological measures, left-sided deficits appear much more predicative of cognitive decline in AD. Right-sided deficits, however, may be most important in predicting aspects of performance skill that are only indirectly assessed in standard paper-and-pencil format. Overall, it appears that both sides make significant, but independent contributions to general functional decline in AD, but that left-sided deficits are more closely associated with cognitive decline in measured by most standard neuropsychological measures.

Reliability of post-mortem chart diagnoses of schizophrenia and dementia.

The reliability of psychiatric diagnosis has a direct effect on the validity of post-mortem analyses of neuropathological data, yet little is known about the reliability of retrospective diagnostic procedures which rely on review of medical records. In this paper, we report on the reliability of DSM-III-R psychiatric diagnoses assigned by a pool of 8 raters to a set of 106 state hospital charts of elderly, chronic patients who had died while institutionalized and were autopsied. Diagnoses were grouped by general diagnostic class, and Kappa coefficients computed for agreement among raters, as well as for agreement between ultimate consensus diagnoses and those made while subjects were living. Interrater agreement for those diagnoses that occurred most frequently in this sample (e.g. Schizophrenia and Dementia) was excellent, and comparable to the the agreement observed for ratings of live patients. Interrater agreement for less frequently occurring diagnoses (e.g. Mental Retardation, Mood Disorders, other non-Schizophrenic Psychoses) ranged from excellent to poor. We found high agreement between our rates diagnoses and those assigned by state hospital personnel while patients were living, although post-mortem review produced lower rates of diagnosis of both schizophrenia and Alzheimer-type dementias. Overall, results suggest that the reliability of chart review diagnosis is comparable to that obtained from interviews of live patients when experienced raters are used and diagnostic base rates are high enough to produce stable estimates of reliability.

Blunted serotonergic responsivity in depressed inpatients.

We found a 38% lower maximal prolactin response to an oral challenge dose of 60 mg of dl-fenfluramine relative to placebo in younger (< 30 years) depressed inpatients compared with the response in age-matched healthy controls (p < .03). Severity of depression did not correlate with prolactin response. Prolactin responses in older depressed patients (> or = 30 years) did not differ from older controls. Younger depressed patients differed from older depressed patients in terms of earlier age of onset of first lifetime episode of major depression, greater degree of suicidal intent during a recent suicide attempt, double the level of hopelessness on admission to hospital, and a higher rate of comorbid borderline personality disorder. A blunted prolactin response to fenfluramine may be interpreted as evidence for reduced serotonergic function in younger depressed patients and may underlie their observed greater suicidality and hopelessness.

Intellectual decline predicts the parietal perfusion deficit in Alzheimer's disease.

UNLABELLED: The pathophysiology of Alzheimer's disease may be reflected more in an individual's decline from premorbid levels of functioning than in current measures of absolute severity. To test this hypothesis, we computed an index of intellectual decline for individual patients and examined its relationship to Alzheimer's disease-related functional brain abnormalities. METHODS: We studied 27 patients with Alzheimer's disease diagnosed by ADRDA-NINCDS criteria. We used patient demographics and published formulas to construct estimates of premorbid Wechsler Adult Intelligence Scale (WAIS-R) IQs for each subject in the sample and used a current IQ assessment to estimate the decline in IQ that occurred during the disease for each subject. Cortical perfusion was quantified by the planar 133Xe regional cerebral blood flow (rCBF) technique. The characteristic abnormality in parietal cortex was expressed by the parietal index (PI). RESULTS: Over the estimated disease duration of 3.8 +/- 2.2 yr, the full-scaled IQ declined by an estimated 28.0 +/- 15.5 points. The current PI was in turn well correlated with the IQ decline (r = 0.66; p < 0.001). This association was linear and stronger than those with other, more common measures of current severity. A multiple stepwise regression analysis suggested that IQ decline alone accounted for the variance in PI related to clinical deterioration. Actual images showed a mild blood flow deficit in patients with the smallest estimated IQ declines but deep and extensive lesions in patients with large declines. CONCLUSION: These results suggest that the decline from the premorbid baseline, rather than current level of functioning, best predicts the extent of brain damage reflected in the rCBF abnormality, a finding independent of demographic variance.