Amphetamine-induced dopaminergic hypersensitivity in guinea pigs. Implications in psychosis and human movement disorders.

Following chronic amphetamine pretreatment, guinea pigs demonstrate an increased sensitivity to both d-amphetamine sulfate- and apomorphine hydrochloride-induced stereotyped behavior. This observation suggests that chronic exposure to high doses of a dopamine agonist (d-amphetamine) alters the response of the brain to the subsequent administration of both indirect (d-amphetamine) and direct (apomorphine) dopamine agonists. This altered response may be due to the development of dopamine receptor site hypersensitivity. Clinical evidence suggests that a similar agonist-induced hypersensitivity may play a role in the development of dyskinetic movement disorders and psychoses in humans following the chronic use of such dopamine agonists as amphetamine and levodopa.

Cognitive neuropsychology. Resolving enigmas about Wernicke's aphasia and other higher cortical disorders.

Cognitive neuropsychology is a young branch of neuroscience whose ancestral influences include a rich pool of experimental (eg, cognitive, psychology), theoretical (eg, epistemology), and clinical (eg, neurology, neuropsychology) disciplines. An essential principle of cognitive neuropsychology is that disorders of higher cortical functions can be understood in terms of breakdowns of one or more information-processing modules. Each module is the most basic element of intelligence that can be defined based on current knowledge. This approach is a refinement of-not a fundamental departure from-the 19th-century "localizationist" view of language disorders. Wernicke's aphasia, for example, classical attributed to a single cognitive deficit (loss of word sounds), is shown in this review to require damage to multiple distinct information-processing modules. Cognitive neuropsychology provides the tools for the type of fine-grained analyses of behavior that are needed to capitalize on recent advances in neuroimaging techniques, including the development of more sophisticated models of brain-behavior relationships.

Cognitive slowing in Parkinson's and Alzheimer's patients: distinguishing bradyphrenia from dementia.

The contribution of cognitive slowing to the slowed performance of patients with Parkinson's disease (PD) is a matter of long-standing debate. In this study, we contrasted the performance of PD patients on two reaction-time tasks with the performance of Alzheimer's disease (AD) patients, young normal subjects, and elderly normal subjects. Both nondemented and demented PD patients showed cognitive as well as motor slowing, and the extent of cognitive slowing varied with overall cognitive status. Moreover, by comparison with the cognitive slowing in AD patients, cognitive slowing in PD patients was disproportionate to their general level of cognitive performance. We suggest that this disproportionality be used to differentiate the concepts of bradyphrenia and nonspecific cognitive slowing.

The hyperkinetic child syndrome and brain monoamines: pharmacology and therapeutic implications.

Decreased catecholaminergic activity within the central nervous system has been associated with altered arousal, attention, learning, and kinetic function in animals and humans. The hyperkinetic child syndrome (HCS) involves dysfunction in all these spheres and may thus reflect diminished catecholamine activity, particularly as related to brain dopamine. Accordingly, the efficacy of catecholaminergic agents in treating the HCS is a predictable rather than a paradoxical effect of these agents. Sufficient evidence is now available to strongly implicate catecholamine hypoactivity in the pathopharmacology of the HCS.

Motor disorder and the timing of repetitive movements.

This paper is concerned with the timing of regular repetitive movements. The two-process model of Wing and Kristofferson attributes variability in self-paced interresponse intervals to imprecision in a timekeeper and to temporal noise in the execution of motor responses triggered by the timekeeper. Assuming independence of timekeeper intervals and motor delays, the variance of each may be estimated from interresponse-interval statistics. Comparison of changes in timing performance associated with alterations in motor-system functioning offer the possibility of a new approach to investigation of this model. Illustrative data are presented from a case study of a patient with Parkinson's disease whose lesions affecting the dopaminergic pathways of the basal ganglia have given rise to asymmetric symptoms, including differences in timing performance of the two hands. Analysis of interresponse-interval variability according to the two-process model indicates that the elevated variability of the side more greatly affected by parkinsonism is attributable to the timekeeper intervals rather than the motor delays.

Efficacy and safety of a loading-dose regimen versus a no-loading-dose regimen of metrifonate in the symptomatic treatment of Alzheimer's disease: a randomized, double-masked, placebo-controlled trial. Metrifonate Study Group.

This prospective, randomized, double-masked, placebo-controlled, parallel-group study assessed the safety and efficacy of 2 dosage regimens of once-daily metrifonate in patients with probable Alzheimer's disease (AD) of mild-to-moderate severity. A total of 395 patients were randomized to receive placebo (n = 134) or metrifonate in 1 of 2 regimens. The loading-dose group (n = 133) received a daily loading dose of metrifonate 100 mg or 150 mg (by weight) for 2 weeks, followed by a daily maintenance dose of metrifonate 50 mg for 4 weeks; the no-loading-dose group (n = 128) received the daily maintenance dose of metrifonate 50 mg for 6 weeks. The primary measure of efficacy was the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog); secondary measures of efficacy included the Mini-Mental State Examination (MMSE), the Clinician's Interview Based Impression of Change with Caregiver Input (CIBIC-Plus), the Clinician's Interview Based Impression of Severity with Caregiver Input (CIBIS-Plus), and the ADAS-Noncognitive Subscale (ADAS-Noncog). Safety was assessed by the prevalence of premature study termination and treatment-emergent adverse events, as well as by changes in vital signs, findings on electrocardiographic and neurologic examinations, and abnormalities on laboratory tests. At 4 weeks of treatment, defined by the protocol as the target efficacy determination, the mean ADAS-Cog scores of the intent-to-treat population (last observation carried forward) favored the loading-dose group versus the placebo group, but the difference was not statistically significant. However, at week 6, the difference in mean ADAS-Cog scores was statistically significant compared with placebo. At neither week 4 nor week 6 was there a statistically significant difference in the mean ADAS-Cog scores of the no-loading-dose and placebo groups. For the CIBIC-Plus, the treatment difference between the placebo and loading-dose groups significantly favored metrifonate at week 6 but not at week 4, whereas the treatment difference between the placebo and no-loading-dose groups was statistically significant at both time points. For the MMSE, CIBIS-Plus, and ADAS-Noncog, treatment differences for both groups versus placebo did not reach statistical significance at either week 4 or 6. Assessment of the frequency of adverse events in metrifonate-treated patients revealed that the no-loading-dose regimen was better tolerated than the loading-dose regimen. Given the overall similar efficacy and more favorable safety profile associated with the no-loading-dose regimen versus the loading-dose regimen observed in this study, the no-loading-dose regimen appears to be the better strategy for initiating metrifonate treatment in patients with probable AD of mild-to-moderate severity.

Naloxone blockade of apomorphine-induced stereotyped behavior: interaction of endogenous opiates with dopamine.

The specific opiate antagonist, naloxone, inhibits the in vivo and in vitro activity of the endogenous opiate compounds which have heretofore been identified. In this study systemic naloxone administration successfully blocked the production of stereotyped behavior induced by the direct dopamine agonist apomorphine. This implies that the endogenous opiates contribute to the production of stereotyped behavior initiated by dopaminergic stimulation and that endogenous opiates may function as central neurotransmitters with dopaminergic activity.

Supersensitivity to d-amphetamine- and apomorphine-induced stereotyped behavior induced by chronic d-amphetamine administration.

Guinea pigs exhibit an increased sensitivity to both d-amphetamine- and apomorphine-induced stereotyped behavior following chronic pretreatment with d-amphetamine. This chronic agonist or "innervation" supersensitivity is believed to be a reflection of an increased sensitivity of dopamine receptor sites within the corpus striatum to dopaminergic agonists. The appearance of dyskinetic movement disorders in humans following the chronic use of levodopa or amphetamine may be a manifestation of similarly increased dopamine receptor site sensitivity within the striatum. It is suggested that the animal model of "innervation" supersensitivity may be useful in the investigation of these human movement disorders.

Multiple component agraphia in a patient with atypical cerebral dominance: an error analysis.

A 52-year-old man with atypical cerebral dominance (left-handed for writing but mixed handedness for other tasks) suffered an extensive right hemisphere stroke, resulting in a combination of deficits that has not been previously reported. There were profound visual constructive and visual perceptual disturbances and a spatial agraphia, which were consistent with a nondominant hemisphere lesion. There was also a severe apraxic agraphia, which is typically associated with a dominant hemisphere lesion, but no other signs of dominant hemisphere dysfunction such as linguistic disturbance or limb-motor apraxia were present. This case serves to highlight the functional and anatomical relationship between handwriting and other forms of praxis; the various sources of error in letter formation; the need to be specific in labeling and describing agraphias ; and the role of a detailed analysis of writing errors in delineating the neuropsychological processes involved in handwriting.

Lexical priming by pictures and words in normal aging and in dementia of the Alzheimer's type.

Alzheimer's disease causes a progressive loss of semantic memory, one manifestation of which is a progressive language deficit. In order to delineate the relationship between cognitive processing deficits and language disturbance, word-word and picture-word lexical-decision priming tasks were administered to patients with mild dementia of the Alzheimer's type (DAT) (n = 6), very mild DATs (n = 7), and older normals (n = 23). The mild DATs differed from the other two groups in both tasks. When pictures were used as primes, significant identity priming was seen in the normals and very mild DATs, but not in the mild DATs. The mild DATs showed an aberrant pattern-responses significantly slower with picture primes than with nonsense primes in all three picture-word conditions. This may reflect residual inhibitory activity within a damaged associational network. In the word-word paradigm, the mild DAT subjects demonstrated significant priming both when the prime and target were identical (identity priming, e.g., dog-dog) and when they were semantically related (semantic priming, e.g., cat-dog). The other two groups showed no significant priming. These data reinforce other studies which have found that DAT subjects show a supranormal amount of word-word lexical-decision priming. This "hyperpriming" may occur due to partially degraded internal representations which benefit from priming more than intact representations (a cognitive crutch). Both paradigms thus exposed information-processing deficits which distinguished mild DATs from the other two groups. DAT-induced changes in selective attention are probably contributing to these results.

Dysnomia in dementia and in stroke patients: different underlying cognitive deficits.

The performance of 11 Alzheimer's (DAT) and 8 anomic aphasic stroke patients is contrasted with that of 32 normal elderly subjects on both the Boston Naming Test (BNT) and the Controlled Oral Word Association Test (COW), a letter-category verbal-fluency test. While both tests require phonological processing, only the BNT requires semantic processing (object recognition). Both DAT and anomic aphasic stroke patients were significantly impaired on the BNT, with mean z scores (based on the performance of the normals) of -4.08 and -2.57, respectively; the DAT patients were significantly farther from normal than were the anomic aphasics. Their relative levels of impairment on the COW were reversed: The anomic aphasics' performance (z = 1.79) was worse than that of the DATs (z = -0.66). This pattern of performance on the two tests is consistent with the hypothesis that impaired word finding reflects impaired processing mainly of semantic information for the DAT subjects, mainly of lexical-phonological information for the anomic aphasic subjects.