Physiological and pathophysiological implications of lipid sensing in the brain.

Fatty acid (FA)-sensitive neurons are present in the brain, especially the hypothalamus, and play a key role in the neural control of energy homeostasis. Through neuronal output, FA may modulate feeding behaviour as well as insulin secretion and action. Subpopulations of neurons in the ventromedial and arcuate hypothalamic nuclei are selectively either inhibited or activated by FA. Molecular effectors of these FA effects probably include chloride or potassium ion channels. While intracellular metabolism and activation of the ATP-sensitive K⁺ channel appear to be necessary for some of the signalling effects of FA, at least half of the FA responses in ventromedial hypothalamic neurons are mediated by interaction with FAT/CD36, an FA transporter/receptor that does not require intracellular metabolism to activate downstream signalling. Thus, FA or their metabolites can modulate neuronal activity as a means of directly monitoring ongoing fuel availability by brain nutrient-sensing neurons involved in the regulation of energy and glucose homeostasis. Recently, the role of lipoprotein lipase in FA sensing has also been shown in animal models not only in hypothalamus, but also in hippocampus and striatum. Finally, FA overload might impair neural control of energy homeostasis through enhanced ceramide synthesis and may contribute to obesity and/or type 2 diabetes pathogenesis in predisposed subjects.

Centrally administered urocortin 2 decreases gorging on high-fat diet in both diet-induced obesity-prone and -resistant rats.

OBJECTIVE: Obesity is a costly, deadly public health problem for which new treatments are needed. Individual differences in meal pattern have been proposed to have a role in obesity risk. The present study tested the hypothesis that (i) the microstructure of chronic high-fat diet intake differs between genetically selected diet-induced obesity (DIO) and diet-resistant (DR) rats, and (ii) central administration of urocortin 2 (Ucn 2), a corticotropin-releasing factor type 2 agonist, decreases high-fat diet intake not only in lean DR rats, but also in obese DIO rats. DESIGN: Male, selectively bred DIO and DR rats (n=10/genotype) were chronically fed a high-fat diet. Food and water intake as well as ingestion microstructure were then compared under baseline conditions and following third intracerebroventricular injection of Ucn 2 (0, 0.1, 0.3, 1, 3 µg). RESULTS: Irrespective of genotype, Ucn 2 reduced nocturnal food intake with a minimum effective dose of 0.3 µg, suppressing high-fat diet intake by ∼40% at the 3 µg dose. Ucn 2 also made rats of both genotypes eat smaller and briefer meals, including at doses that did not reduce drinking. Obese DIO rats ate fewer but larger meals than DR rats, which they ate more quickly and consumed with two-third less water. CONCLUSIONS: Unlike leptin and insulin, Ucn 2 retains its full central anorectic efficacy to reduce high-fat diet intake even in obese, genetically prone DIO rats, which otherwise show a 'gorging' meal pattern. These results open new opportunities of investigation toward treating some forms of DIO.

Smoking is associated with impaired verbal learning and memory performance in women more than men.

Vascular contributions to cognitive impairment and dementia (VCID) include structural and functional blood vessel injuries linked to poor neurocognitive outcomes. Smoking might indirectly increase the likelihood of cognitive impairment by exacerbating vascular disease risks. Sex disparities in VCID have been reported, however, few studies have assessed the sex-specific relationships between smoking and memory performance and with contradictory results. We investigated the associations between sex, smoking, and cardiovascular disease with verbal learning and memory function. Using MindCrowd, an observational web-based cohort of ~ 70,000 people aged 18-85, we investigated whether sex modifies the relationship between smoking and cardiovascular disease with verbal memory performance. We found significant interactions in that smoking is associated with verbal learning performance more in women and cardiovascular disease more in men across a wide age range. These results suggest that smoking and cardiovascular disease may impact verbal learning and memory throughout adulthood differently for men and women.

Two separate, large cohorts reveal potential modifiers of age-associated variation in visual reaction time performance.

To identify potential factors influencing age-related cognitive decline and disease, we created MindCrowd. MindCrowd is a cross-sectional web-based assessment of simple visual (sv) reaction time (RT) and paired-associate learning (PAL). svRT and PAL results were combined with 22 survey questions. Analysis of svRT revealed education and stroke as potential modifiers of changes in processing speed and memory from younger to older ages (ntotal = 75,666, nwomen = 47,700, nmen = 27,966; ages 18-85 years old, mean (M)Age = 46.54, standard deviation (SD)Age = 18.40). To complement this work, we evaluated complex visual recognition reaction time (cvrRT) in the UK Biobank (ntotal = 158,249 nwomen = 89,333 nmen = 68,916; ages 40-70 years old, MAge = 55.81, SDAge = 7.72). Similarities between the UK Biobank and MindCrowd were assessed using a subset of MindCrowd (UKBb MindCrowd) selected to mirror the UK Biobank demographics (ntotal = 39,795, nwomen = 29,640, nmen = 10,155; ages 40-70 years old, MAge = 56.59, SDAge = 8.16). An identical linear model (LM) was used to assess both cohorts. Analyses revealed similarities between MindCrowd and the UK Biobank across most results. Divergent findings from the UK Biobank included (1) a first-degree family history of Alzheimer's disease (FHAD) was associated with longer cvrRT. (2) Men with the least education were associated with longer cvrRTs comparable to women across all educational attainment levels. Divergent findings from UKBb MindCrowd included more education being associated with shorter svRTs and a history of smoking with longer svRTs from younger to older ages.

Synergy of nature and nurture in the development of childhood obesity.

Epidemiological studies suggest that maternal undernutrition, obesity and diabetes during gestation and lactation can all produce obesity in human offspring. Animal models provide a means of assessing the independent consequences of altering the pre- vs postnatal environments on a variety of metabolic, physiological and neuroendocrine functions, which lead to the development of offspring obesity, diabetes, hypertension and hyperlipidemia. During the gestational period, maternal malnutrition, obesity, type 1 and type 2 diabetes, and psychological and pharmacological stressors can all promote offspring obesity. Normal postnatal nutrition can sometimes reduce the adverse effect of some of these prenatal factors, but may also exacerbate the development of obesity and diabetes in offspring of dams that are malnourished during gestation. The genetic background of the individual is also an important determinant of outcome when the perinatal environment is perturbed. Individuals with an obesity-prone genotype are more likely to be adversely affected by factors such as maternal obesity and high-fat diets. Many perinatal manipulations are associated with reorganization of the central neural pathways which regulate food intake, energy expenditure and storage in ways that enhance the development of obesity and diabetes in offspring. Both leptin and insulin have strong neurotrophic properties so that an excess or an absence of either of them during the perinatal period may underlie some of these adverse developmental changes. As perinatal manipulations can permanently and adversely alter the systems that regulate energy homeostasis, it behooves us to gain a better understanding of the factors during this period that promote the development of offspring obesity as a means of stemming the tide of the emerging worldwide obesity epidemic.

Presynaptic location and axonal transport of beta 1-adrenoreceptors in the rat brain.

Interruption of the ascending noradrenergic neurons of the locus coeruleus in the rat forebrain with 6-hydroxydopamine produced a progressive accumulation, proximal to the lesion, of tritiated dihydroalprenolol binding activity over 2 days. This accumulation could be blocked by interrupting the neurons closer to their cell bodies. Competitive binding studies with the beta 2 agonist Zinterol suggested that the accumulated beta-receptors were primarily of the beta 1 subtype. These results suggest that, in the rat brain, some beta 1-adrenoreceptors are located in presynaptic, noradrenergic locus coeruleus neurons and are transported in their axons.

Presumed apoptosis and reduced arcuate nucleus neuropeptide Y and pro-opiomelanocortin mRNA in non-coma hypoglycemia.

Hypoglycemia reduces sympathoadrenal responses to subsequent hypoglycemic bouts by an unknown mechanism. To assess whether such hypoglycemia-associated autonomic failure is due to actual brain damage, male Sprague-Dawley rats underwent 1-h bouts of insulin-induced (5 U/kg i.v.) hypoglycemia (1.6-2.8 mmol/l) 1 or 3 times on alternate days. Rats remained alert and were rescued with intravenous glucose at 60-80 min. Plasma epinephrine and corticosterone responses were significantly reduced during the second and third bouts. Brains from these rats were processed by the terminal transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) procedure as an index of apoptotic cell death at 24, 48, or 96 h after their first bout. At 48 h, but not 24 h, TUNEL+ cells were consistently seen only in the arcuate nucleus (arcuate hypothalamic nucleus [ARC]). Hypoglycemic rats had 188% more apoptotic ARC cells (1 bout 39+/-5; 3 bouts 37+/-4) than euglycemic controls (13+/-3;P = 0.001). In situ hybridization for neuropeptide Y (NPY) and proopiomelanocortin (POMC) mRNA was performed in sections of ARC containing maximal numbers of apoptotic cells as well as in other fresh frozen brains. After 1 bout, NPY (0.041+/-0.003) and POMC (0.119+/-0.022) mRNA were decreased, respectively, by 52 and 55% vs. controls (NPY 0.076+/-0.007; POMC 0.222+/-0.020; P = 0.01). NPY (0.029+/-0.002) but not POMC (0.093+/-0.013) fell 29% further after a third bout. NPY (r = -0.721; P = 0.001) and POMC (r = -0.756; P = 0.001) mRNA levels correlated negatively with the number of apoptotic ARC cells in the same sections. Thus, non-coma hypoglycemia produces apparent apoptotic cell death with reduced NPY and POMC expression selectively in the ARC. This may contribute to the reduced counterregulatory response following repeated bouts of hypoglycemia.

Convergence of pre- and postsynaptic influences on glucosensing neurons in the ventromedial hypothalamic nucleus.

Glucosensing neurons in the ventromedial hypothalamic nucleus (VMN) were studied using visually guided slice-patch recording techniques in brain slices from 14- to 21-day-old male Sprague-Dawley rats. Whole-cell current-clamp recordings were made as extracellular glucose levels were increased (from 2.5 to 5 or 10 mmol/l) or decreased (from 2.5 to 0.1 mmol/l). Using these physiological conditions to define glucosensing neurons, two subtypes of VMN glucosensing neurons were directly responsive to alterations in extracellular glucose levels. Another three subtypes were not directly glucose-sensing themselves, but rather were presynaptically modulated by changes in extracellular glucose. Of the VMN neurons, 14% were directly inhibited by decreases in extracellular glucose (glucose-excited [GE]), and 3% were directly excited by decreases in extracellular glucose (glucose-inhibited [GI]). An additional 14% were presynaptically excited by decreased glucose (PED neurons). The other two subtypes of glucosensing neurons were either presynaptically inhibited (PIR; 11%) or excited (PER; 8%) when extracellular glucose was raised to > 2.5 mmol/l. GE neurons sensed decreased glucose via an ATP-sensitive K(+) (K(ATP)) channel. The inhibitory effect of increased glucose on PIR neurons appears to be mediated by a presynaptic gamma-aminobutyric acid-ergic glucosensing neuron that probably originates outside the VMN. Finally, all types of glucosensing neurons were both fewer in number and showed abnormal responses to glucose in a rodent model of diet-induced obesity and type 2 diabetes.

Localization of glucokinase gene expression in the rat brain.

The brain contains a subpopulation of glucosensing neurons that alter their firing rate in response to elevated glucose concentrations. In pancreatic beta-cells, glucokinase (GK), the rate-limiting enzyme in glycolysis, mediates glucose-induced insulin release by regulating intracellular ATP production. A similar role for GK is proposed to underlie neuronal glucosensing. Via in situ hybridization, GK mRNA was localized to hypothalamic areas that are thought to contain relatively large populations of glucosensing neurons (the arcuate, ventromedial, dorsomedial, and paraventricular nuclei and the lateral area). GK also was found in brain areas without known glucosensing neurons (the lateral habenula, the bed nucleus stria terminalis, the inferior olive, the retrochiasmatic and medial preoptic areas, and the thalamic posterior paraventricular, interpeduncular, oculomotor, and anterior olfactory nuclei). Conversely, GK message was not found in the nucleus tractus solitarius, which contains glucosensing neurons, or in ependymal cells lining the third ventricle, where others have described its presence. In the arcuate nucleus, >75% of neuropeptide Y-positive neurons also expressed GK, and most GK+ neurons also expressed KIR6.2 (the pore-forming subunit of the ATP-sensitive K+ channel). The anatomic distribution of GK mRNA was confirmed in micropunch samples of hypothalamus via reverse transcription-polymerase chain reaction (RT-PCR). Nucleotide sequencing of the recovered PCR product indicated identity with nucleotides 1092-1411 (within exon 9 and 10) of hepatic and beta-cell GK. The specific anatomic localization of GK mRNA in hypothalamic areas known to contain glucosensing neurons and the coexpression of KIR6.2 and NPY in GK+ neurons support a role for GK as a primary determinant of glucosensing in neuropeptide neurons that integrate multiple signals relating to peripheral energy metabolism.

The regulation of glucose-excited neurons in the hypothalamic arcuate nucleus by glucose and feeding-relevant peptides.

Glucosensing neurons in the hypothalamic arcuate nucleus (ARC) were studied using electrophysiological and immunocytochemical techniques in neonatal male Sprague-Dawley rats. We identified glucose-excited and -inhibited neurons, which increase and decrease, respectively, their action potential frequency (APF) as extracellular glucose levels increase throughout the physiological range. Glucose-inhibited neurons were found predominantly in the medial ARC, whereas glucose-excited neurons were found in the lateral ARC. ARC glucose-excited neurons in brain slices dose-dependently increased their APF and decreased their ATP-sensitive K+ channel (KATP channel) currents as extracellular glucose levels increased from 0.1 to 10 mmol/l. However, glucose sensitivity was greatest as extracellular glucose decreased to <2.5 mmol/l. The glucokinase inhibitor alloxan increases KATP single-channel currents in glucose-excited neurons in a manner similar to low glucose. Leptin did not alter the activity of ARC glucose-excited neurons. Although insulin did not affect ARC glucose-excited neurons in the presence of 2.5 mmol/l (steady-state) glucose, they were stimulated by insulin in the presence of 0.1 mmol/l glucose. Neuropeptide Y (NPY) inhibited and alpha-melanocyte-stimulating hormone stimulated ARC glucose-excited neurons. ARC glucose-excited neurons did not show pro-opiomelanocortin immunoreactivity. These data suggest that ARC glucose-excited neurons may serve an integrative role in the regulation of energy balance.

Ultradian rhythm of plasma norepinephrine in rats.

This study examined the possibility that laboratory rats exhibit ultradian plasma catecholamine rhythms. Four rats were prepared with chronic venous cannulas. After recovery, blood was sampled every 15 min for 8 h. Spectrum analysis revealed ultradian norepinephrine rhythms with spectral peaks around 80-90 min and around 40 min. However, no reliable ultradian rhythms were found for epinephrine. Ultradian norepinephrine rhythms appeared to be synchronized across three of the four rats, suggesting that the rhythm can be synchronized by some environmental stimulus. Thus, rats exhibit ultradian norepinephrine rhythms similar to those found in humans and in rhesus monkeys, indicating (a) that laboratory rats can be used to study the biological mechanisms of ultradian rhythms and (b) that ultradian oscillations of sympathetic function are a common property of mammalian systems.

Vibrissectomy induced changes in GAP-43 immunoreactivity in the adult rat barrel cortex.

Within the rat primary somatosensory cortex, neurons responding principally to movement of each individual mystacial vibrissa are grouped together in structures termed barrels. Previous studies have examined changes in the area of cortex showing increased 2-deoxyglucose uptake in response to vibrissal stimulation. These studies have shown that chronic removal of all but the central (C3) vibrissa in adult rats induces an enlarged representation of the remaining C3 barrel in the contralateral cortex. This increase is prevented by cortical norepinephrine depletion. The major question raised by such studies is whether such plasticity is due to structural rearrangement or unmasking of otherwise silent synapses. In this study, antibodies to GAP-43, a presynaptic protein whose synthesis is related to neuronal development and regeneration, were used to investigate this issue. In adult rat brain, tangential sections through layer IV of the barrel receptor field normally show moderate levels of GAP-43 immunoreactivity (GAP-IR) in the inter-barrel septa and low levels within the barrels themselves. The present study examined changes in the pattern of GAP-IR from 1 to 8 weeks after vibrissectomy with sparing of C3 as an index of possible physical reorganization of cortical circuits. Quantitative analysis of the cortices of animals with unilateral vibrissectomy with sparing of C3 showed that the area of low GAP-IR within the barrels surrounding C3 was decreased at 1 week (8.4% shrinkage; P less than 0.01) and 8 weeks (12.0% shrinkage; P less than 0.015), relative to the cortex ipsilateral to the surgery. Both bilateral vibrissectomy with sparing of C3 and ibotenic acid lesions of the ventrobasal thalamus produced similar results. Some evidence was also seen that the area of low GAP-IR in the C3 barrel shrank to a similar degree after such manipulations. Cortical norepinephrine depletion had no apparent effect on vibrissectomy-induced GAP-IR changes. These results suggest that removal of vibrissal input to the adult rat barrel cortex produces transynaptic induction of axonal sprouting within the barrel cortex.

The clinical significance of spontaneous pulsations of the retinal vein.

A search for spontaneous retinal venous pulsations was carried out in 218 subjects. Spontaneous venous pulsations were present in 87.6% of 146 unselected subjects 20 to 90 years of age and absent in 100% of 33 patients with raised intracranial pressure without papilledema and ten patients with papilledema. Lumbar puncture in nine patients with raised intracranial pressure established the upper level at which spontaneous pulsations disappear as 190 mm H2O, and no pressure above 180 mm H2O was found in 29 patients with venous pulsations present prior to lumbar puncture. There was no correlation between the presence or absence of venous pulsations and blood pressure. Some normal subjects with absent pulsations showed definite pulsations on subsequent examinations. These findings confirm that the presence of spontaneous venous pulsations is a reliable indicator of an intracranial pressure below 180 to 190 mm H2O, while the absence of pulsations may be found with normal intracranial pressure and is therefore not a reliable guide to raised intracranial pressure.

A longitudinal examination of crossed aphasia.

OBJECTIVE: To longitudinally examine neuropsychological performance in an adult dextral man with crossed aphasia after cerebrovascular accident. DESIGN: Case report using longitudinal neuropsychological, neurological, and radiological examinations performed in close temporal proximity to one another. SETTING: The patient was seen on both an inpatient and an outpatient basis by members of the Department of Neurology and Radiology of the University of Miami (Fla) School of Medicine. PATIENT: Thirty-four-year-old right-handed monolingual Hispanic man without family history of left-handedness. RESULTS: Initial neuropsychological testing revealed classic Broca's dysphasia, visual neglect, and visuospatial disturbances. The visuospatial disturbance resolved within 6 months whereas expressive language remained severely impaired. There was a dissociation between praxis and language. Mood was jovial with indifference toward his neurologic and cognitive limitations. Serial magnetic resonance imaging studies unequivocally localized the lesions to the right hemisphere, involving the right frontal, anterior parietal, and subcortical white matter. CONCLUSIONS: The clinicoanatomic correlation is compatible with the view that crossed aphasia is a "mirror" representation of that seen in cases of uncrossed aphasia. The course of recovery suggests complete lateralization of language to the right hemisphere with bilateral or crossed representation of nonverbal skills.

Comprehensive evaluation of left hemisphere type I schizencephaly.

We report the neuropsychological, magnetic resonance imaging, electroencephalographic telemetry, and sodium amytal test findings of a 32-year-old, left-handed man with unilateral left hemisphere type I schizencephaly. The patient was referred for treatment of medically refractory left temporal complex partial seizures that developed at age 26 years. Sodium amytal testing revealed complete incorporation of speech and language function by the right hemisphere. Detailed neuropsychological evaluation indicated average to above-average performance on all measures of language skills, judgment and reasoning, visuospatial abilities, and memory function. This case demonstrates that extensive but lateralized neuronal migration disorders can be associated with complete reorganization and full recovery of function by the contralateral hemisphere. Furthermore, this case supports the view that the degree of recovery is greatest when compensatory mechanisms are activated antenatally.

Dorsal column stimulation: Effect on human cerebrospinal fluid and plasma catecholamines.

Plasma and cerebrospinal fluid catecholamines were measured in three patients with multiple sclerosis who had dorsal column stimulators placed at the T5-7 levels. Stimulation for 3 minutes and 20 minutes increased release of plasma norepinephrine, epinephrine, and dopamine, as well as norepinephrine into the cerebrospinal fluid. Neither dopamine nor epinephrine was released into the spinal fluid during or after stimulation. Percutaneous stimulation did not release catecholamines into the plasma or spnal fluid, suggesting that these findings were not simply related to sensory stimulation or stress. Plasma catecholamine levels were inconsistently correlated with pulse rate changes during and after stimulation but not with blood pressure, although the changes in pulse rate and blood pressure were relatively small compared to changes in plasma catecholamines. This study suggests that plasma catecholamines and spinal fluid norepinephrine reflect central activation of sympathetic nervous system pathways and are more reliable indicators of sympathetic activity than changes in cardiovascular function.

Cognitive impairments associated with early Parkinson's disease.

We administered a battery of cognitive tests to 41 recently diagnosed Parkinson patients and 41 controls to assess the early neuropsychological changes associated with Parkinson's disease (PD). Parkinson subjects did as well as controls on tasks assessing attention and select language and visuospatial measures. However, PD subjects did significantly worse on embedded figures, facial recognition, proverbs, and verbal and figural memory measures, and made more perseverative responses on a set shifting task. A discriminant function of measures of proverbs, embedded figures, and memory accounted for 22% of the variance between groups. These data suggest that the cognitive changes in early PD are more pervasive than originally described and may reflect the onset of a more widespread pathologic process.

Cognitive outcome of children with epilepsy and malformations of cortical development.

OBJECTIVE: To assess intellectual functioning (IQ) in 54 children and adolescents with intractable epilepsy who later underwent cortical resection due to unilateral malformations of cortical development acquired in utero. METHODS: Lesion type was classified into circumscribed mass lesions and diffuse cortical dysplasia based on histopathologic analysis of surgical tissue. Cortical dysplastic lesions were further graded as mild, moderate, or severe according to specific microscopic features. Laterality of lesion was determined through neurologic examination and electrophysiologic and neuroradiologic procedures. Classification of lesion type was corroborated by its significant relationship with other disease-related variables known to be related to clinical severity (age at seizure onset, age at resection, and extent of lesion). RESULTS: Analyses of covariance revealed that circumscribed lesions had a less deleterious effect on nonverbal IQ than did diffuse cortical dysplasia, after controlling for age at seizure onset and extent of lesion. This effect was also found on verbal IQ measures, but only in subjects with right-sided lesions. Subjects with left-sided lesions performed significantly more poorly on verbal IQ measures than those with right-sided lesions. Additionally, younger age at onset and greater extent of lesion were associated with poorer cognitive outcome. CONCLUSIONS: Cortical dysplasia and early left hemisphere lesions have a significantly worse impact on cognitive functioning than circumscribed lesions or right hemisphere developmental lesions in children with epilepsy.

Effects of unbalanced diets on cerebral glucose metabolism in the adult rat.

We measured regional cerebral metabolic rates for glucose and selected cerebral metabolites in rats fed one of the following diets for 6 to 7 weeks: (1) regular laboratory chow; (2) high-fat, carbohydrate-free ketogenic diet deriving 10% of its caloric value from proteins and 90% from fat; and (3) high-carbohydrate diet deriving 10% of its caloric value from proteins, 78% from carbohydrates, and 12% from fat. In preliminary experiments, we found that moderate ketosis could not be achieved by diets deriving less than about 90% of their caloric value from fat. Rats maintained on the ketogenic diet had moderately elevated blood beta-hydroxybutyrate (O.4 mM) and acetoacetate (0.2 mM), and a five- to 10-fold increase in their cerebral beta-hydroxybutyrate level. Cerebral levels of glucose, glycogen, lactate, and citrate were similar in all groups. 2-Deoxyglucose studies showed that the ketogenic diet did not significantly alter regional brain glucose utilization. However, rats maintained on the high-carbohydrate diet had a marked decrease in their brain glucose utilization and increased cerebral concentrations of glucose 6-phosphate. These findings indicate that long-term moderate ketonemia does not significantly alter brain glucose phosphorylation. However, even marginal protein dietary deficiency, when coupled with a carbohydrate-rich diet, depresses cerebral glucose utilization to a degree often seen in metabolic encephalopathies. Our results support the clinical contention that protein dietary deficiency coupled with increased carbohydrate intake can lead to CNS dysfunction.

Visuospatial impairment in Parkinson's disease.

We explored the nature of the visuospatial deficit in Parkinson's disease (PD) and its progression as a function of disease duration. We compared the performance of 183 patients with idiopathic PD and 90 control subjects matched for age and education on six visuospatial measures. We divided patients into three groups according to the disease duration: early (1 to 4 years), middle (5 to 10 years), and advanced (greater than 10 years). Performance deteriorated in five of the six visuospatial measures, as a function of disease duration. However, the pattern of visuospatial decline depended on whether dementia was present. The results were not influenced by age or anticholinergic medication. These findings support the presence of visuospatial deficits in PD patients, with a changing pattern of impairment related to dementia and progression of the disease.