Receptor characteristics and recovery of function following kainic acid lesions and fetal transplants of the striatum. I. Cholinergic systems

The relationship between striatal muscarinic cholinergic receptor development and locomotor activity/T-maze alternation behavior in adult female rats with kainic acid lesions (kal) and fetal transplants of the striatum (str) was examined. Kal led to a number of deficits under conditions of spontaneous locomotion, including: (1) decreased stereotypical and increased horizontal movements during spontaneous overnight locomotion, (2) decreased spontaneous alternation on a T-maze, and (3) deficits on a sensorimotor neurological exam. Lesion-induced deficits following injection with cholinergic agonists (pilocarpine)/antagonists (scopolamine) included: (1) hypoactivity on vertical activity and stereotypical activity following scopolamine injection, and (2) increased stereotypical activity and decreased horizontal activity following pilocarpine injection. Transplants differentially affected the different types of behavioral deficits. Transplants reversed some of the deficits under conditions of spontaneous locomotion, including the hyperactivity noted during the night period, but only partially reversed the sensorimotor neurological exam and had no effect on spontaneous alternations in the T-maze. The transplants did not reverse the lesion-induced deficits following scopolamine injection, but partially reversed the lesion-induced changes in locomotion following pilocarpine injection. The striatal transplants had reduced numbers of M1 but increased numbers of M2 muscarinic cholinergic receptors. Cholinergic receptor density correlated with scores on the sensorimotor functioning and alternation tasks, but not with the locomotor measures. Conversely, the cross-sectional area of the str correlated strongly with the transplant-induced recovery in the lesion group. These results suggest that the development of cholinergic receptor systems within the transplants proceeds abnormally, and that the abnormal development of the transplant may impact on the transplant's ability to remediate lesion-induced deficits.     

Gender differences in spontaneous and MK-801-induced activity after striatal lesions

At different times post-lesion, the excitotoxically lesioned striatum has been shown to undergo significant neuroanatomical and neurochemical changes, which could be expressed behaviorally. Gender and dose of excitotoxin are other variables that may modify the behavioral effects of the lesion. Consequently, the purpose of this study was to determine the effect of dose, gender, and time post-lesion on spontaneous and drug-induced locomotor behavior after intrastriatal KA lesions. Results showed that dose and time post-lesion had a significant effect on the deficits observed. Hyperactivity induced by the lesion with KA (5 nm) subsided as time post-lesion increased. Both the pattern of spontaneous and MK-801-induced locomotor activity were different for male and female rats. In female animals with KA lesions (5 nm), MK-801 did not stimulate ambulatory activity nor reduce vertical activity. Both female and male rats lesioned with KA (5 nm) showed an exaggerated response to amphetamine, at a time when spontaneous locomotor activity was reduced to control levels. Haloperidol significantly reduced locomotor activity in all groups.     

Asymmetrical motor behavior in rats with unilateral striatal excitotoxic lesions as revealed by the elevated body swing test

Severe degeneration of basal ganglia neurons, particularly the intrinsic neurons of the striatum, is the major underlying neuropathology implicated in clinical attributes of Huntington's disease (HD). The excitotoxin-lesioned striatum provides a useful model for evaluating behavioral parameters of HD. Animals with unilateral excitotoxic lesions exhibit asymmetrical rotational behavior in response to dopamine agonists, such as apomorphine. However, the observed behavior is a pharmacological reaction, and subject to sensitization effects. A behavioral test using undrugged animals may demonstrate a more natural response of the animals to the lesion effects. Recently, we have developed the ‘drug-free’ elevated body swing test (EBST), and demonstrated that hemiparkinsonian rats exhibited significant biased swing activity. In the present study, we observed that animals with unilateral intrastriatal 3-nitropropionic acid or quinolinic acid lesions displayed a significant biased swing activity with the direction ipsilateral to the lesioned side of the brain. This ipsilateral swing corresponded to the ipsilateral rotational behavior exhibited by the lesioned animals when challenged with apomorphine. The present results demonstrated that the EBST is a sensitive measure for characterizing asymmetrical behavior in animals with striatal lesions.     

Genes on distal chromosome 18 determine vulnerability to excitotoxic neurodegeneration following status epilepticus, but not striatal neurodegeneration induced by quinolinic acid

Previous studies have provided evidence that a quantitative trait locus (QTL) on the distal part of chromosome 18 (chr18) is a major determinant of vulnerability to hippocampal neurodegeneration following kainic acid (KA)-induced seizures in inbred mouse strains. We assessed excitotoxic vulnerability in two congenic, “genome tagged” mouse strains carrying segments of either distal or proximal/medial chr18 from vulnerable DBA/2J mice on a resistant C57BL/6 background. Systemic KA injections triggered brain-wide neurodegeneration in the distal chr18 congenic strain, and specifically in the hilus of the dentate gyrus, but not in CA3. In contrast, the proximal/medial chr18 congenic strain exhibited enhanced degeneration in CA1 and CA3, but little neurodegeneration elsewhere. Both strains exhibited low levels of QUIN-induced striatal neurodegeneration comparable to what is seen in C57BL/6 mice. These results suggest that gene(s) on distal chr18 are important determinants of vulnerability to KA-induced hippocampal neurodegeneration, but not QUIN-induced striatal neurodegeneration.     

Human striatal neuroblasts develop and build a striatal-like structure into the brain of Huntington's disease patients after transplantation

Rebuilding brain structure and neural circuitries by transplantation of fetal tissue is a strategy to repair the damaged nervous system and is currently being investigated using striatal primordium in Huntington's disease (HD) patients. Four HD patients underwent bilateral transplantation with human fetal striatal tissues (9-12 week gestation). Small blocks of whole ganglionic eminencies were processed to obtain cell suspension and then stereotactically grafted in the caudate head and in the putamen. Follow-up period ranged between 18 and 34 months (mean, 24.7 months). Surgery was uneventful. Starting from the fourth month after grafting, neo-generation of metabolically active tissue with striatal-like MRI features was observed in 6 out of 8 grafts. The increase in D2 receptor binding suggested striatal differentiation of the neo-generated tissue in 3 patients. New tissue, connecting the developing grafts with the frontal cortex and, in one case, with the ventral striatum, was also observed. The new tissue growth halted after the ninth month post transplantation. All patients showed stabilization or improvement in some neurological indices. No clinical and imaging signs, suggestive of graft uncontrolled growth, were seen. This study provides the first evidence in humans that neuroblasts of a striatal primordium can develop and move into the brain after neurotransplantation. Primordium development resulted in the building of a new structure with the same imaging features as the corresponding mature structure, combined with short- and long-distance targeted migration of neuroblasts. The results of this study support both the reconstructive potential of fetal tissue and the remarkably retained plasticity of adult brain. Further studies are necessary to assess the clinical efficacy of the human fetal striatal transplantation.     

MK801 prevents quinolinic acid-induced behavioral deficits and neurotoxicity in the striatum

Bilateral intrastriatal injections of quinolinic acid (QA) (180 nmoles) induced weight loss and neurologic and behavioral deficits including convulsions, decreased catalepsy response to haloperidol, increased nocturnal locomotor activity, and abnormal feeding behavior in adult male Sprague-Dawley rats. Pretreatment with the noncompetitive N-methyl-D-aspartate (NMDA) antagonist, MK801 (4 mg/kg IP) 30 min prior to stereotaxic surgery prevented the appearance of all QA-induced behavioral abnormalities and prevented weight loss. Twelve weeks after surgery the QA-lesioned animals recovered to sham levels on feeding behavior and nocturnal locomotor activity, but showed persistent reductions in haloperidol-induced catalepsy. Histological examination of the QA-lesioned brains showed extensive lesions of the dorsolateral striatum and frontoparietal cortex. MK801 pretreatment protected against these lesions. These results confirm that MK801 treatment prevents the appearance of neuropathological damage after QA neurotoxicity, and further show that neuronal protection with MK801 is correlated with the absence of QA-induced behavioral deficits.     

The role of the striatum in sentence processing: evidence from a priming study in early stages of Huntington's disease

The role of sub-cortical structures such as the striatum in language remains a controversial issue. Based on linguistic claims that language processing implies both recovery of lexical information and application of combinatorial rules it has been shown that striatal damaged patients have difficulties applying conjugation rules while lexical recovery of irregular forms is broadly spared (e.g., Ullman, M. T., Corkin, S., Coppola, M., Hickok, G., Growdon, J. H., Koroshetz, W. J., et al. (1997). A neural dissociation within language: Evidence that the mental dictionary is part of declarative memory, and that grammatical rules are processed by the procedural system. Journal of Cognitive Neuroscience, 9(2), 266-276). Here we bolstered the striatum-rule hypothesis by investigating lexical abilities and rule application at the phrasal level. Both processing aspects were assessed in a model of striatal dysfunction, namely Huntington's disease (HD). Using a semantic priming task we compared idiomatic prime sentences involving lexical access to whole phrases (e.g., "Paul has kicked the bucket") with idiom-derived sentences that contained passivation changes involving syntactic movement rules (e.g., "Paul was kicked by the bucket"), word changes (e.g., "Paul has crushed the bucket") or either. Target words that were either idiom-related (e.g., "death") reflecting lexical access to idiom meanings, word-related (e.g., "bail") reflecting lexical access to single words, or unrelated (e.g., "table"). HD patients displayed selective abnormalities with passivated sentences whereas priming was normal with idioms and sentences containing only word changes. We argue that the role of the striatum in sentence processing specifically pertains to the application of syntactic movement rules whereas it is not involved in canonical rules required for active structures or in lexical processing aspects. Our findings support the striatum-rule hypothesis but suggest that it should be refined by tracking the particular kind of language rules depending on striatal computations.     

Picolinic acid modulates kainic acid-evoked glutamate release from the striatum in vitro

Since picolinic acid, a tryptophan metabolite yielded by the kynurenine pathway, selectively attenuates quinolinic and kainic acid excitotoxicity that is dependent on the presence of a glutamatergic afferent input, it was hypothesized that this agent may inhibit the presynaptic release of glutamate. Using superfused rat striatal slices, this study examined the potential of picolinic acid, and related pyridine monocarboxylic acids, to modify kainic acid-induced glutamate release. Kainic acid (0.25, 0.5 and 1.0 mM) stimulated the release of glutamate, an effect which was calcium dependent and was attenuated in the presence of the kainate/AMPA receptor antagonist, 6,7-dinitroquinoxalene-2,3-dione (500 μM). Picolinic acid significantly decreased glutamic acid release evoked by exposure of striatal slices to 1 mM kainate in the presence of calcium. The inhibitory action of picolinic acid on kainate-induced release was also shared by nicotinic and isonicotinic acid. In the absence of external calcium, kainic acid-induced glutamate release was significantly reduced by approximately 65%. Under this condition, picolinic acid (100 μM) failed to influence kainic acid-induced release. Picolinic acid (100 μM) itself increased glutamate release by 35% over basal release. While the ability of picolinic acid to inhibit excitotoxin-induced release supports the notion that it may act presynaptically to modify excitotoxicity, lack of structural specificity in its action tends to cast doubt on this mechanism of action.     

Striatal implants of fetal striatum or gelfoam protect against quinolinic acid lesions of the striatum

Previous studies in our laboratory have shown that intrastriatal implants of fetal striatum significantly attenuate excitotoxic damage resulting from a 240 nmol quinolinic acid (QA) challenge delivered 7 days later. In contrast, animals with intrastriatal implants of other tissue types (adipose tissue, peripheral nerve or adrenal medulla) demonstrate a more limited, but consistent trend in protection from QA excitotoxicity. The present study was designed to test the hypothesis that partial striatal protection found in animals receiving peripheral tissue grafts is due to the transplantation procedure eliciting a host response which attenuates excitotoxicity. Adult female Long-Evans rats received either cellular (fetal striatum) or acellular (gelfoam) implants followed 1 week later by a unilateral injection of 240 nmol QA into the grafted striatum. Animals were tested for rotational asymmetries before grafting, post-implantation, and after lesioning. Compared to baseline rotational behavior, rats which received implants did not show changes in ipsilateral turning after QA lesions. This protective effect was not limited to rotational behavior since improvements in spontaneous locomotor activity were evident. In addition, the adipsia and aphagia often associated with striatal lesions were ameliorated in both groups of grafted animals. Morphometric analysis demonstrated that endogenous dopaminergic, cholinergic and enkephalinergic systems in the two transplanted groups sustained less excitotoxic damage than in the QA lesioned, non-grafted animals. These results are consistent with the hypothesis that a host generated response activated by the implantation provides a protective effect against QA excitotoxicity.     

Synaptophysin expression in the striatum in Huntington's disease

Summary This immunohistochemical study compares the expression of synaptophysin (SYP) in the striatum in Huntington's disease (HD) with that of calcineurin (CaN), a marker for striatal medium-sized spinous neurons. As compared to controls, in the HD striatum there was a significant loss of SYP immunoreactivity with residual staining displaying an inhomogeneous pattern, which strikingly resembled that of CaN. Our results may indicate that there is a synaptic loss in the striatum with HD and this is most likely due to loss of medium-sized spinous neurons characteristic of this disease.     

The role of the striatum in phonological processing. Evidence from early stages of Huntington's disease

The linguistic role of subcortical structures such as the striatum is still controversial. According to the claim that language processing is subdivided into a lexical memory store and a computational rule system (Pinker, 1999) several studies on word morphology (e.g., Ullman et al., 1997) and on syntax (e.g., Teichmann et al., 2005) have suggested that the striatum is specifically dedicated to the latter component. However, little is known about whether the striatum is involved in phonological operations and whether its role in linguistic rule application generalizes to phonological processing. We investigated this issue by assessing perceptual compensation for assimilation rules in a model of striatal disorders, namely in the early stages of Huntington's disease (HD).In Experiment 1 we used a same-different task with isolated words to evaluate whether phoneme perception is intact in HD. In Experiment 2 a word detection task in phrasal contexts allowed for assessing both phoneme perception and perceptual compensation for the French regressive assimilation rule. Results showed that HD patients have normal performance with both phoneme perception in isolated words and regressive assimilation rules. However, in phrasal contexts they display reduced abilities of phoneme discrimination.These findings challenge the striatum-rule claim and suggest a more fine-grained function of striatal structures in linguistic rule processing. Alternative explanatory frameworks of the striatum-language link are discussed.     

The effects of lateralized training on spontaneous forelimb preference, lesion deficits, and graft-mediated functional recovery after unilateral striatal lesions in rats

The ability of striatal embryonic grafts to promote functional recovery on complex behavioral tasks depends on various factors, including the amount of striatal-like tissue within the grafts and the duration of post-graft training. However, how the innate paw bias of animals is affected by experience, or influences recovery following injury, is less known. Here, we have examined the effects of intrinsic side bias and lateralized limb use training on spontaneous forelimb preference and graft-mediated functional recovery in a skilled reaching task in a rodent model of Huntington's disease. Na?ve rats were assessed on their baseline paw preferences when reaching between the bars of their cage to retrieve sugar pellets from a tray attached outside. Next, rats were lesioned unilaterally in the lateral dorsal striatum with quinolinic acid, and 7-10 days later, half of the animals were given suspension grafts prepared from E15 whole ganglionic eminence implanted into the lesioned striatum. The animals then received extensive unilateral training, either ipsi- or contralateral to the side of the lesion and graft in separate subgroups, on the 'staircase' task until asymptotic performance was obtained. As reported previously, the grafts alleviated lesion-induced deficits in retrieving pellets from the contralateral staircase. Spontaneous biases were then reassessed in the cage-reaching task. Irrespective of whether the animal received ipsilateral or contralateral staircase training, the unilateral lesions induced a significant shift in spontaneous bias towards the ipsilateral paw. Grafted animals showed a similar shift in bias if staircase training was given to the ipsilateral paw but showed no change in spontaneous bias (similar to controls) if they had received contralateral training during the post-transplantation period. The results suggest that striatal grafts can alleviate lesion-induced changes in their spontaneous side preferences, but only if they receive extensive training in the use of the contralateral limb, compatible with the notion that recovery is use-dependent.     

Phosphodiesterase 10 inhibition reduces striatal excitotoxicity in the quinolinic acid model of Huntington's disease

Decreased activity of cAMP responsive element-binding protein (CREB) is thought to contribute to the death of striatal medium spiny neurons in Huntington's disease (HD). Therefore, therapies that increase levels of activated CREB, may be effective in fighting neurodegeneration in HD. In this study, we sought to determine whether the phosphodiesterase type 10 (PDE10A) inhibitor TP10 exerts a neuroprotective effect in an excitotoxic model of HD. Rats were surgically administered with quinolinic acid into striatum and subsequently treated with TP10 daily for two or eight weeks. After 2 weeks of TP10 treatment, striatal lesion size was 52% smaller and the surviving cell number was several times higher than in the vehicle-treated group. These beneficial effects of TP10 were maintained through 8 weeks. TP10 treatment also increased significantly the levels of activated CREB in the striatal spiny neurons, which is hypothesized to be a contributing mechanism for the neuroprotective effect. Our findings suggest PDE10A inhibition as a novel neuroprotective approach to the treatment of HD and confirm the importance of phosphodiesterase inhibition in fighting the disease.     

Blockade of quinolinic acid-induced neurotoxicity by pyruvate is associated with inhibition of glial activation in a model of Huntington's disease

In this study, we have examined the mechanisms involved in pyruvate-mediated neuroprotection against quinolinic acid (QA)-induced striatal damage. QA injection into the striatum caused widespread neuronal damage and extensive areas of lesions in core and penumbra. The involvement of oxidative-mediated striatal damage was suggested by increased expressions of peroxynitrite, marked lipid peroxidation, and formation of DNA oxidative damage products. Administration of pyruvate, a glycolysis end product with antioxidant activity, significantly reduced QA-mediated striatal lesions, neuronal degeneration, and oxidative damage, whereas another energy substrate, lactate, was ineffective against oxidative damage and only partially effective in reducing lesions and neuronal degeneration. Treatment with the iNOS inhibitor aminoguanidine attenuated QA-mediated striatal lesions and reduced oxidative damage, indicating that iNOS activation may be involved in the striatal oxidative damage induced by QA. A role for glial cells in mediating oxidative damage was suggested because pyruvate blocked the expression of iNOS and nitrotyrosine in activated microglia and astrocytes in QA-injected striatum. These data suggest that pyruvate reduces oxidative free radical damage in QA-injected striatum and could have clinical utility in the treatment of Huntington's disease (HD).     

Amelioration of behavioral deficits in a rat model of Huntington's disease by an excitotoxic lesion to the globus pallidus

Four groups of rats, sustaining a striatal quinolinic acid (QA) lesion, a pallidal QA lesion, a combined striatal + pallidal lesion, or sham operation, were tested in spontaneous and amphetamine-induced activity, spatial navigation in a water maze, position discrimination and reversal in a wet T maze, and food manipulation. The striatal lesion markedly impaired rats' performance on the motor and cognitive tasks. In contrast, rats sustaining a bilateral lesion to the GP in addition to the striatal lesion performed similarly to sham-operated rats on the motor and cognitive tasks, although they showed a transient decrease in activity levels. Given that a similar dysfunction of basal ganglia circuitry is thought to subserve the behavioral alterations seen in QA-lesioned rats and Huntington's disease (HD) patients, the present results raise the possibility that manipulations of the external segment of the globus pallidus (the primate analogue of the rat GP) could ameliorate some of HD symptoms.     

Excitotoxic effects of non-NMDA receptor agonists in organotypic corticostriatal slice cultures

The excitotoxic effects of the glutamate receptor agonists kainic acid (KA) and 2-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and the corresponding neuroprotective effects of the AMPA/KA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) were examined in corticostriatal slice cultures. The purpose was to examine the feasibility of these cultures for excitotoxic studies, and to demonstrate possible differential excitotoxic effects of KA and AMPA on striatal and cortical neurons. Slices of dorsolateral striatum with overlying neocortex were obtained from neonatal rats and grown on semiporous membranes in serum-free medium for 3-4 weeks before exposure to KA or AMPA for 48 h. The uptake by injured cells of the fluorescent dye propidium iodide (PI) added to the culture medium was used as a quantifiable measure for neuronal degeneration and compared with efflux of the cytosolic enzyme lactate dehydrogenase (LDH) into the culture medium and loss of glutamic acid decarboxylase (GAD) activity in the tissue. Histological sections were also stained by the fluorescent dye Fluoro-Jade (FJ), for degenerating neurons and by immunocytochemical staining for gamma-aminobutyric acid (GABA). Digitized images showed a dose (0-24 microM KA, 0-6 microM AMPA) and time (0-48 h) dependent increase in PI uptake in both striatum and cortex. In other cultures exposed to KA (24 microM) or AMPA (6 microM) together with NBQX (0.1-9 microM), NBQX was found to exert a differential neuroprotective effect on striatum and cortex at low doses. NBQX was thus more protective against KA in the cortex than in the striatum, while the opposite was seen in relation to AMPA. Regarding neurodegenerative markers, PI uptake was significantly correlated with (1) LDH release into the culture medium, (2) optical density of Fluoro-Jade staining, (3) loss of GAD-activity in tissue homogenates, and (4) loss of GABA-immunostained neurons. We conclude that both differences between compounds (AMPA vs. KA) and brain areas (striatum vs. cortex) can be demonstrated in corticostriatal slice cultures, which in conjunction with an established set of markers for neuronal cell damage appears to be a feasible model for studies of the neurotoxic and neuroprotective effects of glutamate receptor agonists and antagonists.     

Cortical and striatal neurone number in Huntington's disease

The total cortical and striatal neurone and glial numbers were estimated in five cases of Huntington's disease (three males, two females) and five age-and sex-matched control cases. Serial 500-m-thick gallocyanin-stained frontal sections through the left hemisphere were analysed using Cavalieri's principle for volume and the optical disector for cell density estimations. The average cortical neurone number of five controls (mean age 53±13 years, range 36–72 years) was 5.97×10⁹±320×10⁶, the average number of small striatal neurones was 82×10⁶±15.8×10⁶. The left striatum (caudatum, putamen, and accumbens) contained a mean of 273×10⁶±53×10⁶ glial cells (oligodendrocytes, astrocytes and unclassifiable glial profiles). The mean cortical neurone number in Huntington's disease patients (mean age 49±14 years, range 36–75 years) was diminished by about 33% to 3.99×10⁹±218×10⁶ nerve cells (P0.012, Mann-Whitney U-test). The mean number of small striatal neurones decreased tremendously to 9.72×10⁶±3.64×10⁶ (–88%). The decrease in total glial cells was less pronounced (193×10⁶±26×10⁶) but the mean glial index, the numerical ratio of glial cells per neurone, increased from 3.35 to 22.59 in Huntington's disease. Qualitatively, neuronal loss was most pronounced in supragranular layers of primary sensory areas (Brodmann's areae 3,1,2; area 17, area 41). Layer IIIc pyramidal cells were preferentially lost in association areas of the temporal, frontal, and parietal lobes, whereas spared layer IV granule cells formed a conspicuous band between layer III and V in these fields. Methodological issues are discussed in context with previous investigations and similarities and differences of laminar and lobar nerve cell loss in Huntington's disease are compared with nerve cell degeneration in other neuropsychiatric diseases.Supported by a grant from the Deutsche Forschungsgemeinschaft (He 1430/3-3)     

Executive dysfunction in early stages of Huntington's disease is associated with striatal and insular atrophy: a neuropsychological and voxel-based morphometric study

BACKGROUND: Huntington's disease (HD) is characterized by a progressive multisystem neuronal atrophy in the brain. Apart from motor signs, cognitive symptoms, particularly executive dysfunctions, are proposed to be recognizable in early stages of disease. The aim of the present study was to clarify if cognitive dysfunction in early stages of HD is correlated with loco-regional structural changes in 3D-MRI. METHODS: Twenty-five patients with genetically confirmed HD in early clinical stages were included in the study and underwent neuropsychological testing, i.e., the executive tasks Tower of Hanoi (ToH), Stroop Colour Word Interference Test (STROOP), and modified Wisconsin Card Sorting Test (mWCST). High-resolution volume-rendering MRI scans (MP-RAGE) were acquired on a 1.5 T scanner in all patients and were analyzed by statistical parametric mapping and voxel-based morphometry (VBM) in comparison to an age-matched control group. RESULTS: Group analysis of HD patients demonstrated robust regional decreases of gray matter volumes (p<0.05, corrected for multiple comparisons) in the caudate and the putamen bilaterally with a global maximum at Talairach coordinates 11/4/11 (Z-score=7.06). Executive dysfunction was significantly correlated with the areas of highest significant differences out of VBM results which were located bilaterally in the caudate (ToH: r=0.647, p<0.001; STROOP: r=0.503, p<0.01; mWCST: r=0.452, p<0.05). Moreover, subgroup analyses revealed marked insular atrophy (Talairach coordinates 43/-3/1; Z-score=5.64) in HD patients who performed worse in the single executive tasks. CONCLUSION: Two aspects were most remarkable in this correlational study: (i) striatal atrophy in HD patients in early stages plays an important role not only in impaired motor control but also in executive dysfunction, and (ii) extrastriatal cortical areas, i.e., the insular lobe, seem to be involved in executive dysfunction as assessed by neuropsychological tests requiring for planning and problem solving, stimulus response selectivity and concept formation.     

High suicidal ideation in persons testing for Huntington's disease

This study examined the first participants who registered for the Huntington's disease predictive testing program 1990-1995 in Stockholm, Sweden. A psychosocial investigation was performed to evaluate potential effects of the presymptomatic testing. The results showed no significant differences between 13 gene carriers and 21 noncarriers in pretest attitudes, expectations, general well-being, life satisfaction and lifestyle, the need for support, estimated sense of wellbeing or degree of health. However, both groups showed high suicidal ideation and self-injurious behavior. Noncarriers had a very high frequency of attempted suicide, and both groups had similarly pronounced psychiatric dysfunction. Their relatives also had high frequencies of psychiatric diseases, suicide or suicidal attempts. Most of the participants had a desire to meet a psychologist or a social worker. The need for counseling, using a well designed protocol, and the importance of focusing on suicide risk of participants in predictive testing programs is emphasized.     

Regional distribution of pre- and postsynaptic glutamatergic function in Alzheimer''s disease

The selective D₁-dopamine receptor antagonist SCH23390 and the more D₂-selective antagonist haloperidol produced marked catalepsy in rats. The novel excitotoxin quinolinic acid (QA) selectively destroys striatal neurons when injected directly into the striatum. Bilateral QA lesions of the rat striatum (150 nmol and 225 nmol per side) abolished the cataleptic response to both SCH23390 and haloperidol. These data indicate that the D₁- and/or D₂-dopamine receptors which mediate the cateleptic response are restricted to QA-sensitive neurons in the rat striatum.