Noradrenergic cardiac denervation is associated with gait velocity in Parkinson disease: a dual ligand PET study.

PURPOSE: Preliminary data suggest that gait abnormalities in Parkinson disease (PD) may be associated with sympathetic cardiac denervation. No kinematic gait studies were performed to confirm this observation. We aimed to correlate spatiotemporal kinematic gait parameters with cardiac sympathetic denervation as determined by cardiac [11C]HED PET in PD. METHODS: Retrospective database analysis of 27 PD patients with cardiac sympathetic denervation. All patients underwent spatiotemporal kinematic gait assessment (medication 'off' state), cardiac [11C]HED and dopaminergic brain [11C]DTBZ PET scans. We employed a hierarchical regression approach to examine associations between the extent of cardiac denervation, dopaminergic nigrostriatal neurodegeneration, and three gait parameters - velocity, step length and cadence. RESULTS: More extensive cardiac denervation was associated with slower velocity (estimate: -1.034, 95% CI [-1.65, -0.42], p = 0.002), shorter step length (estimate: -0.818, 95% CI [-1.43, -0.21], p = 0.011) and lower cadence (estimate: -0.752, 95% CI [-1.28, -0.23], p = 0.007) explaining alone 30% (Adjusted-R²: 0.297), 20% (Adjusted-R²: 0.202) and 23% (Adjusted-R²: 0.227) of the variability, respecivetly. These associations remained independent of striatal dopaminergic impairment and confounding factors such as age, Hoehn and Yahr (HY) stages, peripheral neuropathy, cognition, and autonomic symptoms. In contrast, striatal dopaminergic denervation was significantly associated with step length (estimate: 0.883, 95% CI [0.29, 1.48], p = 0.005), explaining about 24% of the variability but was dependent of HY stage. CONCLUSIONS: More severe cardiac noradrenergic denervation was associated with lower gait velocity, independent of striatal dopaminergic denervation and HY stage, impacting both step length and cadence. These results suggest independent contributions of the peripheral autonomic system degeneration on gait dynsfunction in PD.

Cardiac sympathetic denervation and anxiety in Parkinson disease.

BACKGROUND: Anxiety in Parkinson disease (PD) negatively impacts quality of life. While research predominantly focuses on central nervous system changes, some evidence suggests a connection between peripheral autonomic dysfunctions and PD-related anxiety. The role of the peripheral autonomic nervous system in this context may be overlooked. OBJECTIVES: This study explores the link between anxiety symptoms and cardiac sympathetic denervation in PD using 11C-meta-hydroxyephedrine ([11C]HED) PET cardiac imaging. METHODS: We studied 34 non-demented PD subjects, assessing anxiety levels through the Spielberg Anxiety State-Trait test trait section (STAI-T). Patients underwent comprehensive assessments along with [11C]HED cardiac and [11C]DTBZ brain PET. To identify subdimensions of STAI-T, we employed principal components analysis (PCA). We examined associations between the anxiety subdimensions and two measures of cardiac sympathetic denervation from [11C]HED PET. We utilized correlation and linear regression models for these analyses. RESULTS: PCA revealed two STAI-T results components: anxiety-depressive and pure anxiety subcomponents. Only pure anxiety significantly correlated with measures of cardiac sympathetic denervation (rhos -0.40, p = 0.018; 0.35, p = 0.043). Regression models confirmed a significant association, with cardiac sympathetic denervation explaining ∼20 % of pure anxiety variance, independent of sex, dopaminergic impairment, and anxiolytic treatments. DISCUSSION: This study provides preliminary evidence of peripheral autonomic nervous system abnormalities contributing to PD-related anxiety, suggesting dysregulation in peripheral autonomic functions influencing anxiety perception.

Widespread expression of the human and rat Huntington's disease gene in brain and nonneural tissues.

We have used RNA in situ hybridization to study the regional expression of the Huntington's disease gene (HD) and its rat homologue in brain and selected nonneural tissues. The HD transcript was expressed throughout the brain in both rat and human, especially in the neurons of the dentate gyrus and pyramidal neurons of the hippocampal formation, cerebellar granule cell layer, cerebellar Purkinje cells and pontine nuclei. Other brain areas expressed lower levels of the HD transcript without pronounced regional differences. Neuronal expression predominated over glial expression in all regions. HD mRNA was also expressed in colon, liver, pancreas and testes. The regional specificity of neuropathology in HD, which is most prominent in the basal ganglia, thus cannot be accounted for by the pattern of expression of HD.

Predicting Progression from Normal to MCI and from MCI to AD Using Clinical Variables in the National Alzheimer's Coordinating Center Uniform Data Set Version 3: Application of Machine Learning Models and a Probability Calculator.

Clinical trials are increasingly focused on pre-manifest and early Alzheimer's disease (AD). Accurately predicting clinical progressions from normal to MCI or from MCI to dementia/AD versus non-progression is challenging. Accurate identification of symptomatic progressors is important to avoid unnecessary treatment and improve trial efficiency. Due to large inter-individual variability, biomarker positivity and comorbidity information are often insufficient to identify those destined to have symptomatic progressions. Using only clinical variables, we aimed to predict clinical progressions, estimating probabilities of progressions with a small set of variables selected by machine learning approaches. This work updates our previous work that was applied to the National Alzheimer's Coordinating Center (NACC) Uniform Data Set Version 2 (V2), by using the most recent version (V3) with additional analyses. We generated a user-friendly conversion probability calculator which can be used for effectively pre-screening trial participants.

Impaired contrast sensitivity is associated with more severe cognitive impairment in Parkinson disease.

OBJECTIVES: Dopaminergic degeneration affects both nigrostriatal projection neurons and retinal amacrine cells in Parkinson disease (PD). Parkinsonian retinopathy is associated with impaired color discrimination and contrast sensitivity. Some prior studies described associations between color discrimination deficits and cognitive deficits in PD, suggesting that contrast discrimination deficits are due, at least in part, to cognitive deficits in PD. We investigated the relationship between cognitive deficits and impaired contrast sensitivity in PD. METHODS: PD subjects, n = 43; 15F/28M; mean age 66.5 ± 8.2, Hoehn and Yahr stage 2.6 ± 0.6, and duration of disease of 6.2 ± 5.0 years underwent neuropsychological and Rabin contrast sensitivity testing. RESULTS: Mean Rabin contrast sensitivity score was 1.34 ± 0.40. Bivariate analyses showed significant correlation between Rabin contrast sensitivity scores and global cognitive z-scores (R = 0.54, P = 0.0002). Cognitive domain Z-score post hoc analysis demonstrated most robust correlation between Rabin scores and executive functions (R = 0.49, P = 0.0009), followed by verbal learning (R = 0.44, P = 0.0028), visuospatial (R = 0.39, P = 0.001) and attention z-scores (R = 0.32, P = 0.036). CONCLUSIONS: Impaired contrast sensitivity in PD is robustly associated with cognitive deficits, particularly executive function deficits. These results suggest that contrast sensitivity may be a useful biomarker for cognitive changes in PD and may have implications for driving safety evaluations in PD.

Genetics and molecular biology of Huntington's disease.

In 1993, the genetic abnormality responsible for Huntington's disease was identified as a trinucleotide-repeat expansion in a novel gene. Much has been learned about the molecular genetics of Huntington's disease and the possible effects of the trinucleotide expansion in the development of this disease and other neurological disorders. The Huntington's disease locus is widely expressed throughout the brain and in many non-neural tissues. Current speculation about the pathogenesis of neuronal death concentrates on a 'gain of function' effect in which the abnormal protein has acquired a new and lethal property. Future research will define the normal function of the Huntington's disease locus, test hypotheses regarding the putative gain of function, and explore the factors that determine neuronal susceptibility to the effects of the abnormal allele.

The functional anatomy of basal ganglia disorders.

Basal ganglia disorders are a heterogeneous group of clinical syndromes with a common anatomic locus within the basal ganglia. To account for the variety of clinical manifestations associated with insults to various parts of the basal ganglia we propose a model in which specific types of basal ganglia disorders are associated with changes in the function of subpopulations of striatal projection neurons. This model is based on a synthesis of experimental animal and post-mortem human anatomic and neurochemical data. Hyperkinetic disorders, which are characterized by an excess of abnormal movements, are postulated to result from the selective impairment of striatal neurons projecting to the lateral globus pallidus. Hypokinetic disorders, such as Parkinson's disease, are hypothesized to result from a complex series of changes in the activity of striatal projection neuron subpopulations resulting in an increase in basal ganglia output. This model suggests that the activity of subpopulations of striatal projection neurons is differentially regulated by striatal afferents and that different striatal projection neuron subpopulations may mediate different aspects of motor control.

The p75 neurotrophin receptor augments survival signaling in the striatum of pre-symptomatic Q175(WT/HD) mice.

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder characterized by a constellation of motor, cognitive, and psychiatric features. Striatal medium spiny neurons, one of the most affected populations, are dependent on brain-derived neurotrophic factor (BDNF) anterogradely transported from the cortex for proper function and survival. Recent studies suggest both receptors for BDNF, TrkB and p75 neurotrophin receptor (p75), are improperly regulated in the striata of HD patients and mouse models of HD. While BDNF-TrkB signaling almost exclusively promotes survival and metabolic function, p75 signaling is able to induce survival or apoptosis depending on the available ligand and associated co-receptor. We investigated the role of p75 in the Q175 knock-in mouse model of HD by examining the levels and activation of downstream signaling molecules, and subsequently examining Hdh(+/Q175);p75(-/-) mice to determine if p75 represents a promising therapeutic target. In Hdh(+/Q175);p75(+/+) mice, we observed enhanced survival signaling as evidenced by an increase in phosphorylation and activation of Akt and the p65 subunit of NFκB in the striatum at 5 months of age and an increase in XIAP expression compared to Hdh(+/+);p75(+/+) mice; this increase was lost in Hdh(+/Q175);p75(-/-) mice. Hdh(+/Q175);p75(-/-) mice also showed a decrease in Bcl-XL expression by immunoblotting compared to Hdh(+/Q175);p75(+/+) and Hdh(+/+);p75(+/+) littermates. Consistent with diminished survival signaling, DARPP-32 expression decreased both by immunoblotting and by immunohistochemistry in Hdh(+/Q175);p75(-/-) mice compared to Hdh(+/+);p75(+/+), Hdh(+/Q175);p75(+/+), and Hdh(+/+);p75(-/-) littermates. Additionally, striatal volume declined to a greater extent in Hdh(+/Q175);p75(-/-) when compared to Hdh(+/Q175);p75(+/+) littermates at 12 months, indicating a more aggressive onset of degeneration. These data suggest that p75 signaling plays an early role in augmenting pro-survival signaling in the striatum and that disruption of p75 signaling at a pre-symptomatic age may exacerbate pathologic changes in Hdh(+/Q175) mice.

Diabetes, Gray Matter Loss, and Cognition in the Setting of Parkinson Disease.

RATIONALE AND OBJECTIVES: Parkinson disease (PD) is a progressive neurodegenerative disorder affecting motor and cognitive functions. Prior studies showed that patients with PD and diabetes (DM) demonstrate worse clinical outcomes compared to nondiabetic subjects with PD. Our study aimed at defining the relationship between DM, gray matter volume, and cognition in patients with PD. MATERIALS AND METHODS: This study included 36 subjects with PD (12 with DM, 24 without DM, mean age = 66). Subjects underwent high-resolution T1-weighted brain magnetic resonance imaging, [(11)C]dihydrotetrabenazine positron emission tomography imaging to quantify nigrostriatal dopaminergic denervation, clinical, and cognitive assessments. Magnetic resonance images were postprocessed to determine total and lobar cortical gray matter volumes. Cognitive testing scores were converted to z-scores for specific cognitive domains and a composite global cognitive z-score based on normative data computed. Analysis of covariance, accounting for effects of age, gender, intracranial volume, and striatal [(11)C]dihydrotetrabenazine binding, was used to test the relationship between DM and gray matter volumes. RESULTS: Impact of DM on total gray matter volume was significant (P = 0.02). Post hoc analyses of lobar cortical gray matter volumes revealed that DM was more selectively associated with lower gray matter volumes in the frontal regions (P = 0.01). Cognitive post hoc analyses showed that interaction of total gray matter volume and DM status was significantly associated with composite (P = 0.007), executive (P = 0.02), and visuospatial domain cognitive z-scores (P = 0.005). These associations were also significant for the frontal cortical gray matter. CONCLUSION: DM may exacerbate brain atrophy and cognitive functions in PD with greater vulnerability in the frontal lobes. Given the high prevalence of DM in the elderly, delineating its effects on patient outcomes in the PD population is of importance.

Neuronal intranuclear inclusions and neuropil aggregates in HdhCAG(150) knockin mice.

We studied the development of neuronal intranuclear inclusions (NIIs), neuropil aggregates (NAs), and expression of expanded repeat polyglutamine protein in the HdhCAG(150) knockin mouse model of Huntington's disease (HD). Diffuse nuclear localization of huntingtin protein (htt) was noted initially within striatal neurons at approximately 28 weeks, followed by the development of striatal htt immunoreactive NIIs by approximately 40 weeks. Striatal NIIs were observed initially in clusters within the matrix compartment but subsequently became diffusely distributed throughout the striatum. In the oldest animals (107 weeks), NIIs were enlarged and diffuse nuclear htt immunoreactivity reduced. Expression of ubiquitin immunoreactive NIIs paralleled but lagged behind the expression of htt immunoreactive NIIs. Abundant NIIs were found by approximately 75 weeks in layers 3 and 4 of somatosensory cortex and in layer 2 of piriform cortex. In the oldest animals, greater than 100 weeks, some NIIs were found in many brain regions. NAs were found mainly within the globus pallidus and substantia nigra, perhaps reflecting expression in striatal terminals. Cyclic AMP response element binding protein (CBP) was not localized to NIIs, arguing against gross sequestration of this transcriptionally active protein. Comparison of the relative levels of a common polyglutamine epitope in HdhCAG(150) knockin and hprtCAG(146) knockin mice shows greater expression of the polyglutamine epitope in the phenotypically less aggressive HdhCAG(150) knockin line. HdhCAG(150) knockin mice may be a model of early pathologic changes in HD.

GABAB binding sites in early adult and aging rat brain.

The effect of aging on GABAB binding was investigated in rat brain. Receptor autoradiography was used to investigate both GABAB and GABAA binding at 2 months, 3 months, 13 months, and 23 months. GABAB binding decreases significantly between 2 months and 23 months of age, as does GABAA binding, with was investigated in rat brain. Receptor autoradiography was used to investigate both GABAB and GABAA binding at 2 months, 3 months, 13 months, and 23 months. GABAB binding decreases significantly between 2 months and 23 months of age, as does GABAA binding, with the greatest decrease between 2 and 3 months. The decrease in GABAB binding appears to be due to a decrease in binding site affinity rather than a decrease in receptor density. The noncompetitive GABAB antagonist zinc, the competitive GABAB antagonist CGP 35348, and the guanyl nucleotide analogue GTP-gamma-S all inhibit GABAB binding identically in 2 month and 23 month brain. These data indicate subtle age-related changes in the GABAB binding in early adult life but little change with senescence.

Age-related decrease in GABAB receptor binding in the Fischer 344 rat inferior colliculus.

Quantitative receptor autoradiography was used to assess GABAB receptor binding in three primary subdivisions of the inferior colliculus (IC): dorsal cortex (DCIC), external cortex (ECIC), and the central nucleus (CIC) of 3-, 18-20-, and 26-month-old Fischer 344 rats. GABAB binding sites were localized using [3H]GABA in the presence of a saturating concentration of isoguvacine, a selective GABAA receptor agonist, to displace [3H]GABA bound to GABAA receptor sites. In the three IC subdivisions examined, GABAB receptor binding was significantly reduced in 26-month-old rats when compared to 3-month-old rats (DCIC, -44%; ECIC, -36%; CIC, -32%; p < 0.05). For comparison, GABAB binding was determined in the portion of cerebellum located in the recess of the IC. In the molecular layer of this region, there was no statistically significant differences in receptor binding between 3, 18-20-, and 26-month-old rats. In addition, there was not a significant age-related change in the cross-sectional area of the IC. These findings provide additional evidence to support the existence of selective age-related changes in GABA neurotransmitter function in the rat IC.

Autoradiography of L-type and N-type calcium channels in aged rat hippocampus, entorhinal cortex, and neocortex.

The present study examined brains from 6, 17, and 32 month old male (F344x BN)F1 rats to determine whether there was any age-related change in the distribution or density of L-type and N-type Ca2+ channels in hippocampus, entorhinal cortex, and neocortex, areas commonly involved in the generation of epileptic seizures. The L-type channel antagonist PN200-110 and the N-type channel antagonist omega-conotoxin GVIA were used to determine specific binding densities and the autoradiographic distribution of ligand binding was quantified by computer-assisted densitometry. One-way ANOVA noted a significant variance in the mean value of binding density between different age groups only in neocortex laminae IV-VI for [(3)H]PN200-110 binding (P < 0.05). Post-hoc testing indicated that the mean value of the 17 month old group was significantly less than those of the 6 and 32 month old groups (P < 0.05). These results indicate no overall age-related change in the number of L-type and N-type Ca2+ channels in brain areas frequently involved in seizure activity and suggest that age-related changes in brain Ca2+ physiology may be associated with changes in voltage-gated Ca2+ channel function rather than channel number.

Distributions of GABAA, GABAB, and benzodiazepine receptors in the forebrain and midbrain of pigeons.

Autoradiographic and immunohistochemical methods were used to study the distributions of GABAA, GABAB and benzodiazepine (BDZ) receptors in the pigeon fore- and midbrain. GABAA, GABAB and BDZ binding sites were found to be abundant although heterogeneously distributed in the telencephalon. The primary sensory areas of the pallium of the avian telencephalon (Wulst and dorsal ventricular ridge) tended to be low in all three binding sites, while the surrounding second order belt regions of the pallium were typically high in all three. Finally, the outermost rind of the pallium (termed the pallium externum by us), which surrounds the belt regions and projects to the striatum of the basal ganglia, was intermediate in all three GABAergic receptors types. Although both GABAA and benzodiazepine receptors were abundant within the basal ganglia, GABAA binding sites were densest in the striatum and BDZ binding sites were densest in the pallidum. Among the brainstem regions receiving GABAergic basal ganglia input, the anterior and posterior nuclei of the ansa lenticularis showed very low levels of all three receptors, while the lateral spiriform nucleus and the ventral tegmental area/substantia nigra complex contained moderate abundance of the three binding sites. The dorsalmost part of the dorsal thalamus (containing nonspecific nuclei) was rich in all three binding sites, while the more ventral part of the dorsal thalamus (containing specific sensory nuclei), the ventral thalamus and the hypothalamus were poor in all three binding sites. The pretectum was also generally poor in all three, although some nuclei displayed higher levels of one or more binding sites. The optic tectum, inferior colliculus, and central gray were rich in all three sites, while among the isthmic nuclei, the parvicellular isthmic nucleus was conspicuously rich in BDZ sites. The results show a strong correlation of the regional abundance of GABA binding sites with previously described distributions of GABAergic fibers and terminals in the avian forebrain and midbrain. The regional distribution of these binding sites is also remarkably similar to that in mammals, indicating a conservative evolution of forebrain and midbrain GABA systems among amniotes.

The death of Nicholas Bolkonski. Neurology in Tolstoy's War and Peace.

Painstaking realism is an essential feature of the fiction of Count Leo Tolstoy. One example of Tolstoy's attention to detail is the description of the death of Prince Nicholas Bolkonski in War and Peace. The information provided in War and Peace allows the identification of the prince's terminal illness as a brain-stem stroke and is probably the first description of the one-and-a-half syndrome. Prince Bolkonski is also portrayed as suffering from a dementing process. Tolstoy used the character of Prince Bolkonski to exemplify the rationalistic, Western-influenced aristocracy that dominated Russia at the end of the 18th century. Prince Bolkonski's decline and apoplectic death parallel the fate of Enlightenment thought in Eastern Europe. The clinical detail employed in this case illustrates how Tolstoy used symbolic characters without sacrificing the realism of War and Peace.

Alternative excitotoxic hypotheses.

The concept of excitotoxicity, neuronal death produced by overstimulation of excitatory amino acid receptors, has become a popular way of explaining the pathogenesis of neuronal death in a variety of acute and chronic neurologic diseases. While there is strong evidence supporting the role of excitotoxicity in acute processes such as hypoxia/ischemia and hypoglycemia, the role of excitotoxicity in chronic neurologic disease is not firmly established. To account for the inter- and intraregional variations in pathology of different neurodegenerative disorders, we suggest two modified forms of the excitotoxic hypothesis in which specific populations of neurons become more vulnerable to excitotoxic insult either by (1) possessing abnormal excitatory amino acid receptor subtypes or (2) being afflicted by any disease process that impairs cellular energy metabolism or otherwise decreases neuronal membrane potential. In these ways, excitotoxicity may be a final common pathway of neuronal death in a variety of neurodegenerative diseases.

AMPA and NMDA binding sites in the hypothalamic lateral tuberal nucleus: implications for Huntington's disease.

The excitatory amino acid (EAA) hypothesis of neuronal loss in Huntington's disease predicts that structures that show neuronal loss and gliosis will contain receptor-bearing neurons. In accordance with this hypothesis, the hypothalamic lateral tuberal nucleus, severely affected in Huntington's disease, showed a high density of NMDA and AMPA binding sites in four normal subjects.

Paroxysmal dystonic choreoathetosis linked to chromosome 2q: clinical analysis and proposed pathophysiology.

We describe clinical features of a large Polish-American kindred in which autosomal-dominant, paroxysmal dystonic choreoathetosis (PDC) was linked to a locus on chromosome 2q. Episodes of generalized dystonia and choreoathetosis involving the face and all extremities began in early childhood, lasted for 30 minutes to several hours, and occurred up to several times each week. There was no interruption of consciousness and EEGs were normal during the episodes. Paroxysmal dyskinesia occurred at rest both spontaneously and following caffeine or alcohol consumption. Neurologic examinations were normal between attacks. The cause of PDC is unknown. We deduced a model of PDC pathophysiology from analyzing neurophysiologic effects of alcohol and caffeine (which provoke attacks of PDC), the variably beneficial effects of levodopa-carbidopa, and the occurrence of dystonia and paroxysmal dyskinesia in biopterin synthesis disorders. We propose that nigrostriatal neurons in PDC patients have either marginally deficient dopamine synthesis or excessive alcohol- and caffeine-induced dopamine release; and that following alcohol- and caffeine-induced dopamine release, PDC patients experience a period of dopamine deficiency.

(+)-alpha-[11C]Dihydrotetrabenazine PET imaging in familial paroxysmal dystonic choreoathetosis.

Clinical observations suggest a disturbance of striatal dopaminergic function in familial paroxysmal dystonic choreoathetosis (PDC). The authors used PET with [11C]dihydrotetrabenazine (DTBZ) to study striatal dopaminergic innervation in PDC. The results did not reveal abnormal DTBZ binding potential in PDC striatum. This suggests that dopaminergic abnormalities, if present, may be due to altered regulation of dopamine release or to postsynaptic mechanisms, rather than to an altered density of nigrostriatal innervation.