Risky driving and pedunculopontine nucleus-thalamic cholinergic denervation in Parkinson disease

BackgroundIt is unknown whether driving difficulty in Parkinson disease (PD) is attributable to nigrostriatal dopaminergic or extranigral non-dopaminergic neurodegeneration.ObjectiveTo investigate in vivo imaging differences in dopaminergic and cholinergic innervation between PD patients with and without a history of risky driving.MethodsThirty non-demented PD subjects (10 women/20 men) completed a driving survey. These subjects had previously undergone (+)-[¹¹C] dihydrotetrabenazine vesicular monoamine transporter 2 and [¹¹C] methyl-4-piperidinyl propionate acetylcholinesterase PET imaging. Acetylcholinesterase PET imaging assesses cholinergic terminal integrity with cortical uptake largely reflecting basal forebrain and thalamic uptake principally reflecting pedunculopontine nucleus integrity.ResultsEight of thirty subjects reported a history of risky driving (been pulled over, had a traffic citation, or been in an accident since PD onset) while 22 had no such history (safe drivers). There was no difference in striatal dihydrotetrabenazine vesicular monoamine transporter uptake between risky and safe drivers. There was significantly less thalamic acetylcholinesterase activity in the risky drivers compared to safe drivers (0.0513 ± 0.006 vs. 0.0570 ± 0.006, p = 0.022) but no difference in neocortical acetylcholinesterase activity. Using multivariable logistic regression, decreased thalamic acetylcholinesterase activity remained an independent predictor of risky driving in PD even after controlling for age and disease duration.ConclusionsRisky driving is related to pedunculopontine nucleus-thalamic but not neocortical cholinergic denervation or nigrostriatal dopaminergic denervation in PD. This suggests that degeneration of the pedunculopontine nucleus, a brainstem center responsible for postural and gait control, plays a role in the ability of PD patients to drive.     

Neurofibrillary tangles in cholinergic pedunculopontine neurons in Alzheimer's disease

The cholinergic neurons located within the pedunculopontine nucleus (Ch5) of patients with Alzheimer's disease (AD; n = 15), Parkinson's disease (PD; n = 2), and neurologically normal (n = 6) subjects were visualized immunohistochemically using choline acetyltransferase, pharmacohistochemically using acetylcholinesterase, or by reduced histochemical methods using nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d). Each histochemical procedure localized a well-delineated, compact lateral group and a more diffuse medial group of neurons within the pedunculopontine nucleus. Co-localization experiments revealed that all three enzymes marked the same population of cholinergic neurons. The extent of pathological alterations associated with the cholinergic neurons within the compact lateral sector of the pedunculopontine nucleus was examined in sections that reacted for NADPH-d, counterstained with thioflavin-S. The average number of neurofibrillary tangles within this portion of the pedunculopontine nucleus was 25.4 (range 0-70) in patients with AD, 1.5 (range 1-2) in those with PD, and 1.2 (range 0-4) in aged control subjects. Of the total number of neurofibrillary tangles counted in AD cases, 72.7% were end-stage ghosts and 27.3% were tangle-bearing neurons. The pathological alteration of cholinergic neurons of the compact lateral aspect of the pedunculopontine nucleus may play a role in some of the behavioral features characteristic of AD.     

Mitochondrial DNA polymorphisms in pathologically proven Parkinson’s disease

To date, five single base pair changes of the mitochondrial DNA have been reported to occur either exclusively or with increased frequency in Caucasian patients with Parkinson’s disease (PD) and it has been postulated that these mutations might be causally related to the observed inhibition of mitochondrial respiratory chain function in PD. To evaluate these findings, we analysed the frequency of all five polymorphisms in 100 cases of pathologically proven cases of PD. We were either unable to detect the previously described polymorphisms in our series or found them to be present with the same frequency among controls. Our data do not support the hypothesis of an involvement of the mitochondrial DNA in the pathogenesis of PD. Received: 4 October 1996 Accepted: 16 December 1996     

Assessment of sensorimotor gating following selective lesions of cholinergic pedunculopontine neurons

Sensorimotor gating is the state‐dependent transfer of sensory information into a motor system. When this occurs at an early stage of the processing stream it enables stimuli to be filtered out or partially ignored, thereby reducing the demands placed on advanced systems. Prepulse inhibition (PPI) of the acoustic startle reflex (ASR) is the standard measure of sensorimotor gating. A brainstem–midbrain circuitry is widely viewed as mediating both PPI and ASR. In this circuitry, the pedunculopontine tegmental nucleus (PPTg) integrates sensory input and cortico‐basal ganglia output and, via presumed cholinergic signaling, inhibits ASR‐generating neurons within the reticular formation. Non‐selective damage to all neuronal types within PPTg reduces PPI. We assessed whether this effect originates in the loss of cholinergic signaling by examining ASR and PPI in rats bearing non‐selective (excitotoxic) or selective cholinergic (Dtx‐UII) lesions of PPTg. Excitotoxic lesions had no effect on ASR but reduced PPI at all prepulse levels tested. In contrast, selective depletion of cholinergic neurons reduced ASR to the extent that PPI was not measurable with standard (10–20 s) inter‐trial intervals. Subsequent testing revealed appreciable ASRs could be generated when the inter‐trial interval was increased (180 s). Under these conditions, PPI was assessed and no deficits were found after lesions of cholinergic PPTg neurons. These results show that cholinergic output from PPTg is essential for rapidly regenerating the ASR, but has no influence on PPI. Results are discussed in terms of sensorimotor integration circuitry and psychiatric disorders that feature disrupted ASR and PPI.     

The cholinergic system and Parkinson disease

Although Parkinson disease (PD) is viewed traditionally as a motor syndrome secondary to nigrostriatal dopaminergic denervation, recent studies emphasize non-motor features. Non-motor comorbidities, such as cognitive impairment, are likely the result of an intricate interplay of multi-system degenerations and neurotransmitter deficiencies extending beyond the loss of dopaminergic nigral neurons. The pathological hallmark of parkinsonian dementia is the presence of extra-nigral Lewy bodies that can be accompanied by other pathologies, such as senile plaques. Lewy first identified the eponymous Lewy body in neurons of the nucleus basalis of Meynert (nbM), the source of cholinergic innervation of the cerebral cortex. Although cholinergic denervation is recognized as a pathological hallmark of Alzheimer disease (AD), in vivo neuroimaging studies reveal loss of cerebral cholinergic markers in parkinsonian dementia similar to or more severe than in prototypical AD. Imaging studies agree with post-mortem evidence suggesting that basal forebrain cholinergic system degeneration appears early in PD and worsens coincident with the appearance of dementia. Early cholinergic denervation in PD without dementia appears to be heterogeneous and may make specific contributions to the PD clinical phenotype. Apart from well-known cognitive and behavioral deficits, central, in particular limbic, cholinergic denervation may be associated with progressive deficits of odor identification in PD. Recent evidence indicates also that subcortical cholinergic denervation, probably due to degeneration of brainstem pedunculopontine nucleus neurons, may relate to the presence of dopamine non-responsive gait and balance impairments, including falls, in PD.     

Loss of cholinergic neurons in the pedunculopontine nucleus in Parkinson's disease is related to disability of the patients

We investigated neuronal number and size in the pars compacta of the pedunculopontine nucleus (PPN) in Parkinson's disease (PD). In PD, the number of Luxol fast blue (LFB) neurons was reduced by 27% from the mean control value (p=0.04) and the cholinergic (choline acetyltransferase, ChAT-positive) neuron number was reduced by 36% (p=0.03). In addition to neuronal loss, the remaining neurons in the PPN in PD were smaller than in controls. The profile area of LFB neurons was reduced by 14% (p=0.009) and that of ChAT-positive neurons by 26% (p=0.001). There was more severe loss of ChAT-positive neurons with a more severe stage of the disease, evaluated by the modified Hoehn and Yahr scale (r=-0.66, p=0.03). The neuron number decreased much more than could be expected on the basis of decrease in cell size alone.     

Human reticular formation: cholinergic neurons of the pedunculopontine and laterodorsal tegmental nuclei and some cytochemical comparisons to forebrain cholinergic neurons

Choline acetyltransferase immunohistochemistry showed that the human rostral brainstem contained cholinergic neurons in the oculomotor, trochlear, and parabigeminal nuclei as well as within the reticular formation. The cholinergic neurons of the reticular formation were the most numerous and formed two intersecting constellations. One of these, designated Ch5, reached its peak density within the compact pedunculopontine nucleus but also extended into the regions through which the superior cerebellar peduncle and central tegmental tract course. The second constellation, designated Ch6, was centered around the laterodorsal tegmental nucleus and spread into the central gray and medial longitudinal fasciculus. There was considerable transmitter-related heterogeneity within the regions containing Ch5 and Ch6. In particular, Ch6 neurons were intermingled with catecholaminergic neurons belonging to the locus coeruleus complex. The lack of confinement within specifiable cytoarchitectonic boundaries and the transmitter heterogeneity justified the transmitter-specific Ch5 and Ch6 nomenclature for these two groups of cholinergic neurons. The cholinergic neurons in the nucleus basalis (Ch4) and those of the Ch5-Ch6 complex were both characterized by perikaryal heteromorphism and isodendritic arborizations. In addition to choline acetyltransferase, the cell bodies in both complexes also had high levels of acetylcholinesterase activity and nonphosphorylated neurofilament protein. However, there were also marked differences in cytochemical signature. For example, the Ch5-Ch6 neurons had high levels of NADPHd activity, whereas Ch4 neurons did not. On the other hand, the Ch4 neurons had high levels of NGF receptor protein, whereas those of Ch5-Ch6 did not. On the basis of animal experiments, it can be assumed that the Ch5 and Ch6 neurons provide the major cholinergic innervation of the human thalamus and that they participate in the neural circuitry of the reticular activating, limbic, and perhaps also extrapyramidal systems.     

Cardiovascular autonomic responses in patients with Parkinson disease to pedunculopontine deep brain stimulation

Clinical Autonomic Research - Dysautonomia can be a debilitating feature of Parkinson disease (PD). Pedunculopontine nucleus (PPN) stimulation may improve gait disorders in PD, and may also result...     

Gender differences in cholinergic and dopaminergic deficits in Parkinson disease

As Parkinson disease (PD) may affect men and women differentially, we investigated gender differences in regional projection system integrity in 148 PD subjects (36 women, 112 men) using monoaminergic [¹¹C]dihydrotetrabenazine and acetylcholinesterase [¹¹C]PMP positron emission tomography. After controlling for age, disease duration, and Hoehn and Yahr score, men showed 5.9 % greater caudate dopaminergic denervation (p = 0.0018) and 5.8 % greater neocortical cholinergic denervation (p = 0.0097). No significant gender differences were seen in putaminal dopaminergic or thalamic cholinergic denervation.     

Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis

Parkinson disease (PD) is associated with progressive loss of dopaminergic neurons in the substantia nigra, as well as with more-widespread neuronal changes that cause complex and variable motor and nonmotor symptoms. Recent rapid advances in PD genetics have revealed a prominent role for mitochondrial dysfunction in the pathogenesis of the disease, and the products of several PD-associated genes, including SNCA, Parkin, PINK1, DJ-1, LRRK2 and HTR2A, show a degree of localization to the mitochondria under certain conditions. Impaired mitochondrial function is likely to increase oxidative stress and might render cells more vulnerable to this and other related processes, including excitotoxicity. The mitochondria, therefore, represent a highly promising target for the development of disease biomarkers by use of genetic, biochemical and bioimaging approaches. Novel therapeutic interventions that modify mitochondrial function are currently under development, and a large phase III clinical trial is underway to examine whether high-dose oral coenzyme Q10 will slow disease progression. In this Review, we examine evidence for the roles of mitochondrial dysfunction and increased oxidative stress in the neuronal loss that leads to PD and discuss how this knowledge might further improve patient management and aid in the development of 'mitochondrial therapy' for PD.     

Ultrastructural study of cholinergic and noncholinergic neurons in the pars compacta of the rat pedunculopontine tegmental nucleus

A group of medium-to-large cholinergic neurons situated in the dorsolateral mesopontine tegmentum comprises the pedunculopontine tegmental nucleus (PPT). The PPT pars compacta (PPT-pc), which occupies the lateral part of the caudal two-thirds of the nucleus, contains a dense aggregation of cholinergic neurons. In the present study, we have employed immunohistochemistry for choline acetyltransferase (ChAT) and electron microscopy to investigate the ultrastructure and synaptic organization of neuronal elements in the PPT-pc. Our results demonstrate that: (1) ChAT-immunoreactive (i.e., cholinergic) PPT-pc neurons are characterized by abundant cytoplasm and organelles, and have few axosomatic synapses (both asymmetric and symmetric); (2) ChAT-immunoreactive dendrites comprise 6-15% of total dendritic elements in the neuropil; the mean percentage of dendritic membrane covered by synaptic terminals is approximately 15%, and nearly all synapses with ChAT-immunoreactive dendrites are asymmetric; (3) within the boundaries described by cholinergic PPT-pc, there are noncholinergic neurons which, in contrast, exhibit a lucent cytoplasm and a higher frequency of axosomatic synapses (10.5% versus 3.7% for cholinergic neurons); and (4) noncholinergic neurons are morphologically heterogeneous with one subpopulation exhibiting a mean diameter that approximates that of cholinergic cells (i.e., >15 μm and <20 μm) and a very high frequency of axosomatic synapses (>20%). Only 0.2-0.7% of terminal elements in the neuropil were ChAT-immunoreactive and these were not observed to synapse with cholinergic dendrites or somata. This relative paucity of terminal labeling and lack of cholinergic-cholinergic interactions seems inconsistent with the recognized and prominent physiological actions of acetylcholine on cholinergic PPT-pc neurons, and suggests a methodological limitation and/or a potential paracrine-like action of nonsynaptically released acetylcholine in the PPT region. J. Comp. Neurol. 382:285-301, 1997. © 1997 Wiley-Liss, Inc.     

Basal forebrain neurons in the dementia of Parkinson disease

Demented patients with Parkinson disease share certain neuropathological and neurochemical features with patients suffering from Alzheimer disease. Recently, loss of cholinergic neurons in the basal forebrain, particularly the nucleus basalis of Meynert, has been implicated in the pathophysiology of Alzheimer disease. The present investigation of 12 patients with Parkinson disease demonstrates that the demented patients with this disease also show a selective loss of cells in the nucleus basalis of Meynert, thus providing an important link between the dementias of Alzheimer disease and Parkinson disease.     

Mitochondrial DNA analysis in Parkinson's disease

The reduced form of nicotinamide adenine dinucleotide coenzyme Q reductase (complex I) activity has recently been shown to be deficient in the substantia nigra of patients dying with Parkinson's disease. This biochemical defect is identical to that produced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which also produces parkinsonism in humans. Complex I comprises 25 polypeptides, seven of which are encoded by mitochondrial DNA. Restriction fragment analysis of substantia nigra DNA from six patients with Parkinson's disease did not show any major deletion. In two cases, there were different novel polymorphisms that were not observed in control brain (n = 6) or blood (n = 34) samples.     

Dendritic degeneration in neostriatal medium spiny neurons in Parkinson disease

Dysfunction of neostriatal medium spiny neurons (MSNs) is hypothesized to underlie late-stage motor complications of Parkinson disease (PD). The authors demonstrate shortened dendrite length of MSNs that was similar in four regions of neostriatum in late-stage PD. In contrast, MSN dendrite spine degeneration was unevenly distributed with the greatest loss in caudal putamen. The authors propose that these structural changes in MSN may contribute to late-stage motor complications of PD.