{'fraction_non_alphanumeric': 0.029667149059334298, 'fraction_numerical': 0.000964785335262904, 'mean_word_length': 5.217391304347826, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
An evidence base for noradrenergic deficits in Parkinson's disease

The concept of very significant nondopaminergic involvement in Parkinson’s disease (PD) is no longer contentious. This is largely due to the landmark work of Heiko Braak et al., who highlighted the systematic deposition of widespread a-synuclein pathology in PD. In particular, their very detailed anatomical molecular localization of the pathological changes provided a comprehensive evidence base that is being replicated in (and challenged by) other research centers. This pathologically-based concept has invigorated clinical research into focusing more on the assessment of early nondopaminergic symptoms in PD, although the neuroanatomical and pathophysiological bases for many of these symptoms remain to be determined. Unfortunately, there has not been a similar stimulation of studies assessing the nondopaminergic neurochemical changes that must parallel such widespread pathology. In fact, most biochemical measurements of nondopaminergic neurotransmitter changes in pathologicallyconfirmed cases of PD were published more than 20 years ago. At this time there was no consideration of disease staging or phenotypes with overlapping dementia and variable regional pathologies. The importance of relooking at such studies in light of more modern concepts should not be underestimated, as at least symptomatic treatments for many neurotransmitter systems are already available and may have therapeutic benefit in targeted populations of patients or at certain disease stages. A study in this issue of Movement Disorders by Pifl et al. partially addresses this deficit. The authors detail the regional changes in a single neurotransmitter, noradrenaline, within the thalamus of patients with end-stage, well-documented PD. The thalamus was selected because it occupies a pivotal position in the brain. All neocortical areas receive thalamic inputs and large ensembles of cortical and thalamic neurons discharge synchronously at stereotyped frequencies to effect different conscious states and perceive specific events, thoughts, and actions. By assessing some 14 different thalamic territories, neurons involved in processing both motor and nonmotor information were evaluated without having to sample across diverse brain sites. The thalamus is innervated by a single noradrenergic nucleus (the locus coeruleus), and consistent with older biochemical studies, the authors found a noradrenergic deficiency in PD. The surprise was that it occurred in most PD thalamic territories (except the sensory thalamus), and the scale of the deficit was as marked as that of dopamine in the putamen. Although these findings are consistent with the significant loss of noradrenergic locus coeruleus neurons observed by end-stage PD, the comparison to the substantive dopaminergic deficit has been completely underappreciated. As pointed out by the authors, such a deficit would have a more direct impact on thalamic activity than the basal ganglia dopaminergic deficit, and may be a more significant contributor to treatment-resistant pathological thalamic oscillations observed in patients with PD. Although this concept requires further evidence, the study overall adds significantly to the literature on nondopaminergic deficits in PD and their potential impact. Of importance is the potential for direct therapeutic targeting of this major deficit. More work now needs to be done to determine when in the disease such a deficit becomes manifest, whether the deficit actually initiates the multiple functional changes in the thalamus, as suggested, or occurs subsequent to other contributing pathological changes, and also whether other ascending neuromodulators of thalamic activity are involved. There are several studies that suggest central dopamine and noradrenaline changes occur concurrently very early in PD, including cerebrospinal fluid measurements, although imaging suggests an early upregulation of noradrenaline reuptake in the locus coeruleus consistent with enhanced noradrenaline release in response to -