Volumes in this widely revered series present comprehensive reviews of drug substances and additional materials, with critical review chapters that summarize information related to the characterization of drug substances and excipients. This organizational structure meets the needs of the pharmaceutical community and allows for the development of a timely vehicle for publishing review materials on this topic. The scope of the Profiles series encompasses review articles and database compilations that fall within one of the following six broad categories: Physical profiles of drug substances and excipients; Analytical profiles of drug substances and excipients; Drug metabolism and pharmacokinetic profiles of drug substances and excipients; Methodology related to the characterization of drug substances and excipients; Methods of chemical synthesis; and Reviews of the uses and applications for individual drug substances, classes of drug substances, or excipients. * Contributions from leading authorities * Informs and updates on all the latest developments in the field

Profiles of Drug Substances, Excipients, and Related Methodology

The exact pathogenesis of visual hallucinations in Parkinson's disease is not known but an integrated model has been proposed that includes impaired visual input and central visual processing, impaired brainstem regulation of sleep-wake cycle with fluctuating vigilance, intrusion of rapid eye movement dream imagery into wakefulness and emergence of internally generated imagery, cognitive dysfunction and influence of dopaminergic drugs. In a clinical study, we assessed motor and non-motor function, including sleep, mood, autonomic and global, frontal and visuoperceptive cognitive function in patients with and without visual hallucinations. A subgroup of patients underwent detailed ophthalmological assessment. In a separate pathological study, histological specimens were obtained from cases of pathologically proven Parkinson's disease and a retrospective case notes review was made for reporting of persistent formed visual hallucinations. An assessment of Lewy body and Lewy neurite pathology was carried out in five cortical regions as recommended by diagnostic criteria for dementia with Lewy Bodies and in brainstem nuclei. Ninety-four patients (mean age 67.5 ± 9.5 years) participated in the clinical study of whom 32% experienced visual hallucinations. When corrected for multiple comparisons, patients with visual hallucinations had significantly greater disease duration, treatment duration, motor severity and complications, sleep disturbances, in particular excessive daytime somnolence and rapid eye movement sleep behavioural disorder, disorders of mood, autonomic dysfunction and global, frontal and visuoperceptive cognitive dysfunction. Of the 94 patients, 50 (53%) underwent ophthalmological assessment. There were no differences in ocular pathology between the visual hallucination and non-visual hallucination groups. In a logistic regression model the four independent determinants of visual hallucinations were rapid eye movement sleep behavioural disorder (P = 0.026), autonomic function (P = 0.004), frontal cognitive function (P = 0.020) and a test of visuoperceptive function (object decision; P = 0.031). In a separate study, post-mortem analysis was performed in 91 subjects (mean age at death 75.5 ± 8.0 years) and persistent visual hallucinations were documented in 63%. Patients in the visual hallucinations group had similar disease duration but had significantly higher Lewy body densities in the middle frontal (P = 0.002) and middle temporal gyri (P = 0.033) and transentorhinal (P = 0.005) and anterior cingulate (P = 0.020) cortices but not parietal cortex (P = 0.22). Using a comprehensive assessment of the clinical, demographic and ophthalmological correlates of visual hallucinations in Parkinson's disease, the combined data support the hypothesized model of impaired visual processing, sleep-wake dysregulation and brainstem dysfunction, and cognitive, particularly frontal, impairment all independently contributing to the pathogenesis of visual hallucinations in Parkinson's disease. These clinical data are supported by the pathological study, in which higher overall cortical Lewy body counts, and in particular areas implicated in visuoperception and executive function, were associated with visual hallucinations.

Testing an aetiological model of visual hallucinations in Parkinson's disease

Abstract The perception of time is characterized by pronounced variability across individuals, with implications for a diverse array of psychological functions. The neurocognitive sources of this variability are poorly understood, but accumulating evidence suggests a role for inter-individual differences in striatal dopamine levels. Here we present a pre-registered study that tested the predictions that spontaneous eyeblink rates, which provide a proxy measure of striatal dopamine availability, would be associated with aberrant interval timing (lower temporal precision or overestimation bias). Neurotypical adults ( N = 69) underwent resting state eye tracking and completed visual psychophysical interval timing and control tasks. Elevated spontaneous eyeblink rates were associated with poorer temporal precision but not with inter-individual differences in perceived duration or performance on the control task. These results signify a role for striatal dopamine in variability in human time perception and can help explain deficient temporal precision in psychiatric populations characterized by elevated dopamine levels. 

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A proxy measure of striatal dopamine predicts individual differences in temporal precision

The association between idiopathic Parkinson's disease, a paradigmatic dopamine-deficiency syndrome, and problems in the estimation of time has been studied experimentally for decades. I review that literature, which raises a question about whether and if dopamine deficiency relates not only to the motor slowness that is an objective and cardinal parkinsonian sign, but also to a compromised neural substrate for time perception. Why does a clinically (motorically) significant deficiency in dopamine play a role in the subjective perception of time's passage? After a discussion of a classical conception of basal ganglionic control of movement under the influence of dopamine, I describe recent work in healthy mice using optogenetics; the methodology visualizes dopaminergic neuronal firing in very short time intervals, then allows for correlation with motor behaviors in trained tasks. Moment-to-moment neuronal activity is both highly dynamic and variable, as assessed by photometry of genetically defined dopaminergic neurons. I use those animal data as context to review a large experimental experience in humans, spanning decades, that has examined subjective time perception mainly in Parkinson's disease, but also in other movement disorders. Although the human data are mixed in their findings, I argue that loss of dynamic variability in dopaminergic neuronal activity over very short intervals may be a fundamental sensory aspect in the pathophysiology of parkinsonism. An important implication is that therapeutic response in Parkinson's disease needs to be understood in terms of short-term alterations in dynamic neuronal firing, as has already been examined in novel ways—for example, in the study of real-time changes in neuronal network oscillations across very short time intervals. A finer analysis of a treatment's network effects might aid in any effort to augment clinical response to either medications or functional neurosurgical interventions in Parkinson's disease.

Review: Subjective Time Perception, Dopamine Signaling, and Parkinsonian Slowness

Occipital Glucose Metabolic Decrease by Donepezil Treatment Correlated with the Improvement of Visual Hallucinations in Dementia with Lewy Bodies: the Osaki-Tajiri Project

Although animal studies and studies on Parkinson's disease (PD) suggest that dopamine deficiency slows the pace of the internal clock, which is corrected by dopaminergic medication, timing deficits in parkinsonism remain to be characterized with diverse findings. Here we studied patients with PD and progressive supranuclear palsy (PSP), 3-4 h after drug intake, and normal age-matched subjects. We contrasted perceptual (temporal bisection, duration comparison) and motor timing tasks (time production/reproduction) in supra- and sub-second time domains, and automatic versus cognitive/short-term memory-related tasks. Subjects were allowed to count during supra-second production and reproduction tasks. In the time production task, linearly correlating the produced time with the instructed time showed that the "subjective sense" of 1 s is slightly longer in PD and shorter in PSP than in normals. This was superposed on a prominent trend of underestimation of longer (supra-second) durations, common to all groups, suggesting that the pace of the internal clock changed from fast to slow as time went by. In the time reproduction task, PD and, more prominently, PSP patients over-reproduced shorter durations and under-reproduced longer durations at extremes of the time range studied, with intermediate durations reproduced veridically, with a shallower slope of linear correlation between the presented and produced time. In the duration comparison task, PD patients overestimated the second presented duration relative to the first with shorter but not longer standard durations. In the bisection task, PD and PSP patients estimated the bisection point (BP50) between the two supra-second but not sub-second standards to be longer than normal subjects. Thus, perceptual timing tasks showed changes in opposite directions to motor timing tasks: underestimating shorter durations and overestimating longer durations. In PD, correlation of the mini-mental state examination score with supra-second BP50 and the slope of linear correlation in the reproduction task suggested involvement of short-term memory in these tasks. Dopamine deficiency didn't correlate significantly with timing performances, suggesting that the slowed clock hypothesis cannot explain the entire results. Timing performance in PD may be determined by complex interactions among time scales on the motor and sensory sides, and by their distortion in memory.

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Time Distortion in Parkinsonism.

Visual hallucinations are a common symptom of Parkinson’s disease dementia. These can cause delusions and violent behaviors that can be significant burdens on patients and caregivers. The cause of visual hallucinations is considered to be the dysregulation of the default mode network due to the presence of Lewy bodies in the cortex and the degeneration of dopaminergic and cholinergic neurons. Dopaminergic agents, especially non-ergoline dopamine agonists, can exacerbate visual hallucinations. Reducing the dosage can ameliorate symptoms in many cases; however, this frequently worsens parkinsonism. In contrast, the administration of cholinesterase inhibitors is effective and rarely worsens motor symptoms. In advanced cases, antipsychotic drugs are required; clinical studies have shown that some drugs are beneficial while the adverse events are acceptable. An optimal treatment protocol should be selected depending on the patient’s condition.

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Etiology and Treatment Approach for Visual Hallucinations in PD Dementia

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a brainstem predominant lymphocytic inflammatory disease, which often relapses without oral immunosuppressants. This report describes a 37-year-old male case of CLIPPERS without relapse for 1 year after early steroid treatment. He was admitted to our hospital because of sensory disturbance in the left side of his body and ataxic gait. Gadolinium-enhanced T1-weighted MRI revealed multiple punctate and curvilinear enhancements in the pons and right middle cerebellar peduncle. We started treatment with high-dose intravenous methylprednisolone (IVMP) therapy on the 20th day of the illness. His neurological symptoms dramatically improved. Follow-up MRI showed that the enhancing lesions disappeared. We diagnosed him with CLIPPERS based on the clinical course, radiological findings, and steroid response. He did not take any oral immunosuppressant after discharge. However, there was no clinical and radiological relapse for 1 year after the IVMP therapy. Although this case requires careful follow-up because of recurrence risk, early steroid treatment was possibly related to 1-year remission.

A case of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) without relapse after early steroid treatment

Anosmia is a frequently experienced symptom in coronavirus disease 2019 (COVID-19). Previous studies have suggested the potential use of olfactometry to identify infected individuals. We performed a sequential olfactometry using the odor stick identification test for Japanese (OSIT-J) in a COVID-19 patient without pneumonia. The test uses 12 odorants that are familiar to the Japanese population. Our patient was a 56-year-old man diagnosed with COVID-19 who was admitted to our hospital following the development of anosmia. He had no respiratory symptoms except pharyngeal pain. Chest CT findings did not reveal the presence of pneumonia. The patient underwent OSIT-J on the 1st hospital day, and his score was 1 out of 12. Following the olfactometry, ciclesonide was administered. The patient did not develop any new symptoms during hospitalization, and his anosmia was gradually improved. The OSIT-J scores were 9 and 11 on the 7th and 16th hospital day, respectively. The patient was discharged on the 25th hospital day after two negative PCR test results. In our case, OSIT-J could identify anosmia in a COVID-19 patient. Some COVID-19 patients are asymptomatic, expect for olfactory disturbances, and OSIT-J may help identify such patients in the Japanese population.

Yuki Asahara

Papers

Time Distortion in Parkinsonism.

Etiology and Treatment Approach for Visual Hallucinations in PD Dementia

A case of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) without relapse after early steroid treatment

[The odor stick identification test for Japanese (OSIT-J) in a case of coronavirus disease 2019 (COVID-19) without pneumonia].