Parkinsonian Population Research Articles

Adjustment for theAge- and Gender-Related Metabolic Changes Improves the Differential Diagnosis of Parkinsonism.

The online version contains supplementary material available at 10.1007/s43657-022-00079-6.

Continuous and advanced treatment strategies in the old to very old parkinsonian population

Parkinson's disease (PD) is a neurodegenerative disorder with an incidence and a prevalence increasing with age, predicted to increase drastically in the next 10 years among the geriatric population aged above 80 in France. There are two distinct groups of patients in which therapeutic issues are different. On the one hand, old to very old patients in which PD started at a late age above 80. These patients present with a more severe PD with earlier onsets of cognitive defects and dopa-resistant axial signs, and more comorbidities needing to be taken into account while treating them. Because of their limited life expectancy, these patients would not likely need second line treatments over their disease course. On the other hand, patients presenting with advanced PD, in which fluctuations and dyskinesia induced by dopamine replacement therapy and dopa-resistant axial symptoms impede patient's daily life. These patients are often treated with multiple antiparkinsonian medications, sometimes at high doses. Some patients will also be treated with advanced therapies such as continuous subcutaneous apomorphine infusion, continuous levodopa-carbidopa intestinal gel or, more rarely, even subthalamic or pallidal deep brain stimulations. Because of the specificities of the old to very old parkinsonian patients, tolerance and efficacy of these treatments can be decreased. What is at stake is to aim for the best motor state possible while limiting iatrogenic adverse events. New emerging, potentially less invasive, techniques, such as gamma knife thalamotomy or high-intensity focused ultrasound thalamotomy or sub-thalamotomy, are also discussed here.

Explaining Parkinsonian postural sway variabilities using intermittent control theory

Postural impairment due to neuro-degenerative disorders such as Parkinson’s Disease (PD) leads to restricted gait patterns, fall-related injuries, decreased mobility, and loss of functional independence. Though several clinical and posturographic studies have attempted to reveal the complex pathophysiology involved in PD, the diversity of Parkinsonian population makes them unclear and sometimes even contradictory. For instance, studies related to the Center of Pressure (CoP) sway during quiet stance in PD patients highlight both increase and reduction of magnitude in contrast to age-matched healthy individuals. A possible explanation for this contradiction is presented in this article. While the presence of intermittent control has been observed in postural control in human quiet stance, we hypothesize that one of the factors that affects postural instability in PD might be the increase in intermittency in active feedback control. Using a simulation model representing the Anterior-Posterior dynamics of human quiet standing, the intermittent control strategy is first contrasted against continuous control strategy in terms of stability, energy efficiency and settling time, thus establishing the inherent advantages of an intermittent control strategy. Further, the ability of the intermittent control strategy to explain several clinical observations in PD is demonstrated. An experimental pilot study is also conducted to support the simulation study, and several body sway parameters derived from recordings of CoP are presented. The presented results are in close agreement with reported clinical observations and may also prove useful for the assessment of disease progression and future fall risk.

No Structural Differences Are Revealed by VBM in 'De Novo' Parkinsonian Patients.

The identification of brain morphological alterations in newly diagnosed PD patients (i.e. 'de novo') could potentially serve as a biomarker and accelerate diagnosis. However, presently no consensus exists in the literature possibly due to several factors: small size cohorts, differences in segmentation techniques or bad control of false positive rates. In this study, we use the CAT12 pipeline, to seek for morphological brain differences in gray and white matter of 66 controls and 144 de novo PD patients from the PPMI database. Moreover, we search for subcortical structure differences using the VolBrain pipeline. We found no structural brain differences in this de novo Parkinsonian population, neither in tissues using a whole brain analysis nor in any of nine subcortical structures analyzed separately. We conclude that some results published in the literature may appear as false positives and we contest their reproductibility.

Descriptive analysis of the French NS-Park registry: Towards a nation-wide Parkinson's disease cohort?

IntroductionParkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's. The French clinical research network for PD (NS-Park) has created a national patient registry to i)report medical activity of Parkinson Expert Centers (PECs) to the Ministry of Health, ii)facilitate PD patients pre-screening for clinical trials, iii) provide a source for pharmaco-epidemiology studies. ObjectiveAssess the French Parkinsonian population at a nation-wide level and discover new clinical characteristics. MethodsIn this feasibility study, PECs prospectively collected clinical data in a standardized manner. The population main clinical characteristics are described, focusing on motor and non-motor symptoms and treatments, assessing its representativeness. By using an unbiased clustering with multiple correspondence analysis (MCA), we also investigate potential relationships between multiple variables like symptoms and treatments, as clues for future studies. ResultsBetween 2012 and 2016, among 11,157 included parkinsonian syndromes, 9454 (85%) had PD. MCA identified various profiles depending on disease duration. Occurrences of motor complications, axial signs, cognitive disorders and Levodopa use increase over time. Neurovegetative symptoms, psychiatric disorders, sleep disturbances and impulse control disorders (ICDs) seem stable over time.As expected, ICDs were associated to dopaminergic agonist use but other associations, such as ICDs and sleep disturbances for instance, or anxiety and depression, were found. ConclusionsOur results report one of the biggest PD registries ever reported and demonstrate the feasibility of implementing a nation-wide registry of PD patients in France, a potent tool for future longitudinal studies and clinical trials’ population selection, and for pharmaco-epidemiology and cost-effectiveness studies.

Descriptive study of the parkinsonian population in the north of France: Epidemiological analysis and healthcare consumption

BackgroundThe “neurodegenerative diseases plan” under elaboration for the Hauts-de-France region requires better knowledge of the patient population and care pathways. In France, the prevalence of Parkinson's disease (PD) has been estimated from cohorts to be about 1–3 per 1000 inhabitants, but exhaustive data are scarce for the general population. The purpose of this study was to evaluate the prevalence of PD in the Hauts-de-France region and to assess PD-related healthcare consumption. MethodA descriptive study was conducted to identify the parkinsonian population in the Hauts-de-France region (including the administrative districts of Pas-de-Calais and Picardie) for the year 2014. Parkinsonian patients were identified from health insurance fund reimbursement data using the following criteria: (i) reimbursement for a PD-specific medication; (ii) attribution of long-duration disease status coded as PD; (iii) hospital stay with PD diagnosis in the standard discharge report contained in the French medico-economic database on hospital activity (PMSI). ResultsThe raw prevalence of PD in the region was 5.03 per 1000 inhabitants aged 20 years and older. The standardized prevalence by health territory ranged from 4.0 to 9.0 per 1000 inhabitants aged 20 years and older. During the 1-year study period, 33.5% of patients had a neurology consultation, 57.1% attended a physiotherapy session, and 7.7% received speech therapy. Most of patients (79.6%) were treated with levodopa, sometimes in combination with a catechol-O-methyl transferase inhibitor (14.4%). Dopaminergic agonists were prescribed in 33.5% of cases. A neuroleptic was prescribed for 6.9% of the population (clozapine for 25.9%). ConclusionThe prevalence of PD is high in the Hauts-de-France region with a heterogeneous distribution by health territory. Neurology consultations were attended by a minority of patients in 2014. This work provides perspectives for necessary improvement in specialized care for this disease, both in terms of follow-up consultations and home care.

Genetic analysis for five LRRK2 mutations in a Sardinian parkinsonian population: Importance of G2019S and R1441C mutations in sporadic Parkinson's disease patients

Mutations in the LRRK2 gene are the most common known cause of familial and sporadic Parkinson's disease (PD). Few studies performed to date to assess frequency of these mutations are actually only representative of specific areas. Here we study the frequency and clinical phenotype of LRRK2 G2019S, I2020T and R1441C/G/H mutations in 356 Sardinian patients with idiopathic PD and 208 controls. Seventeen additional subjects, relatives of PD mutated probands, were enrolled. Eight patients were mutated in heterozygosis for LRRK2 gene (2.3%): six carried the G2019S (1.7%) and two the R1441C (0.6%) mutation. Three PD patients G2019S carriers (50%) were detected in two contiguous villages comprising 3921 inhabitants while the other three (50%) were identified in the remaining population of 796,079 inhabitants. Only one mutated proband had a family history of PD. LRRK2 G2019S and R1441C mutations associated with PD were not an uncommon mutation in a Sardinian population, especially in sporadic PD patients. The detection of the G2019S variant in ten unaffected relatives confirms a reduced penetrance of the underlying mutation and might explain its prevalence among patients with sporadic PD. These findings may provide new insights into the importance of studies of frequency of LRKK2 mutations in PD patients originating from small ethnically homogeneous populations.

Depression et Maladie de Parkinson: étude d’une série de 135 parkinsoniens

The prevalence of depression in Parkinson's disease (PD) raises the issues of the difficulties of diagnosing the condition and of the relationships between depression and the natural history of the disease. A cohort of 135 consecutive patients with idiopathic PD underwent psychiatric (DSM-III-R, Goldberg depression scale), neurological (distinguishing "axial" signs from other signs of parkinsonism), and neuropsychological (particularly frontal tests) evaluations. Depression is present in more than half of the patients and it seems to be more frequent in patients with the akinetic and fluctuating forms of the disease. The subjects who are depressed do not have a greater degree of cognitive impairment, but their scores on frontal tests are higher. Moreover, the axial signs of the disease (postural instability, axial rigidity) are more severe in depressed parkinsonians suggesting a link between depression and the non-dopaminergic lesions of the disease. Even though slowness, appetite and sleep disturbances, and fatigue may be encountered in non-depressed parkinsonian patients, separation of the parkinsonian population into subgroups shows that certain symptoms are never seen in parkinsonians who are not depressed: it is thus evident that "the impression that life is not worth living", "the hopelessness", "the impression of being worthless and incompetent", "the low level of energy", "the morning sadness" are characteristic of parkinsonian depression. Parkinsonian depression has two major clinical forms. The first one is associated with a greater number of somatic manifestations: sleep disturbances, morning fatigue. corresponding to more severe depression with hopelessness and loss of self confidence. The second exhibits few somatic manifestations with apathy and slowness as frequent complaints. This study defines the symptoms of parkinsonian depression which should be better recognised in order to be treated. The link between depression and axial signs of the disease may explain why L-dopa and dopaminergic agonists improve the motor signs of depression without influencing depressive manifestations in most cases.

Efficacy and tolerability of dopamine agonists in a parkinsonian population.

A clinical retrospective study was carried out in a population of 366 Parkinson's disease (PD) outpatients, to analyse the efficacy and tolerability of nonergoline and ergoline dopamine agonist (DA), in monotherapy or in combination with L-dopa. Safety was comparable in both groups except for higher occurrence of gastrointestinal symptoms in ergoline group and somnolence in nonergoline group. No significant difference concerning efficacy and tolerability was found during DA monotherapy. Mean age at PD onset was slightly higher in patients withdrawing DA monotherapy for adverse events comparing to patients who needed the addition of L-dopa (60.36 +/- 7.53 versus 54.88 +/- 10.75; p<0.05), suggesting that older age at the onset of the disease increases the risk for adverse events during DA monotherapy. The follow-up of the remaining patients still in monotherapy with DA will allow a better evaluation of these aspects.

The Surgical Treatment of Parkinson's Disease

Parkinson’s disease (PD) is a debilitating disorder characterized by degeneration of the nigrostriatal pathway resulting in decreased caudoputaminal dopamine (DA) levels. Nigrostriatal pathway degeneration and reduced DA stores may lead to increased rigidity, gait and speech disturbances, bradykinesia and resting tremors. Currently there is no cure for PD. but early treatment consists of Levodopa (L-dopa) therapy. With long-term L-dopa use, there is development of the ‘on-off phenomenon’ and dyskinesias. In the majority of PD cases, L-dopa adequately controls the motor symptoms inherent to PD. but a small percentage of the Parkinsonian population is medically-incalcitrant to this therapy. Many clinical trials are currently being conducted world-wide to investigate the efficacy of surgery to treat this disease. These surgical therapies include ablative procedures, chronic deep brain stimulation, as well as the transplantation of dopaminergic cells. Neurosurgical treatment of PD is not a new concept, being attempted as early as the 1930’s, but these procedures were plagued with many side effects that led to their abandonment. Currently, a resurgence in these techniques has evolved due to our increased understanding of basal ganglia anatomy and physiology along with recent advances in medical technology. This review will briefly discuss the benefits and short-comings of these surgical paradigms as well as the rationale behind their application. Normal 0 false false false EN-CA X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:Table Normal; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin-top:0in; mso-para-margin-right:0in; mso-para-margin-bottom:10.0pt; mso-para-margin-left:0in; line-height:115%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:Calibri,sans-serif; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;}

Randomized double‐blind trial of injectable heptaminol for controlling spontaneous or bromocriptine‐induced orthostatic hypotension in parkinsonians

Heptaminol is a molecule with experimental cardiovascular analeptic properties. In this double-blind vs placebo trial, the potency, so far unproven, of the injectable form of a 626 mg dose of heptaminol chlorhydrate on spontaneous or induced orthostatic hypotension (OH), was assessed. Nineteen patients were included in the study: 7 displayed spontaneous OH, and in the other 12 OH was induced by bromocriptine, as monitored 103 min/after an oral intake of 6.6 mg on average. Neither spontaneous nor induced OH were recorded in 32% of the Parkinsonian population registered, with no obvious distinctive characteristics. Potency tilt-trials, performed 15, 30 and 45 min after parenteral administration of heptaminol, revealed a significant and expressive potency of the molecule on the systolic blood pressure after 15 min (P less than 0.05). Clinical and biological tolerance was excellent. Low plasma renin activity and the absence of response to orthostatism indicated, in this population of Parkinsonian extrapyramidal syndromes, a loss in positive tonus likely to be of sympathetic origin. The anti-hypotensive action of heptaminol does not seem to be related to any renal or even sympathetic interaction.

Clinical pharmacokinetics of anti-parkinsonian drugs.

Of the neurological disorders, none can claim a battery of therapeutic agents based upon as rational a pharmacology as can Parkinson's disease. In this review, the clinical pharmacokinetics of the major classes of anti-Parkinsonian drugs is discussed. Although they are the oldest drugs in the anti-Parkinsonian armamentarium, little pharmacokinetic data are available regarding the anticholinergic and antihistaminic agents. Based on elimination half-lives of 10 to 18 hours, most could probably be effectively given on a twice-daily schedule. Amantadine is unique among anti-Parkinsonian agents both in lacking a clearly defined mechanism of action and in being eliminated from the body exclusively by renal excretion of unchanged drug. Thus the normal decline of renal function in the elderly Parkinsonian population becomes an important factor in avoiding potential drug toxicity. The pharmacokinetics and pharmacodynamics of levodopa are complex. Since it is an amino acid, it follows metabolic pathways and must compete for absorption and brain uptake with a number of large neutral amino acids. It has a short elimination half-life and, as Parkinson's disease progresses, the brain loses its capacity to store the drug and becomes dependent in a moment-to-moment fashion on plasma levodopa concentrations, creating therapeutic response fluctuations in over 50% of patients. Pharmacokinetic considerations in the management of these response fluctuations are discussed. The newest class of anti-Parkinsonian agents are the direct acting dopamine receptor agonists. These drugs, all derivatives of ergot, have more prolonged durations of anti-Parkinsonian action than levodopa. However, other than bromocriptine, clinical experience with members of this class of drugs is still limited.

Epidemiology of Parkinson’s Disease

Epidemiology of parkinsonism for 13 years (1967 to 1979) in Rochester, Minnesota is evaluated. For each patient, two age- and sex-matched controls with comparable medical follow-up (mean 40 years before diagnosis) were selected from the same community. Smoking habits, dementia, acute and chronic illnesses and mortality patterns in the two groups are compared. The annual incidence rate was 20.5/100,000, which is virtually unchanged from previous reports on Rochester population. Cigarette smoking habits of cases and the controls before the index date were not significantly different. Prior to diagnosis of Parkinson's disease, dementia was diagnosed significantly more frequently among the patients than the controls (P = 0.048). After diagnosis of parkinsonism dementia emerged nearly three times more frequently in patients than among the controls. Mortality rate in the entire parkinsonian population was similar to that reported from the same community between 1935 and 1966. Only 50% of the patients were treated with levodopa. Among those treated with levodopa the mortality rate was comparable to their controls. Because there were no definite criteria for administering levodopa therapy, higher frequency of dementia and prolonged survival in those treated with this drug could be attributed to the bias of case selection for treatment.

Characteristic clinical aspects of Parkinson patients with intellectual impairment.

The present study is based on the hypothesis that Parkinson's disease is not a single homogeneous entity and that parkinsonians with intellectual impairment are a distinct subgroup of the parkinsonian population. An assessment of cognitive functions was performed on 70 patients with Parkinson's disease and on 90 control patients. Analysis of their performances led to the division of parkinsonians into two subgroups: with and without neuropsychological impairment. Investigation of the clinical characteristics of the two subgroups showed that parkinsonians who are mentally impaired differ from other parkinsonians in that they present a more marked severity of the extrapyramidal syndrome with predominant bradykinesia and an earlier deteriorating response to levodopa treatment.

Sleep disruption in the course of chronic levodopa therapy: an early feature of the levodopa psychosis.

Sleep disruption is a common complaint in levodopa-treated parkinsonian patients. A survey of 100 parkinsonian patients revealed prominent sleep complaints in 74%. Sleep complaints were unrelated to patient age and the duration of disease but increased in prevalence with longer periods of levodopa therapy. Sleep abnormalities tended to increase in severity with continued treatment and insomnia tended to be followed by daytime somnolence, altered dream events, and episodic nocturnal vocalization and myoclonus. While dyskinetic side effects and on-off syndrome were encountered in patients with and without sleep complaints, 98% of patients experiencing psychiatric side effects also reported sleep disruption. It is suggested that sleep-related symptoms constitute an early stage of levodopa-induced dopaminergic psychiatric toxicity in the parkinsonian population. Clinical and experimental observations suggest that serotonergic mechanisms are important in this symptom complex.

Organic mental syndrome and confusional states in Parkinson's disease. Relationship to computerized tomographic signs of cerebral atrophy.

Ninety-three patients with a diagnosis of Parkinson's disease, otherwise unselected, were specifically evaluated for organic mental syndrome (OMS) and other neurologic motor signs other than those referrable to extrapyramidal dysfunction; in addition, they had cranial computerized tomography (CT) to measure any structural changes in brain parenchyma. Cortical (sulci) atrophy and ventricular enlargement as CT signs of cerebral atrophy were correlated with different clinical patterns of the disease. An age-adjusted control population, with intact mentation, was similarly studied. The presence of classic OMS in a sizable segment of the usual parkinsonian population was invariably associated with CT signs of cerebral atrophy. Atrophic changes on CT scans, however, were not necessarily correlated with any intellectual dysfunction, or only weakly so, independent of age. The "typical" parkinsonian patients without evidence of OMS were indistinguishable from an age-adjusted control group with regard to structural changes in their scans. However, the parkinsonian patients with definite, permanent OMS and other focal neurologic deficit probably constitute a separate or distinct subset of the parkinsonian population, with a pathologic substrate more likely to be similar to that of the so-called Alzheimer-type dementias. Duration of the parkinsonian syndrome was not predictive of either mental status or scan findings, after adjustment for age as a factor.

DEMENTIA IN PARKINSON'S DISEASE

The occurrence of dementia in patients with Parkinson's disease was studied in a Parkinsonian population consisting of all traceable patients residing in a defined area. The prevalence of dementia was found to be 29 per cent in 444 patients studied. The frequency of dementia increased with advancing age and the patients showing signs of clinical arteriosclerosis were more often demented than the patients without arteriosclerosis. There was, however, an evident association between the stage of the disease and the frequency of dementia. The most severely disabled patients displayed dementia more often than the mildly affected, both among the patients with and without arteriosclerosis. The demented patients showed significantly more severe rigidity and hypokinesia when compared with the non-demented. Increasing severity of rigidity and hypolinesia, in particular was found to have a positive correlation with the degree of dementia. The association between dementia and the degree of motor involvement is considered to suggest the role of subcortical structures in the patholophysiology of dementia in Parkinson's disease.

Clinical pharmacokinetics of levodopa in parkinson's disease.

Although levodopa has provided a major advance in the treatment of parkinsonism, its maximum benefits have not yet been realised, in part because of its complicated pharmacokinetics. This review summarises that available pharmacokinetic data involving levodopa, especially as it relates to therapeutic response of parkinsonian patients. A large number of factors, including protein intake, gastric emptying time, pyridoxine ingestion, and dopa decarboxylase activity, affect plasma levels of levodopa attained following oral administration of this drug. Other variables influence the rate of brain uptake of levodopa from the blood. Even so, plasma levodopa concentration correlates significantly with dosage size in a large parkinsonian population and also coincides with therapeutic response in many, but not all, patients. Therefore, in certain instances, valuable information may be derived by correlating clinical response with plasma levodopa concentration. Cerebrospinal fluid levels of homovanillic acid, a major metabolite of dopamine, may have some value in predicting clinical response to levodopa. This relationship, however, has not been firmly established. Concentration of homovanillic acid or levodopa in body fluids may also be closely related to certain adverse side-effects, including abnormal involuntary movements, gastric discomfort and psychiatric disturbances. Evidence indicates that a clearer understanding of levodopa pharmacokinetics may improve the clinical management of parkinsonism.

The choreoathetoid movement disorder induced by levodopa.

Dyskinesia as a side effect induced by long‐term treatment with levodopa is reported on the basis of experience with 100 patients with Parkinson's disease receiving the agent for at least one year. The sex ratio of the patients was approxirrwtely 2:1 male to ferrwle, and their ages, duration of illness, and the etiologic distribution of idiopathic to postencephalic types were characteristic of a parkinsonian population. Concomitant with clinical improvement demonstrated by patients under levodopa treatment, choreoathetosis appeared as irregularly occurring involuntary movements, involVing head, face, jaw, tongue, shoulder, limbs, or trunk. These movements were usually exaggerated by voluntary movements, and the dyskinesia varied in severity throughout the day, being most severe soon after taking a regular dose of the drug. Since for most patients the dosage producing choreoathetoid movements is at or just below the effective dose of symptom control, a compromise between partial control of symptoms and disabling drug‐induced movements seems inevitable. Measures to control dyskinesia consisted mainly of lowering the dosage. No correlation was noted between the development of dyskinesia and previous stereotaxic surgery, etiology of Parkinson's disease, or its duration or severity. Choreoathetoid movements did not occur in normal control subjects receiving the drug or in patients with dystonia musculorum deformans or spastic torticollis, suggesting a strong specific predisposition in parkinsonian patients to this side effect.