Molecular genetics of familial parkinsonism

Parkinson's disease (PD) is a progressive, neurodegenerative disorder associated with tremor, rigidity, bradykinesia, and postural instability. There exists a familial form of PD that is indistinguishable from the sporadic form. In addition, there exists a class of syndromes classified as parkinsonism-plus syndromes (PPS), in which parkinsonism is an essential but not the only phenotypic characteristic. The etiology of PD remains unclear. Both environmental and genetic factors contribute to the disease pathogenesis. Recent progress in the molecular genetics of parkinsonism has demonstrated that six different chromosomal regions are associated with forms of familial parkinsonism. Mutations in four candidate genes have been identified and include both point mutations and deletions. Both gain-of-function and loss-of-function mutational mechanisms have been implicated. The molecular genetic characterization has led to a new classification of PD and PPS based on the type of genetic defect. Understanding the mechanisms by which these mutations lead to disease should provide further insights into the etiology of parkinsonism.     

Prevalence of axial postural abnormalities and their subtypes in Parkinson’s disease: a systematic review and meta-analysis

Journal of Neurology - Axial postural abnormalities, mainly involving the spinal deformities, are disabling symptoms of Parkinson’s disease (PD). However, the prevalence of axial postural...     

Parkinson's disease: clinical manifestations and treatment

This review describes and synthesizes the clinical manifestations, differential diagnosis, and treatment of Parkinson's disease (PD). PD is a common neurodegenerative disorder affecting approximately 0.5 to 1% of the population over the age of 65.The cardinal features of PD include tremor, bradykinesia, rigidity and postural instability.There are also a number of secondary features that are important to recognize and treat, including cognitive dysfunction, depression, anxiety, autonomic dysfunction, and disturbances of sleep. Only approximately 75-80% of patients that present with parkinsonian features have idiopathic PD. Other disease entities that can present with parkinsonism are reviewed. It is important to recognize these disorders since treatment and prognosis for the parkinsonian syndromes are markedly different from idiopathic PD.In addition, current medical and surgical approaches for the treatment of PD are reviewed.The mainstay of treatment for PD remains levodopa, but there are a number of supplementary medications including anticholinergics and dopamine agonists, which are useful in the treatment of PD. Surgical approaches including thalamotomy, pallidotomy and deep brain stimulation are receiving increased attention as adjunctive therapy for treatment of PD.     

Differential diagnosis of Parkinson's disease and the parkinsonism plus syndromes.

Although Parkinson's disease (PD) is thought to represent a specific clinical-pathologic entity, up to 20% of patients diagnosed as having PD will have another disorder at autopsy. Furthermore, pathologic features typically associated with PD can also be observed in patients with other neurodegenerative disorders. This article attempts to point out the difficulties in differentiating PD from progressive supranuclear palsy and other parkinsonism plus syndromes and various causes of parkinsonism associated with cognitive changes. The clinical and pathologic differentiation of these disorders are discussed. These disorders are usually associated with postsynaptic receptor changes and therefore levodopa and dopamine agonists provide limited benefit.     

Vascular parkinsonism: a distinct, heterogeneous clinical entity

OBJECTIVES: The aim of this study was to define the symptoms and signs of suspected vascular parkinsonism (VP) which is still a debatable concept. MATERIAL AND METHODS: Patients with parkinsonism were grouped into patients with suspected VP and Parkinson's disease (PD) after other causes for secondary parkinsonism, and parkinsonism-plus syndromes were excluded. The clinical features of 16 patients with suspected VP to those of 50 diagnosed with PD were compared. All patients were assessed using unified Parkinson's disease rating scale (UPDRS) and all had cerebral MRIs. RESULTS: Patients with VP had significantly older onset age and shorter duration of disease with gait disorder as the most frequent initial symptom. All PD patients had satisfactory response to levodopa treatment, whereas only 38% VP patients had satisfactory response to levodopa treatment. Vascular risk factors were more common in VP (81%) than PD (32%). Postural instability, freezing, gait disturbance, pyramidal signs, and postural tremor were significantly more prevalent in patients with VP than in PD. In VP patients these features were more prominent in the lower limbs. Twenty-five percent had acute onset VP. All patients with VP had ischemic lesions, mainly in subcortical white matter, to a lesser extent basal ganglia and brainstem, in their cerebral MRIs, while 70% of PD patients had normal MRIs. CONCLUSION: The differences in the clinical features support the concept that VP is a distinct clinical entity with heterogeneous clinical, MRI, and possibly pathophysiological features.     

The role of <Superscript>123</Superscript>I-FP-CIT-SPECT in the differential diagnosis of Parkinson and tremor syndromes: a critical assessment of 125 cases

¹²³I-FP-CIT-SPECT is useful in the differential diagnosis of Parkinson’s disease (PD) and tremor syndromes. Recently, there have been reports on normal nigrostriatal uptake of radio ligands in PD patients, referred to as scans without evidence of dopaminergic deficit (SWEDDs). Furthermore, a dopaminergic deficit has been described in some cases of different tremor types. We sought to clarify the occurrence of SWEDDs in PD and a possible association of various tremor types with PD. We performed a retrospective case analysis of 125 patients with diagnostically uncertain Parkinsonian or non-Parkinsonian tremor syndromes with clinical assessments and ¹²³I-FP-CIT-SPECT. A total of 36/40 (90%) patients with the predominant clinical feature of a postural and/or kinetic tremor showed normal DAT SPECT; 73/85 (86%) with predominant clinical symptoms of PD showed abnormal DAT SPECT with lower overall radio ligand uptake and a significant asymmetry contralateral to the clinically more affected side. In all, 4/40 (10%) of non-Parkinsonian tremor patients had abnormal DAT SPECT, but no corresponding asymmetry of radio ligand uptake. Probable essential tremor was considered clinically in follow-up assessments although final diagnosis of these four tremor cases remains inconclusive. A total of 12/85 (14%) clinically suspected PD patients had normal DAT SPECT (SWEDDs). Clinical reassessment identified two patients with dystonic tremor. Five patients with a positive response to levodopa remained unclear. In four cases of suspected PD with normal DAT SPECT, non-neurologic diseases were identified. One case showed a complete and spontaneous remission of symptoms. DAT SPECT offers an objective method to confirm or exclude a dopaminergic deficit in tremor predominant parkinsonism for clinically inconclusive cases. There was no evidence of a decrease in DAT binding in the majority of patients with postural and/or kinetic tremor. The striatal asymmetry index is a further helpful tool for differentiating PD from non-PD tremor syndromes.     

Parkinson disease

Parkinson disease (PD) is the most common neurodegenerative movement disorder. In Europe, prevalence and incidence rates for PD are estimated at approximately 108–257/100 000 and 11–19/100 000 per year, respectively. Risk factors include age, male gender and some environmental factors. The aetiology of the disease in most patients is unknown, but different genetic causes have been identified. Although familial forms of PD account for only 5%–15% of cases, studies on these families provided interesting insight on the genetics and the pathogenesis of the disease allowing the identification of genes implicated in its pathogenesis and offering critical insights into the mechanisms of disease. The cardinal motor symptoms of PD are tremor, rigidity, bradykinesia/akinesia and postural instability, but the clinical picture includes other motor and non‐motor symptoms. Its diagnosis is principally clinical, although specific investigations can help the differential diagnosis from other forms of parkinsonism. Pathologically, PD is characterized by the loss of dopaminergic neurons in the pars compacta of the substantia nigra and by accumulation of misfolded α‐synuclein, which is found in intra‐cytoplasmic inclusions called Lewy bodies. Currently available treatments offer good control of motor symptoms but do not modify the evolution of the disease. This article is intended to provide a comprehensive, general and practical review of PD for the general neurologist.     

Diffusion-weighted imaging and its relationship to microglial activation in parkinsonian syndromes

Microglial activation has been implicated in the pathogenesis of Parkinson's disease (PD) and atypical parkinsonian syndromes, and regional microstructural changes have been identified using diffusion-weighted MR imaging. It is not known how these two phenomena might be connected.We hypothesized that changes in regional apparent diffusion coefficient (rADC) in atypical parkinsonian syndromes would correlate with microglial activation.In our study we have evaluated changes in rADC in 11 healthy controls, 9 patients with PD and 11 with either multiple system atrophy or progressive supranuclear palsy. The patients also underwent [¹¹C]-(R)-PK11195 positron emission tomography, a marker of microglial activation.Increased rADC was found compared to controls in the thalamus and midbrain of all parkinsonian patients, and in the putamen, frontal and deep white matter of patients with atypical parkinsonian syndromes. Putaminal rADC alone did not reliably differentiate PD from atypical parkinsonism. There was no correlation between [¹¹C]-(R)-PK11195 binding potential and rADC in the basal ganglia in atypical parkinsonian syndromes. However, pontine PK11195 binding and rADC were positively correlated in atypical parkinsonism (r = 0.794, p = 0.0007), but not PD patients.In conclusion, microglial activation does not appear to contribute to the changes in putaminal water diffusivity associated with atypical parkinsonian syndromes, but may correlate with tissue damage in brainstem regions.     

Dyskinesias and impulse control disorders in Parkinson's disease: From pathogenesis to potential therapeutic approaches

Dopaminergic treatment in Parkinson's disease (PD) reduces the severity of motor symptoms of the disease. However, its chronic use is associated with disabling motor and behavioral side effects, among which levodopa-induced dyskinesias (LID) and impulse control disorders (ICD) are the most common. The underlying mechanisms and pathological substrate of these dopaminergic complications are not fully understood. Recently, the refinement of imaging techniques and the study of the genetics and molecular bases of LID and ICD indicate that, although different, they could share some features. In addition, animal models of parkinsonism with LID have provided important knowledge about mechanisms underlying such complications. In contrast, animal models of parkinsonism and abnormal impulsivity, although useful regarding some aspects of human ICD, do not fully resemble the clinical phenotype of ICD in patients with PD, and until now have provided limited information. Studies on animal models of addiction could complement the previous models and provide some insights into the background of these behavioral complications given that ICD are regarded as behavioral addictions. Here we review the most relevant advances in relation to imaging, genetics, biochemistry and pharmacological interventions to treat LID and ICD in patients with PD and in animal models with a view to better understand the overlapping and unique maladaptations to dopaminergic therapy that are associated with LID and ICD.     

Clinical correlates of anterior and lateral flexion of the thoracolumbar spine and dropped head in patients with Parkinson's disease

IntroductionParkinson’s disease (PD) is often accompanied by postural disorders such as anterior and lateral flexion of the thoracolumbar spine and dropped head. We examined frequencies and clinical correlates of postural disorders in patients with PD.MethodsWe interviewed 365 consecutive PD patients between 40 and 80 years of age, at Hoehn and Yahr stages 1, 2, 3 and 4, and evaluated postural deformities, including anterior and lateral flexion of the trunk and dropped head as well as other clinical characteristics. Control subjects were 65 age-matched patient spouses without neurological or spinal disorders.ResultsThere were no differences in age or sex between PD patients and controls. The frequencies of anterior and lateral flexion of the trunk were significantly higher in PD patients than in controls. The frequency and severity of anterior and lateral flexion and the incidence of dropped head increased as the disease progressed. Other factors related to anterior and lateral flexion included age, disease duration, lower MMSE score, lumbago and levodopa equivalent daily dose of dopaminergic drugs. Women tended to develop more severe anterior flexion than men. Anterior flexion severity also correlated with that of lateral flexion and the emergence of dropped head.ConclusionsPostural disorders are frequent complications in PD patients and their severity increases with disease progression. Advancing age and disease severity may be the major risks for developing postural disorders.     

Slowing of Frontal β Oscillations in Atypical Parkinsonism

Background

Diagnosis of atypical parkinsonian syndromes (APS) mostly relies on clinical presentation as well as structural and molecular brain imaging. Whether parkinsonian syndromes are distinguishable based on neuronal oscillations has not been investigated so far.

Objective

The aim was to identify spectral properties specific to atypical parkinsonism.

Methods

We measured resting-state magnetoencephalography in 14 patients with corticobasal syndrome (CBS), 16 patients with progressive supranuclear palsy (PSP), 33 patients with idiopathic Parkinson's disease, and 24 healthy controls. We compared spectral power as well as amplitude and frequency of power peaks between groups.

Results

Atypical parkinsonism was associated with spectral slowing, distinguishing both CBS and PSP from Parkinson's disease (PD) and age-matched healthy controls. Patients with atypical parkinsonism showed a shift in β peaks (13–30 Hz) toward lower frequencies in frontal areas bilaterally. A concomitant increase in θ/α power relative to controls was observed in both APS and PD.

Conclusion

Spectral slowing occurs in atypical parkinsonism, affecting frontal β oscillations in particular. Spectral slowing with a different topography has previously been observed in other neurodegenerative disorders, such as Alzheimer's disease, suggesting that spectral slowing might be an electrophysiological marker of neurodegeneration. As such, it might support differential diagnosis of parkinsonian syndromes in the future. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

Late-stage Parkinson disease

The cardinal symptoms of Parkinson disease (PD) are asymmetrical bradykinesia, rigidity, resting tremor and postural instability. However, the presence and spectrum of, and disability caused by, nonmotor symptoms (NMS) are being increasingly recognized. NMS include dementia, psychosis, depression and apathy, and are a major source of disability in later stages of PD, in association with axial symptoms that are resistant to levodopa therapy. The model of clinical progression of PD should, therefore, incorporate NMS, instead of being restricted to motor signs and levodopa-induced motor complications. Patients with disabling motor complications are classified as having advanced PD, which has been thought to represent the ultimate stage of disease. However, deep brain stimulation to treat motor complications has dramatically changed this scenario, with implications for the definition of advanced-stage disease. As treatment improves and survival times increase, patients are increasingly progressing to a later phase of disease in which they are highly dependent on caregivers, and disability is dominated by motor symptoms and NMS that are resistant to levodopa. In this article, we review the changing landscape of the later stages of PD, and propose a definition of late-stage PD to designate patients who have progressed beyond the advanced stage.     

Gene–environment interactions in Parkinson's disease and other forms of parkinsonism

It is widely recognized that both genetic and environmental factors are likely to contribute to the pathogenesis of human parkinsonism. While the identification of specific predisposing conditions and mechanisms of disease development remain elusive, new discoveries coupled with technological advances over the past decade have provided important clues. From the genetic standpoint, both causal and susceptibility genes have been identified, with some of these genes pointing to gene–environment interactions. The application of emerging genomic technologies, such as Genome Wide Association Studies (GWAS), will certainly further our knowledge of Parkinson's disease (PD)-related genes. From the environmental perspective, toxicant-induced models of parkinsonian syndromes, such as those associated with exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or β-N-methylamino-l-alanine (BMAA), have revealed potential mechanisms of increased susceptibility based on genetic predisposition. Finally, new hypotheses on mechanisms of disease development include the possibility that exposure to neurotoxicants triggers an upregulation and pathological modifications of α-synuclein. Mutations in the α-synuclein gene are responsible for rare familial cases of parkinsonism, and polymorphisms in the promoter region of this gene confer a higher susceptibility to idiopathic PD. Thus, toxicant–α-synuclein interactions could have deleterious consequences and play a role in pathogenetic processes in human parkinsonism.     

Clinical Aspects of the Differential Diagnosis of Parkinson’s Disease and Parkinsonism

Parkinsonism is a clinical syndrome presenting with bradykinesia, tremor, rigidity, and postural instability. Nonmotor symptoms have recently been included in the parkinsonian syndrome, which was traditionally associated with motor symptoms only. Various pathologically distinct and unrelated diseases have the same clinical manifestations as parkinsonism or parkinsonian syndrome. The etiologies of parkinsonism are classified as neurodegenerative diseases related to the accumulation of toxic protein molecules or diseases that are not neurodegenerative. The former class includes Parkinson’s disease (PD), multiple-system atrophy, progressive supranuclear palsy, and corticobasal degeneration. Over the past decade, clinical diagnostic criteria have been validated and updated to improve the accuracy of diagnosing these diseases. The latter class of disorders unrelated to neurodegenerative diseases are classified as secondary parkinsonism, and include drug-induced parkinsonism (DIP), vascular parkinsonism, and idiopathic normal-pressure hydrocephalus (iNPH). DIP and iNPH are regarded as reversible and treatable forms of parkinsonism. However, studies have suggested that the absence of protein accumulation in the nervous system as well as managing the underlying causes do not guarantee recovery. Here we review the differential diagnosis of PD and parkinsonism, mainly focusing on the clinical aspects. In addition, we describe recent updates to the clinical criteria of various disorders sharing clinical symptoms with parkinsonism.     

Predictors of falls and fractures in bradykinetic rigid syndromes: a retrospective study

BACKGROUND: Falls and fractures contribute to morbidity and mortality in bradykinetic rigid syndromes. METHODS: The authors performed a retrospective case notes review at the Queen Square Brain Bank for Neurological Disorders and systematically explored the relation between clinical features and falls and fractures in 782 pathologically diagnosed cases (474 with Parkinson's disease (PD); 127 progressive supranuclear palsy (PSP); 91 multiple system atrophy (MSA); 46 dementia with Lewy bodies (DLB); 27 vascular parkinsonism; nine Alzheimer's disease; eight corticobasal degeneration). RESULTS: Falls were recorded in 606 (77.5%) and fractures in 134 (17.1%). In PD, female gender, symmetrical onset, postural instability, and autonomic instability all independently predicted time to first fall. In PD, PSP, and MSA latency to first fall was shortest in those with older age of onset of disease. Median latency from disease onset to first fall was shortest in Richardson's syndrome (12 months), MSA (42), and PSP-parkinsonism (47), and longest in PD (108). In all patients fractures of the hip were more than twice as common as wrist and forearm fractures. Fractures of the skull, ribs, and vertebrae occurred more frequently in PSP than in other diseases. CONCLUSION: Measures to prevent the morbidity associated with falls and fractures in bradykinetic rigid syndromes may be best directed at patients with the risk factors identified in this study.     

Chronic bilateral subthalamic deep brain stimulation in a patient with homozygous deletion in the parkin gene.

Chronic subthalamic nucleus deep brain stimulation (STN-DBS) is an efficacious treatment for idiopathic Parkinson's disease (PD) that cannot be further improved by medical therapy. We present a case of an individual with juvenile parkinsonism caused by homozygous deletion of exon 3 in the parkin gene with disabling long-term side-effects from levodopa who underwent bilateral STN neuromodulation. Parkin-linked parkinsonism may show clinical features different from sporadic PD, yet it shares levodopa responsiveness. Because levodopa responsiveness is a predictor of STN-DBS efficacy, we argued that this kind of surgical approach might be efficacious in hereditary parkin-linked juvenile parkinsonism. We evaluated clinical and functional assessment before and 12 months after surgery. The results showed that the Unified Parkinson Disease Rating Scales Motor score improved by 84% in our patient, the levodopa equivalent daily dose medication (LEDD) was reduced by 66%, and, finally, disabling and severe dyskinesias disappeared.     

Action observation improves sit-to-walk in patients with Parkinson's disease and freezing of gait. Biomechanical analysis of performance

IntroductionFreezing of gait (FoG) is one of the most disabling gait disorders in Parkinson's disease (PD), reflecting motor and cognitive impairments, mainly related to dopamine deficiency. Recent studies investigating kinematic and kinetic factors affecting gait in these patients showed a postural instability characterized by disturbed weight-shifting, inappropriate anticipatory postural adjustment, worse reactive postural control, and a difficulty executing complex motor tasks (i.e. sit-to-walk). These symptoms are difficult to alleviate and not very responsive to Levodopa. For this reason, additional therapeutic actions based on specific therapeutic protocols may help patients with their daily lives. We conducted a randomized control trial aimed to test if two clinical protocols for PD patients with FoG were effective to improve postural control.MethodsRehabilitation protocols, conceived to improve gait, were based on learning motor exercises with the Action Observation plus Sonification (AOS) technique, or by the use of external sensory cues. We collected biomechanical data (Center of Mass COM, Center of Pressure COP, and moving timings), using the sit-to-walk task as a measure of motor and gait performance.ResultsKinetic and kinematic data showed that when treatment effects consolidate, patients treated with AOS protocol are more efficient in merging subsequent motor tasks (sit-to-stand and gait initiation), and diminished the total moving time and the area of the COP positions.ConclusionWe demonstrated for the first time that PD patients with FoG treated with an AOS protocol aimed at relearning appropriate gait patterns increased balance control and re-acquired more efficient postural control.     

Prevalence of essential tremor in patients with Parkinson's disease vs. Parkinson-plus syndromes.

Clinical literature suggests an association between essential tremor (ET) and Parkinson's disease (PD), and recent pathological studies describe Lewy bodies in some ET patients. If some ET were an expression of Lewy body disease, one could hypothesize that ET patients who develop parkinsonism would more likely develop PD (a Lewy body disease) than non-Lewy body forms of parkinsonism. The objective was to compare the proportions of patients with PD vs. Parkinson-plus syndromes who had diagnoses of ET. Retrospective chart review at the Neurological Institute (NI) of New York. A larger proportion of the 210 PD than 210 Parkinson-plus syndrome patients had kinetic tremor on examination (119 [56.7%] vs. 70 [33.3%], P < 0.001). Patients with PD were more likely to have a prior diagnosis of ET than were patients with Parkinson-plus syndromes (7.1% vs. 2.4%, OR 3.16, 95% CI 1.13-8.85, P = 0.02) and more likely to have a diagnosis of ET assigned by an NI neurologist (5.3% vs. 0.0%, OR 12.85, 95% CI 1.66-99.8, P = 0.001). Patients with PD were three to thirteen times more likely to have diagnoses of ET than were patients with Parkinson-plus syndromes. These data further confirm the link between ET and PD, and possibly, between ET and Lewy body disease.     

Diagnostic accuracy of parkinsonism syndromes by general neurologists

IntroductionMovement disorder specialists can achieve a high level of accuracy when clinically diagnosing parkinsonism syndromes. However, data about the diagnostic accuracy among general neurologists is limited.ObjectivesThis study investigated the recent diagnostic accuracy of parkinsonism syndromes by general neurologists.MethodsA retrospective examination of 1362 post-mortem cases diagnosed in the years 2000–2012 by neuropathologists was performed. Out of these cases, we identified 111 patients who received a clinical parkinsonism diagnosis during life and 122 patients who received a neuropathological diagnosis of a parkinsonism syndrome post-mortem including 11 incidental cases.ResultsFifty-eight (75.3%) of the 77 patients who had received clinical Parkinson's disease (PD) diagnoses were confirmed after the neuropathological examination. The sensitivity of the clinical diagnosis for idiopathic Parkinson's disease (PD) was 89.2% and the specificity was 57.8%. The corresponding numbers for progressive supranuclear palsy (PSP) were 52.9% and 100%, and for multiple system atrophy (MSA) were 64.3% and 99.0%, respectively.ConclusionsParkinson's disease is heavily overdiagnosed by general neurologists, whereas parkinsonism plus syndromes are underdiagnosed. Despite improvements in the diagnostic methods during recent decades and the development of diagnostic clinical criteria for parkinsonian syndromes, the diagnostic accuracy of Parkinson's disease remains relatively low, and 1/4 of diagnoses are incorrect.