Which Drug for Parkinsonism? Walking, Stiffness, Tremor, and Slowness

Author(s):  
J. Eric Ahlskog

In Chapters 1 and 4, we briefly summarized the symptoms of parkinsonism. Parkinsonism implies movement problems that are typical of Parkinson’s disease. They remain treatment issues during the lifetime of people with Parkinson’s disease, even if dementia develops. Similarly, parkinsonism also typically occurs in DLB, although to variable degrees. In these disorders parkinsonism primarily reflects low brain dopamine levels and improves with dopamine replacement therapy, often markedly. Parkinsonism occurs when a region of the brain called the basal ganglia ceases to work properly (see Figure 4.2 in Chapter 4). As discussed in Chapter 4, the substantia nigra is a crucial regulator of basal ganglia activity, which is mediated by dopamine release in the striatum. The substantia nigra degenerates in these Lewy disorders and, as a result, brain dopamine declines. With a decline in dopamine, movement slows. Bradykinesia is the medical term for such slowness. This manifests as not only slowed movement but also less movement and smaller than normal movements. Unconscious automatic movements, such as blinking or arm swing, diminish. A unique tremor of the hands (sometimes legs) often develops when these limbs are in a relaxed position (rest tremor). For unknown reasons, the brain is not affected symmetrically, hence, neither is the body. Typically, one side of the body is much more impaired than the other. The extent to which these symptoms develop differs from person to person and includes various combinations of the following components. The slowness may be apparent on one or both sides of the body. For example, one leg may lag behind when walking. The overall appearance is characterized by moving much slower than expected for one’s age. The person feels as if they are moving in molasses—everything slows down. Many of our daily activities involve repeated small movements, such as writing or brushing teeth. In the Lewy conditions of DLB and PDD, the size (amplitude) of repetitive movements diminishes, impairing the activity. This is exemplified by the small handwriting of someone with parkinsonism, termed micrographia. Clinicians assess repetitive motor function by asking the patient to repetitively tap the thumb and index finger.

1989 ◽  
Vol 28 (03) ◽  
pp. 92-94 ◽  
Author(s):  
C. Neumann ◽  
H. Baas ◽  
R. Hefner ◽  
G. Hör

The symptoms of Parkinson’s disease often begin on one side of the body and continue to do so as the disease progresses. First SPECT results in 4 patients with hemiparkinsonism using 99mTc-HMPAO as perfusion marker are reported. Three patients exhibited reduced tracer uptake in the contralateral basal ganglia One patient who was under therapy for 1 year, showed a different perfusion pattern with reduced uptake in both basal ganglia. These results might indicate reduced perfusion secondary to reduced striatal neuronal activity.


Author(s):  
Antonina Kouli ◽  
Marta Camacho ◽  
Kieren Allinson ◽  
Caroline H. Williams-Gray

AbstractParkinson’s disease dementia is neuropathologically characterized by aggregates of α-synuclein (Lewy bodies) in limbic and neocortical areas of the brain with additional involvement of Alzheimer’s disease-type pathology. Whilst immune activation is well-described in Parkinson’s disease (PD), how it links to protein aggregation and its role in PD dementia has not been explored. We hypothesized that neuroinflammatory processes are a critical contributor to the pathology of PDD. To address this hypothesis, we examined 7 brain regions at postmortem from 17 PD patients with no dementia (PDND), 11 patients with PD dementia (PDD), and 14 age and sex-matched neurologically healthy controls. Digital quantification after immunohistochemical staining showed a significant increase in the severity of α-synuclein pathology in the hippocampus, entorhinal and occipitotemporal cortex of PDD compared to PDND cases. In contrast, there was no difference in either tau or amyloid-β pathology between the groups in any of the examined regions. Importantly, we found an increase in activated microglia in the amygdala of demented PD brains compared to controls which correlated significantly with the extent of α-synuclein pathology in this region. Significant infiltration of CD4+ T lymphocytes into the brain parenchyma was commonly observed in PDND and PDD cases compared to controls, in both the substantia nigra and the amygdala. Amongst PDND/PDD cases, CD4+ T cell counts in the amygdala correlated with activated microglia, α-synuclein and tau pathology. Upregulation of the pro-inflammatory cytokine interleukin 1β was also evident in the substantia nigra as well as the frontal cortex in PDND/PDD versus controls with a concomitant upregulation in Toll-like receptor 4 (TLR4) in these regions, as well as the amygdala. The evidence presented in this study show an increased immune response in limbic and cortical brain regions, including increased microglial activation, infiltration of T lymphocytes, upregulation of pro-inflammatory cytokines and TLR gene expression, which has not been previously reported in the postmortem PDD brain.


Author(s):  
Vaibhav Walia ◽  
Ashish Gakkhar ◽  
Munish Garg

Parkinson's disease (PD) is a neurodegenerative disorder in which a progressive loss of the dopaminergic neurons occurs. The loss of the neurons is most prominent in the substantia nigra region of the brain. The prevalence of PD is much greater among the older patients suggesting the risk of PD increases with the increase of age. The exact cause of the neurodegeneration in PD is not known. In this chapter, the authors introduce PD, demonstrate its history, pathogenesis, neurobiology, sign and symptoms, diagnosis, and pharmacotherapy.


2002 ◽  
Vol 14 (2) ◽  
pp. 311-322 ◽  
Author(s):  
Chara Malapani ◽  
Bernard Deweer ◽  
John Gibbon

Dysfunction of the basal ganglia and the brain nuclei interconnected with them leads to disturbances of movement and cognition exemplified in Parkinson's disease (PD) and Huntington's disease, including disordered timing of movements and impaired time estimation. Previous research has shown that whereas striatal damage in animals can result in the loss of temporal control over behavior, dopaminergic deregulation in the human striatum associated with PD distorts the memory for time. Here we show a dissociation between deficits in storage (writing to) and retrieval (reading from) temporal memory processes. Both are dysfunctional in PD and sensitive to treatment with dopaminergic agents, but produce dissimilar distortions. When time intervals are stored in memory while the subjects are dopamine depleted, the process is slowed, leading to overestimation of two different time intervals. Conversely, when retrieval occurs in a dopamine-depleted state, interference or coupling occurs between two remembered time intervals, producing overestimation of the shorter and underestimation of the longer one. Whether those two separable patterns of dysfunction in storing and retrieving temporal memories rely on distinct neural networks within the basal ganglia and/or their cortical targets remains to be answered by future research.


2021 ◽  
Vol 6 (3) ◽  
pp. 78-84
Author(s):  
D. S. Yaroshenko ◽  

The review article presents data on the history of research of extrapyramidal system dysfunctions, modern ideas about the etiology and diagnosis of Parkinson's disease, as the most common disease of the group of extrapyramidal disorders. Currently, no concept of effective therapy for patients with extrapyramidal system dysfunction has been developed, but it has been proven that the probability of developing the disease largely depends on the genetic predisposition and the level of environmental pollution. In the early stages, the disease is slow and asymptomatic, but gradually more than half of patients with Parkinson's disease die, and others need outside care. According to experts, in the near future, Parkinson's disease will become a problem for a significant part of people, because today it affects more and more people of working age. Under such conditions, reliable and early diagnosis of the disease is of great importance, which guarantees timely and most effective treatment. Modern therapies fail to stop the progressive death of the dopaminergic neurons of the substantia nigra, but traditional treatment can achieve symptomatic relief. Currently, it is known that the probability of developing Parkinson's disease depends on the genetic predisposition and the level of man-made environmental stress. The researchers consider that the pathological development of Parkinson's disease in the brain begins in the lower structures of the brain stem with the involvement of the caudal-Rostral nuclei, as well as the involvement of the cortico-basal ganglia-cerebellar pathways. The pathological process affects the ascending pathways and gradually passes to the midbrain, directly to the black substance, spreads from there and weakens the mesocortex and neocortex. Injuries in the brain stem lead to disorganization of the cortico-basal ganglia and cerebellar pathways, followed by the formation of alternative pathways to compensate for the initial disorders in the early stages of the disease. In addition, in Parkinson's disease, intracellular Lewy bodies and neurites formed by the protein alpha-synuclein are created, which are found in the autopsy material of most patients. Poor results of diagnostic evaluation and treatment of Parkinson's disease are usually associated with a lack of understanding of the pathogenesis of Parkinson's disease. The study of the biological basis and pathogenesis of Parkinson's disease is an important task of a whole complex of scientific studies of extrapyramidal system dysfunction. Conclusion. The article discusses the creation of toxic models of Parkinson's disease in vivo and in vitro, which help to recreate the pathogenesis of the disease for early diagnosis and the development of new ways to treat neurodegenerative diseases. In toxic models of Parkinsonism, not only deficits of motor functions such as bradykinesia, tremor, and posture disorders are actively studied, but also non-motor symptoms such as sleep disorders, neuropsychiatric and cognitive abnormalities


2012 ◽  
Vol 26 (S1) ◽  
Author(s):  
Nandhini Kanagaraj ◽  
S Thameem Dheen ◽  
Zhao Feng Peng ◽  
Dinesh Kumar Srinivasan ◽  
Samuel S W Tay

2020 ◽  
Author(s):  
Shahan Mamoor

Parkinson’s Disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra of the basal ganglia (1). We mined published microarray datasets (2, 3) to identify genes whose expression was most different in the substantial nigra of patients with PD as compared to that of non-affected patients. We identified significant changes in expression of the gene encoding autophagin-3 (ATG4C) in the substantia nigra of patients with PD.


2018 ◽  
Author(s):  
Pedro D. Maia ◽  
Sneha Pandya ◽  
Justin Torok ◽  
Ajay Gupta ◽  
Yashar Zeighami ◽  
...  

AbstractParkinson’s Disease (PD) is a the second most common neurodegenerative disorder after Alzheimer’s disease and is characterized by cell death in the amygdala and in substructures of the basal ganglia such as the substantia nigra. Since neuronal loss in PD leads to measurable atrophy patterns in the brain, there is clinical value in understanding where exactly the pathology emerges in each patient and how incipient atrophy relates to the future spread of disease. A recent seed-inference algorithm combining an established network-diffusion model with an L1-penalized optimization routine led to new insights regarding the non-stereotypical origins of Alzheimer’s pathologies across individual subjects. Here, we leverage the same technique to PD patients, demonstrating that the high variability in their atrophy patterns also translates into heterogeneous seed locations. Our individualized seeds are significantly more predictive of future atrophy than a single seed placed at the substantia nigra or the amygdala. We also found a clear distinction in seeding patterns between two PD subgroups – one characterized by predominant involvement of brainstem and ventral nuclei, and the other by more widespread frontal and striatal cortices. This might be indicative of two distinct etiological mechanisms operative in PD. Ultimately, our methods demonstrate that the early stages of the disease may exhibit incipient atrophy patterns that are more complex and variable than generally appreciated.


2019 ◽  
Author(s):  
Isabel Cristina Echeverri ◽  
Maria de la Iglesia Vayá ◽  
Jose Molina Mateo ◽  
Francia Restrepo de Mejia ◽  
Belarmino Segura Giraldo

Context: Parkinson’s disease (PD) is catalogued as a disorder that causes motor symptoms; the evidence of literature shows the PD starts with non-motor signs, which can be detected in prodromal phases. These previous phases can be analyzed and studied through magnetic resonance images (MRI), electroencephalography (EEG) and microbiome.Objective: To systematically review the areas of the brain and brain-gut axis which affect in early Parkinson’s disease that can possibly be visualized and analyzed by MRI, EEG and the microbiome.Evidence acquisition: Pubmed and Embase databases were used until July 30, 2018 as to search for early Parkinson’s disease at its earliest non-motor symptoms stage by using MRI, EEG, and microbiome. The search was performed according to the requirements of a systematic review. In order to identify reports, we evaluated them following the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) criteria. Evidence synthesis: MRI and EEG have provided the advances to find features for PD over the last decade. Those techniques identify motor symptoms on substantia nigra where the patient shows a dopamine deficiency. However, over recent years, researchers have found that PD has prodromal phases, that is, PD is not simply a neurodegenerative disorder characterized by the dysfunction of dopaminergic. Thus, high field MRI, event-related potential (ERP) and microbiota data shows a significant change on the brain cortex, white and grey matter, the extrapyramidal system, brain signals and the gut.Conclusion: The structural MRI is a useful technique in detecting the stages of motor symptoms on the substantia nigra in patients with PD. The use of magnetic resonance as an early detector requires a high magnetic field, as to identify the areas which diagnose that the patient could be in the premotor stages. On the other hand, EEG performed well in detecting PD features. Furthermore, microbiome sequencing might include the classification of bacterial families that could help to detect PD in its prodromal phase. Thus, the combination of all these techniques can support the possibility of diagnosing PD in its very early stages.


2022 ◽  
Author(s):  
Min Hyung Seo ◽  
Sujung Yeo

Abstract Parkinson’s disease (PD) is known as the second most common neurodegenerative disease, which is caused by destruction of dopaminergic neurons in the substantia nigra (SN) of the brain; however, the reason for the death of dopaminergic neurons remains unclear. An increase in α-synuclein (α-syn) is considered an important factor in the pathogenesis of PD. In the current study, we investigated the association between PD and serine/arginine-rich protein specific kinase 3 (Srpk3) in MPTP-induced parkinsonism mice model and in SH-SY5Y cells treated with MPP+. Srpk3 expression was significantly downregulated, while tyrosine hydroxylase (TH) decreased and α-synuclein (α-syn) increased after 4 weeks of MPTP intoxication treatment. Dopaminergic cell reduction and α-syn increase were demonstrated by inhibiting Srpk3 expression by siRNA in SH-SY5Y cells. Moreover, a decrease in Srpk3 expression upon siRNA treatment promoted dopaminergic cell reduction and α-syn increase in SH-SY5Y cells treated with MPP+. These results suggest that the decrease in Srpk3 expression due to Srpk3 siRNA caused both a decrease in TH and an increase in α-syn. This raises new possibilities for studying how Srpk3 controls dopaminergic cells and α-syn expression, which may be related to the pathogenesis of PD. Our results provide an avenue for understanding the role of Srpk3 during dopaminergic cell loss and α-syn increase in the SN. Furthermore, this study could support a therapeutic possibility for PD in that the maintenance of Srpk3 expression inhibited dopaminergic cell reduction.


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