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Laterality and Symptom Association in Parkinson's Disease
Abstract
To the Editror.
—Direnfeld and colleagues1 suggested a relationship of laterality of motor signs to neuropsychological and neurochemical abnormalities in Parkinson's disease (PD). By comparing nine patients with PD who had asymmetric motor findings, the authors concluded that patients more affected on the left side (PDL, N=5) had more neuropsychological impairment than those predominantly affected on the right side (PDR, N=4). Unfortunately, the population sample was small, the selection criteria were not defined, and the degree of asymmetry was not stated. The laterality of the clinical manifestations was established by asking the patients which side they believed was more affected and by rating (on a scale of 0 to 4) tremor, rigidity, and bradykinesia. Of these motor signs, bradykinesia was given the most weight, although the weighing criteria were not specified.In most clinical studies the bradykinesia score represents an overall assessment of slowness and poverty of
... Specific signs of PD frequently cluster together in specific patients, suggesting that there are symptomatic subtypes of PD. There is no general consensus on how to define specific subtypes of PD; however, the most widely used classification method divides patients into a postural instability/gait difficulty or tremor dominant category (Doder et al., 2003;Zetusky and Jankovic, 1985). Others have attempted to classify PD subtypes based on cardinal motor signs, patterns of cognitive dysfunction, and age of onset (for review see Selikhova et al., 2009). ...
... Importantly, the time-course and severity of sub-groups of parkinsonian signs vary independently between patients (Evarts et al., 1981;Jordan et al., 1992;Meyer, 1982;Nieuwboer et al., 1998;Selikhova et al., 2009;Temperli et al., 2003;Zetusky and Jankovic, 1985). It is therefore possible that different parkinsonian signs have distinct pathophysiologic substrates. ...
... In PD patients, the magnitude of levodopa-induced improvements in gait freezing is unrelated to the magnitude of improvement in bradykinesia (Bartels et al., 2003). Furthermore, specific parkinsonian signs tend to cluster together in PD patients, such that PD can be divided into subtypes such as a postural instability/gait difficulty or tremor dominant subtype (Doder et al., 2003;Zetusky and Jankovic, 1985). The time-course and severity of sub-groups of parkinsonian signs also vary independently between patients (Evarts et al., 1981;Jordan et al., 1992;Meyer, 1982;Nieuwboer et al., 1998;Selikhova et al., 2009;Temperli et al., 2003;Zetusky and Jankovic, 1985), lending further support to the idea that different signs have separate pathophysiologic substrates. ...
The pathophysiology of Parkinson's disease (PD) has long been attributed to dopamine (DA) loss in the striatum. However, it remains unclear whether simple underactivation of striatal DA receptors is sufficient to induce parkinsonian signs. To test this hypothesis, we performed unilateral infusions of cis-flupenthixol (cis-flu; D1/D2 antagonist) into the macaque putamen, while the macaque performed a reaching task. Twenty-six cis-flu and three saline infusions were performed across three hemispheres in two macaques. Neuronal and local field potential activity was recorded simultaneously from cortex, globus pallidus externa (GPe), and globus pallidus interna (GPi) during most infusions. The reaching task required each macaque to make visually-cued reaching movements to a target for a reward. The macaque was then required to return its hand to a home position without external cues. Injection-related slowing of movement initiation or execution was thought to reflect akinetic- or bradykinetic-like effects, respectively. Following 8/26 cis-flu infusions, macaques exhibited a marked slowing in the initiation of self-generated return movements (95% increase). This was the most severe behavioral effect of cis-flu infusions. The initiation and execution of externally-cued movements were also prolonged following 9/26 and 6/26 injections, but only by 20% and 15% respectively. In general, akinetic-like effects occurred twice as often as bradykinetic-like effects (p<0.05, 2= 4.1). Interestingly, akinetic and bradykinetic effects could be elicited independently. In addition to affecting behavior, intrastriatal DA receptor blockade also reduced resting and peri-movement activity in the cortex and suppressed resting GPe activity. Burstiness, synchrony, and oscillatory activity in cortex were increased following intrastriatal DA receptor blockade as well. Oscillatory activity was also increased in the GPe and GPi. In conclusion, suppression of striatal DA activity was sufficient to induce akinetic-like signs, most severely affecting movement initiation during self-generated movements. Furthermore, distinct parkinsonian-like signs could be elicited independently, suggesting that separate signs may have unique pathophysiologic substrates. Intrastriatal DA receptor blockade also induced changes in cortical and BG activity that were consistent with findings in the parkinsonian state. Interestingly, many of these neuronal activity changes were specific to cortex, implicating an important role for cortical activity in the development of akinetic parkinsonian signs.
... Bradykinesia refers exclusively to slowed execution of movement (measurable as prolonged movement durations, MDs, Hallett and Khoshbin, 1980), while rigidity and tremor manifest as increased muscular resistance to passive joint movement and involuntary 4-6 Hz tremulous movements of one or more body part, respectively (Jankovic, 2008). Each of these parkinsonian signs varies independently in severity, rate of progression, and response to therapy (Espay et al., 2009;Evarts et al., 1981;Jankovic, 2008;Jordan et al., 1992;Kimber et al., 1999;Kishore et al., 2007;Meyer, 1982;Nieuwboer et al., 1998;Selikhova et al., 2009;Temperli et al., 2003;Zetusky and Jankovic, 1985), implying that different parkinsonian signs may have unique pathophysiologic substrates. Similarly, the fact that anatomically-segregated regions of the striatum are devoted to skeletomotor, associative and limbic functions (Alexander et al., 1990;Kelly and Strick, 2004;Worbe et al., 2009) has prompted proposals that dissociable symptoms of PD arise from loss of DA from separate functional regions of the striatum (Alexander et al., 1986;Joel and Weiner, 1994;Wichmann et al., 2011). ...
... More generally, our findings are consistent with the many studies showing that subgroups of parkinsonian signs vary independently. It is now firmly established that patients with PD can be classified into subtypes characterized by postural instability/gait difficulty versus tremor dominant symptoms (Zetusky and Jankovic, 1985). The severity and rate of progression of these symptom subtypes varies independently between patients (Nieuwboer et al., 1998;Selikhova et al., 2009;Temperli et al., 2003;Zetusky and Jankovic, 1985). ...
... It is now firmly established that patients with PD can be classified into subtypes characterized by postural instability/gait difficulty versus tremor dominant symptoms (Zetusky and Jankovic, 1985). The severity and rate of progression of these symptom subtypes varies independently between patients (Nieuwboer et al., 1998;Selikhova et al., 2009;Temperli et al., 2003;Zetusky and Jankovic, 1985). Our data support the idea that impairments in self-initiation and in the control of sensory-cued movement also vary independently in parkinsonism and that each may arise from different pathophysiologic substrates. ...
The diverse and independently-varying signs of Parkinson's disease (PD) are often attributed to one simple mechanism: degeneration of the dopaminergic innervation of the posterolateral striatum. However, growing recognition of the dopamine (DA) loss and other pathology in extra-striatal brain regions has led to uncertainty whether loss of DA in the striatum is sufficient to cause parkinsonian signs. We tested this hypothesis by infusing cis-flupenthixol (cis-flu; a broad-spectrum D1/D2 receptor antagonist) into different regions of the macaque putamen (3 hemispheres of 2 monkeys) while the animal performed a visually-cued choice reaction time task in which visual cues indicated the arm to reach with and the peripheral target to contact to obtain food reward. Following reward delivery, the animal was required to self-initiate release of the peripheral target and return of the chosen hand to its home position (i.e., without the benefit of external sensory cues or immediate rewards). Infusions of cis-flu at 15 of 26 sites induced prolongations of reaction time (9 of 15 cases), movement duration (6 cases), and/or dwell time of the hand at the peripheral target (8 cases). Dwell times were affected more severely (+95%) than visually-triggered reaction times or movement durations (+25% and +15%, respectively). Specifically, the animal's hand often 'froze' at the peripheral target for up to 25-s, similar to the akinetic freezing episodes observed in PD patients. Across injections, slowing of self-initiation did not correlate in severity with prolongations of visually-triggered reaction time or movement duration, although the latter two were correlated with each other. Episodes of slowed self-initiation appeared primarily in the arm contralateral to the injected hemisphere and were not associated with increased muscle co-contraction or global alterations in behavioral state (i.e., inattention or reduced motivation), consistent with the idea that these episodes reflected a fundamental impairment of movement initiation. We found no evidence for an anatomic topography within the putamen for the effects elicited. We conclude that acute focal blockade of DA transmission in the putamen is sufficient to induce marked akinesia-like impairments. Furthermore, different classes of impairments can be induced independently, suggesting that specific parkinsonian signs have unique pathophysiologic substrates.
... Symptoms impacting the ability to move (gait disturbances, postural instability, rigidity, and bradykinesis) are all associated with a more severe PD course (7)(8)(9)(10). Conversely, asymmetric onset of symptoms and tremordominant disease are associated with milder forms of PD and follow a less dramatic disease course (7,11). Finally, contrasting with other degenerative brain disorders and dementias such as Alzheimer, in PD, later age of onset is correlated with more rapidly progressing disease (12)(13)(14). ...
Immune dysfunction plays a role in the development of Parkinson disease (PD). NK cells regulate immune functions and are modulated by killer cell immunoglobulin-like receptors (KIR). KIR are expressed on the surface of NK cells and interact with HLA class I ligands on the surface of all nucleated cells. We investigated KIR-allelic polymorphism to interrogate the role of NK cells in PD. We sequenced KIR genes from 1314 PD patients and 1978 controls using next-generation methods and identified KIR genotypes using custom bioinformatics. We examined associations of KIR with PD susceptibility and disease features, including age at disease onset and clinical symptoms. We identified two KIR3DL1 alleles encoding highly expressed inhibitory receptors associated with protection from PD clinical features in the presence of their cognate ligand: KIR3DL1*015/HLA-Bw4 from rigidity (pc = 0.02, odds ratio [OR] = 0.39, 95% confidence interval [CI] 0.23-0.69) and KIR3DL1*002/HLA-Bw4i from gait difficulties (p
c
= 0.05, OR = 0.62, 95% CI 0.44-0.88), as well as composite symptoms associated with more severe disease. We also developed a KIR3DL1/HLA interaction strength metric and found that weak KIR3DL1/HLA interactions were associated with rigidity (pc = 0.05, OR = 9.73, 95% CI 2.13-172.5). Highly expressed KIR3DL1 variants protect against more debilitating symptoms of PD, strongly implying a role of NK cells in PD progression and manifestation.
... Since 97% of our sample was composed of right-handed persons and the primary outcome measure (O'CT) was determined using the dominant hand, our data suggest that finger and hand dexterity are impaired in the dominant hand, regardless of the side of motor symptoms predominance. is finding is in line with previous data, showing that dopamine deficit in the right caudate correlates with difficulty in bimanual hand movements [29]. ...
Background:
Hand functionality and finger dexterity are impaired in patients with Parkinson's disease (PD). These disturbances lead to a dependency in activities of daily living (ADL) and poor quality of life (QoL).
Objective:
We aimed to evaluate whether a specific occupational therapy (OT) program is effective in improving finger and hand dexterity and its impact on ADL in PD patients.
Methods:
We retrospectively studied PD patients, hospitalized for a 4-week multidisciplinary intensive rehabilitation treatment (MIRT) between January 2015 and June 2018. All patients underwent 1 h/day OT treatment, 5 days a week. The primary outcome measure was the O'Connor finger dexterity test; secondary outcome measures were the Minnesota dexterity test, UPDRS II, and Self-Assessment Parkinson's Disease Disability Scale (SPDDS). These measures were assessed at admission (T0) and discharge (T1).
Results:
Based on the Hoehn and Yahr scale (H&Y), patients were divided into two groups: 262 subjects in H&Y stage <3 (early-stage PD patients) and 220 in H&Y stage ≥3 (medium-advanced stage PD patients). As expected, at baseline, all measures were worse in higher H&Y stages. After treatment, both groups experienced significant improvements in all outcomes. Significant differences between early-stage and medium-advanced stage PD patients were observed only for the changes in UPDRS II, with a better improvement in patients in H&Y stage ≥3.
Conclusions:
We showed that PD patients who underwent a rehabilitation protocol including OT experienced improvements in finger dexterity and hand functionality. Our results underline the relevance of OT in improving autonomy and QoL in PD patients.
... The clinical diagnosis of PD requires the presence of a subset of motor symptoms (e.g., tremor, rigidity, akinesia, bradykinesia and postural imbalance), therefore the diagnostic system allows for patients with different motor symptom profiles (Hughes et al., 1992). Studies often classify PD patients into the tremor-dominant, the akinesia-dominant (also known as akineto-rigid), or the mixed phenotype category (Jankovic et al., 1990;Lee et al., 2012;Lewis et al., 2005;Moustafa and Poletti, 2013;Mure et al., 2011;Poletti et al., 2011b;Rajput, 1993;Schiess et al., 2000;Schillaci et al., 2011;Zaidel et al., 2009;Zetusky and Jankovic, 1985). Although most of these studies did not specify the subtype of tremor that the patients were presenting with, they can help to reveal the clinical correlates and neural substrates of these different motor subtypes (akinesia vs. tremor) in PD. ...
Parkinson's disease (PD) is characterized by a range of motor symptoms. Besides the cardinal symptoms (akinesia and bradykinesia, tremor and rigidity), PD patients show additional motor deficits, including: gait disturbance, impaired handwriting, grip force and speech deficits, among others. Some of these motor symptoms (e.g., deficits of gait, speech, and handwriting) have similar clinical profiles, neural substrates, and respond similarly to dopaminergic medication and deep brain stimulation (DBS). Here, we provide an extensive review of the clinical characteristics and neural substrates of each of these motor symptoms, to highlight precisely how PD and its medical and surgical treatments impact motor symptoms. In conclusion, we offer a unified framework for understanding the range of motor symptoms in PD. We argue that various motor symptoms in PD reflect dysfunction of neural structures responsible for action selection, motor sequencing, and coordination and execution of movement.
... Currently, while the presence of the core motor symptoms remains essential for diagnosis, many PD patients demonstrate marked cognitive impairment even at the time of first presentation (Foltynie et al., 2004). Deficits across various cognitive domains including attention, working memory, and executive function have been described and tend to worsen with disease progression in tremor-dominant and akinesia-dominant (also known as akineto-rigid or non-tremor dominant) phenotypes and young-onset and rapid disease progression subgroups (Zetusky and Jankovic, 1985;Jankovic et al., 1990;Rajput, 1993;Schiess et al., 2000;Lewis et al., 2005;Zaidel et al., 2009;Mure et al., 2011;Poletti et al., 2011b;Schillaci et al., 2011;Lee et al., 2012;Moustafa and Poletti, 2013). Patients in the akinesia-dominant subgroup experience a more rapid disease progression compared to tremor-dominant patients (Louis et al., 1999;Eggers et al., 2012). ...
Parkinson’s disease (PD) is characterized by a range of motor symptoms. Besides the cardinal symptoms (tremor, bradykinesia/akinesia, and rigidity), PD patients also show other motor deficits, including gait disturbance, speech deficits, and impaired handwriting. However, along with these key motor symptoms, PD patients also experience cognitive deficits in attention, executive function, working memory, and learning. Recent evidence suggests that these motor and cognitive deficits of PD are not completely dissociable, as aspects of cognitive dysfunction can impact motor performance in PD. In this article, we provide a review of behavioral and neural studies on the associations between motor symptoms and cognitive deficits in PD, specifically akinesia/bradykinesia, tremor, gait, handwriting, precision grip, and speech production. This review paves the way for providing a framework for understanding how treatment of cognitive dysfunction, for example cognitive rehabilitation programs, may in turn influence the motor symptoms of PD.
... It is unknown how these biochemical differences by initial symptom relate to cognition. Cross-sectional [29][30][31] and community-based longitudinal studies [32][33][34] indicate that non-tremor dominant PD is associated with greater prevalence and incidence of overall cognitive impairments, likely stemming from greater posterior dysfunction as indicated by performance on neuropsychological tests. For example, Williams-Gray and colleagues [34] reported that the increased risk of developing dementia in non-tremor PD (4.1 times greater) is further increased (to 5.3 times) in non-tremor patients with baseline problems copying intersecting pentagons, a visuospatial task. ...
Background/objectives:
Visuospatial problems are common in Parkinson's disease (PD) and likely stem from dysfunction in dopaminergic pathways and consequent disruption of cortical functioning. Characterizing the motor symptoms at disease onset provides a method of observing how dysfunction in these pathways influences visuospatial cognition. We examined two types of motor characteristics: Body side (left or right) and type of initial symptom (tremor or symptom other than tremor).
Methods:
31 non-demented patients with PD, 16 with left-side onset (LPD) and 15 with right-side onset (RPD), as well as 17 healthy control participants (HC). The PD group was also divided by type of initial motor symptom, 15 having tremor as the initial symptom and 16 having an initial symptom other than tremor. Visuospatial function was assessed with the Clock Drawing Test.
Results:
Of the four Clock Drawing scoring methods used, the Rouleau method showed sensitivity to subgroup differences. As predicted, the LPD and non-tremor subgroups, but not the other subgroups, performed more poorly than the HC group.
Conclusion:
The findings provide further evidence for differences in cognition between these subtypes of PD and highlight the importance of considering disease subtypes when examining cognition.
... Others found widespread cognitive deficits in participants with worse left-sided dysfunction while participants with worse rightsided dysfunction were relatively cognitively spared (Direnfeld et al., 1984; Tomer, Levin, & Weiner, 1993). Still others found no cognitive differences in regard to motor asymmetry (Barber, Tomer, Sroka, & Myslobodsky, 1985; Huber, Freidenberg, Shuttleworth, Paulson, & Clapp, 1989; St. Clair, Borod, Sliwinski, Cote, & Stern, 1998) or suggest that type, rather than side, of predominant or initial motor manifestation is the most important factor (Riklan, Stellar, & Reynolds, 1990; Zetusky & Jankovic, 1985). Some of this work was limited by use of non-specific or poorly validated tasks, small sample sizes or participants in varied stages of disease progression. ...
Studies suggest motor deficit asymmetry may help predict the pattern of cognitive impairment in individuals with Parkinson disease (PD). We tested this hypothesis using a highly validated and sensitive spatial memory task, spatial delayed response (SDR), and clinical and neuroimaging measures of PD asymmetry. We predicted SDR performance would be more impaired by PD-related changes in the right side of the brain than in the left. PD (n=35) and control (n=28) participants performed the SDR task. PD participants either had worse motor deficits on the right (RPD) or left (LPD) side of the body. Some participants also had magnetic resonance imaging for measurement of their substantia nigra (SN) volumes. The LPD group performed worse on the SDR task than the RPD and control groups. Right SN volume accounted for a unique and significant portion of the variance in SDR error, with smaller volume predicting poorer performance. In conclusion, left motor dysfunction and smaller right SN volume are associated with poorer spatial memory.
Patients with predominantly unilateral parkinsonian signs may provide a unique opportunity to evaluate the cerebral representation of cognitive functions characteristically affected in idiopathic Parkinson’s disease. Twenty hemiparkinsonian patients (ten left and ten right) and 10 healthy controls, matched for age and education, were studied with neuropsychological tests and positron emission tomography. Both right and left hemiparkinsonians evidenced impairments in visuospatial and verbal episodic memory function, but had no deficits in executive abilities, compared to controls. None of the neuropsychological test scores distinguished right from left hemiparkinsonians. Glucose metabolic profiles were identical for the three groups in all cortical areas assessed; in the subcortex however, lenticular hypermetabolism contralateral to the predominant side of motor involvement was evident in the left hemiparkinsonian group. Correlational analysis revealed that higher glucose metabolic rates in the basal ganglia of these hemiparkinsonians were associated with lower visuospatial test scores. In frontal and parietal cortex, decreasing glucose metabolism was positively associated with neurobehavioral function; in temporal cortex, measures of attention and memory decreased with increasing glucose metabolic rates.
Parkinson’s disease (PD) is characterized as a chronic and progressive neurodegenerative disorder that results in a variety of debilitating symptoms, including bradykinesia, resting tremor, rigidity, and postural instability. Research spanning several decades has emphasized basal ganglia dysfunction, predominantly resulting from dopaminergic cell loss, as the primarily cause of the aforementioned parkinsonian features. But, why those particular features manifest themselves remains an enigma. The goal of this paper is to develop a theoretical framework that parkinsonian motor features are behavioral consequence of a long-term adaptation to their inability (inflexibility or lack of capacity) to meet energetic demands, due to neural metabolic deficits arising from mitochondrial dysfunction associated with PD. Here, we discuss neurophysiological changes that are generally associated with PD, such as selective degeneration of dopaminergic neurons in the substantia nigra pars compacta, in conjunction with metabolic and mitochondrial dysfunction. We then characterize the cardinal motor symptoms of PD, bradykinesia, resting tremor, rigidity and gait disturbance, reviewing literature to demonstrate how these motor patterns are actually energy efficient from a metabolic perspective. We will also develop three testable hypotheses: (1) neural metabolic deficits precede the increased rate of neurodegeneration and onset of behavioral symptoms in PD, (2) motor behavior of persons with PD are more sensitive to changes in metabolic/bioenergetic state, and (3) improvement of metabolic function could lead to better motor performance in persons with PD. These hypotheses are designed to introduce a novel viewpoint that can elucidate the connections between metabolic, neural and motor function in PD.
Visual perceptual problems are common in Parkinson's disease (PD) and often affect activities of daily living (ADLs). PD patients with non-tremor symptoms at disease onset (i.e., rigidity, bradykinesia, gait disturbance or postural instability) have more diffuse neurobiological abnormalities and report worse non-motor symptoms and functional changes than patients whose initial symptom is tremor, but the relation of motor symptom subtype to perceptual deficits remains unstudied. We assessed visual ADLs with the Visual Activities Questionnaire in 25 non-demented patients with PD, 13 with tremor as the initial symptom and 12 with an initial symptom other than tremor, as well as in 23 healthy control participants (NC). As expected, the non-tremor patients, but not the tremor patients, reported more impairment in visual ADLs than the NC group, including in light/dark adaptation, acuity/spatial vision, depth perception, peripheral vision and visual processing speed. Non-tremor patients were significantly worse than tremor patients overall and on light/dark adaptation and depth perception. Environmental enhancements especially targeted to patients with the non-tremor PD subtype may help to ameliorate their functional disability.
Studies attempting to relate cognitive impairment to asymmetry of motor symptoms in Parkinson's disease (PD) have found contradictory results. We examined 88 patients with unilateral onset of idiopathic PD who underwent a comprehensive neuropsychological assessment, including language, visuospatial abilities, abstraction and reasoning, attention and mental tracking, set shifting, and memory. Patients whose motor signs began on the left side of the body consistently performed more poorly on the battery of cognitive measures than did patients with right-side onset. Significant differences were found on immediate and delayed verbal recall, word retrieval, semantic verbal fluency, visuospatial analysis, abstract reasoning, attention span, and mental tracking. These differences could not be attributed to differences in the overall severity of motor symptoms at the time of cognitive assessment, or the current pattern of motor asymmetry. This finding suggests that damage to right-hemisphere dopamine systems plays a disproportionately greater role in PD-related cognitive decline than a presumably comparable left-hemisphere dopamine depletion.
It is well known that many patients with Parkinson's disease experience neuropsychological decline. However, the nature and extent of mental status change varies widely, with some patients showing mild or no cognitive impairments and others exhibiting frank dementia. Research has shown that several clinical disease parameters may differentially correlate with patterns of neuropsychological dysfunction. The present study examined side and type of motor symptom at disease onset and their relationship to cognition in idiopathic Parkinson's disease (PD). We identified 58 patients who initially presented with one of the following symptom profiles: right-side tremor onset (RSO-T; n = 15), right-side bradykinesia/rigidity onset (n = 12), left-side tremor onset (n = 19), and left-side bradykinesia/rigidity onset (n = 12). There were no differences between groups in disease duration, overall mental status, education, or depression severity. We administered a battery of neuropsychological measures to the four PD subgroups and a group of matched control subjects (n = 40). MANCOVAs controlling for age revealed patients with RSO-T performed significantly better than the other three PD subgroups across the entire neuropsychological battery. Further, the RSO-T subgroup performed comparably to controls. In contrast, the other three PD subgroups showed widespread cognitive deficits. These findings suggest an intricate relationship between motor symptom and side of disease onset and it is the combination of these factors that may influence the disease course and extent of cognitive deterioration. Furthermore, patients who develop tremor on the right side of their body represent a distinct subgroup of PD patients who exhibit relative sparing of cognitive function.
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