Premotor symptoms and early diagnosis of Parkinson's disease

Parkinson's disease is a disorder characterized by the motor findings of bradykinesia, rest tremor, cogwheel rigidity, and postural instability. As the disease progresses, most patients develop numerous nonmotor signs and symptoms, many of which play a major role in reducing quality of life. What is becoming increasingly clear is that nonmotor findings, including hyposmia, sleep disorders, autonomic abnormalities, cognitive changes, and neurobehavioral changes, often precede the motor findings.     

Lewy pathology and neurodegeneration in premotor Parkinson's disease

The foremost motor manifestations of Parkinson's disease are resting tremor, cogwheel rigidity, hypokinesia/bradykinesia, and postural instability. Epidemiological and clinical data reveal that a wide variety of additional complaints (nonmotor symptoms), also considerably impar patients' quality of life parallel to the chronic-progressive neurodegenerative disorder. This article reviews the neuropathology and anatomy of Lewy pathology-related neurodegeneration in relation to selected nonmotro and prodromal dysfunctions.     

The heterogeneity of Parkinson's disease: clinical and prognostic implications

In 334 patients with idiopathic Parkinson's disease, deterioration in mental status paralleled severity of bradykinesia, postural instability, and gait difficulty. Tremor was relatively independent of the other cardinal signs and was associated with relative preservation of mental status, earlier age at onset, family history of parkinsonism, and more favorable prognosis. There seem to be at least two Parkinson's subgroups: one with postural instability and gait difficulty and another with tremor as the dominant feature.     

Levodopa responsive parkinsonism in an adult with Huntington's disease

A patient is reported on with Huntington's disease who, as anadult, first developed severe parkinsonism with bradykinesia, rigidity,postural instability and festinating gait. His clinical signs weresimilar to those of the Westphal variant of Huntington's diseaseexcept that he also had resting tremor and a supranuclear gaze palsy.Magnetic resonance imaging showed caudate and putamen atrophy. Geneticanalysis disclosed 49 triple CAG repeats in allele 1 and 17 in allele 2 confirming the diagnosis of Huntington's disease. Treatment withlevodopa produced substantial functional motor improvement with a 17 point reduction in the unified Parkinson's disease rating scale(UPDRS) motor subscale including reduction of tremor, bradykinesia, andpostural instability. This is the first report of a patient with adultonset Huntington's disease with parkinsonism responsive to levodopa.

     

Cardiac sympathetic denervation in bradykinesia-dominant Parkinson's disease

Cardiac iodine-123-labeled-metaiodobenzylguanidine uptake is reduced in early-stage Parkinson's disease, suggesting sympathetic nerve degeneration. The scintigraphic findings in patients with Parkinson's disease with different clinical features have, however, not been established. Iodine-123-labeled-metaiodobenzylguanidine myocardial scintigraphy was performed in 143 patients with Parkinson's disease. The early and delayed heart to mediastinum ratios were analyzed according to the dominant motor deficit (tremor, bradykinesia, rigidity, and postural instability), age, sex, age at onset, disease duration, and Hoehn and Yahr stage. Both ratios correlated with bradykinesia, age at disease onset, and disease duration; but not with sex, Hoehn and Yahr stage, tremor, rigidity, and postural instability. Our results suggest a close link between myocardial sympathetic degeneration and bradykinesia, age at onset and disease duration.     

Falls and Parkinson's disease

One hundred patients with Parkinson's disease (PD) and five patients with progressive supranuclear palsy were questioned about the frequency, circumstances, and consequences of falling. Parkinsonian symptoms were scored using the unified rating scale. Thirty-eight percent of parkinsonian patients fell, and 13% fell more than once a week. Broken bones (13%), hospitalization (18%), confinement to wheelchair (3%), and fear of walking occurred. Postural hypotension was uncommon and did not correlate to falling. Sensory loss, dementia, heart disease, and the use of antihypertensive medications were not related to falling. Falling did correlate with postural instability, bradykinesia, and rigidity but not with tremor. Falling was also related to age and duration of disease. The frequency of falling was correlated only to the severity of one parkinsonian symptom, postural instability. Progressive supranuclear palsy patients fell often and had marked postural instability. Factor analysis of parkinsonian characteristics yielded three groups, with tremor being an independent symptom. Frequent fallers and postural instability were not changed by dopaminergic therapy. Some fallers with gait difficulties and bradykinesia were improved with levodopa. Physical therapy was also of benefit to some patients. It is concluded that falling is a common problem in PD and may cause serious disability. Falling may be related to all the major motor signs except for tremor. Frequent falling is caused by postural instability, which is not reversible with dopaminergic therapy.     

Diabetes is associated with postural instability and gait difficulty in Parkinson disease

BackgroundComorbid diabetes may be associated with more severe motor impairment in Parkinson disease. In normal elderly individuals, diabetes is associated with parkinsonian features, including gait difficulty and rigidity, though not tremor. Whether diabetes contributes to increased motor dysfunction in Parkinson disease by exacerbating nigrostriatal dopaminergic denervation or through intensification of extranigral pathology is unknown.MethodsWe performed a case–control study (n = 39) involving 13 Parkinson disease subjects (age 66.4yrs ± 5.5; duration of disease 6.9yrs ± 4.4) with diabetes and 26 age, gender, and duration-of-disease-matched Parkinson disease controls without diabetes. All subjects underwent [¹¹C]dihydrotetrabenazine vesicular monoamine transporter type-2 positron emission tomography imaging to assess striatal dihydrotetrabenazine distribution volume ratio and Unified Parkinson disease rating scale motor examination to determine rigidity, bradykinesia, tremor, and postural instability and gait difficulty subscores. Magnetic resonance imaging scans were analyzed to assess leukoaraiosis burden.ResultsAfter controlling for nigrostriatal dopaminergic denervation, Parkinson disease subjects with diabetes displayed greater postural instability and gait difficulty subscores (t = 3.81, p = 0.0005). There were no differences in bradykinesia, rigidity, or tremor subscores between cases and controls. The association between diabetes and postural instability and gait difficulty persisted after controlling for comorbid hypertension and body mass index. Leukoaraiosis, distal vibratory sense, and levodopa dose equivalents did not differ significantly between cases and controls.ConclusionsDiabetes may contribute to postural instability and gait difficulty in Parkinson disease through mechanisms other than nigrostriatal dopaminergic denervation.     

Parkinsonism in fragile X-associated tremor/ataxia syndrome (FXTAS): Revisited

BackgroundParkinsonian features have been used as a minor diagnostic criterion for fragile X-associated tremor/ataxia syndrome (FXTAS). However, prior studies have examined parkinsonism (defined as having bradykinesia with at least rest tremor or postural instability) mostly in premutation carriers without a diagnosis of FXTAS. The current study was intended to elaborate this important aspect of the FXTAS spectrum, and to quantify the relationships between parkinsonism, FXTAS clinical staging and genetic/molecular measures.MethodsThirty eight (38) FXTAS patients and 10 age-matched normal controls underwent a detailed neurological examination that included all but one item (i.e. rigidity) of the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS).ResultsThe FXTAS patient group displayed substantially higher prevalence of parkinsonian features including body bradykinesia (57%) and rest tremor (26%), compared to the control group. Furthermore, parkinsonism was identified in 29% of FXTAS patients. Across all patients, body bradykinesia scores significantly correlated with FXTAS clinical stage, FMR1 mRNA level, and ataxic gait of cerebellar origin, while postural instability was associated with intention tremor.InterpretationParkinsonian features in FXTAS appear to be characterized as bradykinesia concurrent with cerebellar gait ataxia, postural instability accompanied by intention tremor, and frequent rest tremor, representing distinctive patterns that highlight the need for further clinical studies including genetic testing for the FMR1 premutation. The association between FMR1 mRNA level and bradykinesia implicates pathophysiological mechanisms which may link FMR1 mRNA toxicity, dopamine deficiency and parkinsonism in FXTAS.     

Diagnostic criteria and differential diagnosis of Parkinson disease

The clinical diagnosis of Parkinson's disease is based on the identification of some combination of the clinical motor signs of bradykinesia, rigidity, tremor and postural instability. Three levels of diagnostic confidence are differentiated: possible, probable, and definite. The diagnosis of possible and probable Parkinson's disease based on clinical criteria alone, while definite diagnosis requires neuropathologic confirmation. To differentiate Parkinson's disease (idiopathic Parkinsonian syndrome) and other Parkinsonian syndromes is of increasing importance considering the therapy and life expectancy of the patients. Recently the functional imaging technics have been more and more helpful in the early differential diagnosis of Parkinson's disease.     

Relationship between freezing of gait (FOG) and other features of Parkinson's: FOG is not correlated with bradykinesia.

BACKGROUND: The pathophysiology of freezing of gait (FOG) is unclear. OBJECTIVE: To assess the relationships between FOG and other parkinsonian features in Parkinson's disease (PD), focusing on levodopa effects. METHODS: Nineteen PD patients with significant FOG in "off" were assessed while "off" and "on". Three observers independently viewed videotapes of a 130-m walk and scored FOG frequency. The Unified Parkinson's disease Rating Scale was used to evaluate clinical state. RESULTS: FOG frequency was not correlated with other parkinsonian features in "off" and only with speech and writing in "on". Levodopa significantly decreased FOG frequency (p<0.001). This reduction was strongly correlated with improvement of tremor (R=0.80, p<0.01) and speech (R=0.62, p<0.05), but not with improvement in rigidity, bradykinesia, or balance. CONCLUSION: Levodopa decreases FOG in PD. FOG is apparently an independent motor symptom, caused by a paroxysmal pathology that is different from that responsible for bradykinesia, rigidity or postural instability.     

The role of D J-1 in the pathogenesis of Parkinson＇s disease

Parkinson＇s disease （PD） is a slowly progressive neurodegenerative disorder characterized clinically by bradykinesia, rigidity, tremor, gait dysfunction, and postural instability. Several genes have been identified for monogenic disorders that variably resemble Parkinson＇s disease. Here, we focus on PARK7, a gene relates to an autosomal recessive form of early-onset Parkinsonism and encodes a protein named DJ- 1. Though the exact role of D J- 1 needs to be elucidated, it is generally thought to be functioned as a molecular chaperone and an oxidative sensor （or antioxidative factor）. We will review the protective role of DJ- 1 to prevent dopaminergic neurons in the substantia nigra pars compacta （SNpc） from degeneration and how its dysfunction would lead to neurodegeneration.     

Parkinsonian features in hereditary diffuse leukoencephalopathy with spheroids (HDLS) and CSF1R mutations

Atypical Parkinsonism associated with white matter pathology has been described in cerebrovascular diseases, mitochondrial cytopathies, osmotic demyelinating disorders, leukoencephalopathies leukodystrophies, and others. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant disorder with symptomatic onset in midlife and death within a few years after symptom onset. Neuroimaging reveals cerebral white matter lesions that are pathologically characterized by non-inflammatory myelin loss, reactive astrocytosis, and axonal spheroids. Most cases are caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene.We studied neuropathologically verified HDLS patients with CSF1R mutations to assess parkinsonian features. Ten families were evaluated with 16 affected individuals. During the course of the illness, all patients had at least some degree of bradykinesia. Fifteen patients had postural instability, and seven had rigidity. Two patients initially presented with parkinsonian gait and asymmetrical bradykinesia. These two patients and two others exhibited bradykinesia, rigidity, postural instability, and tremor (two with resting) early in the course of the illness. Levodopa/carbidopa therapy in these four patients provided no benefit, and the remaining 12 patients were not treated. The mean age of onset for all patients was about 45 years (range, 18–71) and the mean disease duration was approximately six years (range, 3–11).We also reviewed HDLS patients published prior to the CSF1R discovery for the presence of parkinsonian features. Out of 50 patients, 37 had gait impairments, 8 rigidity, 7 bradykinesia, and 5 resting tremor. Our report emphasizes the presence of atypical Parkinsonism in HDLS due to CSF1R mutations.     

Freezing of gait in PD: prospective assessment in the DATATOP cohort.

OBJECTIVE: To study the development of freezing of gait in PD. BACKGROUND: Freezing of gait is a common, disabling, and poorly understood symptom in PD. METHODS: The authors analyzed data from 800 patients with early PD from the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) clinical trial who were assigned either placebo, deprenyl, tocopherol, or the combination of deprenyl and tocopherol. The primary outcome measure was the time from randomization until the freezing of gait score on the Unified Parkinson's Disease Rating Scale (UPDRS) became positive. RESULTS: Fifty-seven patients (7.1%) had freezing of gait at study entry and 193 (26%) of the remaining patients experienced the symptom by the end of the follow-up period. Those with freezing of gait at baseline had significantly more advanced disease than those without the symptom, as measured by total UPDRS and Hoehn and Yahr stage. High baseline risk factors for developing freezing of gait during the follow-up period were the onset of PD with a gait disorder; higher scores of rigidity, postural instability, bradykinesia and speech; and longer disease duration. In contrast, tremor was strongly associated with a decreased risk for freezing of gait. At the end of follow-up, the signs most strongly associated with the freezing phenomenon were gait, balance, and speech disorders, not rigidity or bradykinesia. Deprenyl treatment was strongly associated with a decreased risk for developing freezing of gait; tocopherol had no effect. CONCLUSIONS: Freezing of gait is directly related to duration of PD. Risk factors at onset of disease are the absence of tremor and PD beginning as a gait disorder. The development of freezing of gait in the course of the illness is strongly associated with the development of balance and speech problems, less so with the worsening of bradykinesia, and is not associated with the progression of rigidity. These results support the concept that the freezing phenomenon is distinct from bradykinesia. Deprenyl, in the absence of L-dopa, was found to be an effective prophylactic treatment and should be considered for patients with PD who have an onset of gait difficulty.     

Disordered axial movement in Parkinson's disease.

Axial motor impairments are a common cause of disability in patients with Parkinson's disease, become more prominent with longer disease duration, and have been said to be less responsive to levodopa replacement therapy. The ability to turn in bed while lying supine before and after dopaminergic stimulation was studied in a group of 36 patients with Parkinson's disease; 23 were in Hoehn and Yahr stages 3-5 when "off", and 13 were in stages 1-2. Turning was also compared with postural stability and gait before ("off") and after ("on") dopaminergic stimulation. Failure to turn in bed was noted in 19 of the 36 patients in the "off" state, with significant associations between disturbances of gait, postural stability, rising from a chair, whole body bradykinesia, and axial rigidity. Gait, postural stability, rising from a chair, whole body bradykinesia, and axial rigidity were significantly correlated in the "off" state. Disorder of axial movement, gait, and postural stability were not dependent on age at onset of Parkinson's disease, but did relate to duration of disease. After a levodopa challenge, turning in bed returned to normal in all but one patient, and gait, postural stability, rising from a chair, whole body bradykinesia, and axial rigidity also improved in nearly all. It is concluded that in the later stages of Parkinson's disease at least some aspects of axial motor control can remain dopamine responsive.     

What contributes to quality of life in patients with Parkinson's disease?

OBJECTIVE: To identify the factors that determine quality of life (QoL) in patients with idiopathic Parkinson's disease in a population based sample. Quality of life (QoL) is increasingly recognised as a critical measure in health care as it incorporates the patients' own perspective of their health. METHODS: All patients with Parkinson's disease seen in a population based study on the prevalence of parkinsonism were asked to complete a disease-specific QoL questionnaire (PDQ-39) and the Beck depression inventory. A structured questionnaire interview and a complete neurological examination, including the Hoehn and Yahr scale, the Schwab and England disability scale, the motor part of the unified Parkinson's disease rating scale (UPDRS part III), and the mini mental state examination were performed by a neurologist on the same day. RESULTS: The response rate was 78%. The factor most closely associated with QoL was the presence of depression, but disability, as measured by the Schwab and England scale, postural instability, and cognitive impairment additionally contributed to poor QoL. Although the UPDRS part III correlated significantly with QoL scores, it did not contribute substantially to predicting their variance once depression, disability, and postural instability had been taken into account. In addition, patients with akinetic rigid Parkinson's disease had worse QoL scores than those with tremor dominant disease, mainly due to impairment of axial features. CONCLUSION: Depression, disability, postural instability, and cognitive impairment have the greatest influence on QoL in Parkinson's disease. The improvement of these features should therefore become an important target in the treatment of the disease.     

Parkinson's disease motor subtypes and bilateral GPi deep brain stimulation: One-year outcomes

ObjectiveWe aimed to explore the differences in motor symptoms and quality of life (QOL) outcomes following bilateral globus pallidus internus deep brain stimulation (GPi DBS), across well-defined motor subtypes of Parkinson's disease (PD), to improve clinical decision making.MethodsThis single-center retrospective study investigated bilateral GPi DBS outcomes in 65 PD patients. Outcome measures included the Unified Parkinson's Disease Rating Scale (UPDRS) and Parkinson's Disease Questionnaire (PDQ-39) before and one year after surgery. Outcomes were compared between the tremor-dominant (TD) and postural instability and gait difficulty (PIGD) subtypes and between the TD and akinetic-rigid (AR) subtypes.ResultsFor the entire cohort, motor function (UPDRS III) in the Off-medication state, motor complications (UPDRS IV), activities of daily living (ADL, UPDRS II), and the ADL and discomfort domains of PDQ-39 significantly improved one year following GPi implantation compared to baseline (effect size = 1.32, 1.15, 0.25, 0.45, and 0.34, respectively). GPi DBS improved the Off-medication UPDRS III scores regardless of the motor subtypes. However, compared to the PIGD and AR patients, the TD patients showed greater improvement in overall UPDRS III postoperatively primarily due to greater tremor improvement in the Off-medication state. The outcomes in akinesia, rigidity, axial symptoms and QOL were similar among all subtypes.ConclusionBilateral GPi DBS was effective for advanced PD patients regardless of motor subtypes. Greater tremor improvement in the TD patients accounted for greater Off-medication motor improvement. Longer-term GPi DBS outcomes across different motor subtypes and brain targets should be further studied.     

Gabapentin can improve postural stability and quality of life in primary orthostatic tremor.

Primary orthostatic tremor (OT) is characterized by leg tremor and instability on standing. High frequency (13-18 Hz) tremor bursting is present in leg muscles during stance, and posturography has shown greater than normal sway. We report on an open-label add-on study of gabapentin in 6 patients with OT. Six patients were studied with surface electromyography, force platform posturography, and a modified Parkinson's disease questionnaire (PDQ-39) quality of life (QOL) scale before and during treatment with gabapentin 300 mg t.d.s. If on other medications for OT, these were continued unchanged. Of the 6 patients, 4 reported a subjective benefit of 50 to 75% with gabapentin, 3 of whom showed reduced tremor amplitude and postural sway of up to 70%. Dynamic balance improved in all 3 patients who completed the protocol. QOL data from 5 patients showed improvement in all cases. No adverse effects were noted. Gabapentin may improve tremor, stability, and QOL in patients with OT, and symptomatic response correlated with a reduction in tremor amplitude and postural sway. The findings confirm previous reports of symptomatic benefit with gabapentin and provide justification for larger controlled clinical trials. Further work is required to establish the optimal dosage and to validate the methods used to quantify the response to treatment.     

The relation between cognition and motor dysfunction in drug‐naive newly diagnosed patients with Parkinson's disease

Recent studies have reported cognitive decline to be common in the early phase of Parkinson's disease. Imaging data connect working memory and executive functioning to the dopamine system. It has also been suggested that bradykinesia is the clinical manifestation most closely related to the nigrostriatal lesion. Exploring the relationship between motor dysfunction and cognition can help us find shared or overlapping systems serving different functions. This relationship has been sparsely investigated in population‐based studies of untreated Parkinson's disease. The aim of the present study was to investigate the association between motor signs and cognitive performance in the early stages of Parkinson's disease before the intake of dopaminergic medication. Patients were identified in a population‐based study of incident cases with idiopathic parkinsonism. Patients with the postural instability and gait disturbances phenotype were compared with patients with the tremor‐dominant phenotype on demographics and cognitive measures. Associations between cognitive and motor scores were investigated, with age, education, and sex controlled for. Bradykinesia was associated with working memory and mental flexibility, whereas axial signs were associated with episodic memory and visuospatial functioning. No significant differences in the neuropsychological variables were found between the postural instability and gait disturbances phenotype and the tremor phenotype. Our results indicate a shared system for slow movement and inflexible thinking that may be controlled by a dopaminergic network different from dopaminergic networks involved in tremor and/or rigidity. The association between axial signs and memory and visuospatial function may point to overlapping systems or pathologies related to these abilities. © 2011 Movement Disorder Society     

Motor signs in the prodromal phase of Parkinson's disease

Relatively subtle deterioration of the motor system likely occurs well before the patient meets established motor criteria for a clinical diagnosis of Parkinson's disease; ie, the occurrence of at least 2 of the cardinal motor deficits: bradykinesia, rigidity, tremor, and/or postural instability. Powerful compensatory mechanisms may mask these clinical symptoms and make them difficult to identify and evaluate in the earliest stages of the illness. This review summarizes our current knowledge of motor signs that are thought to occur in the prodromal phase of Parkinson's disease and suggests how motor assessment batteries could be designed to detect these subclinical motor deficits with a high degree of accuracy and sensitivity.