Inga Liepelt

Progression of Parkinson's disease in the clinical phase: potential markers

Neuromodulatory or even neuroprotective therapy could soon be available for Parkinsons disease (PD), raising the question of how we should define and measure disease progression. Reported evidence suggests that several symptoms worsen with disease duration. Bradykinesia, rigidity, and activities of daily living deteriorate faster at the beginning of the disease, and this deterioration is paralleled by a decline in functional presynaptic dopaminergic activity, as shown by imaging techniques. Cognitive, speech, sleep, and gait difficulties might progress linearly in proportion to disease duration. Reduced variability in heart rate, orthostatic dysfunction, and visual hallucinations start to develop at mid-stage disease and are more common in late stages than earlier stages. In this Review, we summarise our current understanding of the progression of PD-associated symptoms and markers and conclude that an effective measurement of progression of PD must adapt to the different stages of the disease. In addition to routine clinical rating scales, new quantitative assessments of motor and non-motor symptoms, which should be more broadly available, reasonably priced, and easy-to-use, are needed.

The specificity and sensitivity of transcranial ultrasound in the differential diagnosis of Parkinson's disease: a prospective blinded study

BACKGROUND Increased echogenicity of the substantia nigra (SN), as determined by transcranial sonography (TCS), is characteristic of idiopathic Parkinsons disease (iPD). The results of initial retrospective studies indicate that this ultrasound sign is specific for iPD and can help to differentiate it from atypical parkinsonian syndromes (aPS); however, these early studies were done in patients with later disease stages and known clinical diagnosis. We aimed to determine the diagnostic value of TCS in the early stages of parkinsonian syndromes, when the clinical symptoms often do not enable a definite diagnosis to be made. METHODS 60 patients who presented with the first, but still unclear, clinical symptoms of parkinsonism had TCS in this prospective blinded study. Investigators were blinded to the results of the clinical investigations, the ultrasound findings, and the diagnosis at time of investigation. The patients were followed-up every 3 months for 1 year to assess and re-evaluate the clinical symptoms. The patients in whom a clinical diagnosis could not be made with certainty were investigated with raclopride PET or dopamine transporter single-photon emission computed tomography (SPECT), or both. FINDINGS A clinical diagnosis of parkinsonism could not be established at baseline in 38 patients. At 12 months, 39 patients were clinically categorised as having iPD. Compared with endpoint diagnosis, the sensitivity of TCS at baseline was 90%7% and the specificity was 82.4%; the positive predictive value of TCS for iPD was 92.9% and the classification accuracy was 88.3%. INTERPRETATION TCS is an easy to implement, non-invasive, and inexpensive technique that could help in the early differential diagnosis of parkinsonian syndromes. The routine use of TCS in the clinic could enable disease-specific therapy to be started earlier. FUNDING Michael J Fox Foundation for Parkinsons Research.

Cortical PIB binding in Lewy body disease is associated with Alzheimer-like characteristics

About one fourth of Lewy body disease (LBD) patients show cortical beta-amyloid load, basically a hallmark of Alzheimer disease (AD). Using [11C]PIB-PET, we tested whether LBD patients with beta-amyloid burden differ from those without with respect to demographic, clinical, biochemical and genetic parameters. Thirty-five LBD subjects (9 patients with Lewy body dementia, DLB; 12 demented Parkinson patients, PDD; 14 non-demented PD, PDND) underwent [11C]PIB-PET, and were classified as either PIB(+) or PIB(-) according to cortical PIB uptake. PIB+ and PIB(-) patients were then compared according to demographic, clinical, biochemical and genetic parameters. None of the PDND, but four PDD and four DLB subjects were PIB+. In PIB+ subjects, ApoE4 prevalence was higher, CSF Abeta42 levels were lower and, among demented patients, PIB-binding was associated with a lower MMSE score. Motor symptoms were not associated with PIB binding. Thus, LBD patients with cortical beta-amyloid show characteristics usually observed in AD.

Enlarged Substantia Nigra Hyperechogenicity and Risk for Parkinson Disease: A 37-Month 3-Center Study of 1847 Older Persons

OBJECTIVE To evaluate whether enlarged substantia nigra hyperechogenicity (SN+) is associated with an increased risk for Parkinson disease (PD) in a healthy elderly population. DESIGN Longitudinal 3-center observational study with 37 months of prospective follow-up. SETTING Individuals 50 years or older without evidence of PD or any other neurodegenerative disease. PARTICIPANTS Of 1847 participants who underwent a full medical history, neurological assessment, and transcranial sonography at baseline, 1535 could undergo reassessment. MAIN OUTCOME MEASURE Incidence of new-onset PD in relation to baseline transcranial sonography status. RESULTS There were 11 cases of incident PD during the follow-up period. In participants with SN+ at baseline, the relative risk for incident PD was 17.37 (95% confidence interval, 3.71-81.34) times higher compared with normoechogenic participants. CONCLUSIONS In this prospective study, we demonstrate for the first time a highly increased risk for PD in elderly individuals with SN+. Transcranial sonography of the midbrain may therefore be a promising primary screening procedure to define a risk population for imminent PD.

Substantia nigra hypoechogenicity: Definition and findings in restless legs syndrome

Pathological studies demonstrate a decreased iron content in the substantia nigra (SN) contributing to the pathophysiology of restless legs syndrome (RLS). SN echogenicity as measured by transcranial sonography (TCS) correlates with the SN iron content. The objective of this study was to determine a critical value to define SN hypoechogenicity as a potential marker for RLS. There were 49 RLS patients (39 idiopathic, 10 secondary) and 49 age‐ and sex‐matched controls who underwent TCS by 2 independent and blinded examiners to determine the area of SN echogenicity. We found that SN echogenicity is significantly decreased in RLS patients compared to healthy controls (P < 0.001). SN hypoechogenicity (sum area of SN echogenicity of both sides < 0.2 cm2) is more common in idiopathic than in secondary RLS patients. The area under curve for idiopathic RLS versus controls (receiver operating characteristics) is 0.91, specificity is 0.90, and sensitivity is 0.82. TCS provides an interesting additional instrument in the diagnosis of RLS. Therefore, SN hypoechogenicity (SN sum area < 0.2 cm2), which is supposed to indicate a decreased SN iron content, is a marker for RLS. Further studies are needed to investigate its significance for the pathophysiology of this frequent movement disorder and possible clinical applications.

Cross-sectional study discloses a positive family history for Parkinson’s disease and male gender as epidemiological risk factors for substantia nigra hyperechogenicity

SummaryHyperechogenicity of the substantia nigra (SN) has been proposed to be a typical finding in Parkinson’s disease (PD) and a marker of vulnerability to nigrostriatal dysfunction in healthy subjects. This large cross-sectional study including 1120 subjects older than 50 years without any signs of PD was performed to evaluate the association of SN hyperechogenicity and other proposed epidemiological risk factors for PD. Among all variables assessed only family history of PD and male gender proved to be significantly associated with SN hyperechogenicity, indicating a genetic predisposition for the ultrasound marker.

Pre-motor signs of PD are related to SN hyperechogenicity assessed by TCS in an elderly population.

Much effort has been put in the identification of risk factors and pre-motor markers for Parkinsons disease (PD). In contrast to many of the pre-motor markers, SN hyperechogenicity (SN+) assessed by transcranial sonography (TCS) has been found to be conclusive for vulnerability for PD. In two centers in Germany 1204 individuals ≥50 years without the diagnosis of PD were recruited and the prevalence and relation of SN+ to a range of pre-motor markers was evaluated. SN+ was detected in 193 (16.0%) of 1204 subjects. Hyposmia (25.4%) was the most frequent sign in the cohort, followed by the occurrence of slight motor deficits. Male gender, positive family history of PD as possible risk factors and the pre-motor markers slight parkinsonian signs, one-sided reduced arm swing, and hyposmia were found to be significantly associated with SN+. The number of subjects who had more than one marker was significantly larger in the SN+ subgroup than in the non-hyperechogenic group (9.2% vs. 2.1%). Most of the discussed markers for PD seem to be unspecific with older age, but related to SN+. Co-occurrence of these markers is more probable in SN+ subjects. These findings may have implications for the design of high-risk cohorts for PD.

Cortical hypometabolism assessed by a metabolic ratio in Parkinson's disease primarily reflects cognitive deterioration-[18F]FDG-PET.

In Parkinsons disease patients with cognitive deterioration, regional cortical hypometabolism has been observed with [18F]fluorodeoxyglucose‐positron emission tomography (FDG‐PET). Our aim was to develop a robust method to subsume the overall degree of metabolic deterioration in Parkinsons disease by means of a single index and to investigate which of the clinical features correlates best with hypometabolism. Twenty‐two Parkinsons patients (10 demented) and seven controls underwent FDG‐PET. A metabolic index (mean relative uptake in typically affected regions) was calculated for each patient and compared with scores for cognition [Minimental State Examination (MMSE)], motor performance [Unified Parkinsons Disease Rating Scale (UPDRS III)” and behavior (Neuropsychiatric Inventory). In stepwise linear regression analysis, MMSE (P < 0.001) score showed the only significant effect. Estimated sensitivity and specificity for DSM‐IV diagnosis of dementia were high for the metabolic index (MI), with 91 and 100%. Taken together, the presented data indicate that cerebral hypometabolism in Parkinsons disease is primarily associated with cognitive impairment.

Effect of genetic variation in Kv1.3 on olfactory function.

Olfactory function is reduced in aged humans and diabetes mellitus patients. However, little is known about the pathogenic mechanisms leading to olfactory dysfunction. Recently, it has been shown that the voltage‐gated potassium channel Kv1.3 is regulated by insulin and is highly expressed in the olfactory bulb. Furthermore, the function of this channel is associated with olfaction in mice and with glucose metabolism in mice and men. We therefore hypothesized that a functionally relevant polymorphism in Kv1.3 might alter olfactory function.

Treatment of Dementia in Parkinsonian Syndromes with Cholinesterase Inhibitors

In Parkinsonian syndromes behavioural symptoms and dementia can be even more debilitating than motor symptoms and are an important predictor for nursing home placement and mortality. Neuropathologically, dementia seems to be primarily related to cortical changes rather than to subcortical alterations. Concerning neurotransmitter systems, the cholinergic system has been proposed to play a key role in cognitive disturbances. Based on studies with patients with Alzheimer disease, the application of cholinesterase inhibitors is vividly discussed also for dementia associated with parkinsonian syndromes. This review focuses on the specific symptoms of dementia in different parkinsonian syndromes and critically questions the effect of cholinergic treatment on cognitive functions in patients with extrapyramidal syndromes and dementia. There is evidence that medication with some cholinesterase inhibitors can enhance cognition as well as activities of daily living in dementia with Parkinson’s disease and seems to reduce behavioural disturbances in both dementia with Parkinson’s disease and dementia with Lewy bodies. The effect of treatment with cholinesterase inhibitors in progressive supranuclear palsy and corticobasal degeneration warrants carefully designed studies including a sufficient number of patients and symptom-adopted dementia scales.