Visual symptoms in Parkinson's disease and Parkinson's disease dementia

Visual symptoms are common in PD and PD dementia and include difficulty reading, double vision, illusions, feelings of presence and passage, and complex visual hallucinations. Despite the established prognostic implications of complex visual hallucinations, the interaction between cognitive decline, visual impairment, and other visual symptoms remains poorly understood. Our aim was to characterize the spectrum of visual symptomatology in PD and examine clinical predictors for their occurrence. Sixty-four subjects with PD, 26 with PD dementia, and 32 age-matched controls were assessed for visual symptoms, cognitive impairment, and ocular pathology. Complex visual hallucinations were common in PD (17%) and PD dementia (89%). Dementia subjects reported illusions (65%) and presence (62%) more frequently than PD or control subjects, but the frequency of passage hallucinations in PD and PD dementia groups was equivalent (48% versus 69%, respectively; P = 0.102). Visual acuity and contrast sensitivity was impaired in parkinsonian subjects, with disease severity and age emerging as the key predictors. Regression analysis identified a variety of factors independently predictive of complex visual hallucinations (e.g., dementia, visual acuity, and depression), illusions (e.g., excessive daytime somnolence and disease severity), and presence (e.g., rapid eye movement sleep behavior disorder and excessive daytime somnolence). Our results demonstrate that different "hallucinatory" experiences in PD do not necessarily share common disease predictors and may, therefore, be driven by different pathophysiological mechanisms. If confirmed, such a finding will have important implications for future studies of visual symptoms and cognitive decline in PD and PD dementia.     

Applause sign in advanced Parkinson's disease

BackgroundThe ‘applause sign’ a tendency to continue applauding in response to instructions to clap three times was described in 1995 and was considered specific to degenerative disease, especially to atypical parkinsonian disorders. In early phase Parkinson's disease (PD) the sign has been reported positive as well. In late stage PD it is unknown whether and to what extent the sign may be elicited and it remains unknown if and to what degree the sign correlates to cognitive impairment and PD related dementia.MethodsNursing home residents with PD (MMSE >17) were included. All patients underwent the clapping test and were tested for cognitive disturbance by making use of accepted clinimetrics (MMSE and Scopa-cog). T-testing was performed with the hypothesis that patients expressing the applause sign would score lower on the MMSE or Scopa-cog.ResultsSeventy three nursing home residents (mainly Hoehn and Yahr 4/5) with a mean disease duration of 10 years and a mean age of 78.7 years were included. The applause sign was found positive in 15 of 73 residents (20.5%). Residents expressing the applause sign had significantly lower mean scores on the MMSE (25.1 vs 22.9 points, p < 0.006) and Scopa-cog (14.8 vs 12.0 points, p < 0.039).ConclusionsThe applause sign is present in late stage PD and correlates with a higher degree of cognitive impairment as established with accepted clinimetric tests. A higher degree of frontal lobe involvement explains the presence of the applause sign.     

Glycation in Parkinson's disease and Alzheimer's disease

Glycation is a spontaneous age‐dependent posttranslational modification that can impact the structure and function of several proteins. Interestingly, glycation can be detected at the periphery of Lewy bodies in the brain in Parkinson's disease. Moreover, α‐synuclein can be glycated, at least under experimental conditions. In Alzheimer's disease, glycation of amyloid β peptide exacerbates its toxicity and contributes to neurodegeneration. Recent studies establish diabetes mellitus as a risk factor for several neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. However, the mechanisms underlying this connection remain unclear. We hypothesize that hyperglycemia might play an important role in the development of these disorders, possibly by also inducing protein glycation and thereby dysfunction, aggregation, and deposition. Here, we explore protein glycation as a common player in Parkinson's and Alzheimer's diseases and propose it may constitute a novel target for the development of strategies for neuroprotective therapeutic interventions. © 2016 International Parkinson and Movement Disorder Society     

SPECT findings in Alzheimer's disease and Parkinson's disease with dementia

We examined, with single photon emission tomography (SPECT) and (^99mTc)-HMPAO, 18 patients with idiopathic Parkinson's disease and no dementia (PD), 12 patients with PD and dementia, 24 patients with probable Alzheimer's disease (AD) and 14 controls. While the three patient groups showed significantly lower perfusion in frontal inferior and temporal inferior areas as compared to controls, both demented groups showed significantly more severe bilateral hypoperfusion in superior frontal, superior temporal and parietal areas as compared to non-demented PD patients and controls. On the other hand, no significant differences in cerebral perfusion were found between patients with AD and patients with PD and dementia. In conclusion, our findings demonstrated specific but similar cerebral perfusion deficits in demented patients with either AD or PD.     

Different iron deposition patterns in early- and middle-late-onset Parkinson's disease

BackgroundIron deposition may contribute to the clinical symptoms in Parkinson's disease (PD). With partial different clinical manifestations, the iron deposition patterns between patients with early-onset Parkinson's disease (EOPD) and middle-late-onset Parkinson's disease (M-LOPD) are still unclear. This study was designed to investigate the patterns of iron deposition and their clinical relevance in EOPD and M-LOPD patients, using quantitative susceptibility mapping technique.Materials and methodsThirty-five EOPD patients and 24 matched young controls, 33 M-LOPD patients and 22 matched older controls were recruited in the study. The iron content in the deep grey matter nuclei in the basal ganglia and midbrain were measured, and compared between patients and their corresponding controls. The correlations of regional iron content and clinical features were explored in patient groups.ResultsBoth M-LOPD and EOPD patients showed increased iron content in the substantia nigra (SN) pars compacta and SN pars reticulata. Increased iron content in the putamen was only observed in M-LOPD patients. The relationship between the increased iron content and disease severity (H&Y stages, UPDRS II scores and UPDRS III scores) was observed in M-LOPD patients, but not in EOPD patients.ConclusionOur study suggested that the iron deposition pattern was greatly influenced by the age of PD onset, which increases our understanding of the different pathological underpinnings of EOPD and M-LOPD patients.     

Cognitive profile of Parkinson's disease patients: a comparative study between early-onset and late-onset Parkinson's disease

Aim: To investigate the influence of onset age on the occurrence and progression of cognitive dysfunction using neuropsychological tests and the electrophysiological component P300 in both early-onset Parkinson's disease (EOPD) and late-onset Parkinson's disease (LOPD) patients. Methods: A cohort of 76 EOPD patients and 166 LOPD patients was recruited for this study. Demographic information and clinical features, including age, disease duration, education level, family history, the Unified Parkinson's Disease Rating Scale, the Hoehn and Yahr stage, and depression scores were documented for each patient. The Mini-Mental State Examination, Montreal Cognitive Assessment (MoCA), Wechsler Adult Intelligence Scale – Revised, Chinese version (WAIS-RC) and Wechsler Memory Scale – Revised, Chinese version (WMS-RC) were used. In addition, P300 was also examined to assess cognitive function. Results: Although EOPD patients had longer disease duration, their cognitive dysfunction progressed more slowly. The MoCA tests revealed that EOPD patients had higher scores in visuospatial function, attention, delayed recall, and orientation than the LOPD patients. The difference between the two groups on the WMS-RC test did not reach significance, whereas the scores in executive function, visuospatial function and attention as measured on the WAIS-RC test were significantly lower in the LOPD group. In addition, P300 latencies were markedly delayed and P300 amplitudes were reduced in the LOPD group. Conclusions: The current findings demonstrated that cognitive dysfunction progressed more slowly in the EOPD group. Although the LOPD patients exhibited shorter disease durations, their cognitive abilities, including executive function, visuospatial function and attention, may have been impaired.     

Diagnostic problems in Parkinson's disease

The diagnosis of Parkinson's disease is not as easy as previously claimed, and presents a number of pitfalls. We present three rules, or aphorisms, to help the general practitioner in overcoming these diagnostic difficulties: Know well the basic disease and its symptoms. Use tricks to elicit apparently absent 'primary' symptoms. Beware of unusual symptoms or case histories. Examples of difficulties encountered at each level are given. Such analysis should permit the physician to classify his extrapyramidal patient within one of the many types of 'parkinsonism' as shown in Table 1.     

Homocysteine levels after acute levodopa intake in patients with Parkinson's disease

Levodopa (L ‐dopa) administered with a dopadecarboxylase inhibitor (DDI) increases homocysteine plasma levels. This may support the onset of atherosclerosis‐related disorders and neuropsychiatric complications in patients with Parkinson's disease (PD). This homocysteine elevation is considered as long‐term effect of chronic L ‐dopa/DDI treatment. Little is known about the acute effects of L ‐dopa/DDI intake on homocysteine generation. The objective of this trial was to investigate the relations between L ‐dopa and homocysteine after acute L ‐dopa/DDI administration in PD patients with different L ‐dopa metabolism. Thirty PD patients were divided into groups with superior (I) and less (II) L ‐dopa absorption after standardized intake of 125 mg L ‐dopa/benserazide with determination of L ‐dopa, 3‐O‐methyl‐dopa (3‐OMD) and homocysteine in plasma at baseline, 30, 60, and 90 minutes. There was a homocysteine increase in Group I (F = 5; P = 0.005) and a moderate decrease in Group II (F = 4.27; P = 0.01). A rise of 3‐OMD (F = 10.51; P < 0.0001) appeared in Group I, but not in Group II (F = 0.91; P = 0.44), accordingly L ‐dopa accumulation was better in Group I than in Group II. Thus, in conclusion, L ‐dopa metabolism is an important component for homocysteine elevation after one time L ‐dopa/DDI administration in PD patients. © 2009 Movement Disorder Society     

Skin conditions in early Parkinson's disease

ObjectiveSkin conditions have been associated with increased risk of Parkinson's disease (PD). Little is known about clinical and biomarker differences according to presence of skin conditions among PD patients. Studying these differences might provide insight into PD pathogenesis.MethodsWe examined the association between common skin conditions and risk of PD in a case-control study of 423 early drug-naïve PD cases and 196 healthy controls (HC) in the Parkinson's Progression Markers Initiative (PPMI). Among PD participants, we examined if skin conditions were associated with clinical and PD-relevant biomarkers.ResultsSkin conditions occurred more frequently among PD participants (41%) relative to HC (32%). In multivariate analyses, we observed an association between any skin condition and PD (OR = 1.49, 95% CI = 1.03–2.16) and basal cell carcinoma and PD (OR = 2.05, 95% CI = 1.02–4.08). PD participants who reported skin conditions were older (OR = 1.68, 95% CI = 1.21–2.35) more educated (OR = 1.70, 95% CI = 0.99–2.91), had higher Semantic Fluency Test (SFT) scores (OR = 1.45, 95% CI = 1.07–1.96) and Hopkins Verbal Learning Test (HVLT) retention scores (OR = 1.55, 95% CI = 1.09–2.22) compared to PD patients without skin conditions. None of the associations remained significant after Bonferroni correction for multiple comparisons.ConclusionsWe observed a positive association between any skin condition as well as basal cell carcinoma and PD. PD participants with skin conditions were older, more educated, had higher SFT and HVLT retention scores compared to those without skin conditions. However, all associations were no longer significant after Bonferroni multiple comparisons correction. Observed associations should be confirmed in larger, longitudinal studies.     

Premorbid exercise engagement and motor reserve in Parkinson's disease

BackgroundLife-long experiences of cognitive activity could enhance cognitive reserve, which may lead individuals to show less cognitive deficits in Alzheimer's disease, despite similar pathological changes. We performed this study to test whether premorbid physical activity may enhance motor reserve in Parkinson's disease (PD) (i.e., less motor deficits despite similar degrees of dopamine depletion).MethodsWe assessed engagement in premorbid leisure-time exercise among 102 drug naive PD patients who had been initially diagnosed at our hospital by dopamine transporter scanning. Patients were classified into tertile groups based on the frequency, duration, and intensity of the exercises in which they participated.ResultsAmong patients with mild to moderate reductions in striatal dopaminergic activity (above the median dopaminergic activity), the exercise group of the highest tertile showed significantly lower motor scores (i.e., fewer motor deficits, 15.53 ± 6.25), despite similar degrees of dopamine reduction, compared to the combined group of the middle and the lowest tertiles (21.57 ± 8.34, p = 0.01). Nonetheless, the highest tertile group showed a more rapid decline in motor function related to reductions in striatal dopaminergic activity than the other two groups (p = 0.002 with the middle tertile group and p = 0.001 with the lowest tertile group).ConclusionsThese results suggest that engagement in premorbid exercise acts as a proxy for an active reserve in the motor domain (i.e., motor reserve) in patients with PD.     

Backward walking in Parkinson's disease

We walk backward on a daily basis, such as when backing away from the kitchen sink or stepping back from a curb as a swiftly moving bus passes. This task may be particularly difficult for individuals with Parkinson's disease (PD) who often fall as a result of moving or being perturbed in the backward direction. The aim of this study was to assess backward walking (BW) in individuals with PD. Both forward walking (FW) and BW were assessed in 78 people with idiopathic PD (H&Y range: 0.5–3) in the ON state, and 74 age‐ and sex‐matched controls. In FW, those with PD had significantly shorter strides, lower swing percents, higher stance percents, and lower functional ambulation profiles than controls. Both groups walked significantly slower and with a wider base of support during BW than FW. Additionally, in BW those with PD walked significantly slower with shorter strides, lower swing percents, and higher double support and stance percents, and lower functional ambulation profiles compared with controls. Those with mild to moderate PD have impaired FW and BW, but differences between those with and without PD are more pronounced in BW. © 2008 Movement Disorder Society     

Atypical clinical presentation of pathologically proven Parkinson's disease: The role of Parkinson's disease related metabolic pattern

Regional changes in brain metabolism upgraded with measurements of specific metabolic brain patterns and automated diagnostic algorithms can help to differentiate among neurodegenerative parkinsonisms, but with few reports on pathological confirmation. Here we describe a parkinsonian patient with atypical presentation and ¹⁸F-FDG-PET imaging consistent with idiopathic Parkinson's disease. The latter was confirmed at the pathohistological examination.     

Analysis of 14 LRRK2 mutations in Parkinson's plus syndromes and late-onset Parkinson's disease.

The pleomorphic pathology of postmortem LRRK2-positive patients and the frequent association with late-onset Parkinson's disease (LOPD) symptoms suggest that LRRK2 mutations may play a role in Parkinson's Plus disorders and LOPD. Published studies primarily focus on the common G2019S mutation. Analysis of a spectrum of LRRK2 mutations in Parkinson's Plus disorders has yet to be reported. We investigated 14 leucine-rich repeat kinase 2 (LRRK2) mutations in a cohort of Parkinson's Plus disorders and LOPD. A total of 458 patients with progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal ganglionic degeneration (CBGD), atypical Parkinsonism (AP), and LOPD were screened for 14 mutations that span exons 19 to 41 of the LRRK2 gene. Among the LOPD cases, 1 patient was found to harbor the R1441C mutation. He presented with typical features of PD at age of 58 years old and responded well to levodopa. We did not detect any of the 14 mutations in PSP, MSA, CBGD, and AP patients. We highlight the first case of LRRK2 R1441C mutation in late onset sporadic PD of non-European ancestry. Furthermore, extensive mutational screen found LRRK2 mutations to be rare among patients who presented with PSP, MSA, CBGD, and AP.     

Suicidal and death ideation in Parkinson's disease

Parkinson's disease (PD) is a chronic, disabling illness affecting primarily the elderly and is associated with a high prevalence of depression. Although these are known risk factors for suicidal and death ideation, little is known about the prevalence and correlates of such ideation in PD. A convenience sample of 116 outpatients with idiopathic PD at two movement disorders centers were administered a modified Paykel Scale for suicidal and death ideation, as well as an extensive psychiatric, neuropsychological, and neurological battery. Univariate and multivariate logistic regression models were used to determine the correlates of suicidal or death ideation. Current death ideation (28%) or suicide ideation (11%) were present in 30% of the sample, and 4% had a lifetime suicide attempt. On univariate logistic regression analysis, increasing severity of depression (odds ratio = 2.92, 95% CI 2.01–4.24, P < 0.001), impulse control disorder (ICD) behaviors sometime during PD (odds ratio = 6.08, 95% CI 1.90–19.49, P = 0.002), and psychosis (odds ratio = 2.45, 95% CI 1.05–5.69, P = 0.04) were associated with either ideation. On multivariate logistic regression analysis, only increasing severity of depressive symptoms (odds ratio = 2.76, 95% CI 1.88–4.07, P < 0.001) predicted suicidal or death ideation. In conclusion, active suicidal or death ideation occurs in up to one‐third of PD patients. Comorbid psychiatric disorders, more than PD‐related disease variables, are associated with this ideation, highlighting the need for a comprehensive approach to the clinical care of PD patients. © 2008 Movement Disorder Society     

Common variants in PARK loci and related genes and Parkinson's disease

Rare mutations in PARK loci genes cause Parkinson's disease (PD) in some families and isolated populations. We investigated the association of common variants in PARK loci and related genes with PD susceptibility and age at onset in an outbred population. A total of 1,103 PD cases from the upper Midwest, USA, were individually matched to unaffected siblings (n = 654) or unrelated controls (n = 449) from the same region. Using a sequencing approach in 25 cases and 25 controls, single nucleotide polymorphisms (SNPs) in species‐conserved regions of PARK loci and related genes were detected. We selected additional tag SNPs from the HapMap. We genotyped a total of 235 SNPs and two variable number tandem repeats in the ATP13A2, DJ1, LRRK1, LRRK2, MAPT, Omi/HtrA2, PARK2, PINK1, SNCA, SNCB, SNCG, SPR, and UCHL1 genes in all 2,206 subjects. Case‐control analyses were performed to study association with PD susceptibility, while cases‐only analyses were used to study association with age at onset. Only MAPT SNP rs2435200 was associated with PD susceptibility after correction for multiple testing (OR = 0.74, 95% CI = 0.64–0.86, uncorrected P < 0.0001, log additive model); however, 16 additional MAPT variants, seven SNCA variants, and one LRRK2, PARK2, and UCHL1 variants each had significant uncorrected P‐values. There were no significant associations for age at onset after correction for multiple testing. Our results confirm the association of MAPT and SNCA genes with PD susceptibility but show limited association of other PARK loci and related genes with PD. © 2010 Movement Disorder Society