Search

Repeated data are increasingly collected in studies to investigate the trajectory of change in measurements over time. Determining a link between one repeated measurement with another that is considered as the biomarker for disease progression, may provide a new target for drug development. When a third variable is associated with one of the two measurements, partial correlation after eliminating the effect of that variable is able to provide reliable estimate for association as compared to the existing raw correlation for repeated data. We propose using linear regression models to compute residuals by modeling a relationship between each measurement and a third variable. The computed residuals are then used in a linear mixed model (implemented by SAS Proc Mixed) to compute partial correlation for repeated data. Alternatively, the partial correlation may be computed as the average of partial correlations at each visit. We provide two real examples to illustrate the application of the proposed partial correlation, and conduct extensive numerical studies to compare the proposed partial correlation coefficients.

Objective:To evaluate the sex differences in cognitive course over 4 years in Parkinson’s disease (PD) patients with and without mild cognitive impairment (MCI) compared to controls.Methods:Four-year longitudinal cognitive scores of 257 cognitively intact PD, 167 PD-MCI, and 140 controls from the Parkinson’s Progression Markers Initiative were included. Longitudinal scores of men and women, and PD with and without MCI were compared.Results:Women had better verbal memory, men had better visuospatial function. There was no interaction between sex, diagnostic group, and/or time (4-year follow-up period).Conclusions:Sex differences in cognitive course in de novo PD are similar to healthy aging. Cognitive decline rates in PD with and without MCI are similar for the first 4 years of PD.

More than half of the patients with Alzheimer’s disease (AD) have comorbidities including TDP-43 and Lewy bodies, which are also associated with frontotemporal lobar degeneration and dementia with Lewy bodies, respectively. These comorbidities may help explain the overlapping neuropsychiatric symptoms between AD and other dementias. Data on 221 AD patients with Neuropsychiatric Inventory-Questionnaire were obtained from the National Alzheimer’s Coordinating Center. TDP-43 was associated with aberrant motor activity, whereas Lewy bodies were associated with anxiety, irritability, sleep behavior, and appetite problems. The associations between these comorbidities and neuropsychiatric symptoms were more significant for patients with sparse diffuse plaques.

Cognitive impairment is a common non-motor symptom in Parkinson’s Disease (PD) and an important source of patient disability and caregiver burden. The timing, profile and rate of cognitive decline varies widely among individuals with PD and can range from normal cognition to mild cognitive impairment (PD-MCI) and dementia (PDD). Beta-amyloid and tau brain accumulation, oxidative stress and neuroinflammation are reported risk factors for cognitive impairment. Traumatic brain injury and pesticide and tobacco exposure have also been described. Genetic risk factors including genes such as COMT, APOE, MAPT and BDNF may also play a role. Less is known about protective factors, although the Mediterranean diet and exercise may fall in this category. Nonetheless, there is conflicting evidence for most of the factors that have been studied. The use of inconsistent criteria and lack of comprehensive assessment in many studies are important methodological issues. Timing of exposure also plays a crucial role, although identification of the correct time window has been historically difficult in PD. Our understanding of the mechanism behind these factors, as well as the interactions between gene and environment as determinants of disease phenotype and the identification of modifiable risk factors will be paramount, as this will allow for potential interventions even in established PD.

Several genetic and environmental factors have been reported in progressive supranuclear palsy (PSP), although none were identified as a definitive cause. We aimed to explore potential gene-environment interactions in PSP. Two hundred and ninety two PSP cases and 292 controls matched for age, sex, and race from the ENGENE-PSP were analyzed to determine the association between PSP and minor alleles of 5 single nucleotide polymorphisms (SNPs) in 4 genes (MAPT, MOBP, EIF2AK3, and STX6), which were previously associated with PSP risk. Interactions between these SNPs and environmental factors, including previously reported occupational and agricultural risk factors for PSP, were assessed for PSP odds and age of symptom onset. Minor alleles of MAPTrs242557 and EIF2AK3rs7571971 were individually associated with increased odds; MAPTrs8070723 minor alleles were associated with lower PSP odds. There were several gene-environment interactions for PSP odds and age of symptom onset, however, they did not remain significant after FDR-correction. Larger scale studies are required to determine potential interactions.

IntroductionSex differences in dementia with Lewy bodies (DLB) have been reported in clinically defined cohorts; however, clinical diagnostic accuracy in DLB is suboptimal and phenotypic differences have not been assessed in pathologically confirmed participants.MethodsCore DLB features were compared across 55 women and 156 men with pathologically defined DLB in the National Alzheimer’s Coordinating Center. These analyses were repeated for 55 women and 55 men matched for age, education and tau burden.ResultsIn the total sample, women died older, had fewer years of education, had higher tau burden but were less likely to be diagnosed with dementia and clinical DLB. In the matched sample, visual hallucinations continued to be less common in women, and fewer women met clinical DLB criteria.DiscussionSex impacts clinical manifestations of underlying pathologies in DLB. Despite similar underlying Lewy body pathology, women are less likely to manifest core DLB features and may be clinically underdiagnosed.

Author(s): Wu, Melanie; Ceponiene, Rita; Bayram, Ece; Litvan, Irene | Abstract: BackgroundNiemann-Pick disease type C (NPC) is a rare, autosomal recessive lysosomal lipid storage disorder. It may present with cerebellar ataxia, vertical supranuclear gaze palsy, and cognitive impairment, and the age of symptom onset in adult-onset NPC is usually earlier than the fourth decade.CasesWe present 2 patients with adult-onset NPC diagnosed in the seventh decade of life. The slow motor progression and subtle findings of supranuclear vertical gaze palsy and ataxia can lead to a delayed diagnosis and misdiagnosis with parkinsonian disorders, particularly progressive supranuclear palsy.ConclusionThis report highlights and differentiates key clinical characteristics between NPC and parkinsonian disorders. It is important to consider NPC in the differential diagnosis when patients present with slowed vertical saccades, vertical supranuclear gaze palsy, ataxia, and cognitive impairment present at any age. This will allow appropriate and prompt treatment with miglustat and novel experimental therapies.

Author(s): Bayram, Ece; Litvan, Irene | Abstract: This scientific commentary refers to ‘Diabetes medications and risk of Parkinson’s disease: a cohort study of patients with diabetes’, by Brauer etal. (doi:10.1093/brain/awaa262).

Introduction: Cognitive impairment and orthostatic hypotension (OH) are common, disabling Parkinson disease (PD) symptoms that are strongly correlated. Whether the relationship is causative or associative remains unknown. OH may occur without classic orthostatic symptoms of cerebral hypoperfusion (i.e., lightheadedness or dizziness). Whether longitudinal differences in cognition occur between symptomatic and asymptomatic OH patients has not been explored. Objectives: We characterized the prevalence of OH, orthostatic symptoms, and cognitive impairment among PD patients and compared cognition between patients with and without OH, and between patients with symptomatic and asymptomatic OH. Methods: Our cross-sectional, retrospective, observational study included 226 clinically diagnosed PD patients who underwent repeated standardized evaluations. Among these, 62 had longitudinal follow-up of > 3.5 years. We compared longitudinal Montreal Cognitive Assessment (MoCA) scores between patients remaining OH-free (n = 14) and those without baseline OH that developed OH (n = 28), matched for age, sex, education, and PD duration. We also compared MoCA scores between groups with asymptomatic OH (n = 13) and symptomatic OH (n = 13) matched for the same factors. Results: In the cross-sectional analysis, OH patients had worse cognition. In the longitudinal analysis (mean follow-up = 5.3 years), OH patients had worse cognitive decline (p = 0.027). Cognitive impairment was similar between asymptomatic and symptomatic OH patients in the cross-sectional and longitudinal analyses. Conclusions: OH is associated with cognitive impairment in PD. Further studies are needed in larger cohorts to expand our findings and to determine whether treating OH can prevent or delay cognitive dysfunction.

Background The etiology of freezing of gait in Parkinson’s disease (PD) is yet to be clarified. Non-motor risk factors including cognitive impairment, sleep disturbance and mood disorders have been shown in freezing of gait. Research question We aimed to determine the predictive value of non-motor features in freezing of gait development. Methods Data were obtained from the Parkinson’s Progression Markers Initiative. Fifty PD patients with self-reported freezing of gait, and 50 PD patients without freezing of gait at the fourth year visit were included. Groups were matched for Movement Disorders Society-Unified Parkinson’s Disease Rating Scale Part III scores. Several cognitive and non-cognitive tests were used for non-motor features at baseline and over time. Executive function, visuospatial function, processing speed, learning and memory tests were used for cognition. Non-cognitive tests included sleepiness, REM sleep behavior disorder, depression and anxiety scales. Results Patients with freezing of gait had higher scores on sleepiness, REM sleep behavior disorder, depression and anxiety scales. However, predictor model analysis revealed that baseline processing speed, learning and sleepiness scores were predictive of self-reported freezing of gait development over time. Significance Our findings suggest that specific cognitive deficits and sleep disorders are predictive of future freezing of gait. These features may be helpful in identifying underlying networks in freezing of gait and should be further investigated with neuroimaging studies.

Parkinson’s disease (PD), which is one of the most common neurodegenerative disorders, is a disorder that affects quality of life due to non-motor symptoms in addition to motor symptoms. The non-motor symptoms of this disease vary greatly and affect patients starting from early stages. These symptoms also include language deficits. Besides motor language disorders such as hypophonia and dysarthria, which are common in PD, deficits in morphosyntax, semantics, and understanding metaphors have been reported. Various studies have also shown deficits in action language in PD, in which the ability of action is affected. Although language deficits are thought to be caused by cognitive deficits in this disease, there are studies showing language deficits being independent of cognitive deficits. These language deficits in PD, caused by basal ganglia dysfunctions, may provide valuable information in determining brain areas related to language. In this review, we aimed to assess action language deficits in PD and to evaluate the location of action language in the brain in light of this disorder

INTRODUCTION: Cognitive decline and mood symptoms are common in Parkinson’s disease (PD). Reductions in striatal dopaminergic binding have been associated with worse cognition and mood. We investigated whether this association persists throughout the disease progression in newly diagnosed PD. METHODS: Four-year data from Parkinson Progression Markers Initiative (PPMI) were used. Groups consisted of left and right limb dominantly affected PD patients, and controls. Longitudinal relationships between cognition, mood and striatal binding ratios were assessed by repeated measures correlations. RESULTS: Reduced binding was associated with general cognitive decline in controls; reduced processing speed and increased mood symptoms in PD. Anxiety was associated with striatum only in left limb dominantly affected PD. Dominantly affected limb side did not impact striatum and cognition association. CONCLUSION: There are longitudinal associations between striatum, processing speed and anxiety. Dopamine transporter availability imaging may have some prognostic value for cognition and mood in PD.

Visuospatial working memory impairments are common in Parkinson's disease (PD), yet the underlying neural mechanisms are poorly understood. The present study investigated abnormalities in context-dependent functional connectivity of working memory hubs in PD. Cognitively normal PD and control participants underwent fMRI while performing a visuospatial working memory task. To identify sources of dysfunction, distraction, and load-modulated connectivity were disentangled for encoding and retrieval phases of the task. Despite normal working memory performance in PD, two features of abnormal connectivity were observed, one due to a loss in normal context-related connectivity and another related to upregulated connectivity of hubs for which the controls did not exhibit context-dependent connectivity. During encoding, striatal-prefrontal coupling was lost in PD, both during distraction and high memory loads. However, long-range connectivity of prefrontal, medial temporal and occipital hubs was upregulated in a context-specific manner. Memory retrieval was characterized by different aberrant connectivity patterns, wherein precuneus connectivity was upregulated during distraction, whereas prefrontal couplings were lost as memory load approached capacity limits. Features of abnormal functional connectivity in PD had pathological and compensatory influences as they correlated with poorer working memory or better visuospatial skills. The results offer new insights into working memory-related signatures of aberrant cortico-cortical and corticostriatal functional connections, which may portend future declines in different facets of working memory.

Lateralization of default mode network (DMN) functioning has been shown to change with age. Similarly, lateralization of frontal lobe function has been shown to decline in age. The impact of amyloid pathology and the progression of Alzheimer's disease (AD) on resting state lateralization has not been investigated. Due to the preferential involvement of the left hemisphere in verbal tasks, there may be a benefit to higher levels of left-lateralization in the performance of verbal memory tasks. Here we compared functional lateralization of the anterior and posterior DMN between four groups of participants: amyloid negative (Aβ-) and amyloid positive (Aβ+) groups with normal cognition (NC), and Aβ+ groups with mild cognitive impairment (Aβ+MCI) or dementia (Aβ+AD). Differences were evident between groups in posterior DMN; the Aβ-NC group was more left-lateralized than both cognitively impaired Aβ+ groups. There was no difference in anterior DMN. No differences in overall network connectivity between groups were observed, suggesting that the functional lateralization finding is not secondary to general changes in connectivity. Left-lateralization of both networks was associated with better verbal recall performance. Older subjects, overall, had less left functional lateralization of the anterior DMN.

Alzheimer's disease (AD) is caused by a cascade of changes to brain integrity. Neuroimaging biomarkers are important in diagnosis and monitoring the effects of interventions. As memory impairments are among the first symptoms of AD, the relationship between imaging findings and memory deficits is important in biomarker research. The most established magnetic resonance imaging (MRI) finding is hippocampal atrophy, which is related to memory decline and currently used as a diagnostic criterion for AD. While the medial temporal lobes are impacted early by the spread of neurofibrillary tangles, other networks and regional changes can be found quite early in the progression. Atrophy in several frontal and parietal regions, cortical thinning, and white matter alterations correlate with memory deficits in early AD. Changes in activation and connectivity have been detected by functional MRI (fMRI). Task-based fMRI studies have revealed medial temporal lobe hypoactivation, parietal hyperactivation, and frontal hyperactivation in AD during memory tasks, and activation patterns of these regions are also altered in preclinical and prodromal AD. Resting state fMRI has revealed alterations in default mode network activity related to memory in early AD. These studies are limited in part due to the historic inclusion of patients who had suspected AD but likely did not have the disorder. Modern biomarkers allow for more diagnostic certainty, allowing better understanding of neuroimaging markers in true AD, even in the preclinical stage. Larger patient cohorts, comparison of candidate imaging biomarkers to more established biomarkers, and inclusion of more detailed neuropsychological batteries to assess multiple aspects of memory are needed to better understand the memory deficit in AD and help develop new biomarkers. This article reviews MRI findings related to episodic memory impairments in AD and introduces a new study with multimodal imaging and comprehensive neuropsychiatric evaluation to overcome current limitations.

Introduction Freezing of gait is an episodic inability to move the feet forward despite the intention to walk. It is a common cause of falls and subsequent morbidity and mortality in Parkinson's disease. Virtual reality paradigms provide an opportunity to safely evaluate freezing of gait, in order to better understand the underlying pathophysiology. This article focuses on the methodology, threshold used to define freezing of gait, results, limitations of studies using virtual reality paradigms, and proposes future directions of research. Summarizing these articles improves our understanding of freezing of gait in Parkinson's disease, and critical evaluation provides an opportunity for future studies to improve upon these efforts. Methods We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines, of studies using VR paradigms to elucidate the underlying pathophysiology of PD-FOG. Results This review initially identified 57 articles, but after exclusion of duplicates, abstracts, and studies not focused on the underlying pathophysiology of this disorder, 12 peer-reviewed articles using virtual reality paradigms to evaluate freezing of gait in Parkinson's disease were found. Conclusion Virtual reality paradigms are able to reproduce freezing of gait. Studies using MRI compatible virtual reality to evaluate freezing of gait found dysfunctional connectivity between cortical and subcortical structures during episodes. However, several important limitations of these studies should caution our interpretation of these results. Future studies which improve the design and methodology are needed to ultimately identify the cause and subsequent treatments for freezing of gait in Parkinson's disease.

Introduction Freezing of gait (FOG) is a disabling phenomenon characterized by a brief, episodic absence or reduction of forward progression of the feet despite the intention to walk. It is a common cause of falls and mortality in cases with Parkinson's disease (PD). This article reviews neuropsychological and neuroimaging studies to date and introduces a new study of multimodal imaging and cognition in PD-FOG. Methods A comprehensive literature search identified studies using neuropsychological evaluation and/or neuroimaging to evaluate PD-FOG. Results Several studies have evaluated PD-FOG, but few have combined neuropsychological and comprehensive neuroimaging and none longitudinally. Discussion A study using a combined approach longitudinally evaluating cognitive dysfunction and underlying neural networks in FOG is needed. We introduce the framework of a study which demonstrates the use of establishing an infrastructure for studying neurodegenerative disorders using the National Institutes of Health/National Institute of General Medical Science Center of Biomedical Research Excellence grant mechanism.

WOS: 000424114000007, PubMed ID: 30363359, Background: Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and Unified Dyskinesia Rating Scale (UDysRS) were developed as standard tools to rate Parkinson's disease (PD) and drug-induced dyskinesias of PD. As these scales have become widely used, there is a need for translation to non-English languages. Here we present the standardization for the Turkish translations. Methods: The scales were translated into Turkish and then back-translated to English. These back-translations were reviewed by the MDS team. After cognitive pretesting, movement disorder specialists from nine centers tested 352 patients for MDS-UPDRS, and 250 patients for UDysRS. Confirmatory factor analyses (CFAs) were used to determine if the factor structures for the reference standards could be confirmed in the Turkish data. The comparative fit indexes (CFIs) for the scales were required to be 0.90 or higher. Exploratory factor analyses (EFAs) were conducted to explore the underlying factor structure without the constraint of a pre-specified factor structure. Results: For both scales, the CFIs were 0.94 or greater as compared to the reference standard factor structures. The factor structures were consistent with that of reference standards, although there were some differences in some areas as compared to the EFA of the reference standard dataset. This may be due to the inclusion of patients with different stages of PD and different cultural properties of raters and patients. Conclusions: These results demonstrate that the Turkish translations of MDS-UPDRS and UDysRS have adequate clinimetric properties. They are established as the official translations and can be reliably used in Turkish speaking populations., International Parkinson and Movement Disorder Society, All authors received financial support provided by the International Parkinson and Movement Disorder Society for this study.

In this study we present a picture database of 160 nouns and 160 verbs. All verbs and nouns are divided into two groups as action and non-action words. Age of acquisition, familiarity, imageability, name agreement and complexity norms are reported alongside frequency, word length and morpheme count for each word. Data were collected from 600 native Turkish adults in total. The results show that although several measures have weak correlations with each other, only age of acquisition had moderate downhill relationships with familiarity and frequency with familiarity and frequency having a rather strong positive correlation with each other. The norms and the picture database are available as supplemental materials for use in psycholinguistic studies in Turkish.