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Quantitative susceptibility mapping (QSM) demonstrates elevated iron content in Parkinson’s disease (PD) patients within the basal ganglia, though it has infrequently been studied in relation to gait difficulties including freezing of gait (FOG). Our purpose was to relate QSM of basal ganglia and extra-basal ganglia structures with qualitative and quantitative gait measures in PD.
This case–control study included PD and cognitively unimpaired (CU) participants from the Comprehensive Assessment of Neurodegeneration and Dementia study. Whole brain QSM was acquired at 3T. Region of interests (ROIs) were drawn blinded manually in the caudate nucleus, putamen, globus pallidus, pulvinar nucleus of the thalamus, red nucleus, substantia nigra, and dentate nucleus. Susceptibilities of ROIs were compared between PD and CU. Items from the FOG questionnaire and quantitative gait measures from PD participants were compared to susceptibilities.
Twenty-nine participants with PD and 27 CU participants were included. There was no difference in susceptibility values in any ROI when comparing CU versus PD (p > 0.05 for all). PD participants with gait impairment (n = 23) had significantly higher susceptibility in the putamen (p = 0.008), red nucleus (p = 0.01), and caudate nucleus (p = 0.03) compared to those without gait impairment (n = 6). PD participants with FOG (n = 12) had significantly higher susceptibility in the globus pallidus (p = 0.03) compared to those without FOG (n = 17). Among quantitative gait measures, only stride time variability was significantly different between those with and without FOG (p = 0.04).
Susceptibilities in basal ganglia and extra-basal ganglia structures are related to qualitative measures of gait impairment and FOG in PD.
To describe the neuroimaging and other methods for assessing vascular contributions to neurodegeneration in the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study, a Canadian multi-center, prospective longitudinal cohort study, including reliability and feasibility in the first 200 participants.
COMPASS-ND includes persons with Alzheimer’s disease (AD; n = 150), Parkinson’s disease (PD) and Lewy body dementias (LBDs) (200), mixed dementia (200), mild cognitive impairment (MCI; 400), subcortical ischemic vascular MCI (V-MCI; 200), subjective cognitive impairment (SCI; 300), and cognitively intact elderly controls (660). Magnetic resonance imaging (MRI) was acquired according to the validated Canadian Dementia Imaging Protocol and visually reviewed by either of two experienced readers blinded to clinical characteristics. Other relevant assessments include history of vascular disease and risk factors, blood pressure, height and weight, cholesterol, glucose, and hemoglobin A1c.
Analyzable data were obtained in 197/200 of whom 18 of whom were clinically diagnosed with V-MCI or mixed dementia. The overall prevalence of infarcts was 24.9%, microbleeds was 24.6%, and high white matter hyperintensity (WMH) was 31.0%. MRI evidence of a potential vascular contribution to neurodegeneration was seen in 12.9%–40.0% of participants clinically diagnosed with another condition such as AD. Inter-rater reliability was good to excellent.
COMPASS-ND will be a useful platform to study vascular brain injury and its association with risk factors, biomarkers, and cognitive and functional decline across multiple age-related neurodegenerative diseases. Initial findings show that MRI-defined vascular brain injury is common in all cognitive syndromes and is under-recognized clinically.
Parkinson’s disease (PD) and other synucleinopathies, namely dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), are common degenerative neurological disorders that share synuclein pathology. Although certain cardinal features of parkinsonism, including bradykinesia and rigidity, respond well to levodopa, axial features, such as gait and balance impairment, are less reliably responsive to dopaminergic therapy and surgical interventions. Consequently, falls are common in PD and other synucleinopathies and are a major contributor toward injury and loss of independence. This underscores the need for appropriate fall risk assessment and implementation of preventative measures in all patients with parkinsonism. The aim of this review is therefore to explore modifiable and non-modifiable risk factors for falls in synucleinopathies. We next review and evaluate the evidence for pharmacological, nonpharmacological, and surgical approaches for fall prevention, and emphasize individualized and multifaceted approaches.
The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) cohort study of the Canadian Consortium on Neurodegeneration in Aging (CCNA) is a national initiative to catalyze research on dementia, set up to support the research agendas of CCNA teams. This cross-country longitudinal cohort of 2310 deeply phenotyped subjects with various forms of dementia and mild memory loss or concerns, along with cognitively intact elderly subjects, will test hypotheses generated by these teams.
The COMPASS-ND protocol, initial grant proposal for funding, fifth semi-annual CCNA Progress Report submitted to the Canadian Institutes of Health Research December 2017, and other documents supplemented by modifications made and lessons learned after implementation were used by the authors to create the description of the study provided here.
The CCNA COMPASS-ND cohort includes participants from across Canada with various cognitive conditions associated with or at risk of neurodegenerative diseases. They will undergo a wide range of experimental, clinical, imaging, and genetic investigation to specifically address the causes, diagnosis, treatment, and prevention of these conditions in the aging population. Data derived from clinical and cognitive assessments, biospecimens, brain imaging, genetics, and brain donations will be used to test hypotheses generated by CCNA research teams and other Canadian researchers. The study is the most comprehensive and ambitious Canadian study of dementia. Initial data posting occurred in 2018, with the full cohort to be accrued by 2020.
Availability of data from the COMPASS-ND study will provide a major stimulus for dementia research in Canada in the coming years.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition that primarily affects motor neurons. Cognitive changes are reported in 25%-50% of patients, secondary to frontotemporal involvement. The objective of this study was to evaluate the utility of a screening tool, the Addenbrooke’s Cognitive Examination (ACE), in ALS patients.
In this retrospective cross-sectional study, performance on the ACE was compared between 55 ALS patients and 49 healthy controls. The validation of the ACE in ALS patients was explored using a neuropsychometric battery. Correlations between the ACE and clinical variables such as the ALS Functional Rating Scale-Revised (ALSFRS-R) and forced vital capacity were computed.
A higher percentage of patients were below cut-off scores, although this remained non-significant between the patient and control groups. The ACE did not reveal significant differences between ALS patients and controls. The scores on the ACE displayed moderate correlations with our neuropsychometric battery for some domains, whereas others showed poor or no associations. Poor ACE Total was associated with lower ALSFRS-R and finger-tapping scores.
Performance on the ACE was comparable between patients and controls. Associations with motor function pose a challenge to accurate interpretation of ACE performance. It is likely that patients with poor cognition have greater disability, or that poor ACE performance reflects reduced motor ability to perform the task. This raises concern for the utility of the ACE as a screening tool in ALS patients, especially since recent versions of the ACE continue to include motor-based tasks.
We thank Ms. Horne et al. for the clarification of our misquoting of their paper (Wood et al., 2016). They clarify that 21% of their overall sample of patients with Parkinson's disease (PD-MCI) converted to dementia in over four years, which we erroneously attributed to the mild cognitive impairment (MCI) group in our discussion (McDermott et al., 2017). This was virtually identical to our overall conversion rate of 20%. Their conversion rate of patients with PD-MCI, as defined by two cognitive tests impaired (1.5 SD) within a single cognitive domain, was 51%, whereas the conversion rate was 38% when the PD-MCI group included patients with impairment within and between cognitive domains. Their conversion rates are similar to our rate of 42% (as defined with 1.5 SD impairment within or across domains) and the rate of 39% in a study with five-years of follow-up of incident cases (Pedersen et al., 2017). Our overall conversion occurred over a slightly shorter time span. In addition to conversion rates, all the studies acknowledge that some patients can revert to normal cognitive status, which varies based on classification criteria and length of follow-up. Comparable conversion across studies using similar criteria is reassuring and can encourage planning of targeted interventions (Hoogland et al., 2017).
Some nonmotor symptoms (NMS) of Parkinson’s disease (PD) have been shown to increase the risk of developing dementia. A total of 52 PD patients without dementia at baseline were examined for NMS over 36 months. Mini-Mental State Examination, Dementia Rating Scale–2, and caregiver-derived (Clinical Dementia Rating) scores were employed to rate patients as having either clear progression or not. Some 20 of 48 participants (41.7%) had clear cognitive decline. Univariate binary regression analysis was statistically significant for age (odds ratio [OR] (CI95%)=1.24, 1.07–1.45, p=0.006) and orthostatic hypotension (OH) (OR (CI95%)=4.91, 1.24–19.5, p=0.024). Multivariate analysis showed that only age (OR (CI95%)=1.19, 1.0–1.41, p=0.05) and OH (OR (CI95%)=5.57, 1.0–30.97, p=0.05) were correlated with an increased risk of cognitive decline. The presence of OH at baseline may be a significant predictor of progression to dementia in PD.
We apply recently recommended Parkinson's disease mild cognitive impairment (PD-MCI) classification criteria from the movement disorders society (MDS) to PD patients and controls and compare diagnoses to that of short global cognitive scales at baseline and over time. We also examine baseline prevalence of neuropsychiatric symptoms across different definitions of MCI.
51 PD patients and 50 controls were classified as cognitively normal, MCI, or demented using MDS criteria (1.5 or 2.0 SD below normative values), Clinical Dementia Rating Scale (CDR), and the Dementia Rating Scale (DRS). All subject had parallel assessment with the Neuropsychiatric inventory (NPI).
We confirmed that PD-MCI (a) is frequent, (b) increases the risk of PDD, and (c) affects multiple cognitive domains. We highlight the predictive variability of different criteria, suggesting the need for further refinement and standardization. When a common dementia outcome was used, the Level II MDS optimal testing battery with impairment defined as two SD below norms in 2+ tests performs the best. Neuropsychiatric symptoms were more common in PD across all baseline and longitudinal cognitive classifications.
Our results advance previous findings on the utility of MDS PD-MCI criteria for PD patients and controls at baseline and over time. Additionally, we emphasize the possible utility of other cognitive scales and neuropsychiatric symptoms.
Background: Parkinson disease (PD) presents with motor and non-motor symptoms (NMS). The NMS often precede the onset of motor symptoms, but may progress throughout the disease course. Tremor dominant, postural instability gait difficulty (PIGD), and indeterminate phenotypes can be distinguished using Unified PD Rating scales (UPDRS-III). We hypothesized that the PIGD phenotype would be more likely to develop NMS, and that the non-dopamine–responsive axial signs would correlate with NMS severity. Methods: We conducted a retrospective cross-sectional chart review to assess the relationship between NMS and PD motor phenotypes. PD patients were administered the NMS Questionnaire, the UPDRS-III, and the Mini-Mental State Examination score. The relationship between NMS burden and PD subtypes was examined using linear regression models. The prevalence of each NMS among difference PD motor subtypes was analyzed using chi-square test. Results: PD patients with more advanced disease based on their UPDRS-III had higher NMS Questionnaire scores. The axial component of UPDRS-III correlated with higher NMS. There was no correlation between NMS and tremor scores. There was a significant correlation between PIGD score and higher NMS burden. PIGD group had higher prevalence in most NMS domains when compared with tremor dominant and indeterminate groups independent of disease duration and severity. Conclusions: NMS profile and severity vary according to motor phenotype. We conclude that in the PD population, patients with a PIGD phenotype who have more axial involvement, associated with advanced disease and poor motor response, have a higher risk for a higher NMS burden.
Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) are pathological overlapping and important causes of dementia for which clinical trials are in their infancy. Cholinesterase inhibitors may be of benefit in DLB and PDD, as suggested by placebo-controlled clinical trials of rivastigmine and donepezil. The anti-psychotic agent clozapine has been of benefit in PD and PDD, but other agents, such as quetiapine, require adequate assessment. Barriers to trials include pathological overlap that can lead to inaccuracies in clinical diagnosis, unavailability of a consensus definition for PDD, unanswered questions regarding natural history and the paucity of validated outcome measures. Motor impairment must be considered in patients with PDD and DLB; conversely, cognitive impairment should be assessed in trials targeting motor impairment in advanced PD. Potential targets for treatment include onset of dementia, cognitive impairment, behavioral impairment, functional decline, falls, nursing home placement, mortality, quality of life and economic impact. Biomarkers including neuroimaging and cerebrospinal fluid markers are not currently established. At present PDD and DLB are distinct entities by definition. Future studies, including clinical trials and biomarker studies, will help to further define the clinical and therapeutic implications of this distinction.
Dementia occurs in up to 30% of people with Parkinson's disease and is a major cause of disability. Pathologically, Parkinson's dementia, where dementia follows the onset of parkinsonism by at least one year, overlaps with dementia with Lewy bodies. We review the functional impact, definitions, neuropsychology, epidemiology and pathophysiology of Parkinson's dementia, dementia with Lewy bodies and their overlap. Associated psychiatric and imaging findings are also considered. Lastly, current and emerging approaches to assessment and treatment in patients with these Lewy body associated dementias are presented.
Age-related brain changes may contribute to axial features in Parkinson's disease (PD).
To determine if ventricular volume and white matter high signal changes (WMC) are related to motor signs in PD and controls independent of age.
Patients were rated with the Unified Parkinson's Disease Rating Scale (subscore A: tremor, rigidity, bradykinesia, and facial expression; subscore B: speech and axial impairment). Steps and time taken to walk 9.144 meters were measured. Total ventricular volume (TVV) and intracranial volume (ICV) were measured on T1-weighted MRI using manual tracing software. WMC were rated on axial T2-weighted, dual-echo or FLAIR MR images using a visual scale.
TVV (cm3) (PD: 36.48 ± 15.93; controls: 32.16 ± 14.20, p = 0.21) and WMC did not differ between groups (PD: 3.7 ± 4.2; controls: 3.2 ± 3.1, p = 0.55). Age correlated positively with ICV-corrected TVV and WMC in PD (cTVV: r = 0.48, p = 0.003; WMC: r=0.42, p=0.01) and controls (cTVV: r = 0.31, p = 0.04; WMC: r=0.44, p=0.003). Subscore B (r = 0.42, p = 0.01) but not subscore A (r = 0.25, p = 0.14) correlated with cTVV in PD. Steps and walking time correlated with cTVV and WMC in PD; cadence correlated with cTVV and steps with WMC in controls. Age-adjustment eliminated correlations.
Subscore B, but not subscore A correlated positively with ventricular volume in PD, though this association was accounted for by age. Age-related brain change super-imposed on PD may contribute to axial features.
In Parkinson's disease (PD) cell loss in the substantia nigra is known to result in motor symptoms; however widespread pathological changes occur and may be associated with non-motor symptoms such as cognitive impairment. Diffusion tensor imaging is a quantitative imaging method sensitive to the micro-structure of white matter tracts.
To measure fractional anisotropy (FA) and mean diffusivity (MD) values in the corpus callosum and cingulum pathways, defined by diffusion tensor tractography, in patients with PD, PD with dementia (PDD) and controls and to determine if these measures correlate with Mini-Mental Status Examination (MMSE) scores in parkinsonian patients.
Patients with PD (17 Males [M], 12 Females [F]), mild PDD (5 M, 1F) and controls (8 M, 7F) underwent cognitive testing and MRI scans. The corpus callosum was divided into four regions and the cingulum into two regions bilaterally to define tracts using the program DTIstudio (Johns Hopkins University) using the fiber assignment by continuous tracking algorithm. Volumetric MRI scans were used to measure white and gray matter volumes.
Groups did not differ in age or education. There were no overall FA or MD differences between groups in either the corpus callosum or cingulum pathways. In PD subjects the MMSE score correlated with MD within the corpus callosum. These findings were independent of age, sex and total white matter volume.
The data suggest that the corpus callosum or its cortical connections are associated with cognitive impairment in PD patients.
Chronic cerebrovascular disease and large ischemic stroke are both associated with cognitive impairment. Much less is known about the acute cognitive sequelae of transient ischemic attack (TIA). Although often overlooked, there is increasing evidence that cognitive impairment does occur following TIA. In some patients, cognitive changes persist after resolution of focal neurological deficits, but the temporal profile of these symptoms is unknown. In addition, clinical and imaging correlates of cognitive impairment after TIA have not been systematically studied. This under-studied and recognized problem has significant implications for TIA patient management. In this review, we summarize the evidence currently available and identify future research priorities.