Low and high-order topological disruption of functional networks in multiple system atrophy with freezing of gait: A resting-state study.

OBJECTIVE: Freezing of gait (FOG), a specific survival-threatening gait impairment, needs to be urgently explored in patients with multiple system atrophy (MSA), which is characterized by rapid progression and death within 10 years of symptom onset. The objective of this study was to explore the topological organisation of both low- and high-order functional networks in patients with MAS and FOG. METHOD: Low-order functional connectivity (LOFC) and high-order functional connectivity FC (HOFC) networks were calculated and further analysed using the graph theory approach in 24 patients with MSA without FOG, 20 patients with FOG, and 25 healthy controls. The relationship between brain activity and the severity of freezing symptoms was investigated in patients with FOG. RESULTS: Regarding global topological properties, patients with FOG exhibited alterations in the whole-brain network, dorsal attention network (DAN), frontoparietal network (FPN), and default network (DMN), compared with patients without FOG. At the node level, patients with FOG showed decreased nodal centralities in sensorimotor network (SMN), DAN, ventral attention network (VAN), FPN, limbic regions, hippocampal network and basal ganglia network (BG), and increased nodal centralities in the FPN, DMN, visual network (VIN) and, cerebellar network. The nodal centralities of the right inferior frontal sulcus, left lateral amygdala and left nucleus accumbens (NAC) were negatively correlated with the FOG severity. CONCLUSION: This study identified a disrupted topology of functional interactions at both low and high levels with extensive alterations in topological properties in MSA patients with FOG, especially those associated with damage to the FPN. These findings offer new insights into the dysfunctional mechanisms of complex networks and suggest potential neuroimaging biomarkers for FOG in patients with MSA.

Cholinergic basal forebrain system degeneration underlies postural instability/gait difficulty and attention impairment in Parkinson's disease.

BACKGROUND AND PURPOSE: The specific pathophysiological mechanisms underlying postural instability/gait difficulty (PIGD) and cognitive function in Parkinson's disease (PD) remain unclear. Both postural and gait control, as well as cognitive function, are associated with the cholinergic basal forebrain (cBF) system. METHODS: A total of 84 PD patients and 82 normal controls were enrolled. Each participant underwent motor and cognitive assessments. Diffusion tensor imaging was used to detect structural abnormalities in the cBF system. The cBF was segmented using FreeSurfer, and its fiber tract was traced using probabilistic tractography. To provide information on extracellular water accumulation, free-water fraction (FWf) was quantified. FWf in the cBF and its fiber tract, as well as cortical projection density, were extracted for statistical analyses. RESULTS: Patients had significantly higher FWf in the cBF (p < 0.001) and fiber tract (p = 0.021) than normal controls, as well as significantly lower cBF projection in the occipital (p < 0.001), parietal (p < 0.001) and prefrontal cortex (p = 0.005). In patients, a higher FWf in the cBF correlated with worse PIGD score (r = 0.306, p = 0.006) and longer Trail Making Test A time (r = 0.303, p = 0.007). Attentional function (Trail Making Test A) partially mediated the association between FWf in the cBF and PIGD score (indirect effect, a*b = 0.071; total effect, c = 0.256; p = 0.006). CONCLUSIONS: Our findings suggest that degeneration of the cBF system in PD, from the cBF to its fiber tract and cortical projection, plays an important role in cognitive-motor interaction.

Greater prefrontal activation during sitting toe tapping predicts severer freezing of gait in Parkinson's disease: an fNIRS study.

OBJECTIVE: Previous studies have revealed that, compared with Parkinson's disease (PD) patients without freezing of gait (FoG), the ones with FoG showed greater prefrontal activation while doing lower-limb movements involving standing, walking and turning, which require both locomotor and balance control. However, the relation between FoG and pure locomotor control as well as its underlying mechanism remain unclear. METHODS: A total of 56 PD subjects were recruited and allocated to PD-FoG and PD-noFoG subgroups, and 34 age-matched heathy adults were included as heathy control (HC). Functional near-infrared spectroscopy was used to measure their prefrontal activation in a sitting lower-limb movement task, wherein subjects were asked to sit and tap their right toes as big and as fast as possible. RESULTS: Result of one-way ANOVA (Group: PD-FoG vs. PD-noFoG vs. HC) revealed greater activation in the right prefrontal cortex in the PD-FoG group than in the other 2 groups. Linear mixed-effects model showed consistent result. Furthermore, the right prefrontal activation positively correlated with the severity of FoG symptoms in PD-FoG patients. CONCLUSION: These findings suggested that PD patients with FoG require additional cognitive resources to compensate their damaged automaticity in locomotor control, which is more pronounced in severe FoG patients than milder ones.

Dynamic functional connectivity reveals hyper-connected pattern and abnormal variability in freezing of gait of Parkinson's disease.

BACKGROUND: Freezing of gait (FOG) is an intractable and paroxysmal gait disorder that seriously affects the quality of life of Parkinson's disease (PD) patients. Emerging studies have reported abnormal brain activity of distributed networks in FOG patients, whereas ignoring the intrinsic dynamic fluctuations of functional connectivity. The purpose of this study was to examine the dynamic functional network connectivity (dFNC) of PD-FOG. METHODS: In total, 52 PD patients with FOG (PD-FOG), 73 without FOG (PD-NFOG) and 38 healthy controls (HCs) received resting state functional magnetic resonance imaging (rs-fMRI). Sliding window method, k-means clustering and graph theory analysis were employed to retrieve dynamic characteristics of PD-FOG. Partial correlation analysis was conducted to verify whether the dFNC was related to freezing gait severity. RESULTS: Seven brain networks were identified and configured into seven states. Compared to PD-NFOG, significant spatial pattern was identified for state 2 in freezers, showing increased functional coupling between default mode network (DMN) and basal ganglia network (BG), as a concrete manifestation of increased precuneus-caudate coupling. The mean dwell time and fractional window of state 2 had a positive correlation with FOG severity. Furthermore, PD-FOG group exhibited lower variance in nodal efficiency of independent components (IC) 7 (left precuneus). CONCLUSIONS: Our study suggested that aberrant coupling of precuneus-caudate and disrupted variability of precuneus efficiency might be associated to the neural mechanisms of FOG.

Levodopa responsive freezing of gait is associated with reduced norepinephrine transporter binding in Parkinson's disease.

BACKGROUND: Freezing of gait (FOG) is a major cause of falling in Parkinson's disease (PD) and can be responsive or unresponsive to levodopa. Pathophysiology is poorly understood. OBJECTIVE: To examine the link between noradrenergic systems, the development of FOG in PD and its responsiveness to levodopa. METHODS: We examined norepinephrine transporter (NET) binding via brain positron emission tomography (PET) to evaluate changes in NET density associated with FOG using the high affinity selective NET antagonist radioligand [11C]MeNER (2S,3S)(2-[α-(2-methoxyphenoxy)benzyl]morpholine) in 52 parkinsonian patients. We used a rigorous levodopa challenge paradigm to characterize PD patients as non-freezing (NO-FOG, N = 16), levodopa responsive freezing (OFF-FOG, N = 10), and levodopa-unresponsive freezing (ONOFF-FOG, N = 21), and also included a non-PD FOG group, primary progressive freezing of gait (PP-FOG, N = 5). RESULTS: Linear mixed models identified significant reductions in whole brain NET binding in the OFF-FOG group compared to the NO-FOG group (-16.8%, P = 0.021) and regionally in the frontal lobe, left and right thalamus, temporal lobe, and locus coeruleus, with the strongest effect in right thalamus (P = 0.038). Additional regions examined in a post hoc secondary analysis including the left and right amygdalae confirmed the contrast between OFF-FOG and NO-FOG (P = 0.003). A linear regression analysis identified an association between reduced NET binding in the right thalamus and more severe New FOG Questionnaire (N-FOG-Q) score only in the OFF-FOG group (P = 0.022). CONCLUSION: This is the first study to examine brain noradrenergic innervation using NET-PET in PD patients with and without FOG. Based on the normal regional distribution of noradrenergic innervation and pathological studies in the thalamus of PD patients, the implications of our findings suggest that noradrenergic limbic pathways may play a key role in OFF-FOG in PD. This finding could have implications for clinical subtyping of FOG as well as development of therapies.

Association of choroid plexus volume with motor symptoms and dopaminergic degeneration in Parkinson's disease.

BACKGROUND: The choroid plexus (CP) is involved in the clearance of harmful metabolites from the brain, as a part of the glymphatic system. This study aimed to investigate the association between CP volume (CPV), nigrostriatal dopaminergic degeneration and motor outcomes in Parkinson's disease (PD). METHODS: We retrospectively searched drug-naïve patients with early-stage PD who underwent dopamine transporter (DAT) scanning and MRI. Automatic CP segmentation was performed, and the CPV was calculated. The relationship between CPV, DAT availability and Unified PD Rating Scale Part III (UPDRS-III) scores was assessed using multivariate linear regression. We performed longitudinal analyses to assess motor outcomes according to CPV. RESULTS: CPV was negatively associated with DAT availability in each striatal subregion (anterior caudate, ß=-0.134, p=0.012; posterior caudate, ß=-0.162, p=0.002; anterior putamen, ß=-0.133, p=0.024; posterior putamen, ß=-0.125, p=0.039; ventral putamen, ß=-0.125, p=0.035), except for the ventral striatum. CPV was positively associated with the UPDRS-III score even after adjusting for DAT availability in the posterior putamen (ß=0.121; p=0.035). A larger CPV was associated with the future development of freezing of gait in the Cox regression model (HR 1.539, p=0.027) and a more rapid increase in dopaminergic medication in the linear mixed model (CPV×time, p=0.037), but was not associated with the risk of developing levodopa-induced dyskinesia or wearing off. CONCLUSION: These findings suggest that CPV has the potential to serve as a biomarker for baseline and longitudinal motor disabilities in PD.

Abnormal cerebellum connectivity patterns related to motor subtypes of Parkinson's disease.

Cerebellar dysfunction may substantially contribute to the clinical symptoms of Parkinson's disease (PD). The role of cerebellar subregions in tremors and gait disturbances in PD remains unknown. To investigate alterations in cerebellar subregion volumes and functional connectivity (FC), as well as FC between the dentate nucleus (DN) and ventral lateral posterior nucleus (VLp) of the thalamus, which are potentially involved in different PD motor subtypes. We conducted morphometric and resting-state functional connectivity analyses in various cerebellar subregions in 22 tremor-dominant (TD)-PD and 35 postural instability gait difficulty dominant (PIGD)-PD patients and 38 sex- and age-matched healthy controls (HCs). The volume and FC alterations in various cerebellar subregions and the neural correlates of these changes with the clinical severity scores were investigated. The PIGD-PD group showed greater FC between the right motor cerebellum (CBMm) and left postcentral gyrus than the HC group, and a higher FC was associated with less severe PIGD symptoms. In contrast, the TD-PD group had decreased FC between the right DN and left VLp compared with the PIGD-PD and HC groups, and lower FC was associated with worse TD symptoms. Furthermore, the PIGD-PD group had higher FC between the left DN and left inferior temporal gyrus than the TD-PD group. Morphometric analysis revealed that the TD-PD group showed a significantly higher volume of left CBMm than the HC group. Our findings point to differential alteration patterns in cerebellar subregions and offer a new perspective on the pathophysiology of motor subtypes of PD.

Comparative analysis of freezing of gait in distinct Parkinsonism types by diffusion tensor imaging method and cognitive profiles.

Freezing of gait (FOG) is an episodic gait pattern that is common in advanced Parkinson's disease (PD) and other atypical parkinsonism syndromes. Recently, disturbances in the pedunculopontine nucleus (PPN) and its connections have been suggested to play a critical role in the development of FOG. In this study, we aimed to demonstrate possible disturbances in PPN and its connections by performing the diffusion tensor imaging (DTI) technique. We included 18 patients of PD with FOG [PD-FOG], 13 patients of PD without FOG [PD-nFOG] and 12 healthy subjects as well as a group of patients with progressive supranuclear palsy (PSP), an atypical parkinsonism syndrome which is very often complicated with FOG [6 PSP-FOG, 5 PSP-nFOG]. To determine the specific cognitive parameters that can be related to FOG, deliberate neurophysiological evaluations of all the individuals were performed. The comparative analyses and correlation analyses were performed to reveal the neurophysiological and DTI correlates of FOG in either group. We have found disturbances in values reflecting microstructural integrity of the bilateral superior frontal gyrus (SFG), bilateral fastigial nucleus (FN), left pre-supplementary motor area (SMA) in the PD-FOG group relative to the PD-nFOG group. The analysis of the PSP group also demonstrated disturbance in left pre-SMA values in the PSP-FOG group likewise, while negative correlations were determined between right STN, left PPN values and FOG scores. In neurophysiological assessments, lower performances for visuospatial functions were demonstrated in FOG ( +) individuals for either patient group. The disturbances in the visuospatial abilities may be a critical step for the occurrence of FOG. Together with the results of DTI analyses, it might be suggested that impairment in the connectivity of disturbed frontal areas with disordered basal ganglia, maybe the key factor for the occurrence of FOG in the PD group, whereas left PPN which is a nondopaminergic nucleus may play a more prominent role in the process of FOG in PSP. Moreover, our results support the relationship between right STN, and FOG as mentioned before, as well as introduce the importance of FN as a new structure that may be involved in FOG pathogenesis.

α4ß2* Nicotinic Cholinergic Receptor Target Engagement in Parkinson Disease Gait-Balance Disorders.

OBJECTIVE: Attentional deficits following degeneration of brain cholinergic systems contribute to gait-balance deficits in Parkinson disease (PD). As a step toward assessing whether α4ß2* nicotinic acetylcholine receptor (nAChR) stimulation improves gait-balance function, we assessed target engagement of the α4ß2* nAChR partial agonist varenicline. METHODS: Nondemented PD participants with cholinergic deficits were identified with [18 F]fluoroethoxybenzovesamicol positron emission tomography (PET). α4ß2* nAChR occupancy after subacute oral varenicline treatment was measured with [18 F]flubatine PET. With a dose selected from the nAChR occupancy experiment, varenicline effects on gait, balance, and cognition were assessed in a double-masked placebo-controlled crossover study. Primary endpoints were normal pace gait speed and a measure of postural stability. RESULTS: Varenicline doses (0.25mg per day, 0.25mg twice daily [b.i.d.], 0.5mg b.i.d., and 1.0mg b.i.d.) produced 60 to 70% receptor occupancy. We selected 0.5mg orally b.i.d for the crossover study. Thirty-three participants completed the crossover study with excellent tolerability. Varenicline had no significant impact on the postural stability measure and caused slower normal pace gait speed. Varenicline narrowed the difference in normal pace gait speed between dual task and no dual task gait conditions, reduced dual task cost, and improved sustained attention test performance. We obtained identical conclusions in 28 participants with treatment compliance confirmed by plasma varenicline measurements. INTERPRETATION: Varenicline occupied α4ß2* nicotinic acetylcholine receptors, was tolerated well, enhanced attention, and altered gait performance. These results are consistent with target engagement. α4ß2* agonists may be worth further evaluation for mitigation of gait and balance disorders in PD. ANN NEUROL 2021;90:130-142.

Cholinergic brain network deficits associated with vestibular sensory conflict deficits in Parkinson's disease: correlation with postural and gait deficits.

To examine regional cerebral vesicular acetylcholine transporter (VAChT) ligand [18F]fluoroethoxybenzovesamicol ([18F]-FEOBV) PET binding in Parkinson' disease (PD) patients with and without vestibular sensory conflict deficits (VSCD). To examine associations between VSCD-associated cholinergic brain deficits and postural instability and gait difficulties (PIGD). PD persons (M70/F22; mean age 67.6 ± 7.4 years) completed clinical assessments for imbalance, falls, freezing of gait (FoG), modified Romberg sensory conflict testing, and underwent VAChT PET. Volumes of interest (VOI)-based analyses included detailed thalamic and cerebellar parcellations. VSCD-associated VAChT VOI selection used stepwise logistic regression analysis. Vesicular monoamine transporter type 2 (VMAT2) [11C]dihydrotetrabenazine (DTBZ) PET imaging was available in 54 patients. Analyses of covariance were performed to compare VSCD-associated cholinergic deficits between patients with and without PIGD motor features while accounting for confounders. PET sampling passed acceptance criteria in 73 patients. This data-driven analysis identified cholinergic deficits in five brain VOIs associating with the presence of VSCD: medial geniculate nucleus (MGN) (P < 0.0001), para-hippocampal gyrus (P = 0.0043), inferior nucleus of the pulvinar (P = 0.047), fusiform gyrus (P = 0.035) and the amygdala (P = 0.019). Composite VSCD-associated [18F]FEOBV-binding deficits in these 5 regions were significantly lower in patients with imbalance (- 8.3%, F = 6.5, P = 0.015; total model: F = 5.1, P = 0.0008), falls (- 6.9%, F = 4.9, P = 0.03; total model F = 4.7, P = 0.0015), and FoG (- 14.2%, F = 9.0, P = 0.0043; total model F = 5.8, P = 0.0003), independent of age, duration of disease, gender and nigrostriatal dopaminergic losses. Post hoc analysis using MGN VAChT binding as the single cholinergic VOI demonstrated similar significant associations with imbalance, falls and FoG. VSCD-associated cholinergic network changes localize to distinct structures involved in multi-sensory, in particular vestibular, and multimodal cognitive and motor integration brain regions. Relative clinical effects of VSCD-associated cholinergic network deficits were largest for FoG followed by postural imbalance and falls. The MGN was the most significant region identified.

Cerebral blood flow alterations specific to freezing of gait in Parkinson's disease.

BACKGROUND: Freezing of gait (FOG) have been associated with deficits in the cortico-basal ganglia-thalamic network. However, the resting-state cerebral blood flow (CBF) alterations specific to FOG in Parkinson's disease (PD) remain unknown. METHODS: In total, sixty PD individuals, including 30 PD with FOG (PD-FOG) and 30 PD without FOG (PD-NFOG), and 30 healthy controls (HC) underwent arterial spin labeling magnetic resonance image. The CBF were voxel-wise compared among the three groups and validated in a different cohort of PD-FOG and PD-NFOG. RESULTS: The results revealed that patients with PD-FOG had increased CBF in bilateral thalamus and the left caudate nucleus and decreased CBF in the left inferior parietal cortex compared to patients with PD-NFOG. The inter-group differences of CBF between PD-FOG and PD-NFOG was confirmed in a different cohort in the validation analysis. Moreover, the CBF in left caudate nucleus was positively correlated with severity of FOG in PD-FOG patients. CONCLUSIONS: Perfusion alterations in both cortical and subcortical regions in the cortico-basal ganglia-thalamic network are related to the development of FOG in PD patients.

Tractography patterns of pedunculopontine nucleus deep brain stimulation.

Deep brain stimulation of the pedunculopontine nucleus is a promising surgical procedure for the treatment of Parkinsonian gait and balance dysfunction. It has, however, produced mixed clinical results that are poorly understood. We used tractography with the aim to rationalise this heterogeneity. A cohort of eight patients with postural instability and gait disturbance (Parkinson's disease subtype) underwent pre-operative structural and diffusion MRI, then progressed to deep brain stimulation targeting the pedunculopontine nucleus. Pre-operative and follow-up assessments were carried out using the Gait and Falls Questionnaire, and Freezing of Gait Questionnaire. Probabilistic diffusion tensor tractography was carried out between the stimulating electrodes and both cortical and cerebellar regions of a priori interest. Cortical surface reconstructions were carried out to measure cortical thickness in relevant areas. Structural connectivity between stimulating electrode and precentral gyrus (r = 0.81, p = 0.01), Brodmann areas 1 (r = 0.78, p = 0.02) and 2 (r = 0.76, p = 0.03) were correlated with clinical improvement. A negative correlation was also observed for the superior cerebellar peduncle (r = -0.76, p = 0.03). Lower cortical thickness of the left parietal lobe and bilateral premotor cortices were associated with greater pre-operative severity of symptoms. Both motor and sensory structural connectivity of the stimulated surgical target characterises the clinical benefit, or lack thereof, from surgery. In what is a challenging region of brainstem to effectively target, these results provide insights into how this can be better achieved. The mechanisms of action are likely to have both motor and sensory components, commensurate with the probable nature of the underlying dysfunction.

Relating Response Inhibition, Brain Connectivity, and Freezing of Gait in People with Parkinson's Disease.

OBJECTIVE: Freezing of gait (FoG) in Parkinson's disease (PD) has been associated with response inhibition. However, the relationship between response inhibition, neural dysfunction, and PD remains unclear. We assessed response inhibition and microstructural integrity of brain regions involved in response inhibition [right hemisphere inferior frontal cortex (IFC), bilateral pre-supplementary motor areas (preSMA), and subthalamic nuclei (STN)] in PD subjects with and without FoG and elderly controls. METHOD: Twenty-one people with PD and FoG (PD-FoG), 18 without FoG (PD-noFoG), and 19 age-matched controls (HC) completed a Stop-Signal Task (SST) and MRI scan. Probabilistic fiber tractography assessed structural integrity (fractional anisotropy, FA) among IFC, preSMA, and STN regions. RESULTS: Stop-signal performance did not differ between PD and HC, nor between PD-FoG and PD-noFoG. Differences in white matter integrity were observed across groups (.001 < p < .064), but were restricted to PD versus HC groups; no differences in FA were observed between PD-FoG and PD-noFoG (p > .096). Interestingly, worse FoG was associated with higher (better) mean FA in the r-preSMA, (ß = .547, p = .015). Microstructural integrity of the r-IFC, r-preSMA, and r-STN tracts correlated with stop-signal performance in HC (p ≤ .019), but not people with PD. CONCLUSION: These results do not support inefficient response inhibition in PD-FoG. Those with PD exhibited white matter loss in the response inhibition network, but this was not associated with FoG, nor with response inhibition deficits, suggesting FoG-specific neural changes may occur outside the response inhibition network. As shown previously, white matter loss was associated with response inhibition in elderly controls, suggesting PD may disturb this relationship.

Freezing of gait: understanding the complexity of an enigmatic phenomenon.

Diverse but complementary methodologies are required to uncover the complex determinants and pathophysiology of freezing of gait. To develop future therapeutic avenues, we need a deeper understanding of the disseminated functional-anatomic network and its temporally associated dynamic processes. In this targeted review, we will summarize the latest advances across multiple methodological domains including clinical phenomenology, neurogenetics, multimodal neuroimaging, neurophysiology, and neuromodulation. We found that (i) locomotor network vulnerability is established by structural damage, e.g. from neurodegeneration possibly as result from genetic variability, or to variable degree from brain lesions. This leads to an enhanced network susceptibility, where (ii) modulators can both increase or decrease the threshold to express freezing of gait. Consequent to a threshold decrease, (iii) neuronal integration failure of a multilevel brain network will occur and affect one or numerous nodes and projections of the multilevel network. Finally, (iv) an ultimate pathway might encounter failure of effective motor output and give rise to freezing of gait as clinical endpoint. In conclusion, we derive key questions from this review that challenge this pathophysiological view. We suggest that future research on these questions should lead to improved pathophysiological insight and enhanced therapeutic strategies.

Functional MRI in Parkinson's disease with freezing of gait: a systematic review of the literature.

BACKGROUND: Freezing of gait (FOG), a common and disabling symptom of Parkinson's disease (PD), is characterized by an episodic inability to generate effective stepping. Functional MRI (fMRI) has been used to evaluate abnormal brain connectivity patterns at rest and brain activation patterns during specific tasks in patients with PD-FOG. This review has examined the existing functional neuroimaging literature in PD-FOG, including those with treatment. Summarizing these articles provides an opportunity for a better understanding of the underlying pathophysiology in PD-FOG. METHODS: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we performed a literature review of studies using fMRI to investigate the underlying pathophysiological mechanisms of PD-FOG. RESULTS: We initially identified 201 documents. After excluding the duplicates, reviews, and other irrelevant articles, 39 articles were finally identified, including 18 task-based fMRI studies and 21 resting-state fMRI studies. CONCLUSIONS: Studies using fMRI techniques to evaluate PD-FOG have found dysfunctional connectivity in widespread cortical and subcortical regions. Standardized imaging protocols and detailed subtypes of PD-FOG are furthered required to elucidate current findings.

Association between freezing of gait and bone mineral density in patients with Parkinson's disease.

Parkinson's disease (PD) patients are at risk for developing bone health problems, and freezing of gait (FOG) in PD is associated with a high risk of falling and fracture. This study aimed to determine the association between FOG and bone mineral density (BMD) in patients with PD. We included 148 PD patients. FOG was assessed using the FOG Questionnaire (FOG-Q), and BMD was measured by dual-energy X-ray absorptiometry. Of 148 PD patients, 102 (68.9%) had FOG. PD patients with FOG were older and had longer disease duration, higher levodopa equivalent dose, higher modified Hoehn and Yahr stage, higher Unified PD Rating Scale motor score, higher FOG-Q score, higher total Non-Motor Symptom Scale score, and lower BMD scores in the femoral neck area than those without FOG. Pearson correlation analysis revealed that age, sex, body mass index, and age at onset were significantly correlated with areal BMDs in all areas. FOG-Q scores correlated negatively with areal BMDs in the total hip area and femoral neck, but not with areal BMD in the lumbar spine. Multivariate regression analysis showed that FOG-Q score was significantly correlated with areal BMD in the femoral neck, but not with areal BMDs in the lumbar spine or total hip. FOG in PD patients correlates significantly with BMD in the femoral neck area. Therefore, PD patients with FOG should be screened for osteoporosis.

Quantitative Gait Impairments in Patients With Stroke or Transient Ischemic Attack: A Population-Based Approach.

BACKGROUND AND PURPOSE: Gait is a complex process involving various cortical and subcortical brain regions. An acute stroke or transient ischemic attack (TIA) may disrupt white and gray matter integrity and, therefore, affect gait in patients without evident neurological signs. We determined whether patients with stroke and TIA experience subtle changes in global gait and several independent gait domains. METHODS: In the population-based Rotterdam Study, 4456 participants (median age, 65 years; 55% women) underwent detailed quantitative gait assessment (GAITRite) between 2009 and 2016. We summarized 30 gait parameters into a global gait score and 7 mutually independent gait domains. First, we assessed the association between prior stroke or TIA and global and domain-specific gait using linear regression models adjusted for age, sex, vascular risk factors, and cognition. Subsequently, we repeated the analysis stratified by the presence of different neurological symptoms in a subgroup of participants with ischemic stroke after study entry. RESULTS: Compared with participants without prior stroke, patients with stroke had a worse global gait (SD, -0.49 [95% CI, -0.64 to -0.34]), especially in the gait domains Pace, Phases, and Turning. The detrimental effect of stroke on gait was amplified in participants with worse cognition. No gait differences were found between participants with and without prior TIA. Ischemic stroke patients without lower limb weakness, loss of coordination, or visuospatial problems still had a worse gait compared with participants without stroke. Stratification by different stroke symptoms showed that different gait domains were affected in each group. CONCLUSIONS: Prior stroke without neurological signs that affect gait is still associated with gait difficulties compared with individuals without stroke. Our study suggests that stroke not only has a direct impact on gait through neurological impairments but also includes an indirect effect possibly through disruption of gray and white matter integrity and accelerated neurodegeneration.

Cholinergic system changes of falls and freezing of gait in Parkinson's disease.

OBJECTIVE: Postural instability and gait difficulties (PIGDs) represent debilitating disturbances in Parkinson's disease (PD). Past acetylcholinesterase positron emission tomography (PET) imaging studies implicate cholinergic changes as significant contributors to PIGD features. These studies were limited in quantification of striatal cholinergic synapse integrity. Vesicular acetylcholine transporter (VAChT) PET ligands are better suited for evaluation of high binding areas. We examined associations between regional VAChT expression and freezing of gait (FoG) and falls. METHODS: Ninety-four PD subjects underwent clinical assessment and VAChT ([18 F]FEOBV) PET. RESULTS: Thirty-five subjects (37.2%) reported a history of falls, and 15 (16%) had observed FoG. Univariate volume-of-interest analyses demonstrated significantly reduced thalamic (p = 0.0016) VAChT expression in fallers compared to nonfallers. VAChT expression was significantly reduced in the striatum (p = 0.0012) and limbic archicortex (p = 0.004) in freezers compared to nonfreezers. Whole-brain voxel-based analyses of FEOBV PET complemented these findings and showed more granular changes associated with falling history, including the right visual thalamus (especially the right lateral geniculate nucleus [LGN]), right caudate nucleus, and bilateral prefrontal regions. Freezers had prominent VAChT expression reductions in the bilateral striatum, temporal, and mesiofrontal limbic regions. INTERPRETATION: Our findings confirm and extend on previous PET findings of thalamic cholinergic deficits associated with falling history and now emphasize right visual thalamus complex changes, including the right LGN. FoG status is associated with reduced VAChT expression in striatal cholinergic interneurons and the limbic archicortex. These observations suggest different cholinergic systems changes underlying falls and FoG in PD. Ann Neurol 2019;85:538-549.

Motor Cerebellar Connectivity and Future Development of Freezing of Gait in De Novo Parkinson's Disease.

OBJECTIVE: To investigate the role of motor cerebellar connectivity in future development of freezing of gait, because it is a complex network disorder in Parkinson's disease (PD). METHODS: We recruited 26 de novo patients with PD who experienced freezing of gait within 5 years from magnetic resonance imaging acquisition (vulnerable PD group), 61 patients with PD who had not experienced freezing of gait within 5 years (resistant PD group), and 27 healthy control subjects. We compared the resting state functional connectivity between the motor cerebellum and the whole brain between the groups. In addition, we evaluated the relationship between motor cerebellar connectivity and freezing of gait latency. RESULTS: The vulnerable PD group had increased functional connectivity between the motor cerebellum and parieto-occipito-temporal association cortices compared with the control group or the resistant PD group. Connectivity between lobule VI and the right superior parietal lobule, right fusiform gyrus, and left inferior temporal gyrus; between lobule VIIb and the right superior parietal lobule, right hippocampus, and right middle temporal gyrus; and between lobule VIIIb and the bilateral fusiform gyri, right middle occipital gyrus, and bilateral parietal lobes was inversely proportional to freezing of gait latency. The freezing of gait latency-related cortical functional connectivity from the motor cerebellum was also significantly higher in the vulnerable PD group compared with the control group, as well as the resistant PD group. CONCLUSIONS: The data suggest that the motor cerebellar functional connectivity with the posterior cortical areas play an important role in future development of freezing of gait in PD. © 2020 International Parkinson and Movement Disorder Society.

Pedunculopontine Nucleus Microstructure Predicts Postural and Gait Symptoms in Parkinson's Disease.

BACKGROUND: There is an urgent need to identify individuals at risk of postural instability and gait difficulties, and the resulting propensity for falls, in Parkinson's disease. OBJECTIVES: Given known relationships between posture and gait and degeneration of the cholinergic pedunculopontine nucleus, we investigated whether metrics of pedunculopontine nucleus microstructural integrity hold independent utility for predicting future postural instability and gait difficulties and whether they could be combined with other candidate biomarkers to improve prognostication of these symptoms. METHODS: We used stereotactic mapping of the pedunculopontine nucleus and diffusion tensor imaging to extract baseline pedunculopontine nucleus diffusivity metrics in 147 participants with Parkinson's disease and 65 controls enrolled in the Parkinson's Progression Markers Initiative. We also recorded known candidate markers of posture and gait changes: loss of caudate dopamine and CSF ß-amyloid 1-42 levels at baseline; as well as longitudinal progression motor symptoms over 72-months. RESULTS: Survival analyses revealed that reduced dopamine in the caudate and increased axial diffusivity in the pedunculopontine nucleus incurred independent risk of postural instability and gait difficulties. Binary logistic regression and receiver operating characteristics analysis in 117 participants with complete follow-up data at 60 months revealed that only pedunculopontine nucleus microstructure provided more accurate discriminative ability for predicting future postural instability and gait difficulties than clinical and demographic variables alone. CONCLUSION: Dopaminergic and cholinergic loss incur independent risk for future postural instability and gait difficulties, and pedunculopontine nucleus microstructure can be used to prognosticate these symptoms from early Parkinson's disease stages. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.