Sex and freezing of gait in Parkinson’s disease: a systematic review and meta-analysis

Journal of Neurology - It is unknown how sex affects the prevalence of freezing of gait (FOG). We conducted a systematic review and meta-analysis to establish the sex-specific prevalence of FOG in...     

High-level gait and balance disorders in the elderly: a midbrain disease?

The pathophysiology of gait and balance disorders in elderly people with ‘higher level gait disorders’ (HLGD) is poorly understood. In this study, we aimed to identify the brain networks involved in this disorder. Standardised clinical scores, biomechanical parameters of gait initiation and brain imaging data, including deep white matter lesions (DWML) and brain voxel-based morphometry analyses, were assessed in 20 HLGD patients in comparison to 20 age-matched controls. In comparison to controls, HLGD patients presented a near-normal preparatory phase of gait initiation, but a severe alteration of both locomotor and postural parameters of first-step execution, which was related to ‘axial’ hypokinetic-rigid signs. HLGD patients showed a significant grey matter reduction in the mesencephalic locomotor region (MLR) and the left primary motor cortex. This midbrain atrophy was related to the severity of clinical and neurophysiologically determined balance deficits. HLGD patients also showed a reduction in speed of gait, related to ‘appendicular’ hypokinetic-rigid signs and frontal-lobe-like cognitive deficits. These last two symptoms were correlated with the severity of DWML, found in 12/20 HLGD patients. In conclusion, these data suggest that the gait and balance deficits in HLGD mainly result from the lesion or dysfunction of the network linking the primary motor cortex and the MLR, brain regions known to be involved in the control of gait and balance, whereas cognitive and ‘appendicular’ hypokinetic-rigid signs mainly result from DWML that could be responsible for a dysfunction of the frontal cortico-basal ganglia loops.     

Interventions to improve gait in Parkinson’s disease: a systematic review of randomized controlled trials and network meta-analysis

Journal of Neurology - Disabling gait symptoms, especially freezing of gait (FoG), represents a milestone in the progression of Parkinson’s disease (PD). This systematic review and network...     

Reduced StartReact effect and freezing of gait in Parkinson’s disease: two of a kind?

Freezing of gait (FOG) is a disabling feature of Parkinson’s disease. Emerging evidence suggests that dysfunction of the pedunculopontine nucleus (PPN) and pontomedullary reticular formation (pmRF) plays a role in the causation of FOG. These brainstem structures can be examined by the StartReact paradigm, which utilizes a startling stimulus to accelerate reaction times (StartReact). Here, we examined gait initiation in PD patients with and without FOG using this paradigm. Twenty-six patients with Parkinson’s disease (12 freezers and 14 non-freezers) and 15 controls performed two tasks: rapid gait initiation in response to an imperative ‘go’ signal; and a control condition, involving a simple reaction-time task involving ankle dorsiflexion. During both tasks, a startling acoustic stimulus was combined with the imperative signal in 25 % of trials. In controls, the startle accelerated gait initiation and shortened the onset latency of tibialis anterior responses during ankle dorsiflexion. This acceleration was intact in non-freezers, but was significantly attenuated in the freezers. Independent of the occurrence of a startle, freezers showed a reduced length of the first step compared to non-freezers and controls. The diminished StartReact effect in freezers probably reflects deficient representation or release of motor programs at the brainstem reticular level due to dysfunction of the PPN, the pmRF, or both. These brainstem structures are presumably involved in integrating anticipatory postural adjustments with subsequent stepping movements. We suggest that with time-varying demands, these structures may no longer be able to coordinate the integration of anticipatory postural adjustments with steps, leading to FOG episodes.     

Brain network topology and future development of freezing of gait in Parkinson’s disease: a longitudinal study

Journal of Neurology - Freezing of gait (FOG) is a common disabling gait disturbance in Parkinson’s disease (PD). The objectives of this study were to explore alterations in the topological...     

Does a volume reduction of the parietal lobe contribute to freezing of gait in Parkinson's disease?

BackgroundFreezing of gait (FOG) is as a brief, episodic absence or marked reduction of forward progression of the feet despite the intention to walk. Structural neuroimaging studies on FOG in PD using volumetric techniques yielded variable and partially conflicting findings, probably reflecting the heterogeneity and complexity of the phenomenon. The aim of this study was to further explore the differences in local gray matter (GM) volume in patients with PD with and without FOG by using Voxel-Based Morphometry (VBM).Materials and methodsWe enrolled 26 patients (7 women and 19 men) with a diagnosis of PD in stable treatment with dopaminergic therapy. Thirteen patients classified as FOG+ were matched with thirteen nonfreezer (FOG−) PD patients. All 26 participants underwent a detailed neuropsychological assessment as well as a VBM analysis derived from T1 weighted 3T MRI.ResultsThe patient groups did not significantly differ for age, disease duration, H&Y stage, UPDRS part-III or educational attainment. No significant differences of cognitive profile emerged. PD-FOG+ patients showed a pattern of relative GM atrophy in left posterior parietal gyrus compared with PD-FOG−.DiscussionOur results suggest that a specific pattern of cortical volume reduction involving posterior parietal cortex contributes to the occurrence of FOG in PD. These data agree with the growing body of evidence considering the parietal posterior cortex as an associative area involved in spatial control of motor behavior, partaking in response selection to sensory evaluation.     

Mild cognitive impairment in Parkinson’s disease: Diagnosis and progression to dementia

Introduction: Mild cognitive impairment is common in nondemented Parkinson disease patients (PD-MCI) and is considered as a risk factor for dementia (PDD). Recently, the Movement Disorder Society (MDS) published guidelines for PD-MCI, although the studies available are still limited. The aim of this work was to characterize PD-MCI and its progression to dementia. Moreover, the study variables could be considered as predictors for the progression of cognitive impairment. Method: The study included 43 patients with idiopathic PD (mean age = 59.19 years, SD = 9.64) and 20 healthy and neurologically normal controls (mean age = 60.85 years, SD = 12.26). The criteria proposed by the MDS Task Force were applied for the PD-MCI diagnosis. Follow-up assessments were conducted within six to eight years after the diagnosis of PD-MCI. Results: The results showed that 60.5% of the patients were diagnosed with PD-MCI when a comprehensive assessment was performed (MDS criteria Level 2), while 23.3% of the patients met MCI criteria when a brief assessment was used (MDS criteria Level 1). Multiple domain impairment was the most frequent impairment (96.2%). A total of 42.3% of PD-MCI patients had dementia in the follow-up study. Logistic regression showed that the Hoehn and Yahr stage and education significantly contributed to the prediction of PD-MCI. Moreover, the Hoehn and Yahr stage and memory domain significantly contributed to the prediction of dementia. Conclusions: The results of the study: (a) provide relevant data about the process of validation of the MDS PD-MCI criteria, (b) reinforce the hypothesis that PD-MCI is more frequent than previous studies showed without applying MDS criteria, and (c) confirm that PD-MCI is a risk factor for the onset of dementia. Finally, the study shows that neurological impairment, educational level and memory impairment were predictors for the progression of cognitive impairment.     

A decade of pre-diagnostic assessment in a case of familial Alzheimer’s disease: tracking progression from asymptomatic to MCI and dementia

Detailed study of the very earliest phases of Alzheimer’s disease (AD) is seldom possible, especially those changes preceding the development of mild cognitive impairment (MCI), which may occur years before diagnosis. Knowledge of imaging and neuropsychological features of these early stages would add insight into this poorly understood phase of the disease. We present data from a subject who entered a longitudinal study of individuals at risk of familial Alzheimer’s disease (FAD), as a healthy volunteer with no memory complaints, undergoing 12 assessments between 1992 and 2003. Longitudinal MRI, neuropsychological and clinical data are presented over the decade preceding this man’s diagnosis, through the asymptomatic and prodromal preludes to his presentation with MCI and on to eventual conversion to AD.     

SPECT and PET analysis of subthalamic stimulation in Parkinson’s disease: analysis using a manual segmentation

The subthalamic nucleus (STN) has become an effective target of deep-brain stimulation (DBS) in severely disabled patients with advanced Parkinson’s disease (PD). Clinical studies have reported DBS-induced adverse effects on cognitive functions, mood, emotion and behavior. STN DBS seems to interfere with the limbic functions of the basal ganglia, but the limbic effects of STN DBS are controversial. We measured prospectively resting regional cerebral metabolism (rCMb) with 18-fluorodeoxyglucose and PET, and resting regional cerebral blood flow (rCBF) with HMPAO and SPECT in six patients with Parkinson’s disease. We compared PET and SPECT 1 month before and 3 months after STN DBS. On cerebral MRI, 13 regions of interest (ROI) were manually delineated slice by slice in frontal and limbic lobes. We obtained mean rCBF and rCMb values for each ROI and the whole brain. We normalized rCBF and rCMB values to ones for the whole brain volume, which we compared before and following STN DBS. No significant difference emerged in the SPECT analysis. PET analysis revealed a significant decrease in rCMb following STN DBS in the superior frontal gyri and left and right dorsolateral prefrontal cortex (p < 0.05). A non-significant decrease in rCMb in the left anterior cingulate gyrus appeared following STN DBS (p = 0.075). Our prospective SPECT and PET study revealed significantly decreased glucose metabolism of the two superior frontal gyri without any attendant perfusion changes following STN DBS. These results suggest that STN DBS may change medial prefrontal function and therefore the integration of limbic information, either by disrupting emotional processes within the STN, or by hampering the normal function of a limbic circuit.     

Cognitive aspects of freezing of gait in Parkinson’s disease: a challenge for rehabilitation

Freezing of gait (FOG) is a very disabling symptom affecting up to half of the patients with Parkinson’s disease (PD). Evidence is accumulating that FOG is caused by a complex interplay between motor, cognitive and affective factors, rather than being a pure motor phenomenon. In the current paper, we review the evidence on the specific role of cognitive factors in FOG. Results from behavioral studies show that patients with FOG experience impairments in executive functioning and response selection which predict that motor learning may be compromised. Brain imaging studies strengthen the neural basis of a potential association between FOG and cognitive impairment, but do not clarify whether it is a primary or secondary determinant of FOG. A FOG-related reduction of cognitive resources implies that adaptation of rehabilitation interventions is indicated for patients with FOG to promote the consolidation of learning.     

Freezing of gait and fall detection in Parkinson’s disease using wearable sensors: a systematic review

Despite the large number of studies that have investigated the use of wearable sensors to detect gait disturbances such as Freezing of gait (FOG) and falls, there is little consensus regarding appropriate methodologies for how to optimally apply such devices. Here, an overview of the use of wearable systems to assess FOG and falls in Parkinson’s disease (PD) and validation performance is presented. A systematic search in the PubMed and Web of Science databases was performed using a group of concept key words. The final search was performed in January 2017, and articles were selected based upon a set of eligibility criteria. In total, 27 articles were selected. Of those, 23 related to FOG and 4 to falls. FOG studies were performed in either laboratory or home settings, with sample sizes ranging from 1 PD up to 48 PD presenting Hoehn and Yahr stage from 2 to 4. The shin was the most common sensor location and accelerometer was the most frequently used sensor type. Validity measures ranged from 73–100% for sensitivity and 67–100% for specificity. Falls and fall risk studies were all home-based, including samples sizes of 1 PD up to 107 PD, mostly using one sensor containing accelerometers, worn at various body locations. Despite the promising validation initiatives reported in these studies, they were all performed in relatively small sample sizes, and there was a significant variability in outcomes measured and results reported. Given these limitations, the validation of sensor-derived assessments of PD features would benefit from more focused research efforts, increased collaboration among researchers, aligning data collection protocols, and sharing data sets.     

Freezing of gait in Parkinson’s disease: gray and white matter abnormalities

Freezing of gait (FOG) is a disabling disorder that often affects Parkinson’s disease (PD) patients in advanced stages of the disease. To study structural gray matter (GM) and white matter (WM) changes in PD patients with and without FOG, twenty-one PD patients with FOG (PD-FOG), 16 PD patients without FOG (PD-nFOG) and 19 healthy subjects (HS) underwent a standardized MRI protocol. For the gray matter evaluation, cortical volume (CV), cortical thickness (CTh), and surface area (SA) were analyzed using the FreeSurfer pipeline. For the white matter evaluation, DTI images were analyzed using tracts constrained by underlying anatomy (TRACULA) toolbox in FreeSurfer. PD-FOG patients exhibited lower CTh than HS in the mesial surface of both cerebral hemispheres, including the superior frontal gyrus, paracentral lobule, posterior cingulate cortex, precuneus and pericalcarine cortex, and in the right dorsolateral prefrontal cortex. Moreover, significant WM changes were observed in PD-FOG patients in comparison with HS in the superior longitudinal fasciculus, uncinate fasciculus, cingulum cingulate gyrus and inferior longitudinal fasciculus (prevalently in the right hemisphere) and in the frontal radiations of the corpus callosum. DTI abnormalities in specific WM bundles correlated significantly with cognitive measures. The damage of multiple cortical areas involved in high-level gait control together with WM disruption between motor, cognitive and limbic structures may represent the anatomical correlate of FOG.     

Three-dimensional motion analysis of the effects of auditory cueing on gait pattern in patients with Parkinson’s disease: a preliminary investigation

Auditory cueing enhances gait in parkinsonian patients. Our aim was to evaluate its effects on spatiotemporal (stride length, stride time, cadence, gait speed, single and double support duration) kinematic (range of amplitude of the hip, knee and ankle joint angles registered in the sagittal plane) and kinetic (maximal values of the hip and ankle joint power) gait parameters using three-dimensional motion analysis. Eight parkinsonian patients performed 12 walking tests: 3 repetitions of 4 conditions (normal walking, 90, 100, and 110% of the mean cadence at preferred pace cued walking). Subjects were asked to uniform their cadence to the cueing rhythm. In the presence of auditory cues stride length, cadence, gait speed and ratio single/double support duration increased. Range of motion of the ankle joint decreased and the maximal values within the pull-off phase of the hip joint power increased. Thus, auditory cues could improve gait modifying motor strategy in parkinsonian patients.     

Cognitive correlates of cortical cholinergic denervation in Parkinson’s disease and parkinsonian dementia

We recently reported findings that loss of cortical acetylcholinesterase (AChE) activity is greater in parkinsonian dementia than in Alzheimer’s disease (AD). In this study we determined cognitive correlates of in vivo cortical AChE activity in patients with parkinsonian dementia (PDem, n = 11), Parkinson’s disease without dementia (PD, n = 13), and in normal controls (NC, n = 14) using N–[¹¹C]methyl–piperidin–4–yl propionate ([¹¹C]PMP) AChE positron emission tomography (PET). Cortical AChE activity was significantly reduced in the PDem (–20.9%) and PD (–12.7 %) subjects (P < 0.001) when compared with the control subjects. Analysis of the cognitive data within the patient groups demonstrated that scores on the WAIS-III Digit Span, a test of working memory and attention, had most robust correlation with cortical AChE activity (R = 0.61, p < 0.005). There were also significant correlations between cortical AChE activity and other tests of attentional and executive functions, such as the Trail Making and Stroop Color Word tests. There was no significant correlation between cortical AChE activity and duration of motor disease (R = –0.01, ns) or severity of parkinsonian motor symptoms (R = 0.14, ns). We conclude that cortical cholinergic denervation in PD and parkinsonian dementia is associated with decreased performance on tests of attentional and executive functioning. Supported by grants from the Department of Veterans Affairs, National Institute of Aging (Alzheimer Disease Research Center, AG05133), and The Scaife Family Foundation, Pittsburgh, PA, USA.