Abnormal functional connectivity density involvement in freezing of gait and its application for subtyping Parkinson's disease.

The pathophysiological mechanisms at work in Parkinson's disease (PD) patients with freezing of gait (FOG) remain poorly understood. Functional connectivity density (FCD) could provide an unbiased way to analyse connectivity across the brain. In this study, a total of 23 PD patients with FOG (PD FOG + patients), 26 PD patients without FOG (PD FOG- patients), and 22 healthy controls (HCs) were recruited, and their resting-state functional magnetic resonance imaging (rs-fMRI) images were collected. FCD mapping was first performed to identify differences between groups. Pearson correlation analysis was used to explore relationships between FCD values and the severity of FOG. Then, a machine learning model was employed to classify each pair of groups. PD FOG + patients showed significantly increased short-range FCD in the precuneus, cingulate gyrus, and fusiform gyrus and decreased long-range FCD in the frontal gyrus, temporal gyrus, and cingulate gyrus. Short-range FCD values in the middle temporal gyrus and inferior temporal gyrus were positively correlated with FOG questionnaire (FOGQ) scores, and long-range FCD values in the middle frontal gyrus were negatively correlated with FOGQ scores. Using FCD in abnormal regions as input, a support vector machine (SVM) classifier can achieve classification with good performance. The mean accuracy values were 0.895 (PD FOG + vs. HC), 0.966 (PD FOG- vs. HC), and 0.897 (PD FOG + vs. PD FOG-). This study demonstrates that PD FOG + patients showed altered short- and long-range FCD in several brain regions involved in action planning and control, motion processing, emotion, cognition, and object recognition.

Distinct hippocampal subfield atrophy in Parkinson's disease regarding motor subtypes.

INTRODUCTION: Global hippocampal atrophy has been repeatedly reported in patients with Parkinson's disease (PD). However, there is limited literature on the differential involvement of hippocampal subfields among PD motor subtypes. This study aimed to investigate hippocampal subfield alterations in patients with PD based on their predominant symptoms. METHOD: We enrolled 31 PD patients with the tremor-dominant (TD) subtype, 27 PD patients with postural instability and gait disturbance-dominant (PIGD) subtype, and 40 healthy controls (HCs). All participants underwent high-spatial-resolution T1-weighted magnetic resonance imaging. The volume of hippocampal subfields was measured using FreeSurfer software, compared across groups, and correlated with clinical features. RESULTS: We found volumetric reductions in the hippocampal subfield in both patient subtypes compared to HCs, which were more pronounced in the PIGD subtype. The PIGD subtype had accelerated age-related alterations in the hippocampus compared to the TD subtype. Bilateral hippocampal volumes were positively associated with cognitive performance levels, but not with disease severity and duration in patients. CONCLUSIONS: Alterations in the hippocampal subfields of patients with PD differed based on their predominant symptoms. These findings are of relevance for understanding the pathophysiology of the increased risk of cognitive impairment in PIGD.

Loss of zinc-finger protein 212 leads to Purkinje cell death and locomotive abnormalities with phospholipase D3 downregulation.

Although Krüppel-associated box domain-containing zinc-finger proteins (K-ZNFs) may be associated with sophisticated gene regulation in higher organisms, the physiological functions of most K-ZNFs remain unknown. The Zfp212 protein was highly conserved in mammals and abundant in the brain; it was mainly expressed in the cerebellum (Cb). Zfp212 (mouse homolog of human ZNF212) knockout (Zfp212-KO) mice showed a reduction in survival rate compared to wild-type mice after 20 months of age. GABAergic Purkinje cell degeneration in the Cb and aberrant locomotion were observed in adult Zfp212-KO mice. To identify genes related to the ataxia-like phenotype of Zfp212-KO mice, 39 ataxia-associated genes in the Cb were monitored. Substantial alterations in the expression of ataxin 10, protein phosphatase 2 regulatory subunit beta, protein kinase C gamma, and phospholipase D3 (Pld3) were observed. Among them, Pld3 alone was tightly regulated by Flag-tagged ZNF212 overexpression or Zfp212 knockdown in the HT22 cell line. The Cyclic Amplification and Selection of Targets assay identified the TATTTC sequence as a recognition motif of ZNF212, and these motifs occurred in both human and mouse PLD3 gene promoters. Adeno-associated virus-mediated introduction of human ZNF212 into the Cb of 3-week-old Zfp212-KO mice prevented Purkinje cell death and motor behavioral deficits. We confirmed the reduction of Zfp212 and Pld3 in the Cb of an alcohol-induced cerebellar degeneration mouse model, suggesting that the ZNF212-PLD3 relationship is important for Purkinje cell survival.

Postural and gait symptoms in de novo Parkinson's disease patients correlate with cholinergic white matter pathology.

INTRODUCTION: The postural instability gait difficulty motor subtype of patients with Parkinson's disease (PIGD-PD) has been associated with more severe cognitive pathology and a higher risk on dementia compared to the tremor-dominant subtype (TD-PD). Here, we investigated whether the microstructural integrity of the cholinergic projections from the nucleus basalis of Meynert (NBM) was different between these clinical subtypes. METHODS: Diffusion-weighted imaging data of 98 newly-diagnosed unmedicated PD patients (44 TD-PD and 54 PIGD-PD subjects) and 10 healthy controls, were analysed using diffusion tensor imaging, focusing on the white matter tracts associated with cholinergic projections from the NBM (NBM-WM) as the tract-of-interest. Quantitative tract-based and voxel-based analyses were performed using FA and MD as the estimates of white matter integrity. RESULTS: Voxel-based analyses indicated significantly lower FA in the frontal part of the medial and lateral NBM-WM tract of both hemispheres of PIGD-PD compared to TD-PD. Relative to healthy control, several clusters with significantly lower FA were observed in the frontolateral NBM-WM tract of both disease groups. Furthermore, significant correlations between the severity of the axial and gait impairment and NBM-WM FA and MD were found, which were partially mediated by NBM-WM state on subjects' attentional performance. CONCLUSIONS: The PIGD-PD subtype shows a loss of microstructural integrity of the NBM-WM tract, which suggests that a loss of cholinergic projections in this PD subtype already presents in de novo PD patients.

Skilled reach training enhances robotic gait training to restore overground locomotion following spinal cord injury in rats.

Rehabilitative training has been shown to improve motor function following spinal cord injury (SCI). Unfortunately, these gains are primarily task specific; where reach training only improves reaching, step training only improves stepping and stand training only improves standing. More troublesome is the tendency that the improvement in a trained task often comes at the expense of an untrained task. However, the task specificity of training does not preclude the benefits of combined rehabilitative training. Here we show that robot assisted gait training alone can partially reduce the deficits in unassisted overground locomotion following a C4/5 overhemisection injury in rats. When robot-assisted gait training is done in conjunction with skilled forelimb training, we observe a much greater level of recovery of unassisted overground locomotion. In order to provide reach training that would not interfere with our robotic gait training schedule, we prompted rats to increase the use of their forelimbs by replacing the standard overhead feeder with a custom made, deep welled hopper that dispensed nutritionally equivalent small milled pellets. We speculate that the increase in recovery from combined training is due to a more robust interneuronal relay network around the injury site. in vivo manganese-enhanced magnetic resonance imaging of the spinal cord indicated that there was no increase in the cellular activity, however ex vivo diffusion tensor imaging (DTI) suggested an increase in collateralization around the injury site in rats that received both reach training and robot assisted gait training.

Normal-sized basal ganglia perivascular space related to motor phenotype in Parkinson freezers.

Changes in basal ganglia (BG) perivascular spaces (PVSs) are related to motor and cognitive behaviors in Parkinson's disease (PD). However, the correlation between the initial motor phenotype and PVSs distribution/burden in PD freezing of gait (FOG) remains unclear. In addition, the normal-sized PVSs (nPVSs) have not been well-studied. With high-resolution 7T-MRI, we studied nPVSs burden in BG, thalamus, midbrain and centrum semiovale. The numbers and volume of nPVSs were assessed in 10 healthy controls, 10 PD patients without FOG, 20 with FOG [10 tremor dominant (TD), 10 non-TD subtype]. Correlation analyses were further performed in relation to clinical parameters. In this proof of concept study, we found that the nPVS burden of bilateral and right BG were significantly higher in freezers. A negative correlation existed between the tremor score and BG-nPVSs count. A positive correlation existed between the levodopa equivalent daily dose and BG-nPVSs count. The nPVS burden correlated with the progression to FOG in PD, but the distribution and burden of nPVS differ in TD vs. non-TD subtypes. High resolution 7T-MRI is a sensitive and reliable tool to evaluate BG-nPVS, and may be a useful imaging marker for predicting gait impairment that may evolve into FOG in PD.

Subcortical microstructural diffusion changes correlate with gait impairment in Parkinson's disease.

BACKGROUND: Gait impairments are common in Parkinson's Disease (PD) and are likely caused by degeneration in multiple brain circuits, including the basal ganglia, thalamus and mesencephalic locomotion centers (MLC). Diffusion tensor imaging (DTI) assesses fractional anisotropy (FA) and mean diffusivity (MD) that reflect the integrity of neuronal microstructure. We hypothesized that DTI changes in motor circuits correlate with gait changes in PD. OBJECTIVE: We aimed to identify microstructural changes of brain locomotion control centers in PD via DTI and their correlations with clinical and quantitative measures of gait. METHODS: Twenty-one PD patients reporting gait impairment and 15 controls were recruited. Quantitative gait and clinical tests were recorded in PD subjects' medication ON and OFF states. Region of Interest (ROI) analysis of the thalamus, basal ganglia and MLC was performed using ExploreDTI. Correlations between FA/MD with clinical gait parameters were examined. RESULTS: Microstructural changes were seen in the thalamus, caudate and MLC in the PD compared to the control group. Thalamic microstructural changes significantly correlated with gait parameters in the pace domain including the Timed Up and Go in the ON state. Caudate changes correlated with cadence and stride time in the OFF state. CONCLUSIONS: Our pilot study suggests that PD is associated with a characteristic regional pattern of microstructural degradation in the thalamus, caudate and MLC. The DTI changes may represent subcortical locomotion network failure. Overall, DTI ROI analyses might provide a useful tool for assessing PD for functional status and specific motor domains, such as gait, and potentially could serve as an imaging marker.

White matter hyperintensities mediate the impact of amyloid ß on future freezing of gait in Parkinson's disease.

BACKGROUND: Freezing of gait (FOG) is a common symptom in Parkinson's Disease (PD) patients. Previous studies have reported relationships between FOG, substantia nigra (SN) degeneration, dopamine transporter (DAT) concentration, as well as amyloid ß deposition. However, there is a paucity of research on the concurrent impact of white matter damage. OBJECTIVES: To assess the inter-relationships between these different co-morbidities, their impact on future FOG and whether they act independently of each other. METHODS: We used baseline MRI and longitudinal gait data from 423 de novo PD patients from the Parkinson's Progression Markers Initiative (PPMI). We used deformation based morphometry (DBM) from T1-weighted MRI to measure SN atrophy, and segmentation of white matter hyperintensities (WMH) as a measure of WM pathological load. Putamen and caudate DAT levels from SPECT as well as cerebrospinal fluid (CSF) amyloid ß were obtained directly from the PPMI. Following correlation analyses, we investigated whether WMH burden mediates the impact of amyloid ß on future FOG. RESULTS: SN DBM, WMH load, putamen and caudate DAT activity and CSF amyloid ß levels were significantly different between PD patients with and without future FOG (p < 0.008). Mediation analysis demonstrated an effect of CSF amyloid ß levels on future FOG via WMH load, independent of SN atrophy and striatal DAT activity levels. CONCLUSIONS: Amyloid ß might impact future FOG in PD patients through an increase in WMH burden, in a pathway independent of Lewy body pathology.

Differences in the association between white matter hyperintensities and gait performance among older adults with and without cognitive impairment.

AIM: Gait impairment implies subtle cognitive impairment (CI) and is associated with severity of white matter hyperintensities (WMHs). However, cognitive differences in such an association are not yet fully understood. This study examined the association between WMHs and gait performance among three cognitively different older groups. METHODS: Gait performance and WMHs were assessed in 150 community-dwelling older adults, comprising 53 with CI (Mini-Mental State Examination [MMSE] score <24), 63 with mild CI (MMSE score ≥24 and Montreal Cognitive Assessment [MoCA] score <25), and 34 who were cognitively normal or preserved (MMSE ≥24 and MoCA score ≥25). Gait velocity and variability were assessed on a 5-m electronic walkway. Furthermore, WMH volume was derived by automated segmentation using 1.5 T magnetic resonance imaging. RESULTS: Adjusted multiple regression analyses showed that greater WMHs were associated with slower gait velocity and greater temporal (stride time) and spatial (stride and step lengths) variabilities among older adults with CI. In contrast, WMH was only associated with spatial variability in older adults with mild CI and in cognitively normal or preserved older adults. CONCLUSIONS: Our findings suggest that gait variability measures are more sensitive to subtle underlying neurological pathologies including WMHs in older adults. The cognitive-dependent differences found in the association between WMHs and gait performance suggests that the level of cognitive function interferes with the association between WMH and gait performance. Geriatr Gerontol Int 2021; ••: ••-••.

Guidelines for Management of Idiopathic Normal Pressure Hydrocephalus (Third Edition): Endorsed by the Japanese Society of Normal Pressure Hydrocephalus.

Among the various disorders that manifest with gait disturbance, cognitive impairment, and urinary incontinence in the elderly population, idiopathic normal pressure hydrocephalus (iNPH) is becoming of great importance. The first edition of these guidelines for management of iNPH was published in 2004, and the second edition in 2012, to provide a series of timely, evidence-based recommendations related to iNPH. Since the last edition, clinical awareness of iNPH has risen dramatically, and clinical and basic research efforts on iNPH have increased significantly. This third edition of the guidelines was made to share these ideas with the international community and to promote international research on iNPH. The revision of the guidelines was undertaken by a multidisciplinary expert working group of the Japanese Society of Normal Pressure Hydrocephalus in conjunction with the Japanese Ministry of Health, Labour and Welfare research project. This revision proposes a new classification for NPH. The category of iNPH is clearly distinguished from NPH with congenital/developmental and acquired etiologies. Additionally, the essential role of disproportionately enlarged subarachnoid-space hydrocephalus (DESH) in the imaging diagnosis and decision for further management of iNPH is discussed in this edition. We created an algorithm for diagnosis and decision for shunt management. Diagnosis by biomarkers that distinguish prognosis has been also initiated. Therefore, diagnosis and treatment of iNPH have entered a new phase. We hope that this third edition of the guidelines will help patients, their families, and healthcare professionals involved in treating iNPH.

Gait parameters of Parkinson's disease compared with healthy controls: a systematic review and meta-analysis.

We systematically reviewed observational and clinical trials (baseline) studies examining differences in gait parameters between Parkinson's disease (PD) in on-medication state and healthy control. Four electronic databases were searched (November-2018 and updated in October-2020). Independent researchers identified studies that evaluated gait parameters measured quantitatively during self-selected walking speed. Risk of bias was assessed using an instrument proposed by Downs and Black (1998). Pooled effects were reported as standardized mean differences and 95% confidence intervals using a random-effects model. A total of 72 studies involving 3027 participants (1510 with PD and 1517 health control) met the inclusion criteria. The self-selected walking speed, stride length, swing time and hip excursion were reduced in people with PD compared with healthy control. Additionally, PD subjects presented higher cadence and double support time. Although with a smaller difference for treadmill, walking speed is reduced both on treadmill (.13 m s-1) and on overground (.17 m s-1) in PD. The self-select walking speed, stride length, cadence, double support, swing time and sagittal hip angle were altered in people with PD compared with healthy control. The precise determination of these modifications will be beneficial in determining which intervention elements are most critical in bringing about positive, clinically meaningful changes in individuals with PD (PROSPERO protocol CRD42018113042).

Genetic polymorphisms for BDNF, COMT, and APOE do not affect gait or ankle motor control in chronic stroke: A preliminary cross-sectional study.

Background: Motor deficits after stroke are a primary cause of long-term disability. The extent of functional recovery may be influenced by genetic polymorphisms. Objectives: Determine the effect of genetic polymorphisms for brain-derived neurotrophic factor (BDNF), catechol-O-methyltransferase (COMT), and apolipoprotein E (APOE) on walking speed, walking symmetry, and ankle motor control in individuals with chronic stroke. Methods: 38 participants with chronic stroke were compared based upon genetic polymorphisms for BDNF (presence [MET group] or absence [VAL group] of a Met allele), COMT (presence [MET group] or absence [VAL group] of a Met allele), and APOE (presence [ε4+ group] of absence [ε4- group] of ε4 allele). Comfortable and maximal walking speed were measured with the 10-m walk test. Gait spatiotemporal symmetry was measured with the GAITRite electronic mat; symmetry ratios were calculated for step length, step time, swing time, and stance time. Ankle motor control was measured as the accuracy of performing an ankle tracking task. Results: No significant differences were detected (p ≥ 0.11) between the BDNF, COMT, or APOE groups for any variables. Conclusions: In these preliminary findings, genetic polymorphisms for BDNF, COMT, and APOE do not appear to affect walking speed, walking symmetry, or ankle motor performance in chronic stroke.

Foot ulcer recurrence, plantar pressure and footwear adherence in people with diabetes and Charcot midfoot deformity: A cohort analysis.

AIMS: To investigate people with Charcot midfoot deformity with regard to plantar pressure, footwear adherence and plantar foot ulcer recurrence. METHODS: Twenty people with diabetes, Charcot midfoot deformity, plantar foot ulcer history and custom-made footwear were assessed with regard to barefoot and in-shoe plantar pressures during walking, footwear adherence (% of daily steps over 7-day period) and plantar foot ulcer recurrence over 18 months. In a cohort design, they were compared to 118 people without Charcot foot (non-Charcot foot group) with custom-made footwear and similar ulcer risk factors. RESULTS: Median (interquartile range) barefoot midfoot peak pressures were significantly higher in the Charcot foot group than in the non-Charcot foot group [756 (260-1267) vs 146 (100-208) kPa; P<0.001]. In-shoe midfoot peak pressures were not significantly higher in the Charcot foot group [median (interquartile range) 152 (104-201) vs 119 (94-160) kPa] and significantly lower for all other foot regions. Participants in the Charcot foot group were significantly more adherent, especially at home, than participants in the non-Charcot foot group [median (interquartile range) 94.4 (85.4-95.0)% vs. 64.3 (25.4-85.7)%; P=0.001]. Ulcers recurred in 40% of the Charcot foot group and in 47% of the non-Charcot foot group (P=0.63); midfoot ulcers recurred significantly more in the Charcot foot group (4/8) than in the non-Charcot foot group (1/55; P=0.001). CONCLUSIONS: Effective offloading and very high footwear adherence were found in people with diabetes and Charcot midfoot deformity. While this may help protect against plantar foot ulcer recurrence, a large proportion of such people still experience ulcer recurrence. Further improvements in adherence and custom-made footwear design may be required to improve clinical outcome.

Sensorimotor conflict tests in an immersive virtual environment reveal subclinical impairments in mild traumatic brain injury.

Current clinical tests lack the sensitivity needed for detecting subtle balance impairments associated with mild traumatic brain injury (mTBI). Patient-reported symptoms can be significant and have a huge impact on daily life, but impairments may remain undetected or poorly quantified using clinical measures. Our central hypothesis was that provocative sensorimotor perturbations, delivered in a highly instrumented, immersive virtual environment, would challenge sensory subsystems recruited for balance through conflicting multi-sensory evidence, and therefore reveal that not all subsystems are performing optimally. The results show that, as compared to standard clinical tests, the provocative perturbations illuminate balance impairments in subjects who have had mild traumatic brain injuries. Perturbations delivered while subjects were walking provided greater discriminability (average accuracy ≈ 0.90) than those delivered during standing (average accuracy ≈ 0.65) between mTBI subjects and healthy controls. Of the categories of features extracted to characterize balance, the lower limb accelerometry-based metrics proved to be most informative. Further, in response to perturbations, subjects with an mTBI utilized hip strategies more than ankle strategies to prevent loss of balance and also showed less variability in gait patterns. We have shown that sensorimotor conflicts illuminate otherwise-hidden balance impairments, which can be used to increase the sensitivity of current clinical procedures. This augmentation is vital in order to robustly detect the presence of balance impairments after mTBI and potentially define a phenotype of balance dysfunction that enhances risk of injury.

Neuronal mitochondrial calcium uniporter deficiency exacerbates axonal injury and suppresses remyelination in mice subjected to experimental autoimmune encephalomyelitis.

High-capacity mitochondrial calcium (Ca2+) uptake by the mitochondrial Ca2+ uniporter (MCU) is strategically positioned to support the survival and remyelination of axons in multiple sclerosis (MS) by undocking mitochondria, buffering Ca2+ and elevating adenosine triphosphate (ATP) synthesis at metabolically stressed sites. Respiratory chain deficits in MS are proposed to metabolically compromise axon survival and remyelination by suppressing MCU activity. In support of this hypothesis, clinical scores, mitochondrial dysfunction, myelin loss, axon damage and inflammation were elevated while remyelination was blocked in neuronal MCU deficient (Thy1-MCU Def) mice relative to Thy1 controls subjected to experimental autoimmune encephalomyelitis (EAE). At the first sign of walking deficits, mitochondria in EAE/Thy1 axons showed signs of activation. By contrast, cytoskeletal damage, fragmented mitochondria and large autophagosomes were seen in EAE/Thy1-MCU Def axons. As EAE severity increased, EAE/Thy1 axons were filled with massively swollen mitochondria with damaged cristae while EAE/Thy1-MCU Def axons were riddled with late autophagosomes. ATP concentrations and mitochondrial gene expression were suppressed while calpain activity, autophagy-related gene mRNA levels and autophagosome marker (LC3) co-localization in Thy1-expressing neurons were elevated in the spinal cords of EAE/Thy1-MCU Def compared to EAE/Thy1 mice. These findings suggest that MCU inhibition contributes to axonal damage that drives MS progression.

Dopaminergic loss of cyclin-dependent kinase-like 5 recapitulates methylphenidate-remediable hyperlocomotion in mouse model of CDKL5 deficiency disorder.

Cyclin-dependent kinase-like 5 (CDKL5), a serine-threonine kinase encoded by an X-linked gene, is highly expressed in the mammalian forebrain. Mutations in this gene cause CDKL5 deficiency disorder, a neurodevelopmental encephalopathy characterized by early-onset seizures, motor dysfunction, and intellectual disability. We previously found that mice lacking CDKL5 exhibit hyperlocomotion and increased impulsivity, resembling the core symptoms in attention-deficit hyperactivity disorder (ADHD). Here, we report the potential neural mechanisms and treatment for hyperlocomotion induced by CDKL5 deficiency. Our results showed that loss of CDKL5 decreases the proportion of phosphorylated dopamine transporter (DAT) in the rostral striatum, leading to increased levels of extracellular dopamine and hyperlocomotion. Administration of methylphenidate (MPH), a DAT inhibitor clinically effective to improve symptoms in ADHD, significantly alleviated the hyperlocomotion phenotype in Cdkl5 null mice. In addition, the improved behavioral effects of MPH were accompanied by a region-specific restoration of phosphorylated dopamine- and cAMP-regulated phosphoprotein Mr 32 kDa, a key signaling protein for striatal motor output. Finally, mice carrying a Cdkl5 deletion selectively in DAT-expressing dopaminergic neurons, but not dopamine receptive neurons, recapitulated the hyperlocomotion phenotype found in Cdkl5 null mice. Our findings suggest that CDKL5 is essential to control locomotor behavior by regulating region-specific dopamine content and phosphorylation of dopamine signaling proteins in the striatum. The direct, as well as indirect, target proteins regulated by CDKL5 may play a key role in movement control and the therapeutic development for hyperactivity disorders.

A multimodal approach to identify clinically relevant biomarkers to comprehensively monitor disease progression in a mouse model of pediatric neurodegenerative disease.

While research has accelerated the development of new treatments for pediatric neurodegenerative disorders, the ability to demonstrate the long-term efficacy of these therapies has been hindered by the lack of convincing, noninvasive methods for tracking disease progression both in animal models and in human clinical trials. Here, we unveil a new translational platform for tracking disease progression in an animal model of a pediatric neurodegenerative disorder, CLN6-Batten disease. Instead of looking at a handful of parameters or a single "needle in a haystack", we embrace the idea that disease progression, in mice and patients alike, is a diverse phenomenon best characterized by a combination of relevant biomarkers. Thus, we employed a multi-modal quantitative approach where 144 parameters were longitudinally monitored to allow for individual variability. We use a range of noninvasive neuroimaging modalities and kinematic gait analysis, all methods that parallel those commonly used in the clinic, followed by a powerful statistical platform to identify key progressive anatomical and metabolic changes that correlate strongly with the progression of pathological and behavioral deficits. This innovative, highly sensitive platform can be used as a powerful tool for preclinical studies on neurodegenerative diseases, and provides proof-of-principle for use as a potentially translatable tool for clinicians in the future.

Strategic Timing of Glial HMOX1 Expression Results in Either Schizophrenia-Like or Parkinsonian Behavior in Mice.

Aims: In this original research communication, we assess the impact of shifting the window of glial HMOX1 overexpression in mice from early-to-midlife to mid-to-late life, resulting in two disparate conditions modeling schizophrenia (SCZ) and Parkinson's disease (PD). Mesolimbic hyperdopaminergia is a widely accepted feature of SCZ, while nigrostriatal hypodopaminergia is the sine qua non of idiopathic PD. Although the advent of parkinsonian features in SCZ patients after treatment with antidopaminergic agents is intuitive, subtle features of parkinsonism commonly observed in young, drug-naïve schizophrenics are not. Similarly, emergent psychosis in PD subjects receiving levodopa replacement is not unusual, whereas spontaneous hallucinosis in nonmedicated persons with idiopathic PD is enigmatic. Investigations using GFAP.HMOX1 mice may shed light on these clinical paradoxes. Results: Astroglial heme oxygenase-1 (HO-1) overexpression in mice throughout embryogenesis until 6 or 12 months of age resulted in hyperdopaminergia, hyperkinesia/stereotypy ameliorated with clozapine, deficient prepulse inhibition of the acoustic startle response, reduced preference for social novelty, impaired nest building, and cognitive dysfunction reminiscent of SCZ. On the contrary, astroglial HO-1 overexpression between 8.5 and 19 months of age yielded a PD-like behavioral phenotype with hypodopaminergia, altered gait, locomotor incoordination, and reduced olfaction. Innovation: We conjecture that region-specific disparities in the susceptibility of dopaminergic and other circuitry to the trophic and degenerative influences of glial HMOX1 induction may permit the concomitant expression of mixed SCZ and PD traits within affected individuals. Conclusion: Elucidation of these converging mechanisms may (i) help better understand disease pathogenesis and (ii) identify HO-1 as a potential therapeutic target in neurodevelopmental and neurodegenerative disorders.

Clinical and Diffusion Tensor Imaging to Evaluate Falls, Balance and Gait Dysfunction in Leukoaraiosis: an Observational, Prospective Cohort Study.

OBJECTIVE: To assess the correlation between leukoaraiosis (LA) and falls, to determine the risk factors for falls in patients with LA, and to detect specific white matter tracts are associated with the falls by using the diffusion tensor magnetic resonance imaging (DTI) screen. METHODS: For the elderly patients with LA, we collected demographic information and scores for the Tinetti Balance and Gait Scale, Berg Balance Scale, Timed up-and-go test, and Cognitive, Emotional, Sleep-related Scale. All the patients underwent DTI scanning and were followed up for 1 year. RESULTS: Ninety-four individuals were prospectively enrolled. After multivariable analyses, age, history of falls in the past year, antidepressants usage, and LA-Fazekas grade were reported to be risk factors for falls. In patients with severe LA, the fall incidence was higher than in those with mild LA. Tract-Based Spatial Statistics showed that fractional anisotropy values of the corpus callosum, cingulate gyrus, anterior limb of internal capsule, cerebral peduncle, anterior corona, and fronto-occipital fasciculus were significantly reduced in the patients who fell. The body of the corpus callosum and anterior corona radiate were significantly related to balance and gait function. CONCLUSIONS: Our findings indicated that age, history of falls in the past year, antidepressants usage, and LA-Fazekas grade were risk factors for falls in elderly patients with LA. Leukoaraiosis was relevant for falls, but LA severity had a threshold effect with falls. The loss of integrity of some white matter tracts might influence balance and gait function. The DTI had preeminent clinical application prospects for identifying fall risk in patients with LA.