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.

Deficiency of Autism-Related Gene Dock4 Leads to Impaired Spatial Memory and Hippocampal Function in Mice at Late Middle Age.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that lasts lifelong and causes noticeably higher premature mortality. Although the core symptoms and other behavioral deficits of ASD can persist or be deteriorated from early development to old age, how aging affects the behaviors and brain anatomy in ASD is largely unknown. DOCK4 is an ASD risk gene highly expressed in the hippocampus, and Dock4 knockout (KO) mice display ASD-like behaviors in adulthood (4- to 6-month-old). In this study, we evaluated the behavioral and hippocampal pathological changes of late-middle-aged (15- to 17-month-old) Dock4 male KO mice. Aged Dock4 KO mice continuously showed similar social deficit, elevated anxiety, and disrupted object location memory as observed in the adulthood, when compared to their wild-type (WT) littermates. Notably, Dock4 KO mice displayed an age-related decline of hippocampal dependent spatial memory, showing decreased spatial memory in Barnes maze than their WT littermates at late middle age. Morphological analysis from WT and Dock4 KO littermates revealed that Dock4 deficiency led to decreased mature neurons and oligodendrocytes but increased astrocytes in the hippocampus of late-middle-aged mice. Together, we report that ASD-like behaviors mostly persist into late-middle age in Dock4 KO mice, with specific alterations of spatial memory and hippocampal anatomy by age, thus providing new evidence for understanding age differences in behavioral deficits of ASD.

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.

Locomotor deficits induced by lumbar muscle inflammation involve spinal microglia and are independent of KCC2 expression in a mouse model of complete spinal transection.

Spinal cord injury (SCI) is associated with damage to musculoskeletal tissues of the spine. Recent findings show that pain and inflammatory processes caused by musculoskeletal injury mediate plastic changes in the spinal cord. These changes could impede the adaptive plastic changes responsible for functional recovery. The underlying mechanism remains unclear, but may involve the microglia-BDNF-KCC2 pathway, which is implicated in sensitization of dorsal horn neurons in neuropathic pain and in the regulation of spinal excitability by step-training. In the present study, we examined the effects of step-training and lumbar muscle inflammation induced by complete Freund's adjuvant (CFA) on treadmill locomotion in a mouse model of complete spinal transection. The impact on locomotor recovery of each of these interventions alone or in combination were examined in addition to changes in microglia and KCC2 expression in the dorsal and ventral horns of the sublesional spinal cord. Results show that angular motion at the hip, knee and ankle joint during locomotion were decreased by CFA injection and improved by step-training. Moreover, CFA injection enhanced the expression of the microglial marker Iba1 in both ventral and dorsal horns, with or without step-training. However, this change was not associated with a modulation of KCC2 expression, suggesting that locomotor deficits induced by inflammation are independent of KCC2 expression in the sublesional spinal cord. These results indicate that musculoskeletal injury hinders locomotor recovery after SCI and that microglia is involved in this effect.

Is Cortical Activation During Walking Different Between Parkinson's Disease Motor Subtypes?

Parkinson's disease (PD) is often classified into tremor dominant (TD) and postural instability gait disorder (PIGD) subtypes. Degeneration of subcortical/cortical pathways is different between PD subtypes, which leads to differences in motor behavior. However, the influence of PD subtype on cortical activity during walking remains poorly understood. Therefore, we aimed to investigate the influence of PD motor subtypes on cortical activity during unobstructed walking and obstacle avoidance. Seventeen PIGD and 19 TD patients performed unobstructed walking and obstacle avoidance conditions. Brain activity was measured using a mobile functional near-infrared spectroscopy-electroencephalography (EEG) systems, and gait parameters were analyzed using an electronic carpet. Concentrations of oxygenated hemoglobin (HbO2) of the prefrontal cortex (PFC) and EEG absolute power from alpha, beta, and gamma bands in FCz, Cz, CPz, and Oz channels were calculated. These EEG channels correspond to supplementary motor area, primary motor cortex, posterior parietal cortex, and visual cortex, respectively. Postural instability gait disorder patients presented higher PFC activity than TD patients, regardless of the walking condition. Tremor dominant patients presented reduced beta power in the Cz channel during obstacle avoidance compared to unobstructed walking. Both TD and PIGD patients decreased alpha and beta power in the FCz and CPz channels. In conclusion, PIGD patients need to recruit additional cognitive resources from the PFC for walking. Both TD and PIGD patients presented changes in the activation of brain areas related to motor/sensorimotor areas in order to maintain balance control during obstacle avoidance, being that TD patients presented further changes in the motor area (Cz channel) to avoid obstacles.

LL-00066471, a novel positive allosteric modulator of α7 nicotinic acetylcholine receptor ameliorates cognitive and sensorimotor gating deficits in animal models: Discovery and preclinical characterization.

α7 nicotinic acetylcholine receptor (α7 nAChR) is an extensively validated target for several neurological and psychiatric conditions namely, dementia and schizophrenia, owing to its vital roles in cognition and sensorimotor gating. Positive allosteric modulation (PAM) of α7 nAChR represents an innovative approach to amplify endogenous cholinergic signaling in a temporally restricted manner in learning and memory centers of brain. α7 nAChR PAMs are anticipated to side-step burgeoning issues observed with several clinical-stage orthosteric α7 nAChR agonists, related to selectivity, tolerance/tachyphylaxis, thus providing a novel dimension in therapeutic strategy and pharmacology of α7 nAChR ion-channel. Here we describe a novel α7 nAChR PAM, LL-00066471, which potently amplified agonist-induced Ca2+ fluxes in neuronal IMR-32 neuroblastoma cells in a α-bungarotoxin (α-BTX) sensitive manner. LL-00066471 showed excellent oral bioavailability across species (mouse, rat and dog), low clearance and good brain penetration (B/P ratio > 1). In vivo, LL-00066471 robustly attenuated cognitive deficits in both procognitive and antiamnesic paradigms of short-term episodic and recognition memory in novel object recognition task (NORT) and social recognition task (SRT), respectively. Additionally, LL-00066471 mitigated apomorphine-induced sensorimotor gating deficits in acoustic startle reflex (ASR) and enhanced antipsychotic efficacy of olanzapine in conditioned avoidance response (CAR) task. Further, LL-00066471 corrected redox-imbalances and reduced cortico-striatal infarcts in stroke model. These finding together suggest that LL-00066471 has potential to symptomatically alleviate cognitive deficits associated with dementias, attenuate sensorimotor gating deficits in schizophrenia and correct redox-imbalances in cerebrovascular disorders. Therefore, LL-00066471 presents potential for management of cognitive impairments associated with neurological and psychiatric conditions.

Self-selected step length asymmetry is not explained by energy cost minimization in individuals with chronic stroke.

BACKGROUND: Asymmetric gait post-stroke is associated with decreased mobility, yet individuals with chronic stroke often self-select an asymmetric gait despite being capable of walking more symmetrically. The purpose of this study was to test whether self-selected asymmetry could be explained by energy cost minimization. We hypothesized that short-term deviations from self-selected asymmetry would result in increased metabolic energy consumption, despite being associated with long-term rehabilitation benefits. Other studies have found no difference in metabolic rate across different levels of enforced asymmetry among individuals with chronic stroke, but used methods that left some uncertainty to be resolved. METHODS: In this study, ten individuals with chronic stroke walked on a treadmill at participant-specific speeds while voluntarily altering step length asymmetry. We included only participants with clinically relevant self-selected asymmetry who were able to significantly alter asymmetry using visual biofeedback. Conditions included targeting zero asymmetry, self-selected asymmetry, and double the self-selected asymmetry. Participants were trained with the biofeedback system in one session, and data were collected in three subsequent sessions with repeated measures. Self-selected asymmetry was consistent across sessions. A similar protocol was conducted among unimpaired participants. RESULTS: Participants with chronic stroke substantially altered step length asymmetry using biofeedback, but this did not affect metabolic rate (ANOVA, p = 0.68). In unimpaired participants, self-selected step length asymmetry was close to zero and corresponded to the lowest metabolic energy cost (ANOVA, p = 6e-4). While the symmetry of unimpaired gait may be the result of energy cost minimization, self-selected step length asymmetry in individuals with chronic stroke cannot be explained by a similar least-effort drive. CONCLUSIONS: Interventions that encourage changes in step length asymmetry by manipulating metabolic energy consumption may be effective because these therapies would not have to overcome a metabolic penalty for altering asymmetry.

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.

Utility of plasma Neurofilament light as a diagnostic and prognostic biomarker of the postural instability gait disorder motor subtype in early Parkinson's disease.

BACKGROUND: The main motor subtypes of Parkinson's disease (PD) include tremor-dominant (TD) and postural instability gait disorder (PIGD), with varying disease course that warrant the development of biomarkers capable of predicting progression according to motor subtype. The PIGD subtype is associated with a poorer prognosis, hence identification of a biomarker associated with PIGD is clinically relevant. Neurofilament light (NfL) chain is a potential biomarker of disease severity in neurological disorders including PD. However, no study has investigated NfL and PD motor subtypes. Here, we aimed to investigate the diagnostic and prognostic utility of plasma NfL for PD motor subtypes in early Parkinson's disease. Given the higher risk for cognitive and motor decline in PIGD, we hypothesized that plasma NfL is a potential biomarker for PIGD. METHODS: Plasma NfL was measured in 199 participants (149 PD and 50 healthy controls, HC) using an ultrasensitive single molecule array. Patients were classified into TD or PIGD based on MDS-UPDRS components. After 2 years, 115 patients were reassessed. Association between NfL and clinical measures in PIGD and TD at baseline and at 2-year follow-up were analysed. RESULTS: At baseline, plasma NfL levels were higher in PD than HC (8.8 ± 3.4 vs 16.2 ± 7.6 pg/ml, p < 0.0001), and differentiated PD from HC with a good diagnostic accuracy (AUC = 0.833, p < 0.001). At 2 years, NfL was higher in PIGD than TD (18.4 ± 14.5 vs 12.6 ± 4.4 pg/ml, p = 0.039). Within the PIGD group, higher NfL associated significantly with worse global cognition and UPDRS motor scores at baseline, and was able to predict motor and cognitive decline at a mean follow-up duration of 1.9 years, controlled for age, sex and disease duration. CONCLUSIONS: In this longitudinal study, we demonstrated for the first time the potential utility of plasma NfL as a diagnostic and prognostic biomarker in PIGD even at early stages of PD. These important novel findings will require further confirmation in larger, longitudinal PD cohorts.

Alpha-synuclein/synapsin III pathological interplay boosts the motor response to methylphenidate.

Loss of dopaminergic nigrostriatal neurons and fibrillary α-synuclein (α-syn) aggregation in Lewy bodies (LB) characterize Parkinson's disease (PD). We recently found that Synapsin III (Syn III), a phosphoprotein regulating dopamine (DA) release with α-syn, is another key component of LB fibrils in the brain of PD patients and acts as a crucial mediator of α-syn aggregation and toxicity. Methylphenidate (MPH), a monoamine reuptake inhibitor (MRI) efficiently counteracting freezing of gait in advanced PD patients, can bind α-syn and controls α-syn-mediated DA overflow and presynaptic compartmentalization. Interestingly, MPH results also efficient for the treatment of attention deficits and hyperactivity disorder (ADHD), a neurodevelopmental psychiatric syndrome associated with Syn III and α-syn polymorphisms and constituting a risk factor for the development of LB disorders. Here, we studied α-syn/Syn III co-deposition and longitudinal changes of α-syn, Syn III and DA transporter (DAT) striatal levels in nigrostriatal neurons of a PD model, the human C-terminally truncated (1-120) α-syn transgenic (SYN120 tg) mouse, in comparison with C57BL/6J wild type (wt) and C57BL/6JOlaHsd α-syn null littermates. Then, we analyzed the locomotor response of these animals to an acute administration of MPH (d-threo) and other MRIs: cocaine, that we previously found to stimulate Syn III-reliant DA release in the absence of α-syn, or the selective DAT blocker GBR-12935, along aging. Finally, we assessed whether these drugs modulate α-syn/Syn III interaction by fluorescence resonance energy transfer (FRET) and performed in silico studies engendering a heuristic model of the α-syn conformations stabilized upon MPH binding. We found that only MPH was able to over-stimulate a Syn III-dependent/DAT-independent locomotor activity in the aged SYN120 tg mice showing α-syn/Syn III co-aggregates. MPH enhanced full length (fl) α-syn/Syn III and even more (1-120) α-syn/Syn III interaction in cells exhibiting α-syn/Syn III inclusions. Moreover, in silico studies confirmed that MPH may reduce α-syn fibrillation by stabilizing a protein conformation with increased lipid binding predisposition. Our observations indicate that the motor-stimulating effect of MPH can be positively fostered in the presence of α-syn/Syn III co-aggregation. This evidence holds significant implications for PD and ADHD therapeutic management.

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.

Neural correlates and gait characteristics for hypoxic-ischemic brain injury induced freezing of gait.

OBJECTIVE: To investigate gait characteristics in patients with freezing of gait (FOG) after hypoxic-ischemic brain injury (HIBI) and to elucidate neural correlates for FOG using F-18 fluoro-2-deoxy-d-glucose positron emission tomography. METHODS: We enrolled 12 patients with FOG after HIBI and 17 patients without FOG after HIBI. We performed three-dimensional gait analyses and compared each parameter and gait variability. Brain metabolism was measured, and we compared regional brain metabolism using a voxel-by-voxel-based statistical mapping analysis. RESULTS: The FOG group revealed a significantly decreased joint range of motion (ROM), particularly in the sagittal plane for three-joint summated ROM (p < 0.0025). Spatiotemporal results demonstrated that stride length and step length were decreased in the with FOG group (p < 0.005). FOG severity was negatively correlated with brain metabolism in the left thalamus, and three-joint summated ROM in the sagittal plane was positively associated with brain metabolism in the left thalamus and midbrain (p < 0.05). CONCLUSIONS: Central organizational level amplitude disorder may play an important role in the pathophysiology, and disturbance in the cholinergic pathway might contribute to the development of FOG in patients with HIBI. SIGNIFICANCE: These findings contribute to understanding FOG in HIBI.

Sex-dependent impaired locomotion and motor coordination in the HdhQ200/200 mouse model of Huntington's Disease.

Huntington's Disease (HD) is a fatal neurodegenerative disease characterized by severe loss of medium spiny neuron (MSN) function and striatal-dependent behaviors. We report that female HdhQ200/200 mice display an earlier onset and more robust deterioration in spontaneous locomotion and motor coordination measured at 8 months of age compared to male HdhQ200/200 mice. Remarkably, HdhQ200/200 mice of both sexes exhibit comparable impaired spontaneous locomotion and motor coordination at 10 months of age and reach moribund stage by 12 months of age, demonstrating reduced life span in this model system. Histopathological analysis revealed enhanced mutant huntingtin protein aggregation in male HdhQ200/200 striatal tissue at 8 months of age compared to female HdhQ200/200. Functional analysis of calcium dynamics in MSNs of female HdhQ200/200 mice using GCaMP6m imaging revealed elevated responses to excitatory cortical-striatal stimulation suggesting increased MSN excitability. Although there was no down-regulation of the expression of common HD biomarkers (DARPP-32, enkephalin and CB1R), we measured a sex-dependent reduction of the astrocytic glutamate transporter, GLT-1, in female HdhQ200/200 mice that was not detected in male HdhQ200/200 mice when compared to respective wild-type littermates. Our study outlines a sex-dependent rapid deterioration of striatal-dependent behaviors occurring in the HdhQ200/200 mouse line that does not involve alterations in the expression of common HD biomarkers and yet includes impaired MSN function.

Autoimmune gait disturbance accompanying adaptor protein-3B2-IgG.

OBJECTIVE: To describe phenotypes, treatment response, and outcomes of autoimmunity targeting a synaptic vesicle coat protein, the neuronal (B2) form of adaptor protein-3 (AP3). METHODS: Archived serum and CSF specimens (from 616,025 screened) harboring unclassified synaptic antibodies mimicking amphiphysin-immunoglobulin G (IgG) on tissue-based indirect immunofluorescence assay (IFA) were re-evaluated for novel IgG staining patterns. Autoantigens were identified by western blot and mass spectrometry. Recombinant western blot and cell-binding assay (CBA) were used to confirm antigen specificity. Clinical data were obtained retrospectively. RESULTS: Serum (10) and CSF (6) specimens of 10 patients produced identical IFA staining patterns throughout mouse nervous system tissues, most prominently in cerebellum (Purkinje neuronal perikarya, granular layer synapses, and dentate regions), spinal cord gray matter, dorsal root ganglia, and sympathetic ganglia. The antigen revealed by mass spectrometry analysis and confirmed by recombinant assays (western blot and CBA) was AP3B2 in all. Of 10 seropositive patients, 6 were women; median symptom onset age was 42 years (range 24-58). Clinical information was available for 9 patients, all with subacute onset and rapidly progressive gait ataxia. Neurologic manifestations were myeloneuropathy (3), peripheral sensory neuropathy (2), cerebellar ataxia (2), and spinocerebellar ataxia (2). Five patients received immunotherapy; none improved, but they did not worsen over the follow-up period (median 36 months; range 3-94). Two patients (both with cancer) died. One of 50 control sera was positive by western blot only (but not by IFA or CBA). CONCLUSION: AP3B2 (previously named ß-neuronal adaptin-like protein) autoimmunity appears rare, is accompanied by ataxia (sensory or cerebellar), and is potentially treatable.

Danhong injection facilitates recovery of post-stroke motion deficit via Parkin-enhanced mitochondrial function.

BACKGROUND: A cerebral ischemic stroke involves mitochondrial dysfunction, motor deficits, and paralysis; and Danhong injection (DHI) might possess mitochondrial protection and functional recovery in a stroke subject through promoting expression of parkin, a ubiquitin ligase playing a key role in the regulation of proteins and mitochondria quality control. OBJECTIVE: To investigate the therapeutic effects of DHI on the histological, cellular, and functional recovery of Wistar rats after middle cerebral artery occlusion/reperfusion (MCAO/R). METHODS: One hundred and twenty healthy male Wistar rats (250-300 g), were randomly assigned to six groups (twenty rats/group). Rats were subjected to 1 h MCAO/R and subsequently administered the intravenous doses of DHI (0.75, 1.5, and 3 mL/kg) to the respective groups (twice a day for 14 days). Unlike the other groups, the sham group received surgery without vessel occlusion. All the animals were tested for gait behavior using the CatWalk system. The body weight/survival rates were recorded daily for 14 days. The parkin protein expression of the brain tissue was quantified by immunohistochemistry analysis. Additionally, cultured cortical neurons were incubation with DHI or minocycline (MC) and then deprived of oxygen and glucose for 2 h (to resemble ischemic/reperfusion), followed by 4 h reoxygenation. Cellular and mitochondrial phenotypes were assayed by high content analysis. RESULTS: Neurological integrity and paw parameters of the animals were altered in the model group but significantly ameliorated by DHI administration. Also, the infarct volume and survival rate were significantly improved in DHI groups. DHI enhanced the expression of parkin protein in the brain and improved the relative mitochondrial reductase activity of the cultured neurons. CONCLUSIONS: The overall result shows that daily intervention with DHI provides neuroprotection and survival to improve gait motion in Wistar rats.

Hair cortisol concentration, cognitive, behavioral, and motor impairment in multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease that is characterized by the demyelinated inflammatory processes that occur within the central nervous system. Hypothalamus-pituitary-adrenal axis (HPA axis) dysfunctions have been associated with the triggering or increase in MS symptoms. We thus aimed at evaluating motor and behavioral functions, planning skills, processing speed, and their relationship with stress through measuring hair cortisol concentration from patients with MS. The sample was composed of 40 volunteers that were clinically diagnosed with MS, along with 33 healthy adults. Evaluations included: Clinical Evaluation Form, Mini-Mental State Exam, Hamilton Depression Rating Scale, Multiple Sclerosis Functional Composite Measure, Expanded Disability Status Scale, Berg Balance Scale, Perceived Stress Scale, Zoo Map task, and a hair sample to analyze cortisol levels in the last 30 days. MS patients showed highly elevated hair cortisol levels in comparison to the control group (p = 0.048). All groups presented some degree of depressive and anxiety symptoms, aside from considerable perceived stress levels. The MS group presented deficits in gait, balance, manual skills and processing speed, and this was particularly so in individuals with moderate impairments when compared to control group (p < 0.001). Individuals with MS spent less time planning on ZooMap1 (p = 0.024) and made more mistakes (p < 0.001). No correlation was found between hair cortisol and the symptoms we assessed. However, depressive symptoms and anxiety were related to perceived stress, and higher hair cortisol suggests a change in levels in the HPA axis in MS. Nevertheless, future studies will be necessary to further understand how basal hair cortisol is related to MS symptoms.

Clinical implications of early caudate dysfunction in Parkinson's disease.

OBJECTIVE: Although not typical of Parkinson's disease (PD), caudate dopaminergic dysfunction can occur in early stages of the disease. However, its frequency and longitudinal implications in large cohorts of recently diagnosed patients remain to be established. We investigated the occurrence of caudate dopaminergic dysfunction in the very early phases of PD (<2 years from diagnosis) using 123I-FP-CIT single photon emission CT and determined whether it was associated with the presence or subsequent development of cognitive impairment, depression, sleep and gait problems. METHODS: Patients with PD and healthy controls were identified from the Parkinson's Progression Markers Initiative (PPMI) database. We defined a clinically significant caudate dysfunction as 123I-FP-CIT binding <-2 SDs compared with the controls' mean and categorised three groups accordingly (no reduction, unilateral reduction, bilateral reduction). All statistical analyses were adjusted for mean putamen binding. RESULTS: At baseline, 51.6% of 397 patients had normal caudate dopamine transporter binding, 26.0% had unilateral caudate involvement, 22.4% had bilaterally impaired caudate.Compared with those with a baseline normal caudate function, at the4-year follow-up patients with a baseline bilateral caudate involvement showed a higher frequency of cognitive impairment (p<0.001) and depression (p<0.001), and worse cognitive (p<0.001), depression (<0.05) and gait (<0.001) ratings. Significant caudate involvement was observed in 83.9% of the population after 4 years (unilateral 22.5%, bilateral 61.4%). CONCLUSIONS: Early significant caudate dopaminergic denervation was found in half of the cases in the PPMI series. Baseline bilateral caudate involvement was associated with increased risk of developing cognitive impairment, depression and gait problems over the next 4 years.

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.

Cerebral Metabolic Changes Related to Freezing of Gait in Parkinson Disease.

Freezing of gait (FOG) in Parkinson disease (PD) often occurs during steering of gait (i.e., complex gait), which is thought to arise from executive dysfunction. Our aim was to test whether cognitive corticobasal ganglia-thalamocortical circuitry is impaired and whether alternate neural circuits are used for complex gait in PD with FOG. Methods: Eighteen individuals with idiopathic PD in the off-medication state, 9 with FOG (aged 68 ± 6 y) and 9 without FOG (aged 65 ± 5 y), were included. PET was used to measure cerebral glucose metabolism during 2 gait tasks, steering and straight walking, performed during the radiotracer uptake period. Results: During steering, there was a reduced change in cerebral glucose metabolism within the cognitive corticothalamic circuit. More specifically, those with FOG had less activation of the posterior parietal cortex, less deactivation of the dorsolateral prefrontal cortex and thalamus, and increased activation in the supplementary motor area. Interestingly, activity in the dorsolateral prefrontal cortex correlated with gait impairment (i.e., reduced stride length) in the FOG group. Conclusion: These results demonstrate decreased parietal control and an alternate control mechanism mediated by prefrontal and supplementary motor areas in PD with FOG.

Aß42/Aß40 and Aß42/Aß38 Ratios Are Associated with Measures of Gait Variability and Activities of Daily Living in Mild Alzheimer's Disease: A Pilot Study.

Gait disturbances are some of the earliest changes in dementia and their monitoring presents an opportunity for early diagnosis. The exact relationship between gait and well-established biomarkers of Alzheimer's disease (AD) remains to be clarified. In this study we compared gait-related measures with cerebrospinal fluid (CSF) markers of AD pathology. We recruited seventeen participants with mild AD in a multi-site study and performed gait assessment as well as lumbar punctures to obtain CSF. CSF Aß42/Aß40 and Aß42/Aß38 correlated positively with measures of variability (step time and step length) in the clinic-based assessments. This was driven by a negative relationship between gait variability and Aß40 and Aß38 but not Aß42.The amyloid ratios and gait variability measures were also associated with more severe functional impairment. We interpret these data as an indication that increasing amyloid production (i.e., increasing Aß40 and Aß38) is associated with diminishing cognitive-motor control of gait. These preliminary results suggest that the two amyloid ratios may be a marker of the earliest disturbances in the interplay between cognitive and motor control which characterize dementia.