Reshaping cortical activity with subthalamic stimulation in Parkinson's disease during finger tapping and gait mapped by near infrared spectroscopy

Exploration of motor cortex activity is essential to understanding the pathophysiology in Parkinson's Disease (PD), but only simple motor tasks can be investigated using a fMRI or PET. We aim to investigate the cortical activity of PD patients during a complex motor task (gait) to verify the impact of deep brain stimulation in the subthalamic nucleus (DBS-STN) by using Near-Infrared-Spectroscopy (NIRS). NIRS is a neuroimaging method of brain cortical activity using low-energy optical radiation to detect local changes in (de)oxyhemoglobin concentration. We used a multichannel portable NIRS during finger tapping (FT) and gait. To determine the signal activity, our methodology consisted of a pre-processing phase for the raw signal, followed by statistical analysis based on a general linear model. Processed recordings from 9 patients were statistically compared between the on and off states of DBS-STN. DBS-STN led to an increased activity in the contralateral motor cortex areas during FT. During gait, we observed a concentration of activity towards the cortex central area in the "stimulation-on" state. Our study shows how NIRS can be used to detect functional changes in the cortex of patients with PD with DBS-STN and indicates its future use for applications unsuited for PET and a fMRI

Variation within the Huntington's Disease Gene Influences Normal Brain Structure

Genetics of the variability of normal and diseased brain structure largely remains to be elucidated. Expansions of certain trinucleotide repeats cause neurodegenerative disorders of which Huntington's disease constitutes the most common example. Here, we test the hypothesis that variation within the IT15 gene on chromosome 4, whose expansion causes Huntington's disease, influences normal human brain structure. In 278 normal subjects, we determined CAG repeat length within the IT15 gene on chromosome 4 and analyzed high-resolution T1-weighted magnetic resonance images by the use of voxel-based morphometry. We found an increase of GM with increasing long CAG repeat and its interaction with age within the pallidum, which is involved in Huntington's disease. Our study demonstrates that a certain trinucleotide repeat influences normal brain structure in humans. This result may have important implications for the understanding of both the healthy and diseased brain

Near-infrared spectroscopy patterns of cortical activity during gait in Parkinson’s disease patients treated with DBS STN

Disorders of gait seriously affect the functional state and quality of life of patients with Parkinson’s disease (PD). Impaired brain function underlies disorders of movement control in PD, however functional brain imaging with magnetic resonance (fMRI) is not feasible during gait. Near-Infrared Spectroscopy (NIRS) is a portable imaging method for measuring brain activity. It uses low-energy optical radiation to detect local changes of (de)oxyhemoglobin concentration in the cerebral cortex, like a fMRI. We included 8 patients with advanced PD chronically treated with DBS STN. Brain activity was recorded with the NIRSport. Gait was examined in 10 cycles, during which the active and resting phases alternated. Changes in oxyhemoglobin concentration were calculated from the native NIRS signal using a modified transformation of the Lambert-Beer Law. The signals were filtered in the 0.015–0.3 Hz band and the least-squares algorithm was fitted with the HRF function for each cycle separately, from which the median was finally calculated. The activity of the motor cortex was significantly higher during gait in the OFF compared to ON state (p = 0.02). In contrast, in other regions no differences were found. A higher motor cortex activity shown in the DBS OFF compared to ON state may reflect the impairment of gait control in PD. In general terms, the present study demonstrates the potential utility of the NIRS method in detecting functional changes of the brain during gait in patients with PD

Leucine-rich repeat kinase-2 (LRRK2) R1441G knockin mice are more susceptible to rotenone toxicity

This journal suppl. entitled: Supplement: Abstracts of the Eighteenth International Congress of Parkinson's Disease and Movement Disorders / Poster PresentationOBJECTIVE: To assess the susceptibility of LRRK2 R1441G knockin mice against (1) striatal dopamine (DA) uptake deficit, (2) locomotor inactivity and, (3) dopaminergic neuronal cell death, as induced by rotenone (mitochondrial complex-I inhibitor). BACKGROUND: LRRK2 mutations are the commonest genetic risk in Parkinson's disease (PD). LRRK2 is linked to synapse functions. However, the pathogenic mechanism of LRRK2 mutation in striatal DA homeostasis and mitochondria dysfunction is unknown. METHODS: Cell viability of primary DA neurons from R1441G knockin mice and their wild-type littermates were compared after rotenone exposure. Total [3H]-DA uptake in isolated striatal synaptosomes incubated with rotenone, and the locomotor activity in open-field test after chronic (20 weeks) oral gavage of rotenone were also assessed. RESULTS: Without rotenone, R1441G mutant mice show no overt phenotype. However, synaptosomes from young (3-month-old) mutant mice exhibited lower DA uptake when incubated with rotenone (100nM), compared with wild-type controls. Number of tyrosine hydroxylase (TH)-positive neurons in mutant culture after rotenone exposure (5nM) was significantly lower. Also, chronic exposure to rotenone (5mg/kg, twice per week orally) for 20 weeks caused significantly lower locomotor activity in mutant mice compared with the wild-type controls. CONCLUSIONS: Similar to R1441C [1], LRRK2 R1441G mutant mice show no overt phenotype. However, R1441G mutant synaptosomes were more vulnerable to rotenone toxicity as shown by lower DA uptake, indicating that R1441G mutation contributes to mitochondrial dysfunction-induced synaptic dysfunction. Re-uptake of extracellular DA requires mitochondrial ATP for synaptic recycling. Uptake deficits associated with LRRK2 mutation may adversely affects striatal neuronal survival and locomotor activity as observed in our mutant mice. This differential susceptibility against rotenone toxicity of the mutant mice suggests that LRRK2 R1441G mutation may be a predisposing genetic factor in synaptic energy deficiency leading to early striatal synaptic dysfunction [2], and later nigrostriatal DA cell death in LRRK2-associated PD.link_to_OA_fulltex

Supplementary Material for: Mutated Huntingtin Causes Testicular Pathology in Transgenic Minipig Boars

<strong><em>Background:</em></strong> Huntington's disease is induced by CAG expansion in a single gene coding the huntingtin protein. The mutated huntingtin (mtHtt) primarily causes degeneration of neurons in the brain, but it also affects peripheral tissues, including testes. <b><i>Objective:</i></b> We studied sperm and testes of transgenic boars expressing the N-terminal region of human mtHtt. <b><i>Methods:</i></b> In this study, measures of reproductive parameters and electron microscopy (EM) images of spermatozoa and testes of transgenic (TgHD) and wild-type (WT) boars of F1 (24-48 months old) and F2 (12-36 months old) generations were compared. In addition, immunofluorescence, immunohistochemistry, Western blot, hormonal analysis and whole-genome sequencing were done in order to elucidate the effects of mtHtt. <b><i>Results:</i></b> Evidence for fertility failure of both TgHD generations was observed at the age of 13 months. Reproductive parameters declined and progressively worsened with age. EM revealed numerous pathological features in sperm tails and in testicular epithelium from 24- and 36-month-old TgHD boars. Moreover, immunohistochemistry confirmed significantly lower proliferation activity of spermatogonia in transgenic testes. mtHtt was highly expressed in spermatozoa and testes of TgHD boars and localized in all cells of seminiferous tubules. Levels of fertility-related hormones did not differ in TgHD and WT siblings. Genome analysis confirmed that insertion of the lentiviral construct did not interrupt any coding sequence in the pig genome. <b><i>Conclusions:</i></b> The sperm and testicular degeneration of TgHD boars is caused by gain-of-function of the highly expressed mtHtt

Supplementary Material for: Mutated Huntingtin Causes Testicular Pathology in Transgenic Minipig Boars

<strong><em>Background:</em></strong> Huntington's disease is induced by CAG expansion in a single gene coding the huntingtin protein. The mutated huntingtin (mtHtt) primarily causes degeneration of neurons in the brain, but it also affects peripheral tissues, including testes. <b><i>Objective:</i></b> We studied sperm and testes of transgenic boars expressing the N-terminal region of human mtHtt. <b><i>Methods:</i></b> In this study, measures of reproductive parameters and electron microscopy (EM) images of spermatozoa and testes of transgenic (TgHD) and wild-type (WT) boars of F1 (24-48 months old) and F2 (12-36 months old) generations were compared. In addition, immunofluorescence, immunohistochemistry, Western blot, hormonal analysis and whole-genome sequencing were done in order to elucidate the effects of mtHtt. <b><i>Results:</i></b> Evidence for fertility failure of both TgHD generations was observed at the age of 13 months. Reproductive parameters declined and progressively worsened with age. EM revealed numerous pathological features in sperm tails and in testicular epithelium from 24- and 36-month-old TgHD boars. Moreover, immunohistochemistry confirmed significantly lower proliferation activity of spermatogonia in transgenic testes. mtHtt was highly expressed in spermatozoa and testes of TgHD boars and localized in all cells of seminiferous tubules. Levels of fertility-related hormones did not differ in TgHD and WT siblings. Genome analysis confirmed that insertion of the lentiviral construct did not interrupt any coding sequence in the pig genome. <b><i>Conclusions:</i></b> The sperm and testicular degeneration of TgHD boars is caused by gain-of-function of the highly expressed mtHtt