Corneliu C. Luca

Clinicopathologic correlations in 172 cases of rapid eye movement sleep behavior disorder with or without a coexisting neurologic disorder.

OBJECTIVE To determine the pathologic substrates in patients with rapid eye movement (REM) sleep behavior disorder (RBD) with or without a coexisting neurologic disorder. METHODS The clinical and neuropathologic findings were analyzed on all autopsied cases from one of the collaborating sites in North America and Europe, were evaluated from January 1990 to March 2012, and were diagnosed with polysomnogram (PSG)-proven or probable RBD with or without a coexisting neurologic disorder. The clinical and neuropathologic diagnoses were based on published criteria. RESULTS 172 cases were identified, of whom 143 (83%) were men. The mean±SD age of onset in years for the core features were as follows - RBD, 62±14 (range, 20-93), cognitive impairment (n=147); 69±10 (range, 22-90), parkinsonism (n=151); 68±9 (range, 20-92), and autonomic dysfunction (n=42); 62±12 (range, 23-81). Death age was 75±9 years (range, 24-96). Eighty-two (48%) had RBD confirmed by PSG, 64 (37%) had a classic history of recurrent dream enactment behavior, and 26 (15%) screened positive for RBD by questionnaire. RBD preceded the onset of cognitive impairment, parkinsonism, or autonomic dysfunction in 87 (51%) patients by 10±12 (range, 1-61) years. The primary clinical diagnoses among those with a coexisting neurologic disorder were dementia with Lewy bodies (n=97), Parkinsons disease with or without mild cognitive impairment or dementia (n=32), multiple system atrophy (MSA) (n=19), Alzheimers disease (AD)(n=9) and other various disorders including secondary narcolepsy (n=2) and neurodegeneration with brain iron accumulation-type 1 (NBAI-1) (n=1). The neuropathologic diagnoses were Lewy body disease (LBD)(n=77, including 1 case with a duplication in the gene encoding α-synuclein), combined LBD and AD (n=59), MSA (n=19), AD (n=6), progressive supranulear palsy (PSP) (n=2), other mixed neurodegenerative pathologies (n=6), NBIA-1/LBD/tauopathy (n=1), and hypothalamic structural lesions (n=2). Among the neurodegenerative disorders associated with RBD (n=170), 160 (94%) were synucleinopathies. The RBD-synucleinopathy association was particularly high when RBD preceded the onset of other neurodegenerative syndrome features. CONCLUSIONS In this large series of PSG-confirmed and probable RBD cases that underwent autopsy, the strong association of RBD with the synucleinopathies was further substantiated and a wider spectrum of disorders which can underlie RBD now are more apparent.

mTERF2 regulates oxidative phosphorylation by modulating mtDNA transcription

Regulation of mitochondrial protein expression is crucial for the function of the oxidative phosphorylation (OXPHOS) system. Although the basal machinery for mitochondrial transcription is known, the regulatory mechanisms are not completely understood. Here, we characterized mTERF2, a mitochondria-localized homolog of the mitochondrial transcription termination factor mTERF1. We show that inactivation of mTERF2 in the mouse results in a myopathy and memory deficits associated with decreased levels of mitochondrial transcripts and imbalanced tRNA pool. These aberrations were associated with decreased steady-state levels of OXPHOS proteins causing a decrease in respiratory function. mTERF2 binds to the mtDNA promoter region, suggesting that it affects transcription initiation. In vitro interaction studies suggest that mtDNA mediates interactions between mTERF2 and mTERF3. Our results indicate that mTERF1, mTERF2, and mTERF3 regulate transcription by acting in the same site in the mtDNA promoter region and thereby mediate fine-tuning of mitochondrial transcription and hence OXPHOS function.

Association of the sirtuin and mitochondrial uncoupling protein genes with carotid plaque

Objective Sirtuins (SIRTs) and mitochondrial uncoupling proteins (UCPs) have been implicated in cardiovascular diseases through the control of reactive oxygen species production. This study sought to investigate the association between genetic variants in the SIRT and UCP genes and carotid plaque. Methods In a group of 1018 stroke-free subjects from the Northern Manhattan Study with high-definition carotid ultrasonography and genotyping, we investigated the associations of 85 single nucleotide polymorphisms (SNPs) in the 11 SIRT and UCP genes with the presence and number of carotid plaques, and evaluated interactions of SNPs with sex, smoking, diabetes and hypertension as well as interactions between SNPs significantly associated with carotid plaque. Results Overall, 60% of subjects had carotid plaques. After adjustment for demographic and vascular risk factors, T-carriers of the SIRT6 SNP rs107251 had an increased risk for carotid plaque (odds ratio, OR = 1.71, 95% CI = 1.23–2.37, Bonferroni-corrected p = 0.03) and for a number of plaques (rate ratio, RR = 1.31, 1.18–1.45, Bonferroni-corrected p = 1.4×10−5), whereas T-carriers of the UCP5 SNP rs5977238 had an decreased risk for carotid plaque (OR = 0.49, 95% CI = 0.32–0.74, Bonferroni-corrected p = 0.02) and plaque number (RR = 0.64, 95% CI = 0.52–0.78, Bonferroni-corrected p = 4.9×10−4). Some interactions with a nominal p≤0.01 were found between sex and SNPs in the UCP1 and UCP3 gene; between smoking, diabetes, hypertension and SNPs in UCP5 and SIRT5; and between SNPs in the UCP5 gene and the UCP1, SIRT1, SIRT3, SIRT5, and SIRT6 genes in association with plaque phenotypes. Conclusion We observed significant associations between genetic variants in the SIRT6 and UCP5 genes and atherosclerotic plaque. We also found potential effect modifications by sex, smoking and vascular risk factors of the SIRT/UCP genes in the associations with atherosclerotic plaque. Further studies are needed to validate our observations.

Comparative Effect of Power Training and High-Speed Yoga on Motor Function in Older Patients With Parkinson Disease.

OBJECTIVES To compare the effects of power training (PWT) and a high-speed yoga program on physical performances in older patients with Parkinson disease (PD), and to test the hypothesis that both training interventions would attenuate PD symptoms and improve physical performance. DESIGN Randomized controlled trial. SETTING A laboratory of neuromuscular research and active aging. PARTICIPANTS Patients with PD (N=41; mean age ± SD, 72.2 ± 6.5y). INTERVENTIONS Two high-speed exercise interventions (specifically designed yoga program and PWT) were given for 12 weeks (twice a week), and 1 nonexercise control group. MAIN OUTCOME MEASURES Unified Parkinson Disease Rating Scale motor score (UPDRSMS), Berg Balance Scale (BBS), Mini-Balance Evaluation Systems Test (Mini-BESTest), Timed Up and Go, functional reach, single leg stance (SLS), postural sway test, 10-m usual and maximal walking speed tests, 1 repetition maximum (RM), and peak power (PPW) for leg press. RESULTS For the posttests, both training groups showed significant improvements (P<.05) in all physical measurements except functional reach on the more affected side, SLS, and postural sway compared with the pretests, and significantly better scores for UPDRSMS, BBS, Mini-BESTest, Timed Up and Go, functional reach on the less affected side, 10-m usual and maximal walking speed tests, 1RM, and PPW than controls, with no differences detected between the yoga program and PWT. CONCLUSIONS Both the specially designed yoga program and PWT programs can significantly improve physical performance in older persons with PD.

Can 4-aminopyridine modulate dysfunctional gait networks in Parkinson's disease?

Gait dysfunction and postural instability represent a major therapeutic challenge in Parkinsons disease (PD). Gait disability in PD has been historically attributed to striato-nigral degeneration, however there is emerging evidence that multiple neurotransmitter deficits contribute to mobility impairment in PD. 4-aminopyridine (4-AP), a potent neurotransmitter modulator, has a wide range of favorable effects on gait in patients with neurological conditions including multiple sclerosis, spinal cord injury and cerebellar ataxia. In this Review we identify the neurobiological pathways involved in gait dysfunction in PD and discuss the mechanisms of action of 4-AP and its effect on gait related neuronal networks. The proposed mechanisms that may facilitate 4-AP favorable effect on gait in Parkinsons disease include 1) neurotransmitter release (dopamine, glutamate, acetylcholine and noradrenaline) 2) modulation of neuronal network oscillations and 3) increased cortical excitation. Recent clinical trials of 4-AP in neurological conditions associated with gait disorders will be highlighted and the importance of studying non-dopaminergic medications such as 4-AP in PD patients with gait impairment will be emphasized.

4-aminopyridine improves freezing of gait in Parkinson's disease.

Walking impairment represents a significant therapeutic challenge in patients with Parkinson’s disease (PD). Medical therapies are limited to dopamine replacement and as the disease progresses, gait dysfunction becomes resistant to treatment [1]. Recently, non-dopaminergic therapies such as donepezil [2], methylphenidate [3], and amantadine [4] have been employed for treatment of dopamine-resistant freezing of gait (FOG), and have demonstrated some benefit. Given the paucity of therapies for gait disturbance, it is very important to find alternative strategies in patients with PD. 4-Aminopyridine (4-AP), a potassium channel blocker that improves walking in patients with multiple sclerosis [5], has the ability to release multiple neurotransmitters including dopamine, noradrenaline and acetylcholine [6], and has been used for many years in spinal cord injury, based on its properties to increase conduction velocity and increase motor evoked potentials [7]. More recently, 4-AP was shown to be effective in treatment of downbeat nystagmus [8], episodic ataxia [9] and various types of cerebellar ataxias [10]. Based on the favorable effects on gait in patients with multiple sclerosis and cerebellar ataxia, we evaluated the effect of 4-AP in a patient with PD-related FOG. The patient had signed an informed consent according to University of Miami regulations. The patient had been diagnosed with Parkinson’s disease 19 years ago, and had been doing relatively well with 600 mg of levodopa, selegiline and amantadine (MDS-UPDRS motor score-52). As the disease progressed, he had worsening of his walking difficulties, and significant FOG and festination for the preceding 4 years. The FOG was unresponsive to levodopa and further augmentation was not possible due to somnolence. He was also unresponsive to dopaminergic agonists. His gait-freezing episodes were present on a daily basis and interfered significantly with his daily activities. His Freezing of Gait Questionnaire (FOGQ) score was 16 while OFF levodopa and did not change in the ON state. For his FOG, dopamine receptor agonists or dopamine augmentation have not been useful. Due to his severe FOG, patient was started on 4-aminopyridine 5 mg po three times daily to evaluate the effects on walking and FOG. Clinical measures of gait, such as Timed Up and Go (TUG), Timed 25 Foot Walk (T25FW), FOG questionnaire (FOGQ) and Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), were assessed pre treatment, 2, 48 h, and 30 days after the initiation of treatment. After 2 days of treatment, the patient reported significant improvement of FOG that persisted at 90 days into the treatment. We repeated the measures pre 4-AP and post 4-AP at this time point. Spatial–temporal gait parameters were recorded using wireless sensors (APDM Inc., Portland) attached to ankles. All the assessments were done while ON levodopa. The patient reported significant improvement in the FOG throughout the course of treatment. Axial MDS-UPDRS and FOG score improved significantly at 2 and 48 h after treatment initiation, whereas the effects on stride length and velocity were not seen until later during treatment (see Table 1). His FOG score improved 50 % (from 16 points pretreatment to 8 post-administration), and the axial UPDRS from 10 points to 3. The effects on FOG have been stable over 30 days, and his FOG returned after 4-AP was briefly interrupted at day 90. C. C. Luca (&) C. Singer Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, USA e-mail: cluca@med.miami.edu

Primary Intramedullary Spinal Cord Lymphoma Presenting as a Cervical Ring–Enhancing Lesion in an AIDS Patient

Abstract Primary intramedullary spinal cord lymphoma (PISCL) is rare and constitutes only 1% of central nervous system lymphomas. We report a case of PISCL in a 37-year-old man with advanced AIDS. To our knowledge, only 4 cases of PISCL in the setting of HIV/AIDS have been reported in the literature. Despite treatment, prognosis remains dismal.

Exercise Guidelines for Gait Function in Parkinson’s Disease: A Systematic Review and Meta-analysis:

This systematic review and meta-analysis is to provide comprehensive evidence-based exercise recommendations targeting walking function for adults with Parkinson’s disease. Methods. Fixed- or random-effect meta-analyses estimated standardized effect sizes (Hedge’s g), comparing treatment effects from exercise with nonexercise and another form of exercise (non-EXE control and EXE control). Cuing and exercise duration were used as moderators for subanalyses. Results. The 40 included randomized controlled trials comprised 1656 patients. The exercise group showed significantly superior performance in timed up-and-go (g = −0.458; g = −0.390) compared with non-EXE control and EXE control; significantly greater improvement in comfortable walking speed (g = 0.449), fast walking speed (g = 0.430), and stride or step length (g = 0.379) compared with non-EXE control; and significantly greater cadence (g = 0.282) compared with EXE controls. No significant differences between intervention and control groups were observed for double-leg support time (DLST), dynamic gait index (DGI), 6-minute walk test, or freezing of gait questionnaire (FOG-Q). Notably, treatment effect from the exercise of interest compared with a standard exercise was greater than for nonexercise for cadence and FOG-Q. Moreover, EXE control was favored for DLST and DGI. Cuing had a significantly positive effect on stride length alone. Exercise duration significantly, but negatively, influenced the treatment effect on comfortable walking speed. Conclusion. Gait-specific training, rather than a general exercise program, should be emphasized if gait is the outcome of interest. Further investigation is needed on exercise dosage and its selective effect on more challenging walking tasks, endurance, and freezing of gait.

Rapid Eye Movement Sleep Behavior Disorder Manifesting as Sign Language in a Patient with Dementia with Lewy Bodies

We present a patient who had a diagnosis of probable dementia with Lewy bodies (DLB) according to consensus guidelines. Rapid eye movement (REM) sleep behavior disorder (RBD) was part of his clinical spectrum. Unrelated to his neurodegenerative process, our patient had severe hearing impairment and was a native signer in American Sign Language (ASL)—his main source of linguistic communication. As part of his dreamenactment behavior, he would fluently sign rather than verbalize in spoken language. This manifestation of RBD has not been previously reported and allows for discussion of the similar neural systems that underlie both spoken and signed language.

Dalfampridine in Parkinson's disease related gait dysfunction: A randomized double blind trial

BACKGROUND Disease-related gait dysfunction causes extensive disability for persons with Parkinsons disease (PD), with no effective therapies currently available. The potassium channel blocker dalfampridine has been used in multiple neurological conditions and improves walking in persons with multiple sclerosis. OBJECTIVES We aimed to evaluate the effect of dalfampridine extended release (D-ER) 10mg tablets twice daily on different domains of walking in participants with PD. METHODS Twenty-two participants with PD and gait dysfunction were randomized to receive D-ER 10mg twice daily or placebo for 4weeks in a crossover design with a 2-week washout period. The primary outcomes were change in the gait velocity and stride length. RESULTS At 4weeks, gait velocity was not significantly different between D-ER (0.89m/s±0.33) and placebo (0.93m/s±0.27) conditions. The stride length was also similar between conditions: 0.96m±0.38 for D-ER versus 1.06m±0.33 for placebo. D-ER was generally well tolerated with the most frequent side effects being dizziness, nausea and balance problems. CONCLUSIONS D-ER is well tolerated in PD patients, however it did not show significant benefit for gait impairment.