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Objective: MAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach., Methods: We studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers' clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson's disease (1), and mild cognitive impairment (1). We performed voxel-based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype., Results: Symptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers., Interpretation: A subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Introduction: Statins were proposed to be neuroprotective; however, the effects are unknown in progressive supranuclear palsy (PSP), a pure tauopathy., Methods: Data of 284 PSP cases and 284 age-matched, sex-matched, and race-matched controls were obtained from the environmental and genetic PSP (ENGENE-PSP) study. Cases were evaluated with the PSP Rating Scale, Unified Parkinson's Disease Rating Scale, Mattis Dementia Rating Scale, and Neuropsychiatric Inventory. Statin associations with PSP risk, onset age, and disease features were analyzed., Results: Univariate models showed lower PSP risk for type 1 statin users (simvastatin, lovastatin, pravastatin). After adjusting for confounding variables, statin use and lower PSP risk association remained only at a trend level. For PSP cases, type 1 statins were associated with 1-year older onset age; type 2 statins (atorvastatin, rosuvastatin) were associated with the lower PSP Rating Scale and Unified Parkinson's Disease Rating Scale., Conclusion: Statins may have inverse associations with PSP risk and motor impairment. Randomized prospective studies are required to confirm this effect. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Background: Negative associations between smoking and Parkinson's disease (PD) are well documented. While common biases may not explain this association, some studies have suggested reverse causality and ease of quitting might be an early sign of PD, possibly related to a reduced nicotinic response. We investigated nicotinic receptor (nAChR) genetics to add to our understanding of possible biologic mechanisms underlying the smoking-PD relationship., Methods: We relied on 612 patients and 691 controls enrolled in the PEG (Parkinson's Environment and Gene) study for whom we obtained information on smoking and quitting ease through interviews. Genotyping in the nAChR genes, i.e. CHRNA5-A3-B4 and CHRNB3-A6 gene regions that have been linked to smoking or quitting behaviors, were based on blood and saliva DNA samples. We assessed associations with logistic regression assuming logit-additive allelic effects and used product terms for genetic allele status and smoking or quitting assessing interactions., Results: As expected, we observed negative associations between smoking and PD that were strongest for current followed by former smokers. In former smokers, high quitting difficulty was negatively associated with PD risk (extremely hard vs. easy: OR = 0.62 [0.39-0.99], p = 0.05), meaning those who developed PD were able to quit smoking with less difficulty than controls. The CHRNA3 rs578776-A allele predicted quitting difficulty in smoking controls (OR = 0.53 [0.32-0.91], p = 0.02), but not in smoking PD patients (OR = 1.09 [0.61-1.95], p = 0.77)., Conclusion: Our study further corroborates previous findings that ease of quitting may be an early sign of PD onset related to a loss of nicotinic response in prodromal stages., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The mechanisms underlying presenilin 1 (PSEN1) mutation-associated spastic paraparesis (SP) are not clear. We compared diffusion and volumetric magnetic resonance measures between 3 persons with SP associated with the A431E mutation and 7 symptomatic persons with PSEN1 mutations without SP matched for symptom duration. We performed amyloid imaging and central motor and somatosensory conduction studies in 1 subject with SP. We found decreases in fractional anisotropy and increases in mean diffusivity in widespread white-matter areas including the corpus callosum, occipital, parietal, and frontal lobes in PSEN1 mutation carriers with SP. Volumetric measures were not different, and amyloid imaging showed low signal in sensorimotor cortex and other areas in a single subject with SP. Electrophysiological studies demonstrated both slowed motor and sensory conduction in the lower extremities in this same subject. Our results suggest that SP in carriers of the A431E PSEN1 mutation is a manifestation of widespread white-matter abnormalities not confined to the corticospinal tract that is at most indirectly related to the mutation's effect on amyloid precursor protein processing and amyloid deposition., Competing Interests: The authors have no conflict of interest to disclose., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Parkinsonism is a clinical syndrome, which is characterized by bradykinesia, rigidity, rest tremor, and postural instability. Idiopathic Parkinson disease (PD) is the most common cause of this syndrome, though there are several other important etiologies that must be considered. These include the atypical Parkinsonian disorders multiple system atrophy (MSA), dementia with Lewy Bodies (DLB), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS); as well as secondary causes of parkinsonism. These various disease entities may be distinguished based on key clinical features, which is critical for the purposes of diagnosis, treatment, and prognosis., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Huntington disease (HD) is an autosomal dominant, adult-onset, progressive neurodegenerative disease characterized by the triad of abnormal movements (typically chorea), cognitive impairment, and psychiatric problems. It is caused by an expanded CAG repeat in the gene encoding the protein huntingtin on chromosome 4 and causes progressive atrophy of the striatum as well as cortical and other extrastriatal structures. Genetic testing has been available since 1993 to confirm diagnosis in affected adults and for presymptomatic testing in at-risk individuals. This review covers HD signs, symptoms, and pathophysiology; current genetic testing issues; and current and future treatment strategies., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects. Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6-5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3-4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.

The motor examination section of the unified Parkinson's disease rating scale (UPDRS) is widely used in research but few studies have examined whether subscales exist that tap relatively distinct motor abnormalities. We analyzed data from 193 persons enrolled in a population-based study in Central California. Patients were examined after overnight PD medication washout ("OFF" state) and approximately one hour after taking medication ("ON" state). We performed confirmatory factor analysis of the UPDRS for OFF and ON state examinations; correlations, reliability, and relative validity of resulting subscales were evaluated. A model with five factors (gait/posture, tremor, rigidity, bradykinesia affecting the left extremities, bradykinesia affecting the right extremities) fit the data well, with similar results for OFF and ON states. Internal consistency reliability coefficients were 0.90 or higher for all subscales. The gait/posture subscale most strongly discriminated across levels of patient reported PD symptom severity and of how PD affects them on a daily basis. Compared to the right sided bradykinesia subscale, the left sided bradykinesia subscale had higher discrimination across levels of self-reported PD symptom severity and functional impairment. This supports motor UPDRS containing multiple subscales that can be analyzed separately and provide information distinct from the total score that may be useful in clinical studies.

We assessed degree of Parkinson disease motor symptom improvement with medication among subjects enrolled in an ongoing, population-based study in Central California. The motor section of the unified Parkinson disease rating scale (UPDRS) was performed on subjects in both OFF and ON medication states, and difference between these scores was used as an indicator of symptomatic benefit. Higher OFF minus ON scores correlated with more severe baseline symptoms. There was equivalent improvement on the motor UPDRS scale for subjects divided according to medication classes used: levodopa alone 7.3 points, levodopa plus other medications 8.5 points, and dopamine agonists but not levodopa 6.1 points. In addition, there was no difference in the magnitude of improvement when subjects were divided according to Parkinson disease subtype, defined as tremor dominant, akinetic-rigid, or mixed. In this community-based sample, these values are within the range of a clinically important difference as defined by previous studies.

Objective: To investigate associations between statin (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor) use and Parkinson disease (PD)., Methods: We used a population-based design to recruit 312 incident idiopathic PD cases and 342 controls from three rural California counties., Results: We observed a higher frequency of statin use among controls vs cases (OR 0.45; 95% CI 0.29 to 0.71) and a strong dose-response relation. The strongest protective association between statin use and PD was observed in long-term (>or=5 years) users (OR 0.37; 95% CI 0.18 to 0.78). There was no difference by gender or age. We noted 60 to 70% risk reductions for each individual statin except pravastatin., Conclusion: Ascribing causality to these associations is premature and further studies are needed to confirm a potential neuroprotective role for statins in PD.

Objective: Markers of neuroinflammation, including activated microglia and increased levels of circulating proinflammatory cytokines, have been observed in the brains and CSF of patients with Parkinson disease (PD). Yet the link between anti-inflammatory agents and PD in humans remains uncertain, despite indications that neuroinflammation may contribute to cell death in the PD brain and experimental evidence of anti-inflammatory agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) exerting neuroprotective effects in animal models., Methods: Using a population-based approach, we studied NSAID use among 293 incident idiopathic PD cases and 286 age-, race-, and gender-matched controls from three rural California counties., Results: Our data suggested a decreased risk of PD among regular (>or=2 pills/week for at least 1 month) aspirin NSAID users (OR, 0.80; 95% CI, 0.56 to 1.15). A stronger protective effect was observed for regular nonaspirin NSAID users (OR, 0.52; 95% CI, 0.35 to 0.79), particularly those who reported 2 or more years of use (OR, 0.44; 95% CI, 0.26 to 0.74). The aspirin effect estimates differed by gender, showing a protective effect only in women, especially among long term (>or=24 months) regular users (OR, 0.51; 95% CI, 0.26 to 1.02)., Conclusion: Our study contributes to the growing body of literature suggesting a protective role for nonsteroidal anti-inflammatory drugs (NSAIDs) in Parkinson disease (PD). Given our results and the biologic plausibility of a neuroprotective function for NSAIDs there is a pressing need for further studies elucidating the protective role such drugs may play in PD.

Movement disorders are not commonly seen during pregnancy. As a result, there are few studies on whether disease manifestations are affected by the hormonal changes that occur during pregnancy or on the teratogenicity of commonly used medications for movement disorders on the developing fetus. This article discusses movement disorders that are seen only during pregnancy (chorea gravidarum) or that may present during pregnancy (restless legs syndrome), the effect that pregnancy has on symptoms and treatment (in Parkinson's disease, essential tremor, dystonia, tic disorders, and Wilson's disease), and the role of genetic testing for movement disorders in genetic counseling for pregnant women.

The phenomenon of ischemic preconditioning was initially observed over 20 years ago. The basic tenant is that if stimuli are applied at a subtoxic level, cells upregulate endogenous protective mechanisms to block injury induced by subsequent stress. Since this discovery, many conserved signaling mechanisms that contribute to activation of this potent protective program have been identified in the brain. A clinical correlate of this basic research finding can be found in patients with a history of transient ischemic attack (TIA), who have a decreased morbidity after stroke. In spite of multidisciplinary efforts to design safer, more effective stroke therapies, we have thus far failed to translate our understanding of endogenous protective pathways to treatments for neurodegeneration. This review is designed to provide clinicians and basic scientists with an overview of stress biology after TIA and preconditioning, discuss new therapeutic strategies to target the protein dysfunction that follows ischemic injury, and propose enhanced biochemical profiling to identify individuals at risk of stroke after TIA. We pay particular attention to the unanticipated consequences of overly aggressive intervention after TIA in which we have found that traditional cytotoxic agents such as free radicals and apoptosis associated proteases is essential for neuroprotection and communication in the stressed brain. These data emphasize the importance of understanding the complex interplay between chaperones, apoptotic proteases including caspases, and the proteolytic degradation machinery in adaptation to neurological injury.

Although excitotoxic injury is thought to play a role in many pathologic conditions, the type of cell death induced by excitotoxins in vivo and the basis for the differential vulnerability of neurons to excitotoxic injury are still poorly understood. Morphologic alterations and the presence of DNA damage were examined in adult rat striatum after an intrastriatal injection of low doses of quinolinic acid, a N-methyl-D-aspartate receptor agonist. Rats were killed 6, 8, 10, or 12 hours after quinolinate or vehicle injection. Numerous neurons with necrotic morphologies were detected in the quinolinate-injected striata. In addition, few neurons with apoptotic morphologies were found in the dorsomedial striatum. DNA strand breaks were detected in tissue sections by in situ nick translation with (35)S-radiolabeled nucleotides and emulsion autoradiography. Labeled cells were first detected outside the needle track 10 hours after quinolinate injection and, on average, 20% of neurons exhibited DNA damage by 12 hours after surgery. DNA damage was found in cells with both apoptotic and necrotic morphologies. A marked differential vulnerability to DNA damage at this time was observed in two striatal compartments, the striosomes, identified as regions of dense [(3)H]naloxone binding, and the extrastriosomal matrix: the great majority of labeled cells were found in the extrastriosomal matrix and extremely few were seen in the striosomes. This preferential distribution was not due to premature cell death in the striosomes which contained numerous unlabeled neurons. The results suggest a greater vulnerability of neurons in the matrix, versus the striosomes, to early excitotoxin-induced DNA damage in rat striatum., (Copyright 1999 Wiley-Liss, Inc.)

The long-term effects of intrastriatal injections of the agonist of N-methyl-D-aspartate receptors, quinolinic acid, have been extensively characterized. Much less is known, however, about the early molecular and neurochemical changes which occur within a few hours of the toxin injection. In the present study, we have performed intrastriatal injections of low doses of quinolinic acid which induce DNA damage 10-12 h post-lesion, and selective death of striatal projection neurons two weeks later. We examined the time-course of alterations in the microtubule-associated protein 2, an early marker of cytoskeletal disruption, and enkephalin and substance P, two neuropeptides present in largely distinct subpopulations of striatal efferent neurons projecting to the globus pallidus and entopeduncular nucleus, respectively. Immunoreactivity for microtubule-associated protein 2 was decreased at the periphery of the lesion 10 h after quinolinate injection. Levels of enkephalin messenger RNA were markedly decreased as early as 6 h post-lesion; however, a significant decrease in enkephalin immunoreactivity was not observed in the globus pallidus (external pallidum) until 12 h post-injection. Levels of substance P messenger RNA were decreased 12 h post-injection in striatal neurons. However, in contrast to enkephalin immunoreactivity, immunolabeling for substance P was not significantly decreased at this time-point in the internal pallidum, a finding reminiscent of early grades of Huntington's disease. The results reveal the time-course of change in messenger RNA and peptide levels in striatal efferent neurons shortly after an excitotoxic insult. These data have implications for the interpretation of findings in post mortem brain and mouse models of Huntington's disease.

Changes in neuronal activity and extracellular concentrations of ions were measured in rat striatum for 60-90 min after intrastriatal injection of quinolinic acid, an agonist of the N-methyl-D-aspartate receptor. The excitotoxin induced bursts of synchronous electrical activity which were accompanied by rises in [K+]e (to approximately 6 mM) and decreases in [Ca2+]e (by less than 0.1 mM); [H+]e usually increased (0.1-0.3 pH unit) after a short and small (< 0.1 pH unit) alkaline shift. The magnitude and frequency of these periodic changes decreased with time; after 90 min the amplitudes fell to 10-20% of the early values and the frequency to about one every 8 min as compared to one every 2-3 min immediately after quinolinate injection. By 90 min there was an increase in [K+]e from 3.3 mM to 4.2 mM and a decrease in [Ca2+]e from 1.34 mM to 1.30 mM. It is postulated that activation of the N-methyl-D-aspartate receptor causes disturbances in neuronal activity and ion gradients; restoration of the original ionic balances raises utilization of ATP and places an additional demand on energy-producing pathways. Increased influx of calcium into neurons may lead to an enhanced accumulation and subsequent overload of mitochondria with the cation. This, in turn, could result in dysfunction of the organelles and account for the decrease in respiration and [ATP]/[ADP] that have been observed previously in this model. The results of the present study lead to the conclusion that quinolinic acid produces early changes in activity of striatal neurons and movements of several cations which may contribute to subsequent abnormalities in energy metabolism and ultimately, cell death.

Impairment of mitochondrial energy metabolism may contribute to the selective neuronal degeneration observed in Huntington's disease and other neurodegenerative disorders. Intrastriatal injection of the excitotoxin, quinolinic acid, produces a pattern of neuronal death similar to that seen in Huntington's disease. However, little is known about the effects of quinolinic acid on striatal energetics. In the present work, time-dependent changes in energy metabolism caused by injection of quinolinic acid into rat striatum were examined. Oxygen consumption by free and synaptic mitochondria was quantified and correlated with the concentrations of nucleotides and amino acids at different times after injection. Compared with saline-treated controls, a decrease in ADP-stimulated (state 3) to basal (state 4) oxygen consumption (respiratory control ratio) by free mitochondria was apparent in quinolinic acid-injected striata as early as 6 h after treatment. No significant changes were seen in nucleotide concentrations at this time. By 12 h after injection, the decline in the respiratory control ratio was more pronounced (45%), and reductions in ATP, NAD, aspartate, and glutamate (30-60%) were also observed. These results show that injection of quinolinic acid in vivo produces progressive mitochondrial dysfunction, which may be a common and critical event in the cell death cascade initiated in Huntington's disease and in animal models of this neurodegenerative disorder. The indicators of mitochondrial function examined in this study, therefore, may be useful in evaluating the efficacy of neuroprotective agents.