Early diagnosis of neurodegenerative disorders such as Alzheimer's (AD) or Parkinson's disease (PD) is needed to slow down or halt the disease at the earliest stage. Cerebrospinal fluid (CSF) biomarkers can be a good tool for early diagnosis. However, their use in clinical practice is challenging due to the high variability found between centers in the concentrations of both AD CSF biomarkers (Aβ42, total tau and phosphorylated tau) and PD CSF biomarker (α-synuclein). Such a variability has been partially attributed to different preanalytical procedures between laboratories, thus highlighting the need to establish standardized operating procedures. Here, we merge two previous consensus guidelines for preanalytical confounding factors in order to achieve one exhaustive guideline updated with new evidence for Aβ42, total tau and phosphorylated tau, and α-synuclein. The proposed standardized operating procedures are applicable not only to novel CSF biomarkers in AD and PD, but also to biomarkers for other neurodegenerative disorders.

This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid-β, tau, and phosphorylated tau in the diagnostic evaluation of patients with mild cognitive impairment (MCI). The recommendations were developed by a multidisciplinary working group and based on the available evidence and consensus from focused group discussions for 1) prediction of clinical progression to Alzheimer's disease (AD) dementia, 2) cost-effectiveness, 3) interpretation of results, and 4) patient counseling. The working group recommended using CSF AD biomarkers in the diagnostic workup of MCI patients, after prebiomarker counseling, as an add-on to clinical evaluation to predict functional decline or conversion to AD dementia and to guide disease management. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Furthermore, the working group provided recommendations for interpretation of ambiguous CSF biomarker results and for pre- and post-biomarker counseling.

The spontaneous behavior of humans can be altered dramatically by repeated exposure to psychomotor stimulants. We have developed a primate model for analyzing the neurobiology underlying such drug-induced behavioral changes. We performed ethogram-based behavioral assays on squirrel monkeys given single or multiple cocaine treatments, and in the same monkeys made anatomical plots of striatal neurons that were activated to express early-gene proteins. A final cocaine challenge after chronic intermittent exposure to cocaine induced highly patterned behavioral changes in the monkeys, affecting individual behavioral motifs in distinct ways. In the striatum, the challenge dose induced striosome-predominant expression combined with intense dorsal early-gene expression, especially in the putamen. These patterns of gene expression were highly predictive of the levels of stereotypy exhibited by the monkeys in response to cocaine challenge. The total levels of expression, on the other hand, appeared to reflect increased spontaneous behavioral activation during the drug-free period after the cocaine exposure. We suggest that in the primate, compartmentally and regionally specific striatal activation patterns contribute to the striatal modulation of psychostimulant-induced behaviors. These observations in nonhuman primates raise the possibility that monitoring such basal ganglia activity patterns could help to delineate the neural mechanisms underlying drug-induced repetitive behaviors and related syndromes in which stereotypies are manifest.

This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid-β, tau, and phosphorylated tau in the diagnostic evaluation of patients with dementia. The recommendations were developed by a multidisciplinary working group based on the available evidence and consensus from focused discussions for (i) identification of Alzheimer's disease (AD) as the cause of dementia, (ii) prediction of rate of decline, (iii) cost-effectiveness, and (iv) interpretation of results. The working group found sufficient evidence to support a recommendation to use CSF AD biomarkers as a supplement to clinical evaluation, particularly in uncertain and atypical cases, to identify or exclude AD as the cause of dementia. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Operational recommendations for the interpretation of ambiguous CSF biomarker results were also provided.

Interneurons are critical for shaping neuronal circuit activity in many parts of the central nervous system. To study interneuron function in the basal ganglia, we tested and characterized an NK-1 receptor-based method for targeted ablation of specific classes of interneuron in the striatum. Our findings demonstrate that the neurotoxin SP-PE35, a substance P-Pseudomonas exotoxin conjugate, selectively targets striatal cholinergic and nitric oxide synthase͞somatostatinergic interneurons when injected locally into the striatum. The effects of this selective cell targeting encompassed alterations in both behavioral and neural responses to dopaminergic stimulation, including altered patterns of early-gene response in striosomes and matrix. We conclude that NK-1-bearing local circuit neurons of the striatum regulate the differential responses of striatal projection neurons to dopamine-mediated signaling.T he striosome and matrix compartments of the striatum are vividly demarcated by their differential expression of neurotransmitter-related compounds ranging from second messengers to neurotransmitters, neuropeptides, and their receptors (1, 2). The different connections of striosomes and matrix suggest that they participate differentially in limbic-based (striosome) and sensorimotor͞associative (matrix) forebrain circuits (3-6). No behavioral or electrophysiological assays have yet identified specific functions for these compartments, but indirect assays with intracranial self-stimulation (7), early-gene activity (8), and metabolic activity (9) suggest different neural operations for striosome-based and matrix-based circuits.How such differential functional activity is brought about in the two compartments is not known, but much interest is focused on the possibility that striatal interneurons differentially regulate activity in the striosomes and surrounding matrix (10-13). Two classes of interneuron have been implicated in such differential regulation: the cholinergic interneurons and the interneurons coexpressing nitric oxide synthase (NOS), somatostatin, and neuropeptide Y (NOS neurons). Both have been implicated in striatal plasticity, including the induction of long-term depression and long-term potentiation (14). Both lie mainly in the matrix and tend to lie at striosome-matrix borders (15-17).These two classes of striatal interneuron both express high levels of NK-1 receptor, the tachykinin receptor at which substance P (SP) acts (18). This differential NK-1 expression pattern suggested the possibility of using a toxin-induced ablation technique to destroy these interneurons selectively (19,20). We implemented this technology by injecting a neuronal toxin that in other systems selectively destroys neurons bearing SP (NK-1) receptors. ¶ SP-PE35 is a site-specific conjugate between a Nterminally derivatized SP peptide and an N-terminally truncated Pseudomonas exotoxin (PE35). SP-PE35 does not contain the native binding domain of the exotoxin (present on the amino end), but it does contain its endosome-release an...

Voluntary movement difficulties in Parkinson's disease are initially relieved by L-DOPA therapy, but with disease progression, the repeated L-DOPA treatments can produce debilitating motor abnormalities known as L-DOPA-induced dyskinesias. We show here that 2 striatum-enriched regulators of the Ras/Rap/ERK MAP kinase signal transduction cascade, matrix-enriched CalDAG-GEFI and striosome-enriched CalDAG-GEFII (also known as RasGRP), are strongly and inversely dysregulated in proportion to the severity of abnormal movements induced by L-DOPA in a rat model of parkinsonism. In the dopamine-depleted striatum, the L-DOPA treatments produce down-regulation of CalDAG-GEFI and upregulation of CalDAG-GEFII mRNAs and proteins, and quantification of the mRNA levels shows that these changes are closely correlated with the severity of the dyskinesias. As these CalDAGGEFs control ERK cascades, which are implicated in L-DOPA-induced dyskinesias, and have differential compartmental expression patterns in the striatum, we suggest that they may be key molecules involved in the expression of the dyskinesias. They thus represent promising new therapeutic targets for limiting the motor complications induced by L-DOPA therapy.dyskinesia ͉ ERK ͉ L-DOPA ͉ Parkinson's disease ͉ striatum

Reemergence of previous stroke-related deficits (or poststroke recrudescence [PSR]) is an underrecognized and inadequately characterized phenomenon. OBJECTIVE To investigate the clinical features, triggers, and risk factors for PSR. DESIGN, SETTING, AND PARTICIPANTS This retrospective study incorporated a crossover cohort study to identify triggers and a case-control study to identify risk factors. The study used the Massachusetts General Hospital Research Patient Data Repository to identify patients for the period January 1, 2000, to November 30, 2015, who had a primary or secondary diagnosis of cerebrovascular disease, who underwent magnetic resonance imaging of the brain at least once, and whose inpatient or outpatient clinician note or discharge summary stated the term recrudescence. In all, 153 patients met the preliminary diagnostic criteria for PSR: transient worsening of residual poststroke focal neurologic deficits or transient recurrence of prior stroke-related focal deficits, admission magnetic resonance imaging showing a chronic stroke but no acute infarct or hemorrhage, no evidence of transient ischemic attack or seizure, no acute lesion on diffusion-weighted imaging, and no clinical or electroencephalographic evidence of seizure around the time of the event. MAIN OUTCOMES AND MEASURES Clinical and imaging features of PSR; triggers (identified by comparing PSR admissions with adjacent admissions without PSR); and risk factors (identified by comparing PSR cases with control cases from the Massachusetts General Hospital Stroke Registry). RESULTS Of the 153 patients, 145 had prior infarct, 8 had hypertensive brain hemorrhage, and 164 admissions for PSR were identified. The patients' mean (SD) age was 67 (16) years, and 92 (60%) were women. Recrudescence occurred a mean (SD) of 3.9 (0.6) years after the stroke, lasted 18.4 (20.4) hours, and was resolved on day 1 for 91 of the 131 episodes with documented resolution time (69%). Deficits were typically abrupt and mild and affected motor-sensory or language function. No patient had isolated gaze paresis, hemianopia, or neglect. During PSR, the National Institutes of Health Stroke Scale (NIHSS) score worsened by a mean (SD) 2.5 (1.9) points, and deficits were limited to a single NIHSS item in 62 episodes (38%). The underlying chronic strokes were variably sized, predominantly affected white matter tracts, and involved the middle cerebral artery territory for 112 patients (73%). Infection, hypotension, hyponatremia, insomnia or stress, and benzodiazepine use were higher during PSR admissions. Compared with the control group (patients who did not experience recrudescence), the PSR group (patients who were hospitalized for recrudescence) had more women, African American individuals, and those who self-identified as being from "other" race. The PSR group also had more diabetes, dyslipidemia, smoking, infarcts from small-vessel disease, and "other definite" causes and worse onset NIHSS scores. Six patients (4%) received intravenous tissue plasminogen activator wi...

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