Esen Saka

Recommendations to standardize preanalytical confounding factors in Alzheimer's and Parkinson's disease cerebrospinal fluid biomarkers: an update

Early diagnosis of neurodegenerative disorders such as Alzheimers (AD) or Parkinsons 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.

Repetitive Behaviors in Monkeys Are Linked to Specific Striatal Activation Patterns

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.

Dysregulation of CalDAG-GEFI and CalDAG-GEFII predicts the severity of motor side-effects induced by anti-parkinsonian therapy

Voluntary movement difficulties in Parkinsons 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 up-regulation 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 CalDAG-GEFs 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.

Compartmental changes in expression of c-Fos and FosB proteins in intact and dopamine-depleted striatum after chronic apomorphine treatment.

Chronic administration of dopaminergic agonists to rats with unilateral 6-OH-dopamine (6-OHDA) lesions of nigrostriatal pathway produces behavioral sensitization to subsequent agonist challenges and may serve as a model for DOPA-induced dyskinesias. In order to understand striatal mechanisms behind this long-term behavioral change we examined striatal c-Fos and FosB immunoreactivity induced by apomorphine challenge (5 mg/kg, s.c.) after 3 days of withdrawal following a 2-week administration (5 mg/kg, b.i.d., s.c.) both in intact and 6-OHDA-lesioned animals. In intact rats, c-Fos induction by acute apomorphine exposure showed a striosomal pattern, whereas FosB immunopositivity was diffusely distributed. Following chronic administration, FosB induction turned to a clear striosome dominant pattern similar to c-Fos expression. In denervated striatum, expression of both proteins was profoundly augmented in a homogeneous pattern after a single dose of apomorphine. A distinct striosomal patterning appeared after chronic apomorphine administration in ventromedial part of the denervated striatum with a down-regulation in the matrix and relative enhancement in striosomes. These results suggest that compartmental reorganization of striatal neuronal activity may play a role in long-term behavioral changes induced by chronic dopaminergic treatments both under normal and dopamine-depleted conditions.

Short latency afferent inhibition in Parkinson's disease patients with dementia†

Cortical cholinergic deficiency occurs in Parkinsons disease (PD) and is more severe in PD dementia (PDD). Short‐latency afferent inhibition (SAI) can be used as an in vivo test for the evaluation of the cholinergic circuit in the cerebral motor cortex.

Recommendations for CSF AD biomarkers in the diagnostic evaluation of dementia

This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid‐β1–42, 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 Alzheimers 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.

Enhanced cued recall and clock drawing test performances differ in Parkinson's and Alzheimer's disease-related cognitive dysfunction

Cognitive impairment either as dementia (PD-D) or mild cognitive impairment (PD-MCI) is common in Parkinsons disease (PD). The clinical features and cognitive profile differs from Alzheimers disease (AD) or amnestic MCI (aMCI). In this study we aim to disclose the utility of pre-selected practical neuropsychological tests in differentiation of PD-D and AD, and also PD-MCI and aMCI. Consecutive cases with mild to moderate AD (n = 32) and PD-D (n = 26); aMCI (n = 34) and PD-MCI (n = 19) were evaluated. Although MMSE scores were similar in PD-D and AD or in PD-MCI and aMCI groups, memory impairment assessed by enhanced cued recall (ECR) was more apparent in AD than PD-D; and ECR scores tended to be worse in aMCI group than PD-MCI group. In contrast, clock drawing was more impaired in PD-D than AD. For differentiation of PD-D from AD, ECR, clock drawing and letter fluency were found to be valuable with moderately high sensitivity and specificities. In differentiation of aMCI and PD-MCI, ECR, clock drawing test and copying of intersecting pentagons were helpful. Stepwise linear discrimination function analysis disclosed that combination of ECR and clock drawing tests correctly classified 70.7% of the overall study population (71.4% of AD, 71.9% of aMCI, 69.6% of PD-D and 68.8% of PD-MCI). These findings suggest that ECR and clock drawing tests can be valuable as an additive to clinical diagnostic criteria in differentiation of PD-D and PD-MCI cases from AD and aMCI.

Recommendations for cerebrospinal fluid Alzheimer's disease biomarkers in the diagnostic evaluation of mild cognitive impairment

This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid‐β1–42, 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 Alzheimers 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.

Differential effects of antipsychotics on hippocampal presynaptic protein expressions and recognition memory in a schizophrenia model in mice

We compared the effects of subchronic clozapine and haloperidol administration on the expression of SNAP-25 and synaptophysin in an animal model of schizophrenia based on the glutamatergic hypothesis. Mice were first treated with a non-competitive NMDA antagonist MK-801 (0.3 mg/kg/day) or saline for 5 days, and then clozapine (5 mg/kg/day), haloperidol (1 mg/kg/day) or saline was administered for two weeks. The locomotion test, as a behavioral model of the positive symptoms of schizophrenia, was applied after MK-801/saline administration on day 6 for acute effects and after antipsychotic/saline administration on day 19 for enduring effects on mice activity. Memory function was assessed by the Novel Object Recognition (NOR) test, one day after the last day of antipsychotic/saline administration (day 20). Western Blotting technique was used to determine SNAP-25 and synaptophysin expressions in the hippocampus and frontal cortex. Both antipsychotics reversed the enhanced locomotion effects of MK-801. MK-801 and haloperidol decreased recognition memory performance. On the other hand, clozapine did not compromise memory. It also did not reverse the negative effects of MK-801 on memory performance. MK-801 did not change SNAP-25 and synaptophysin expressions in the hippocampus and frontal cortex. Clozapine increased hippocampal SNAP-25, decreased hippocampal synaptophysin expression, whereas frontal SNAP-25 and synaptophysin expressions remained unchanged. Haloperidol had no effects on levels of SNAP-25 and synaptophysin in the frontal cortex and hippocampus. These findings support the idea that the differential effects of clozapine might be related to its plastic effects and synaptic reorganization of the hippocampus.

Familial adult onset myoclonic epilepsy associated with migraine

We report a new type of migraine associated epileptic syndrome in a family: adult onset myoclonic epilepsy with benign course and migraine. Affected members of the family had myoclonic and rare generalised tonic-clonic seizures. Most of the patients, but not all, had a history of migraine. Also, some cases of the family had only migraine. This family will be discussed because of two distinct features. Firstly, in this family a different type of epilepsy, adult onset myoclonic epilepsy was diagnosed that has not been classified in the ILAE 1989, classification(s), but was similar to that previously reported in Japanese families. Secondly, in most of the cases migraine was associated with the epilepsy.