Neuroimaging methods applied in Parkinson’s disease

Abstract. Radiotracer methods provide regional in vivo quantified information about specific biochemical activities in brain tissue. The understanding of the principles governing radiotracer uptake into brain tissue determines the potential value of these tracers in assessing pathophysiology of brain diseases. Too often a reductionist view of images is taken to directly point to clinical features or even diagnoses of brain diseases. Parkinsons disease like many other neurodegenerative brain diseases is a multisystem disorder of considerable biological and clinical complexity while the information given by regional cerebral tracer uptake points to a momentary biochemical local tissue feature. Examples applying to the well-known dopaminergic tracers are given.     

Fenestration methods for Sylvian arachnoid cysts—endoscopy or microsurgery

Introduction  

Two different approaches to fenestration, endoscopic and microsurgical, are in use for Sylvian arachnoid cysts (SACs), the most frequent among intracranial arachnoid cysts. We presented the clinical data and compared our results, with regard to technique and clinical success, with either microsurgical or neuroendoscopic fenestration of SACs.     

Evaluation of α-synuclein immunohistochemical methods used by invited experts

The use of α-synuclein immunohistochemistry has altered our concepts of the cellular pathology, anatomical distribution and prevalence of Lewy body disorders. However, the diversity of methodology between laboratories has led to some inconsistencies in the literature. Adoption of uniformly sensitive methods may resolve some of these differences. Eight different immunohistochemical methods for demonstrating α-synuclein pathology, developed in eight separate expert laboratories, were evaluated for their sensitivity for neuronal elements affected by human Lewy body disorders. Identical test sets of formalin-fixed, paraffin-embedded sections from subjects diagnosed neuropathologically with or without Lewy body disorders were stained with the eight methods and graded by three observers for specific and nonspecific staining. The methods did not differ significantly in terms of Lewy body counts, but varied considerably in their ability to reveal neuropil elements such as fibers and dots. One method was clearly superior for revealing these neuropil elements and the critical factor contributing to its high sensitivity was considered to be its use of proteinase K as an epitope retrieval method. Some methods, however, achieved relatively high sensitivities with optimized formic acid protocols combined with a hydrolytic step. One method was developed that allows high sensitivity with commercially available reagents. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Do alternate methods of analysing motor evoked potentials give comparable results?

This study assessed the reliability of alternate methods of analysis of motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS). We recorded two sets of MEPs (Time 1 and Time 2) at the optimal scalp sites for both the right first dorsal interosseous (FDI) and flexor carpi ulnaris (FCU) at two different stimulation intensities in 10 healthy subjects. MEP magnitude was determined in each of the following three ways: the mean peak-to-peak amplitude and area of the 20 individual responses; the amplitude and area of the ensemble averaged waveform; and the amplitude and area of the maximal response. There was no significant difference in amplitude or area for either muscle using any of the three methods between Time 1 and 2. However, the ensemble average (area and amplitude) was significantly smaller that the mean MEP, and the maximal MEP amplitude was significantly larger. Intraclass correlation analysis demonstrated that reliability of MEP measures over time was poor regardless of method. Reliability was similar between methods for FDI, but FCU had lower reliability values for the mean and ensemble average methods than the maximal method.     

New insight in spiral drawing analysis methods – Application to action tremor quantification

Objective

Spiral drawing is one of the standard tests used to assess tremor severity for the clinical evaluation of medical treatments. Tremor severity is estimated through visual rating of the drawings by movement disorders experts. Different approaches based on the mathematical signal analysis of the recorded spiral drawings were proposed to replace this rater dependent estimate. The objective of the present study is to propose new numerical methods and to evaluate them in terms of agreement with visual rating and reproducibility.

Treating Alzheimer's disease: do clinical trial methods produce unnecessary practitioner dilemmas?

Recent clinical trials and critical reviews of Alzheimer's disease (AD) research discourage already relatively sparing clinical uses of cholinesterase inhibitors (ChEIs) considering the prevalence of AD. As evidence against use of this class of drugs, detractors cite critical reviews of ChEIs and lack of long-term health benefits found in one long-term clinical trial. This paper describes the use of standard error of measurement to allow investigators to design clinical trials that address these issues. The new clinical trial procedures afford sufficient precision for two purposes. First, practitioners can assess individual patients with precision and certainty in their observations. Second, clinical trial researchers can study how short-term drug effects on individual patients predict long-term benefits from continued treatment. With these more clinically informative clinical trial designs, investigators would be able to avoid uncertainties currently raised by conflicts between short- and long-term AD clinical trials.     

Assessment of Alzheimer’s disease case–control associations using family-based methods

The genetics of Alzheimer's disease (AD) is heterogeneous and remains only ill-defined. We have recently created a freely available and continuously updated online database (AlzGene; http://www.alzgene.org ) for which we collect all published genetic association studies in AD and perform systematic meta-analyses on all polymorphisms with sufficient genotype data. In this study, we tested 27 genes (ACE, BDNF, CH25H, CHRNB2, CST3, CTSD, DAPK1, GALP, hCG2039140, IL1B, LMNA, LOC439999, LOC651924, MAPT, MTHFR, MYH13, PCK1, PGBD1, PRNP, PSEN1, SORCS1, SORL1, TF, TFAM, TNK1, GWA_14q32.13, and GWA_7p15.2), all showing significant association with AD risk in the AlzGene meta-analyses, in a large collection of family-based samples comprised of 4,180 subjects from over 1,300 pedigrees. Overall, we observe significant association with risk for AD and polymorphisms in ACE, CHRNB2, TF, and an as yet uncharacterized locus on chromosome 7p15.2 [rs1859849]. For all four loci, the association was observed with the same alleles as in the AlzGene meta-analyses. The convergence of case-control and family-based findings suggests that these loci currently represent the most promising AD gene candidates. Further fine-mapping and functional analyses are warranted to elucidate the potential biochemical mechanisms and epidemiological relevance of these genes.     

Olfaction in Parkinson’s disease: methods of assessment and clinical relevance

Several neurological conditions have been reported to be associated with peripheral or central deficits of olfactory system. In recent years particular emphasis has been placed on the early and severe olfactory impairment in Parkinson’s disease (PD), in which limited neuropathological studies have revealed a marked dopaminergic deficit in the olfactory tubercles. Moreover, indirect evidence suggests that dysfunction of the dopaminergic pathways from mesencephalon to the piriform cortex may play a role in olfactory impairment in PD. A large number of clinical studies have reported that olfactory loss in idiopathic PD is bilateral, present in hemiparkinsonism, unrelated to the stage or clinical subtype of the disease, and independent of antiparkinsonian medication. In addition, major olfactory alterations have been reported in familial PD and dementia with Lewy bodies but not in progressive supranuclear palsy and essential tremor. These findings might stimulate further research targeted to determine the biological substrate of dissimilar olfactory performances in these movement disorders. The present review summarizes standardized procedures for the assessment of olfactory acuity (detection threshold), identification (multiple choice odor naming), discrimination (differentiation between similar/dissimilar odorants), and memory (recognition of a substance previously smelled). Specific suggestions concerning the psychometric and neuropsychological evaluation of PD patients are provided. Received: 17 April 1999/Received in revised form: /29 September 1999/Accepted: 1 October 1999     

Evaluation of suprachiasmatic nucleus in Alzheimer’s disease with non-invasive magnetic resonance methods

The suprachiasmatic nucleus and Alzheimer’s disease(AD):AD is the most frequently diagnosed form of dementia,with the total number of AD patients worldwide expected to triple by 2050 compared to 2015(Prince et al.,2015).Despite years of research,much of the AD pathology remains unclear with no treatment or cure available.Besides its two hallmarks,amyloid-β(Aβ)plagues and hyperphosphorylated tau tangles,a distortion of circadian rhythms is commonly observed.Furthermore,poor sleep quality or trouble falling asleep are common AD symptoms,sometimes developing 10-15 years before cognitive symptoms associated with AD(Ju et al.,2014).     

Who comes from where and who goes where? Treatment methods for psychiatric inpatients

Based on data of the psychiatric basic documentation of 4066 patients, predictors of type of referral as well as outpatient aftercare were analyzed by means of logistic regression analyses. Of the patients, 25.7% were admitted without any referral, 18.4% were referred by a general practitioner, and 9.8% by a psychiatrist in private practice. Patients referred by a general practitioner suffered more frequently from an affective disorder or schizophrenia and were residents of senior citizen homes. Inpatients sent by a psychiatrist were more often residents of sheltered homes, showed a present episode lasting more than 3 months, and had undergone psychopharmacological pretreatment with an atypical antipsychotic or SSRI. Outpatient aftercare was recommended to 83.1% of inpatients: 49.4% by a general practitioner and 32.1% by a psychiatrist in private practice. Outpatient aftercare by a general practitioner was more frequent in the elderly and patients with addiction disorders. Referral by a psychiatrist in private practice as well as schizophrenia or an affective disorder led more often to outpatient aftercare by a psychiatrist. The small number of patients referred by general practitioners and psychiatrists in private practice has to become the focus of quality management.     

Age and methods of fatal self harm (FSH). Is there a link?

OBJECTIVES: To examine the methods of fatal self harm (FSH) used by the elderly compared to young adults. METHODS: We compared the methods of FSH used by all the elderly over 60 years of age to those used by all younger adults, over 16 and under 60, in the city of Birmingham and Solihull over a period of 4 years, 1995-1998. We applied the term FSH to all deceased who were subjects of Coroner's inquests and attracted verdicts of suicide and open verdicts. FINDINGS: A significantly higher proportion of the elderly who fatally harmed themselves did so by drowning and asphyxia compared to the younger age group (p < 0.05 and p < 0.01, respectively). Significantly more women over the age of 60 committed acts of FSH by tying a plastic bag around the neck than those under 60 (p < 0.05). Method of death was not ascertained in a much higher proportion of elderly FSH (p < 0.01). The most common method of suicide among elderly men and women were hanging and self-poisoning by overdose, respectively. CONCLUSION: The study shows that the most common method of suicide in the elderly is poisoning by drug overdose. It raises the question about the quantity of drugs prescribed for the elderly, e.g. antidepressants, sedatives and pain killers. The study did not confirm previous reports that violent methods are used more frequently with increasing age.     

Do means matter?: Differences in characteristics of Finnish suicide completers using different methods

It is unclear whether suicides by different methods are distinguishable by their sociodemographic or clinical characteristics. We set out to investigate whether completed suicides by different methods show disparities in their sociodemographic and clinical characteristics. Within the National Suicide Prevention Project in Finland, all 1,397 suicides occurring April 1, 1987, through March 31, 1988, were investigated using the psychological autopsy method. Disparities were found in characteristics of suicide completers using different methods. Intoxication suicides were more often female and had a history of both previous attempts and psychiatric treatment, whereas suicides by shooting were the opposite in character. Victims using vehicle exhaust gas were most frequently younger males who had experienced a recent interpersonal loss or other adverse event and committed suicide while intoxicated with alcohol. Thus, typical characteristics associate with certain suicide methods, probably due to differences in availability and acceptability of the methods. Various restrictions on the availability of suicide methods are likely to exert their possible impact on somewhat different subpopulations at risk. In terms of suicide prevention, it seems reasonable to target availability restrictions for certain identifiable groups of potential suicide attempters. For instance, carefulness in the practice of prescribing of intoxicating substances to particular psychiatric patients seems justified.     

Delayed peripheral nerve repair: methods,including surgical ‘cross-bridging' to promote nerve regeneration

Despite the capacity of Schwann cells to support peripheral nerve regeneration, functional recovery after nerve injuries is frequently poor, especially for proximal injuries that require regenerating axons to grow over long distances to reinnervate distal targets. Nerve transfers, where small fascicles from an adjacent intact nerve are coapted to the nerve stump of a nearby denervated muscle, allow for functional return but at the expense of reduced numbers of innervating nerves. A 1-hour period of 20 Hz electrical nerve stimulation via electrodes proximal to an injury site accelerates axon outgrowth to hasten target reinnervation in rats and humans, even after delayed surgery. A novel strategy of enticing donor axons from an otherwise intact nerve to grow through small nerve grafts(cross-bridges) into a denervated nerve stump, promotes improved axon regeneration after delayed nerve repair. The efficacy of this technique has been demonstrated in a rat model and is now in clinical use in patients undergoing cross-face nerve grafting for facial paralysis. In conclusion, brief electrical stimulation, combined with the surgical technique of promoting the regeneration of some donor axons to ‘protect' chronically denervated Schwa nn cells, improves nerve regeneration and, in turn, functional outcomes in the management of peripheral nerve injuries.     

Middle cerebral artery occlusion methods in rat versus mouse model of transient focal cerebral ischemic stroke

<正>Experimental stroke research commonly employs focal cerebra ischemic rat models(Bederson et al.,1986a;Longa et al.,1989).In human patients,ischemic stroke typically results from thrombotic or embolic occlusion of a major cerebral artery,usually the middle cerebral artery(MCA).Experimental focal cerebral ischemia models have been employed to mimic human stroke(Durukan and Tatlisumak,2007).Rodent models of focal cerebral ischemia that     

Cerebral ischemia: from animal studies to clinical practice. Should the methods be reviewed?

The development of experimental models of focal cerebral ischemia has allowed for a better knowledge of its pathophysiology and for testing therapeutic strategies. However, most neuroprotective substances giving favorable results in these models have later not been shown to be clinically effective. This could be explained by several reasons. First, the homogeneity obtained in animal models in order to achieve results is not seen in clinical practice in humans, in whom a given pathological condition may show a high variability depending on several parameters. This makes it difficult to achieve groups of patients sufficiently large and homogeneous to obtain valid conclusions in the clinical trials. The lack of agreement between the experimental studies and the clinical practice can also be explained by other reasons, such as the methods of the experimental model itself; by the fact that the methods to assess results in these models are not comparable to those used in clinical practice; by pathophysiological differences between experimental animals and man, and even by the fact that the substances tested have different pharmacological properties in the different species. These disadvantages must not invalidate preclinical neuroprotection studies. Rather, the knowledge of the reasons for divergences with the clinical situation can help to optimize experimental models so that both become actually comparable, and the laboratory results can be confirmed by clinical studies.