Does early detection of non-motor symptoms facilitate early treatment of Parkinson's disease?

Parkinson's disease (PD) is the second most common neurodegenerative disorder. The risk of developing of PD increases with age, it is estimated that the prevalence rate is approximately 150/100,000 in Japan. Recently, non-motor symptoms such as anosmia, autonomic failure, sleep disorders, sensory problems, depression, anxiety, cognitive disorders (including dementia), and psychosis are interested in the pathogenetic process of PD. According to the Braak's hypothesis, these non-motor symptoms precede the onset of the classic motor symptoms of PD. Many studies have shown that the number of neurons in the substantia nigra is decreased to approximately -40 to -60% in number when the motorsymptoms of PD are developed. In this article, review of special references regarding the natural history of PD shows that non-motor symptoms are the prodromal signs of PD. If disease modification therapy and/or disease prevention therapy is approved in the future, an early and accurate diagnosis of PD is needed. Accurate early diagnostic biomarkers including symptoms, some compounds, and radiological markers need to be identified.     

Can simultaneously acquired electrodermal activity improve accuracy of fMRI detection of deception?

Observation of changes in autonomic arousal was one of the first methodologies used to detect deception. Electrodermal activity (EDA) is a peripheral measure of autonomic arousal and one of the primary channels used in polygraph exams. In an attempt to develop a more central measure to identify lies, the use of functional magnetic resonance imaging (fMRI) to detect deception is being investigated. We wondered if adding EDA to our fMRI analysis would improve our diagnostic ability. For our approach, however, adding EDA did not improve the accuracy in a laboratory-based deception task. In testing for brain regions that replicated as correlates of EDA, we did find significant associations in right orbitofrontal and bilateral anterior cingulate regions. Further work is required to test whether EDA improves accuracy in other testing formats or with higher levels of jeopardy.     

Does a detection team shorten duration of untreated psychosis?

Introduction: Duration of untreated psychosis (DUP) is shown to be associated with poor outcome in many domains. It has been shown that it is possible to shorten DUP when combining a detection team and an information campaign. The aim of this study was to evaluate whether DUP was shortened during the first 3 years after establishing detection teams without a concomitant information campaign. Methods: All patients included in the OPUS trial were examined with the Instrument for Retrospective Assessment of Onset of Psychosis to determine DUP. A total of 552 patients with first episode psychotic disorder (n = 470) or schizotypal disorder (n = 82) were included in the study. The 3‐year inclusion period was divided into six consecutive periods of 6 months each. Results: The median DUP was 52 weeks. DUP was not significantly reduced during the 3‐year inclusion period, but a larger proportion of patients with symptoms below the threshold for frank psychosis were included compared with the beginning of the trial. The proportion referred from primary care remained small (8–10%) and unchanged during the inclusion period. Discussion: The availability of a detection team increased the referral of patients with schizotypal disorder, but the DUP among psychotic patients remained almost unaltered throughout the period. It seems that an information campaign and possibilities for direct access and self‐referral are necessary in order to shorten DUP.     

Early detection and treatment of schizophrenia: how early?

OBJECTIVE: Whereas early detection and therapy of schizophrenic psychoses until some time ago concentrated on frank schizophrenia, during the last years some centres have also started to treat patients even before a clear diagnosis could be established. This paper attempts to discuss if and when this is justified in the light of recent research. METHOD: Mini review of literature. RESULTS: The rationale for early detection and treatment of schizophrenia is based on several observations: diagnosis and treatment of schizophrenia are often seriously delayed. Consequences of the disease are severe already in the early undiagnosed phase of the disorder and early treatment seems to improve the course of the disease. It can therefore be stated quite safely that patients should be treated as early as possible. However, the question of how early has not been sufficiently answered up to now. CONCLUSION: We are at the moment in an ethical dilemma between either diagnosing and treating this disorder too late or too early. The only way and prerequisite for solving this dilemma is a more reliable identification of individuals at risk and the beginning disease process.     

Can digit symbol-verbal fluency comparisons facilitate detection of pseudodementia?

Depressive psychomotor retardation may impair performance on timed tests. By comparison word association measures of verbal fluency are reportedly unaffected by depression. Comparisons of a brief psychomotor test with a measure of verbal fluency may therefore prove useful when there is a concern that depression may be undermining adaptive functioning, assuming both measures display: (1) broad-spectrum sensitivity to brain impairment, (2) differential vulnerability to depression, and (3) moderate correlation in nondepressed persons. Digit Symbol (DS) and the FAS measure of verbal fluency are sensitive to genuine dementia, satisfying the first criterion. We found that depressed schizophrenics performed at significantly lower levels on DS, but not on FAS, than nondepressed schizophrenics. The two groups differed significantly on a discrepancy score derived by subtracting FAS from DS scores; normals obtained discrepancy scores highly similar to those of nondepressed schizophrenics. As the normals had higher DS and FAS scores, this discrepancy-score similarity suggests that this index may have wide application. The third criterion is satisfied by the findings of a 0.64 correlation between DS and FAS scores adjusted for age (DS and FAS) as well as gender and educational attainment (FAS) in nondepressed samples. Implications for further research and clinical applications are discussed.     

Post-synaptic GABA(B) receptors--possible controllers of coincidence detection?

Post-synaptic GABA(B) responses (slow, late hyperpolarisations which can be eliminated by perfusion with phaclofen) can be recorded in vitro from many, but not all, neurones in the intermediate medial hyperstriatum ventrale (IMHV). The IMHV is an area of the chick forebrain which is remarkable for its plasticity, and for its essential role in two specific types of early learning-imprinting, and a form of one-trial passive-avoidance learning. Post-synaptic GABA(B) responses are strongly statistically associated with other properties (such as high membrane resistance) which are, themselves, dependent on a bird's past history. There is also evidence that their incidence changes with prior training in vivo and with age. GABA(B) hyperpolarisations are always offset to a varying extent by excitatory NMDA components. These two components follow a very similar time-course, so that the duration and (to a lesser extent), the magnitude of a response is controlled by the balance between the two systems. The evidence suggests that this balance fluctuates, and that its fluctuations determine the extent to which any neurone can function as a coincidence detector.     

Simultaneous detection of cerebral metabolism of different substrates by in vivo ¹³C isotopomer MRS

In this report a new method is introduced for simultaneous detection of the metabolism of two 13C-labeled subtracts in brain in vivo. We recognized and experimentally demonstrated that when a 13C-labeled substrate generates [1,2-13C?]acetylCoA ([1-13C]acetylCoA) only, glutamate C5, glutamine C5 and apsartate C4 doublets (singlets) are formed exclusively, regardless of the number of turns of the tricarboxylic acid cycle. We utilized the large one-bond 13C-13C homonuclear J coupling between a carboxylic/amide carbon and an aliphatic carbon (~50 Hz) and demonstrated that it is feasible to simultaneously detect the labeling of brain metabolites by two different substrates using different isotopomer signals of the same carbon atom. Uniformly labeled glucose was used to generate the doublets and a second substrate ([2-13C] lactate or [1,3-13C?]β-hydroxybutyrate or [1-13C] acetate) was used to generate the singlets. It was shown that contribution to cerebral metabolism from different substrates can be simultaneously measured in vivo.     

Extracerebral detection of seizures: a new era in epileptology?

The medical and psycho-socio-economic burden imposed on patients, caregivers, and health systems by pharmacoresistant epilepsies is enormous. Intracranial devices for automated detection, warning, and delivery of therapy, the presently preferred "line of attack" for an abundance of weighty reasons, would be insufficient to adequately address said burden on a global scale. Reliance on signals that, although extracerebral, are under cortical modulation or control and are altered by seizures, such as cardiac or motor signals, emerges as a viable research direction with potentially fruitful clinical applications. The greater ease of implementation and lower cost of automated real-time detection, warning, and therapy systems based on extracerebral signals, compared with those requiring intracranial placement, make them worthy of investigation. This article is part of a Supplemental Special Issue entitled The Future of Automated Seizure Detection and Prediction.     

Vectorcardiography: a tool for non-invasive detection of reperfusion and reocclusion?

In acute myocardial infarction, the perfusion status frequently fluctuates with rapid occurrences of coronary occlusion followed by myocardial ischemia. In patients with unstable angina, most episodes of ischemia are not accompanied by chest pain. In these patients it is important to be able to monitor the results of medical treatment non-invasively to establish the need for further intervention. It is not feasible to perform coronary angiography in all patients with acute myocardial infarction to evaluate patency of the infarct-related artery. Furthermore, even in a patent artery, no reflow may be present in the myocardial tissue. Angiography is therefore not the perfect golden standard to compare noninvasive ischemia monitoring with. Prognosis seems to be a better standard for comparison. This review indicates that vectorcardiography monitoring may identify myocardial reperfusion at an early stage and gives valuable prognostic information both in patients with unstable angina and acute myocardial infarction with low interobserver variability.     

Is transcranial Doppler for the detection of venous-to-arterial circulation shunts reproducible?

BACKGROUND: We investigated the reproducibility of contrast transcranial Doppler (TCD), a safe non-invasive test for investigation of venous-to-arterial circulation shunts (v-aCS), usually patent foramen ovale, in young stroke patients. We also investigated whether microbubble contrast was reproducible and whether the addition of blood to agitated saline contrast affected the number of microbubbles produced. METHODS: TCD investigation for v-aCS was repeated in 42 patients using a standardised protocol (i) by the same investigator and (ii) by a different investigator. Agitated saline was produced by mixing saline and 1 ml of air between two 10-ml syringes. The effect of adding blood and increasing the number of agitations was evaluated by microscopy examination using a haemocytometer to assess bubble numbers and sizes. RESULTS: TCD: no difference was found in the highest microbubble count for the same investigator and between different investigators (p > 0.05). Reproducibility for the detection of v-aCS consistent with a patent foramen ovale was also good (kappa values >0.8). Contrast: both the number of contrast mixes before injection and the presence of blood significantly increased the number of bubbles counted. On average, 18 agitations produced 1.86 (95% CI 1.62-2.13) times more bubbles than 6 agitations. Mixtures with blood produced on average 3.8 times more bubbles (3.08-4.69). The size of the bubbles was similar for all mixtures. CONCLUSIONS: Contrast TCD is reproducible and reliable for the detection of v-aCS. The addition of blood and 18 mixes rather than 6 significantly increased the number of microbubbles produced and may increase the effectiveness of microbubble contrast.     

Does oxytocin influence the early detection of angry and happy faces?

Oxytocin has a crucial role in social behaviour, although its effects on social cognition are not fully understood. Past research shows that oxytocin enhances encoding and conceptual recognition of positive social stimuli over social-threat stimuli. In this study, we evaluated whether oxytocin modified responses to positive and threatening social stimuli at an earlier perceptual stage of processing using the visual search task. In a double-blind, randomized, placebo-controlled, between-subject design, oxytocin (24 IU) or a placebo was administered to 104 healthy volunteers. Participants returned to complete the visual search paradigm 45min later. Results showed that angry faces were detected more efficiently than happy faces. Participants also gazed longer and more frequently toward angry faces. Oxytocin did not, however, influence response time, accuracy, or gaze toward angry or happy faces, even when participants were separated into high- and low-social anxiety. The results of this study suggest that oxytocin may not influence the detection of positive and threatening social stimuli at early perceptual levels of processing. Oxytocin may have greater influence in altering the cognitive processing of social valence at more conceptual and elaborate levels of processing.     

Recent advancements toward non-invasive imaging of retinal amyloid-beta for early detection of Alzheimer’s disease

Alzheimer’s disease(AD)is a neurodegenerative disorder characterized by progressive cognitive impairment suggested to be induced by the accumulation of amyloid-β(Aβ)in the brain,especially in the hippocampus.Cerebral Aβdeposits may be detected through positron emission tomography(PET)as early as two decades before clinically diagnosed AD-associated dementia,which provides the opportunity for early therapeutic interventions(Wang and Mao,2021).PET may not be suitable for AD screening since it is invasive,costly,and inaccessible for routine clinical use or population screening.Aβdeposits have also been identified throughout the retina,which is a developmental outgrowth of the diencephalon and shares physiological and pathological pathways with the central nervous system(London et al.,2013).Patients with mild cognitive impairment and early AD are reported to have visual disturbances involving visual field loss with reported thinning of the retinal layers including the retinal nerve fiber layer,ganglion cell layer,and inner plexiform layer(Koronyo-Hamaoui et al.,2011;Wang and Mao,2021).Retinal Aβdeposits have been detected prior to the manifestation of cerebral Aβdeposits in transgenic mice models of AD(Koronyo-Hamaoui et al.,2011;Habiba et al.,2021).Since the retina provides an easily accessible location for non-invasive imaging,retinal Aβmay have the potential to be a surrogate for cerebral Aβand a biomarker for the detection of AD prior to irreversible cognitive impairment.     

Diagnosis of Pelizaeus–Merzbacher disease: detection of proteolipid protein gene copy number by real-time PCR

Duplication of the proteolipid protein gene (PLP1) is the most frequent cause of Pelizaeus–Merzbacher disease (PMD), a severe X-linked myelination disorder. We developed an assay for the detection of the PLP1 gene dosage by real-time quantitative PCR using the ABI Prism 7700 Sequence Detection System and the TaqMan chemistry. Copy number of the PLP1 gene was determined by the standard curve method using GAPDH as the reference gene. The assay was tested both on 50 normal controls and on 20 subjects whose PLP1 gene copy number was previously determined by quantitative fluorescent multiplex PCR. The procedure confirmed the expected results both on the male and female normal controls as well as on the 20 subjects previously tested. Ratios corresponding to the presence of one, two or three PLP1 gene copies, distributed in three non-overlapping ranges, were obtained by real-time PCR analysis. Subsequently, 29 DNA samples of putative PMD patients and possible female carriers, with unknown PLP1 gene dosage, were analysed. Five affected males carrying the PLP1 gene duplication and four female heterozygotes carrying three PLP1 gene copies were identified among them. The method is suitable for the identification of affected male patients and female carriers. Specific ranges are widely spaced, ensuring a correct assignment of the PLP1 gene copy number.     

The yield of routine electroencephalography in the detection of incidental nonconvulsive status epilepticus – A prospective study

ObjectiveDiagnosis of NCSE is challenging, because the clinical presentation ranges from minimally altered mental status to coma without tonic–clonic activity. According to the largest retrospective study to date the incidence of NCSE is about 0.2%.MethodsWe prospectively investigated electroencephalography (EEG) recordings of 2514 consecutive patients that were referred to the Electrophysiology Unit of Department of Neurology, Vienna General Hospital between November 2009 and February 2011 (i.e. 16 months).ResultsThe incidence of NCSE in our study population was 0.8%, i.e. the EEG of 19 patients fulfilled the criteria of NCSE. In 53% of these patients the NCSE was not suspected by treating physicians. A severely reduced level of consciousness was found in 78% of patients with a suspected NCSE and in 30% of patients with an unsuspected NCSE, although the results were not statistically significant (p = 0.081). The delay between the admission to the hospital and diagnosis ranged between 0 and 51 days.ConclusionsNCSE was an unsuspected finding in more than half of the patients. Consciousness was severely impaired in only one third of these patients.SignificanceThese results highlight the importance of urgent EEG for the diagnosis of NCSE in patients even without significant impairment of consciousness.     

The prodromal stage of psychotic illness: observation,detection or intervention?

Accurate identification of individuals in the earliest symptomatic stages of psychosis offers perhaps the best hope for more effective treatment strategies. Recently, research clinics have been set up to identify and possibly treat individuals who are seen as being at high risk of a psychotic disorder. However, there have been concerns about beginning treatment at this stage. We need to address these concerns so that individuals who are at risk of psychosis come to no harm, yet the development of potential interventions is not delayed. This article briefly reviews some of the newer developments and concerns in this area of psychosis research.