A comparison of the repetitive click and conditioning-testing P50 paradigms

The auditory P50 ERP component has previously been studied either in the repetitive click or the conditioning-testing (C-T) paradigm. For 20 subjects, we compared 4 repetitive click and 4 C-T protocols in a single experimental session with identical recording techniques and with interclick intervals comparable to the C-T intervals. In the C-T protocols, a long interval between click pairs ensured full recovery of P50 to the C click. The analysis of P50 topographies provided strong evidence that the same component was measured in the two paradigms. For both paradigms, P50 amplitude was progressively suppressed as the interclick or C-T interval decreased (P<0.0001), with parallel interval vs. P50 amplitude regression lines for the two paradigms. There was a strong trend (P=0.08) for the repetitive click amplitudes to be smaller than T amplitudes for comparable repetitive click and C-T intervals. Equivalently, this strong trend suggests that repetitive click intervals must be longer (by about 300 ms) than the C-T interval to generate equivalent amplitude P50 responses. We conclude that the same component is measured in both paradigms, that P50 amplitude decreases with decreasing interstimulus intervals in both paradigms, and that in normals, for comparable inter-click and C-T intervals, there is greater P50 suppression in the repetitive click paradigm. Finally, we note that the comparison of paradigms within normals does not necessarily apply to clinical samples.     

Abnormal Pre-Attentive Arousal in Young Children with Autism Spectrum Disorder Contributes to Their Atypical Auditory Behavior: An ERP Study

Auditory sensory modulation difficulties and problems with automatic re-orienting to sound are well documented in autism spectrum disorders (ASD). Abnormal preattentive arousal processes may contribute to these deficits. In this study, we investigated components of the cortical auditory evoked potential (CAEP) reflecting preattentive arousal in children with ASD and typically developing (TD) children aged 3-8 years. Pairs of clicks (‘S1’ and ‘S2’) separated by a 1 sec S1-S2 interstimulus interval (ISI) and much longer (8-10 sec) S1-S1 ISIs were presented monaurally to either the left or right ear. In TD children, the P50, P100 and N1c CAEP components were strongly influenced by temporal novelty of clicks and were much greater in response to the S1 than the S2 click. Irrespective of the stimulation side, the ‘tangential’ P100 component was rightward lateralized in TD children, whereas the ‘radial’ N1c component had higher amplitude contralaterally to the stimulated ear. Compared to the TD children, children with ASD demonstrated 1) reduced amplitude of the P100 component under the condition of temporal novelty (S1) and 2) an attenuated P100 repetition suppression effect. The abnormalities were lateralized and depended on the presentation side. They were evident in the case of the left but not the right ear stimulation. The P100 abnormalities in ASD correlated with the degree of developmental delay and with the severity of auditory sensory modulation difficulties observed in early life. The results suggest that some rightward-lateralized brain networks that are crucially important for arousal and attention re-orienting are compromised in children with ASD and that this deficit contributes to sensory modulation difficulties and possibly even other behavioral deficits in ASD.     

KILLER WHALE (ORCINUS ORCA) AUDITORY EVOKED POTENTIALS TO RHYTHMIC CLICKS

Temporal auditory mechanisms were measured in killer whales ( Orcinus orca ) by recording auditory evoked potentials (AEPs) to clicks. Clicks were presented at rates from 10/sec to 1,600/sec. At low rates, clicks evoked an AEP similar to the auditory brainstem response (ABR) of other odontocetes; however, peak latencies of the main waves were 3–3.7 msec longer than in bottlenose dolphins. Fourier analysis of the ABR showed a prominent peak at 300–400 Hz and a smaller one at 800–1,200 Hz. High-rate click presentation (more than 100/sec) evoked a rate-following response (RFR). The RFR amplitude depended little on rate up to 400/sec, decreased at higher rates and became undetectable at 1,120/sec. Fourier analysis showed that RFR fundamental amplitude dependence on frequency closely resembled the ABR spectrum. The fundamental could follow clicks to around 1,000/sec, although higher harmonics of lower rates could arise at frequencies as high as 1,200 Hz. Both RFR fundamental phase dependence on frequency and the response lag after a click train indicated an RFR group delay of around 7.5 msec. This corresponds to the latency of ABR waves PIII-NIV, which indicates the RFR originates as a rhythmic, overlapping ABR sequence. The data suggest the killer whale auditory system can follow high click rates, an ability that may have been selected for as a function of high-frequency hearing and the use of rapid clicks in echolocation.     

Dopaminergic modulation of the P50 auditory-evoked potential in a computer model of the CA3 region of the hippocampus: its relationship to sensory gating in schizophrenia

 We modeled the neuronal circuits that may underlie a sensory-processing deficit associated with schizophrenia. Schizophrenic patients have small P50 auditory-evoked responses to click stimuli compared to normal subjects. The P50 auditory-evoked response is a positive waveform recorded in the EEG approximately 50 ms after the auditory click stimulus. In addition to relatively small amplitudes, schizophrenic patients do not gate or suppress the P50 auditory-evoked response to the second of two paired-click stimuli spaced 0.5 s apart. Neuropleptic medication, which decreases dopaminergic neuronal transmission, increases the amplitude of the P50 auditory-evoked response but does not improve gating. Normal subjects have large P50 auditory-evoked responses to click stimuli when compared to unmedicated schizophrenic patients, and they gate their response to paired click stimuli or have smaller P50 auditory-evoked response amplitudes to the second of two click stimuli spaced 0.5 s apart. Schizophrenic patients do not gate and have similar response amplitudes to both clicks. We hypothesized that the small amplitudes of unmedicated schizophrenic subjects were due to a state of occlusion whereby excessive background noise in local circuits reduced the ability of cells to respond synchronously to sensory input, thereby reducing the amplitude of the P50 waveform in the EEG. Because the P50 auditory-evoked potential amplitudes increased with neuroleptic medication, which reduces dopaminergic neuronal transmission, we hypothesized a role for dopamine in modulating the signal-to-noise (S/N) in the local circuits responsible for sensory gating. To test the hypothesis that modulation of the S/N ratio reduces sensory gating, we developed a model of the effects of dopaminergic neuronal transmission that modulates the S/N in neuronal circuits. The model uses the biologically relevant computer model of the CA3 region of the hippocampus developed in the companion paper [Moxon et al. (2003) Biol Cybern, this volume]. Modified Hebb cell assemblies represented the response of the network to the click stimulus. The results of our model showed that excessive dopaminergic input impaired the ability of cells to respond synchronously to sensory input, which reduced the amplitudes of the P50 evoked responses. Received: 3 December 2001 / Accepted: 23 October 2002 / Published online: 28 February 2003 Correspondence to: K.A. Moxon (e-mail: karen.moxon@drexel.edu, Tel.: +1-215-8951959, Fax: +1-215-8954983) Supported by USPHS, MH01245 & MH58414, MH-01121, and research grants from the Department of Veterans Affairs and the National Alliance for Research on Schizophrenia and Depression.     

THE CLICK-SOUNDS OF NARWHALS (MONODON MONOCEROS) IN INGLEFIELD BAY, NORTHWEST GREENLAND

We studied the sounds of narwhals ( Monodon monoceros ) foraging in the open waters in Northwest Greenland. We used a linear, vertical array of three hydrophones (depth 10 m, 30 m, 100 m) with a fourth hydrophone (depth 30 m) about 20 m from the vertical array. A smaller fifth hydrophone (depth 2 m) allowed for registering frequencies up to 125 kHz (± 2 dB) when signals were recorded at 762 mm/set on an instrumentation tape recorder. Clicks were the prevalent signals, but we heard whistles occasionally. We separated the clicks into two classes: click trains that had rates of 3-10 clicks/sec and click bursts having rates of 110-150 clicks/sec. The spectra of train clicks had maximum amplitudes at 48 ± 10 kHz and a duration of 29 ± 6 psec. The spectra of burst clicks had maximum amplitudes at 19 ± 1 kHz and a duration of 40 ± 3 psec. By analogy with other dolphin species, narwhals presumably use the clicks for echolocation during orientation and for locating prey. The narwhal click patterns resemble those of insectivorous bats. Click trains might correspond to bat searching signals and click bursts to the bat's terminal "buzz", emitted just before prey capture.     

Inhibitory control of sensory gating in a computer model of the CA3 region of the hippocampus

 A model of the CA3 region of the hippocampus was used to simulate the P50 auditory-evoked potential response to repeated stimuli in order to study the neuronal circuits involved in a sensory-processing deficit associated with schizophrenia. Normal subjects have a reduced P50 auditory-evoked potential amplitude in response to the second of two paired auditory click stimuli spaced 0.5 s apart. However, schizophrenic patients do not gate or reduce their response to the second click. They have equal auditory-evoked response amplitudes to both clicks. When schizophrenic patients were medicated with traditional neuroleptics, the evoked potential amplitude to both clicks increased, but gating of the second response was not restored or improved. Animal studies suggest a role for septohippocampal cholinergic activity in sensory gating. We used a computational model of this system in order to study the relative contributions of local processing and afferent activity in sensory gating. We first compared the effect of information representation as average firing rate to information representation as cell assemblies in order to evaluate the best method to represent the response of hippocampal neurons to the auditory click. We then studied the effects of nicotinic cholinergic input on the response of the network and the effect of GABA_B receptor activation on the ability of the local network to suppress the test response. The results of our model showed that nicotinic cholinergic input from the septum to the hippocampus can control the flow of sensory information from the cortex into the hippocampus. In addition, postsynaptic GABA_B receptor activation was not sufficient to suppress the test response when the interstimulus interval was 500 ms. However, presynaptic GABA_B receptor activity may be responsible for the suppression of the test response at this interstimulus interval. Received: 3 December 2001 / Accepted: 23 October 2002 / Published online: 28 February 2003 Correspondence to: K. A. Moxon (e-mail: karen.moxon@drexel.edu, Tel.:+1-215-8951959, Fax: +1-215-8954983) Supported by USPHS, MH01245, MH58414, MH-50787, MH-01121, and research grants from the Department of Veterans Affairs and the National Alliance for Research on Schizophrenia and Depression.     

Clicks and Communication: The Behavioural and Social Contexts of Hector's Dolphin Vocalizations

Hector's dolphins (Cephalorhynchus hectori) have a simple vocal repertoire, consisting almost entirely of ultrasonic clicks. They produce no whistles, and very few audible sounds. To examine acoustic communication in this species I analysed the relationship between click types and behaviour. The proportion of complex click types was greater in large groups, suggesting that these sounds have social significance. Clicks having 2 peaks in their time envelope and two frequency peaks were strongly associated with behaviours indicative of feeding. High pulse rate sounds, in which the repetition rate of ultrasonic clicks was audible as a “cry”, were most strongly associated with aerial behaviours. These data suggest that echo-location is not the sole function of Hector's dolphin clicks, and that echo-location and communication are likely to be closely linked. I hypothesize that dolphins may have the ability to gather information from the echoes of each other's sonar pulses. This may reduce the need for a large number of vocal signals, and may explain the apparent simplicity of the acoustic repertoires of some odontocetes.     

ACTIGRAPHIC SLEEP-WAKE PATTERNS AND URINARY 6-SULFATOXYMELATONIN EXCRETION IN PATIENTS WITH ALZHEIMER'S DISEASE

Recent studies suggest melatonin, due to its antioxidant and free-radical- scavenging actions, may play a role in the neuroprotection against amyloid, which is implicated in the pathogenesis of Alzheimer's disease (AD). In this study, we determined urinary 6-sulfatoxymelatonin (aMT6s) excretion together with actigraphic sleep-wake patterns of untreated male patients with AD who lived at home. Results were compared with those obtained from normal age-matched elderly and normal young male subjects. Similar measurements were also performed in another group of patients with AD who were treated with a cholinesterase inhibitor (Donepezil, Aricept). Total 24h aMT6s values were significantly reduced in elderly controls (19.9h ± 5.2 μg/24h), in those with untreated AD (12.7 ± 4.4 μg/24h), and in patients treated for AD (12.4 ± 4.4 μ g/24h) compared with normal young men (32.8 ± 3.1 μ g/24h). A day-night difference in aMT6s was evident in all young controls, in 50% of elderly controls, in only 20% of patients with untreated AD, and in 67% of those with AD receiving Aricept. Sleep quality (expressed as sleep efficiency, wake time, and long undisturbed sleep duration) was better in young and elderly controls compared with the two groups of patients with AD. There was no significant correlation between aMT6s values or sleep patterns and the severity of cognitive impairment in patients with AD. Taken together, these data suggest that disrupted sleep, decreased melatonin production, and partial lack of day-night difference in melatonin secretion were observed equally in normal elderly and in patients with AD. Our results do not permit drawing any conclusion as to whether changes in urinary aMT6s excretion is correlated with disturbed sleep in patients with AD. (Chronobiology International, 18(3), 513–524, 2001)     

Comparison of the Levels of Pro-Inflammatory Cytokines Released in the Vastus Lateralis Muscle of Patients with Fibromyalgia and Healthy Controls during Contractions of the Quadriceps Muscle – A Microdialysis Study

Objective

Fibromyalgia is associated with central hyperexcitability, but it is suggested that peripheral input is important to maintain central hyperexcitability. The primary aim was to investigate the levels of pro-inflammatory cytokines released in the vastus lateralis muscle during repetitive dynamic contractions of the quadriceps muscle in patients with fibromyalgia and healthy controls. Secondarily, to investigate if the levels of pro-inflammatory cytokines were correlated with pain or fatigue during these repetitive dynamic contractions.

Material and Methods

32 women with fibromyalgia and 32 healthy women (controls) participated in a 4 hour microdialysis session, to sample IL-1β, IL-6, IL-8, and TNF from the most painful point of the vastus lateralis muscle before, during and after 20 minutes of repeated dynamic contractions. Pain (visual analogue scale; 0–100) and fatigue Borg’s Rating of Perceived Exertion Scale; 6–20) were assessed before and during the entire microdialysis session.

Results

The repetitive dynamic contractions increased pain in the patients with fibromyalgia (P < .001) and induced fatigue in both groups (P < .001). Perceived fatigue was significantly higher among patients with fibromyalgia than controls (P < .001). The levels of IL-1β did not change during contractions in either group. The levels of TNF did not change during contractions in patients with fibromyalgia, but increased in controls (P < .001) and were significantly higher compared to patients with fibromyalgia (P = .033). The levels of IL-6 and IL-8 increased in both groups alike during and after contractions (P’s < .001). There were no correlations between pain or fatigue and cytokine levels after contractions.

Conclusion

There were no differences between patients with fibromyalgia and controls in release of pro-inflammatory cytokines, and no correlations between levels of pro-inflammatory cytokines and pain or fatigue. Thus, this study indicates that IL-1β, IL-6, IL-8, and TNF do not seem to play an important role in maintenance of muscle pain in fibromyalgia.     

An acoustic valve within the nose of sperm whales Physeter macrocephalus

相似文献   

Movement-related cortical potentials preceding sequential and goal-directed finger and arm movements in patients with cerebellar atrophy

To determine the influence of cerebellar involvement on the preparatory state of the cerebral cortex for voluntary movements, we studied the movement-related cortical potentials (Bereitschaftspotential, BP) preceding sequential and goal-directed finger and arm movements in patients with cerebellar atrophy (CA). The first task (paradigm 1) consisted of a sequential finger movement at a self-placed rate of every 3 sec or longer, in which patients and control subjects pushed rapidly 7 keys on a keyboard in a sequence visually predetermined on a screen. The second task (paradigm 2) consisted of a goal-directed self-paced movement with visual feedback on a screen. In both paradigms, control subjects and patients had distinct movement-related cortical potentials, but peak amplitudes (close to movement onset) were reduced in the patient group (paradigm 2), whereas in the overall analysis the mean amplitude 600–800 msec before movement onset (NS1) was larger in the patient group (paradigms 1 and 2). Accordingly, the difference (NS2) between peak amplitude and NS1 was smaller in the patient group (paradigms 1 and 2). Whereas control subjects' peak amplitude (paradigm 2) and NS2 (paradigm 1) were focused at Cz, this topographical differentiation was abolished in the patient group. The onset of the BP was earlier in the patients than in the control subjects (paradigms 1 and 2). Our results suggest that pathways from the cerebellum to the cortex do play a role in generating movement-related cortical potentials. A strong input from the cerebellum seems to be crucial for the generation of a normal motor potential close to the movement onset, reflecting a specific deficit in patients with CA. Patients with CA may try to compensate for their motor deficits by a longer cortical activation preceding voluntary movements (earlier onset of the BP). The increased NS1 could be the result of larger effort, by which patients try to compensate for their motor deficits as well.     

有关猫听觉脑干电反应（ABR）两耳干涉作用的研究

用不同声强稳态白噪声和短声同时分别刺激两耳,观察白噪声负荷侧耳蜗破坏前后另一侧ＡＢＲ的改变,探讨两耳干涉作用及其可能的机制。结果显示,对侧耳蜗破坏前,４０ｄＢ和７５ｄＢ白噪声对０ｄＢ、４５ｄＢ、７０ｄＢ和７５ｄＢＳＰＬ的短声诱发的ＡＢＲ各波振幅均有明显影响（Ｐ＜０．０５０．０１）。耳蜗破坏后,同样条件下记录的ＡＢＲ振幅基本无明显变化（Ｐ＞０．０５）。提示白噪声对短声有一定的干涉作用。短声为７０ｄＢＳＰＬ时ＡＢＲＰ１波振幅的减小可能与中枢离中控制相关。     

Actigraphic sleep-wake patterns and urinary 6-sulfatoxymelatonin excretion in patients with Alzheimer's disease

Recent studies suggest melatonin, due to its antioxidant and free-radical- scavenging actions, may play a role in the neuroprotection against amyloid, which is implicated in the pathogenesis of Alzheimer's disease (AD). In this study, we determined urinary 6-sulfatoxymelatonin (aMT6s) excretion together with actigraphic sleep-wake patterns of untreated male patients with AD who lived at home. Results were compared with those obtained from normal age-matched elderly and normal young male subjects. Similar measurements were also performed in another group of patients with AD who were treated with a cholinesterase inhibitor (Donepezil, Aricept). Total 24h aMT6s values were significantly reduced in elderly controls (19.9h ± 5.2 μg/24h), in those with untreated AD (12.7 ± 4.4 μg/24h), and in patients treated for AD (12.4 ± 4.4 μ g/24h) compared with normal young men (32.8 ± 3.1 μ g/24h). A day-night difference in aMT6s was evident in all young controls, in 50% of elderly controls, in only 20% of patients with untreated AD, and in 67% of those with AD receiving Aricept. Sleep quality (expressed as sleep efficiency, wake time, and long undisturbed sleep duration) was better in young and elderly controls compared with the two groups of patients with AD. There was no significant correlation between aMT6s values or sleep patterns and the severity of cognitive impairment in patients with AD. Taken together, these data suggest that disrupted sleep, decreased melatonin production, and partial lack of day-night difference in melatonin secretion were observed equally in normal elderly and in patients with AD. Our results do not permit drawing any conclusion as to whether changes in urinary aMT6s excretion is correlated with disturbed sleep in patients with AD. (Chronobiology International, 18(3), 513-524, 2001)     

Forward masking in the evoked responses of the guinea pig auditory cortex: effects of variation of the interaural time and phase differences

In anaesthesized guinea pigs the evoked potentials of the auditory cortex were studied in a forward masking paradigm. In-phase and out-of-phase binaurally presented clicks with interaural time delay (ITD) were used as masker, in-phase click with ITD = 0 served as probe signal. Addition of the masking stimulus suppressed the probe-evoked response that followed the masker. The magnitude of the suppression correlated with the amount of the masker-evoked response: an increase in masker-evoked excitation caused a greater reduction in probe response magnitude. Amplitude of masker-evoked response was seen to be a monotonic or non-monotonic function of ITD. The non-monotonic response exhibited a sensitivity to the interaural phase differences when in-phase and out-of-phase maskers were presented, and showed the tendency to be periodic function of ITD in the expanded range of ITD values. Phase-sensitive responses differed in recovery time following the in-phase and out-of-phase masking stimuli. At near-threshold levels of a forward masker an enhancement of the probe-evoked response was observed.     

Impaired mismatch negativity (MMN) generation in schizophrenia as a function of stimulus deviance,probability, and interstimulus/interdeviant interval

Schizophrenia is a severe mental disorder associated with disturbances in perception and cognition. Event-related potentials (ERP) provide a mechanism for evaluating potential mechanisms underlying neurophysiological dysfunction in schizophrenia. Mismatch negativity (MMN) is a short-duration auditory cognitive ERP component that indexes operation of the auditory sensory (`echoic') memory system. Prior studies have demonstrated impaired MMN generation in schizophrenia along with deficits in auditory sensory memory performance. MMN is elicited in an auditory oddball paradigm in which a sequence of repetitive standard tones is interrupted infrequently by a physically deviant (`oddball') stimulus. The present study evaluates MMN generation as a function of deviant stimulus probability, interstimulus interval, interdeviant interval and the degree of pitch separation between the standard and deviant stimuli. The major findings of the present study are first, that MMN amplitude is decreased in schizophrenia across a broad range of stimulus conditions, and second, that the degree of deficit in schizophrenia is largest under conditions when MMN is normally largest. The pattern of deficit observed in schizophrenia differs from the pattern observed in other conditions associated with MMN dysfunction, including Alzheimer's disease, stroke, and alcohol intoxication.     

CLICK CHARACTERISTICS OF NORTHERN BOTTLENOSE WHALES (HYPEROODON AMPULLATUS)

Sounds produced by northern bottlenose whales ( Hyperoodon ampullatus ) recorded in the Gully, a submarine canyon off Nova Scotia, consisted predominately of clicks. In 428 min of recordings no whistles were heard which could unequivocally be attributed to bottlenose whales. There were two major types of click series, initially distinguished by large differences in received amplitude. Loud clicks (produced by nearby whales socializing at the surface) were rapid, with short and variable interclick intervals (mean 0.07 sec; CV 71%). The frequency spectra of these were variable and often multimodal, with peak frequencies ranging between 2 and 22 kHz (mean 11 kHz, CV 59%). Clicks received at low amplitude (produced by distant whales, presumably foraging at depth) had more consistent interclick intervals (mean 0.40 sec, CV 12.5%), generally unimodal frequency spectra with a mean peak frequency of 24 kHz (CV 7%) and 3 dB bandwidth of 4 kHz. Echolocation interclick intervals may reflect the approximate search distance of an animal, in this case 300 m, comparable to that found for sperm whales. The relationship between click frequency and the size of object being investigated, suggests that 24 kHz would be optimal for an object of approximately 6 cm or more, consistent with the size range of their squid prey.     

Whole-head mapping of middle-latency auditory evoked magnetic fields

We recorded middle-latency auditory evoked magnetic fields from 9 healthy subjects with a 122-channel whole-head SQUID gradiometer. The stimuli were click triplets, 2.5 msec in total duration, delivered alternately to the two ears once every 333 msec. Contralateral clicks elicited P30m responses in 16 and P50m responses in 12 out of 18 hemispheres studied; ipsilateral clicks did so in 7 and 13 hemispheres, respectively. The field patterns were satisfactorily explained by current dipoles in 16 and 4 hemispheres for contra- and ipsilateral P30m, and in 4 and 10 hemispheres for contra- and ipsilateral P50m. The peak latencies of P30m and P50m were not affected by stimulation side. The results show that middle-latency auditory evoked responses receive a strong contribution from auditory cortical structures, and that differences of input latency to cortical auditory areas, evaluated from MLAEF latencies, do not explain the latency differences seen in late auditory evoked fields to contralateral vs. ipsilateral stimulation.     

Responses of motor cortex neurons of the cat to auditory stimulation and their role in the instrumental food reflex

The responses of motor cortex neurons in the cat to the presentation of a single auditory click and a series of 10 clicks presented with 1,000/sec frequency were studied under conditions of chronic experiments before and after the development of an instrumental food reflex. After reflex development a single presentation of a positive conditioned stimulus (single click) markedly influenced for 7 sec the appearance of instrumental movements. At the same time, the immediate responses of motor cortex neurons to presentation of the conditioned auditory stimulus had no impact on the appearance in the motor cortex of discharges leading to the realization of instrumental movements. Consequently, motor cortex neurons do not require activation from afferent sensory inputs for the generation of such discharges. The immediate neuronal responses to conditioned stimulation did not inhibit the realization of the instrumental reflex. It is proposed that they are associated with the realization of motor function in the unconditioned defensive response evoked by the presentation of an auditory stimulus. The presence or absence of responses to auditory conditioned stimulation was dependent upon the signal meaning of the stimulus, its physical parameters, and the degree of excitability of the animal.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 17, No. 4, pp. 539–550, July–August, 1985.     

Coenzyme Q10 Levels Are Decreased in the Cerebellum of Multiple-System Atrophy Patients

Background

The objective of this study was to evaluate whether the levels of coenzyme Q10 (CoQ10) in brain tissue of multiple system atrophy (MSA) patients differ from those in elderly controls and in patients with other neurodegenerative diseases.

Methods

Flash frozen brain tissue of a series of 20 pathologically confirmed MSA patients [9 olivopontocerebellar atrophy (OPCA) type, 6 striatonigral degeneration (SND) type, and 5 mixed type] was used for this study. Elderly controls (n = 37) as well as idiopathic Parkinson''s disease (n = 7), dementia with Lewy bodies (n = 20), corticobasal degeneration (n = 15) and cerebellar ataxia (n = 18) patients were used as comparison groups. CoQ10 was measured in cerebellar and frontal cortex tissue by high performance liquid chromatography.

Results

We detected a statistically significant decrease (by 3–5%) in the level of CoQ10 in the cerebellum of MSA cases (P = 0.001), specifically in OPCA (P = 0.001) and mixed cases (P = 0.005), when compared to controls as well as to other neurodegenerative diseases [dementia with Lewy bodies (P<0.001), idiopathic Parkinson''s disease (P<0.001), corticobasal degeneration (P<0.001), and cerebellar ataxia (P = 0.001)].

Conclusion

Our results suggest that a perturbation in the CoQ10 biosynthetic pathway is associated with the pathogenesis of MSA but the mechanism behind this finding remains to be elucidated.     

APP mouse models for Alzheimer's disease preclinical studies

Animal models of human diseases that accurately recapitulate clinical pathology are indispensable for understanding molecular mechanisms and advancing preclinical studies. The Alzheimer's disease (AD) research community has historically used first‐generation transgenic (Tg) mouse models that overexpress proteins linked to familial AD (FAD), mutant amyloid precursor protein (APP), or APP and presenilin (PS). These mice exhibit AD pathology, but the overexpression paradigm may cause additional phenotypes unrelated to AD. Second‐generation mouse models contain humanized sequences and clinical mutations in the endogenous mouse App gene. These mice show Aβ accumulation without phenotypes related to overexpression but are not yet a clinical recapitulation of human AD. In this review, we evaluate different APP mouse models of AD, and review recent studies using the second‐generation mice. We advise AD researchers to consider the comparative strengths and limitations of each model against the scientific and therapeutic goal of a prospective preclinical study.