| Background and purposeWith the aging of the population of our country, the number of patients with Alzheimer's disease (AD) is growing rapidly.The disease has seriously affected the quality of life of the sick, which has brought a heavy burden to the family and society. However, the etiology of AD has so far not clear.There is no satisfactory treatment measures, so the study of AD is of great significance.Electrophysiology techniques and equipments are developing very rapidly.Many electrophysiology techniques have been widely used in the research of AD but the use of electrophysiology techniques specifically for motor pathways in AD research is not systematic.lt has not get breakthrough results yet.In this study, by using electrophysiological techniques the whole motor pathways of AD patients was studied, including motor evoked potential (MEP), motor nerve root potential(MNRP), F waves, motor unit number estimation(MUNE) of median nerves, peripheral motor nerves conduction, and needle electromyography, in order to infer the condition of cortical motor neurons, pyramidal tracts, anterior horn motor neurons and peripheral motor nerves of AD.According to the results of the study, combined with the pathological characteristics of AD and the research results of molecular biology, the pathogenesis of AD was analyzed. At the point of view of neural electrophysiology, the theory of the pathogenesis of AD is further demonstrated, and some suggestions are put forward.MethodsIn this study, we used the neural electrophysiological techniques to conduct a case-control study on the motor pathways of selected AD patients and healthy controls. According to whether there are movement disorders, the case group was subdivided into dyskinesia group and nondyskinesia group, and the motor pathways were compared between the two subgroups.We used magnetic stimulation instrument, and EMG/evoked potential instrument to examine the motor pathways of the research objects. We recorded and measured the relative data, and analyzed the changes of the data.By comparison and analysis, we observed the changes of motor cortex, spinal cord, peripheral motor nerves and muscles.The electrophysiological examination of the motor pathways in the study includes six aspects:motor evoked potentials, motor nerve root potentials, F waves, motor unit number estimation of median nerves, peripheral motor nerve conduction, and needle electromyography.Data recorded and measured in the study included rest motor threshold (RMT), MEP amplitude (MEPamp), central motor conduction time (CMCT), spinal cord motor conduction velocity (SCMCV), motor nerve root potential amplitude(MNRPA) motor nerve root conduction time (MNRCT), F-persistence, minimal latency of F-waves (Fmin/H), average duration of F-waves (Fdur), F-waves amplitude (Famp), motor unit number estimation (MUNE, peripheral motor nerve potential amplitude (Pamp), peripheral motor nerve conduction velocity (PMCV)Results1.Motor cortical excitability increased(1)RMT. There was significant difference between the case group and the control group in AMT. There was no significant difference between the dyskinesia group and the nondyskinesia group.There was no significant correlation between the RMTs and MMSE scores in the case group.These show that the cortical excitability increased in the case group, but the degree of excitability is not related to the severity of the disease.(2)MEP amplitude.There was no significant difference between the case group and the control group in MEP amplitude, and so does that between the dyskinesia group and the nondyskinesia group.This reflects the case group motor cortical neuron number and corticospinal tract axons number, spinal cord anterior horn motor neurons and peripheral motor nerve axons number did not change significantly, even in dyskinesia group.(3)CMCT.There was no significant difference between the case group and the control group in CMCT, and so does that between the dyskinesia group and the nondyskinesia group.This shows that the fast conduction fibers of corticospinal tract dominating the upper limbs and the lower limbs are normal, even in dyskinesia group.2.motor neuronal excitability increased in spinal cord(1)SCMCV.There was no significant difference between the case group and the control group in SCMCV, and so does that between the dyskinesia group and the nondyskinesia group.This shows that the corticospinal fast conduction fibers are normal in the spinal cord part in case group.(2)Spinal cord excitability.The F-waves duration(Fdur) of case group was significantly longer than that of the control group.There was no significant difference between the dyskinesia group and the nondyskinesia group.There was no significant correlation between the RMT and MMSE scores in the case group.In AD patients, the mean Fdur was prolonged, indicating the excitability of the spinal cord was increased, but the degree of excitability was not correlated with the severity of the disease.(3)MUNE.There was no significant difference between the case group and the control group in MUNE of median nerves, and so does that between the dyskinesia group and the nondyskinesia group.This indicates that the number of motor neurons in the anterior horn of the case group is normal.3.Peripheral motor nerves normal(1)Motor nerve root.There was no significant difference between the case group and the control group in MNRPA and MNRCT, and so does that between the dyskinesia group and the nondyskinesia group.This shows that the nerve root axonal and myelin sheath function in the case group is normal.(2)Distal peripheral motor nerve.There was no significant difference between the case group and the control group in potential amplitude and conduction velocity of distal peripheral motor nerves, and so does that between the dyskinesia group and the nondyskinesia group.This shows that the axonal number of the peripheral nerves in the case group is normal, and the fast conduction fibers in the case group are not damaged.4.Muscles normalWe analysed bilateral abductor pollicis brevis muscles and gastrocnemius muscles using concentric needle electrodes, no obvious neurogenic lesions were found.ConclusionBy using electrophysiological techniques to study the whole motor nerve pathways of AD patients, we found AD patients with increased excitability of the cortex and spinal cord.It has been known that cholinergic circuit has central inhibitory effect, and the damage of this circuit can lead to increased central excitability.Therefore, our study support the "cholinergic hypothesis", which insists that functional impairment of cholinergic system is an important cause of AD early dementia.In addition, as the cholinergic neurons, the motor neurons of the spinal cord and their peripheral motor nerves were not obviously injured.The existence of this phenomenon is bound to have the participation of relevant factors. We found that the most severe lesions in AD patients were in the hippocampus, dentate gyrus and prefrontal cortex, which are exactly the right areas the most a7-nAChR distribution in the brain.And the anterior horn motor neurons and the neuromuscular junctions with no obvious lesions are the areas wherea7-nAChR almost no distribution.The consistency between the two suggests that there is a corresponding relationship between the distribution of cholinergic neurons damage in AD and the distribution of nAChRs in the body, which supports the view that nAChRs plays a key role in the pathogenesis of AD.1.The high excitability of cortex and spinal cord supports the "cholinergic hypothesis" of AD pathogenesis.(1)"Cholinergic hypothesis" of AD pathogenesis.There are many theories about the pathogenesis of AD, among which the cholinergic hypothesis argues that the cholinergic disfunction caused by the loss of cholinergic cells and the decrease of acetylcholine is the important reason for the early AD dementia.(2)From the point of view of neural electrophysiology, it is further demonstrated that the damage of the cholinergic system may play an important role in the pathogenesis of AD.In this study, cortical RMT reduced and F wave duration prolonged in AD patients, indicating the hyperexcitability of the cortex and spinal cord in patients with AD.There are tow causes of hyperexcitability of the cortex and spinal cord in patients with AD.One is the enhancement of glutamate neural circuit with excitatory effect; The other is the damage of y-aminobutyric acid neural circuits or Cholinergic neural circuits with inhibitory effect.For the several possibilities, many scholars have studied the central neurotransmitter circuits in AD using transcranial magnetic stimulation techniques. Intracortical facilitation(ICF) reflecting the glutamatergic excitability and short-latency intracortical inhibition(SICI) reflecting the gabaergic excitability were normal, and short latency afferent inhibition(SAI)reflecting the cholinergic excitability was decreased significantly.This shows that the elevated excitability of the cortex and spinal cord in patients with AD may be related to central cholinergic circuit damage.This conclusion coincides with the "cholinergic hypothesis" of AD pathogenesis, and from electrophysiology perspectives further demonstrates that cholinergic system damage may play an important role in the pathogenesis of AD.2.Nicotine acetylcholine receptor (nAChRs) can be summarized as the focus of AD etiology suspicious factors.Cholinergic system damage is the main feature in AD, but as cholinergic neurons, anterior horn motor neurons of the spinal cord are not obviously injured in number and conduction function except the excitement.We found that there is a corresponding relationship between the distribution of cholinergic neurons damage area and the distribution of nAChRs in AD patients,.Thus it is necessary to conclude that nAChRs is a key suspect factor in the etiology of AD.(1)The motor cortical neurons and corticospinal tract axons without obvious changes, confirms the neural lesion region is selective in AD patients.On the selectivity of lesion sites in AD nervous system, many scholars have done a lot of research and demonstration in imaging and pathology. We observed the motor pathway of AD patients using the electrophysiological technique, and made a more indepth study on the AD motor nervous system from electrophysiological perspectives. Through observation we found that the motor cortical neurons and corticospinal tract axons and myelin sheath were intact.It confirms that the neural lesion region is selective, other than diffuse in AD patients.(2)As the cholinergic neurons, the motor neurons of the spinal cord and their peripheral motor nerves were not obviously injured. This study showed that the F waves persistence and MUNE in AD patients were normal.It indicates that there were no significant loss of anterior horn motor neurons of the spinal cord.The normal motor nerve root potential amplitude, motor nerve root conduction time, peripheral motor nerve conduction and needle electromyogram showed that motor nerve axons, neural myelin sheath and the muscles are normal in AD patients.(3)The distribution of cholinergic neurons in AD has a corresponding relationship with the distribution of nAChRs in the body? It Provides a strong argument for the viewpoint that nAChRs plays a key role in the pathogenesis of AD? Summarizing of the research results, we found that there was no significant loss of cortical motor neurons and the conduction function of the corticospinal tracts were relatively intact in motor pathways of AD patients.This could be due to that cholinergic neurons in this region are very few or this region is not a cholinergic projection area.However, the motor neurons of the anterior horn of the spinal cord as well as the peripheral motor nerves are also normal.We think that the distribution of nAChRs in the body can explain this phenomenon.The location of the typical pathological changes of AD is the basal forebrain, where the cholinergic neurons mainly distribute, and its projection areas including limbic system and related cerebral cortex.These brain regions are exactly the areas where a7nAChRs mainly distribute.Furthermore, there was almost no expression of a7nAChR in presynaptic and postsynaptic membrane of the adult neuromuscular junction. It is thus evident that the distribution of cholinergic neurons loss in AD has a corresponding relationship with the distribution of nAChRs in the body, and nAChRs may play a key role in the pathogenesis of AD.SignificanceThe study on the comprehensive and systematic study of the motor pathway in AD by using electrophysiological techniques, combining the electrophysiological findings with the pathological features of AD, is helpful for the further study of the lesion site of AD.According to the electrophysiological and pathological characteristics, the pathogenesis of AD was further speculated.These findings may provide new therapeutic targets for the treatment of AD. |
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