无名质区破坏的Wistar大鼠脑内胆碱乙酰转移酶和生长抑素活性的变化及相互关系

本研究选用Ｗｉｓｔａｒ系雄性大鼠，通过向鼠脑的无名质区注射Ｉｂｏｔｅｎｉｃａｃｉｄ，造成中枢胆碱能系统破坏的动物模型。采用放免方法，测定了无名质区破坏后大鼠不同脑区ＣｈＡＴ活性和ＳＳ含量的变化。结果发现：大鼠一侧无名质区破坏后，同侧大脑皮质额叶，顶叶的ＣｈＡＴ活性显著下降，同时同侧额叶、顶叶及海马的ＳＳ含量也明显降低。结果提示：中枢胆碱能系统和生长抑素系统有极密切的关系，无名质区破坏后脑内ＳＳ含量的下降，可能是伴随着胆碱能系统损伤的继发性改变。推测ＳＳ系统可能接受胆碱能系统的传入，参与对学习、记忆的调节。     

Response to ionising radiation in Duchenne muscular dystrophy

Using lymphoblastoid cell cultures the response to gamma (γ)-radiation, was examined in 6 Duchenne muscular dystrophy (DMD) patients; 2 clinically normal males as negative controls, and 2 patients with ataxia telangiectasia (AT) showing sensitivity to ionising radiation as positive controls.In a series of experiments, cell recovery and growth at day 2 post radiation, was determined after 5 separate γ-irradiation dose levels: 50, 100, 150, 200 and 300 rads.The DMD cell strains showed a radiation dose response that was significantly greater than in cells from 2 normal males, while both DMD and normal cells were significantly less responsive than were AT-sensitive cell strains.     

Dementia in idiopathic Parkinson's disease

Summary Neuronal loss was estimated semiquantitatively in the substantia nigra (SN) and locus coeruleus (LC), and by cell counts in the nucleus basalis of Meynert (NBM), in 32 patients with idiopathic Parkinson's disease (14 non-demented and 18 demented). The number of senile plaques (SP) and neurofibrillary tangles (NFT) was rated in four cortical areas. Neuronal loss in the SN seemed in dependent of mental impairment, while severe lesions of the LC were more frequent in demented patients. In the NBM, neuronal loss and Lewy bodies were observed in most cases (95%) and were associated with significant reductions of choline acetyltransferase (CAT) activity both in the NBM and the cortex (measurements available for 13 cases). This confirms that the cholinergic innominatocortical pathway is damaged in Parkinson's disease and that the lesion is severer in subjects with dementia. SP and NFT were present in the cortex in 75% of the cases and significantly more numerous in demented patients. However, in 37% of the cases (six cases with dementia), the score for cortical changes was low and could be related to age. Cortical SP and NFT were not correlated to the degree of cell loss in LC and NBM, or to CAT activity in the cortex or NBM. Damage to coeruleocortical, innominato-cortical and intra-cortical neurones could each play a role in the appearance of dementia in Parkinsonism. The lesions in the different neuronal systems do not seem to evolve in parallel, but may be additive or potentiate one another in terms of functional expression. Also, the variety in extent and degree of lesions encountered in Parkinson's disease may offer a pathological substrate for the wide variety of mental symptoms described in this illness.This work is dedicated to the memory of Pr. R. Escourolle. As the head of the laboratoire Charles Foix, he had followed this work with great interest     

Neuropathological study on the nucleus basalis of Meynert in Pick's disease

Summary The pathological changes in the nucleus basalis of Meynert (nbM) in 10 autopsied cases with Pick's disease were studied in comparison with 15 agematched controls. Both the number and density of nerve cells and the degree of fibrillary gliosis were examined at the anterior, intermediate, and posterior divisions of the nbM. In only 2 of the 10 Pick cases was the number of neurons significantly reduced, with moderate fibrillary gliosis at the anterior division (case 5: reduced by 64%, case 8: reduced by 46%). This neuronal loss in the anterior nbM division may not be a retrograde degeneration secondary to the cortical lesions, since there were some cases without neuronal loss in the nbM despite the presence of much more severe cortical lesions than in these two cases. In all Pick cases except case 1, mild to moderate fibrillary gliosis was found without an apparent neuronal loss at the posterior division of the nbM. This change in the posterior nbM division may be due to secondary retrograde degeneration, since there was a parallel relationship between the degree of fibrillary gliosis in the posterior nbM division and the severity of cortical lesions in the temporal tip and the superior temporal gyrus, to which the cholinergic fibers are known to project from the posterior division of the nbM. The present study suggests that the mild degeneration of the nbM in most cases with Pick's disease may be secondary, but that there are also some cases of Pick's disease with a primary degeneration in the nbM.     

Apoptotic signals within the basal forebrain cholinergic neurons in Alzheimer's disease

A relatively early and substantial loss of basal forebrain cholinergic neurons is a constant feature of Alzheimer's disease (AD). However, the mechanisms that contribute to the selective vulnerability of these neurons are not fully delineated. In the present series of experiments, we determined the possible contribution of apoptotic processes and other pathologic cascades to the degeneration of the cholinergic neurons of the nucleus basalis of Meynert (NBM) in AD. In contrast to neurons in the frontal cortex which showed prominent DNA fragmentation as detected by the TUNEL method, no DNA fragmentation was observed within the NBM in any of the AD or normal brains. Similarly, immunoreactivity for the apoptotic signals Fas, Fas-ligand, Bax, Bcl-x, caspase-8, caspase-9 and caspase-3 was absent from the NBM of AD and control brains. In contrast, a substantial subpopulation of cholinergic neurons within the NBM in AD displayed prominent immunoreactivity for the apoptotic signal Fas-associated death domain (FADD) in the form of tangles. FADD immunoreactivity was also present in dystrophic neurites. FADD-positive tangle-like structures were localized in neurons which contained immunoreactivity for the cholinergic marker choline acetyltransferase (ChAT) and the low affinity neurotrophin receptor p75NTR. While many of the NBM cholinergic neurons in control brains contained immunoreactivity for the calcium binding protein calbindin-D28K (CB), the NBM neurons in AD displayed a substantial loss of CB immunoreactivity. Importantly, most of FADD-immunoreactive cholinergic neurons were devoid of CB immunoreactivity, and, conversely, most CB-positive cholinergic neurons had no FADD immunoreactivity. FADD immunoreactivity within the basal forebrain was colocalized with phosphorylated tau immunoreactive tangles and dystrophic neurites. In contrast, FADD immunoreactivity did not appear to be related to the primarily diffuse amyloid-beta deposits intermingled between cholinergic neurons in AD NBM. Finally, many CD68-positive microglia were observed surrounding the NBM cholinergic neurons in AD. In conclusion, the findings of the present study indicate that, while the FADD apoptotic signaling pathway may be triggered within the basal forebrain cholinergic neurons in AD, the apoptotic cascade is most likely aborted as no DNA fragmentation was detected and the executioner caspase-3 was not up-regulated within these neurons. The findings also suggest possible relationships between loss of CB, FADD expression and phosphorylation of tau within the basal forebrain cholinergic neurons in AD.     

Experimental transmission of human subacute spongiform encephalopathy to small rodents

Summary In a man of 47 with a 2-month history of Creutzfeldt-Jakob-disease verified neuropathologically a morphometric study of the nucleus basalis of Meynert, the major source of cholinergic innervation of the cortex, revealed a neuronal loss of 45%. The degeneration of these neurones may provide the morphological substrate of the cortical cholinergic deficiency which has been reported in this condition. The six subpopulations of the nucleus basalis were affected in different degrees. Neuronal loss was most pronounced in those subpopulations which project to cortical areas most affected by spongiosis and neuronal loss. It is suggested that maintenance of the nucleus basalis complex is a necessary condition for higher cortical function.     

Neuropathological changes in the nucleus basalis correlate with clinical measures of dementia

The present study correlates the severity of dementia in Alzheimer’s disease with the degree of neuropathology present in the nucleus basalis of Meynert. We assessed neurofibrillary tangles, neuronal loss and morphometric changes in 21 patients with Alzheimer’s disease who underwent extensive neuropsychological testing before death. We report a highly significant correlation between scores in the psychological tests and all of the neuropathological markers examined within the nucleus basalis of Meynert. The test that correlated most closely with these morphological measures was Folstein’s Mini Mental State. Among the different neuropathological changes, the number of neurofibrillary tangles was strongly correlated with the degree of dementia. We also provide evidence for a differential involvement of the three subdivisions of the nucleus basalis in Alzheimer’s disease neuropathology. The posterior subdivision, which provides a substantial cholinergic input to the parahippocampal gyrus, was the more profoundly affected. Taken together, these results point to an important participation of the nucleus basalis in dementia of the Alzheimer type. In addition, the strong correlation between neuropathological changes and neuropsychological scores indicates the reliability of these tests in assessing the progression of the disease. Received: 22 June 1998 / Revised: 22 October 1998 / Accepted: 5 January 1999     

Amyloid deposition in the nucleus basalis of Meynert complex: a topographic marker for degenerating cell clusters in Alzheimer's disease

Summary The deficiency of the cholinergic cortical projection system arising in the different basal forebrain structures collectively referred to as nucleus basalis of Meynert complex is a constant finding in Alzheimer's disease, a disorder which is neuropathologically characterised by the appearance of three intracerebral formes of twisted -pleated sheet (amyloid) fibrils, neurofibrillary tangles, amyloid-containing neuritic plaques and congophilic amyloid angiopathy. In the present study the quantitative relationship between these hallmarks of the disease, amyloid deposition and neuronal loss in the cholinergic basal forebrain system, was investigated in ten cases of Alzheimer's disease. Besides a constant involvement of the cerebral cortex and hippocampus, all cases of Alzheimer's disease show a large amount of amyloid in the medial septal nucleus, in the diagonal band nucleus and in the substantia innominata which is correlated with neuronal loss in these areas. These amyloid deposits in the basal forebrain are due to congophilic angiopathy associated with plaques and neurofibrillary tangles. The distribution of amyloid deposition in the basal forebrain is restricted entirely to those neuronal clusters which represent the origin of cholinergic innervation of the cerebral cortex and hippocampus. Immediately adjacent structures are not affected. These findings suggest a pathogenetic role of amyloid deposition in the mechanism of degeneration of the cholingeric basal forebrain system.     

Galanin-like immunoreactivity within Ch2 neurons in the vertical limb of the diagonal band of Broca in aging and Alzheimer's disease

Summary The neuropeptide galanin is known to inhibit the evoked release of acetylcholine in ventral hippocampus of the rat. Co-localization of this peptide with choline acetyltransferase in neurons of the cholinergic septal nuclei has been demonstrated in the rat and non-human primate. The severe deficiency of the cholinergic hippocampal projection system arising mainly from the vertical limb nucleus of the diagonal band of Broca, also referred to as Ch2 region, is a constant finding in Alzheimer's disease, a disorder which is neuropathologically characterized by the appearance of senile plaques, neurofibrillary tangles and congophilic angiopathy in neo- and archicortical structures. In the present study for the first time galanin immunoreactivity in the human Ch2 region is morphologically investigated and related to the severity of hippocampal plaques and neurofibrillary tangles in Alzheimer's disease. An inverse relationship between decreasing galanin immunoreactivity in the Ch2 region and amounts of senile plaques and neurofibrillary tangles in the hippocampus is indicated. Considering the cholinergic deficiency in Alzheimer's disease as a secondary phenomenon to primary cortical and hippocampal lesions, and realizing the inhibitory effect of galanin upon acetylcholine release in hippocampus, this preliminary study suggests that a decreased galanin immunoreactivity in Ch2 in Alzheimer's disease reflects a possible negative feedback mechanism to a degenerating cholinergic projection system.Supported fully by a research grant from the JANIVO Foundation     

F. H. Lewy on Lewy bodies,parkinsonism and dementia

F. H. Lewy (1885-1950) recognized characteristic globoid and elongated inclusions with a surrounding halo (Lewy bodies) in the nervecells of the dorsal nucleus of the vagus and in Meynert's nucleuls basalis of patients with shaking palsy. Excerpts of his influential publications from 1912 and 1913 are translated. In 1923 he published a monograph which contains neurological, psychiatric and neuropathological data about 43 patients with Parkinsonism; 21 were demented, 10 had affective disturbances and 12 were considered as mentally normal. Alzheimer tangles and/or plaques were found in the cortices of 12 patients. Structures corresponding to Lewy bodies were described in the brains of 13 patients, but only once in the neocortex. Lewy's original work may deserve interest in view of current research on the prevalence and nature of the Lewy body and the nosological confusion caused by its rediscovery.     

The neuroprotective effect of deep brain stimulation at nucleus basalis of Meynert in transgenic mice with Alzheimer's disease

Background

Alzheimer's disease (AD) is the most common type of dementia and mainly treated by drugs, while the therapeutic outcomes are very limited. This study aimed to determine the optimized parameters of deep brain stimulation (DBS) which was applied to the treatment of AD and propose the involved mechanisms.

Dentatorubropallidoluysian atrophy: clinicopathological study of dementia and involvement of the nucleus basalis of Meynert in seven autopsy cases

This report concerns a clinicopathological study including a quantitative pathological study on the nucleus basalis of Meynert (nbM) of seven Japanese autopsy cases (four male, three female) of dentatorubropallidoluysian atrophy (DRPLA) with special reference to the clinicopathological correlation of dementia in DRPLA. In each case the pattern of the inheritance was consistent with that of an autosomal dominant trait. The neurological examination revealed that all seven individuals had cerebellar signs. Six patients had epilepsy and choreoathetoid involuntary movement; myoclonus was evident in five patients. Dementia was noted in all seven patients. Degeneration of the globus pallidus (particularly the lateral segment) and of the dentate nucleus was the principal pathological feature. Brain weights at autopsy ranged from 1020 to 1400 g (average 1241 g: male 1320 g, female 1135 g). The quantitative evaluation revealed no significant loss of neurons in the nbM as compared with a control group. There was no clinicopathological correlation between dementia and involvement of the nbM. We suggest that the dementia of DRPLA is due not to the involvement of the nbM, but to – as yet – unidentified pathology elsewhere. Received: 12 January 1998 / Revised: 28 April 1998 / Accepted: 6 May 1998