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H Braak

Publications and source records attributed to H Braak.

At least 37 records · Page 2Linked to original sources
PubMed2003

Neuropathology of cognitively normal elderly.

Despite general agreement about the boundaries of Alzheimer disease (AD), establishing a maximum limit for Alzheimer-type pathology in cognitively intact individuals might aid in defining more precisely the point at which Alzheimer pathology becomes clinically relevant. In this study, we examined the neuropathological changes in the brains of 39 longitudinally followed. cognitively normal elderly individuals (24 women, 15 men; age range 74-95, median 85 years). Neuropathological changes of the Alzheimer type were quantified by determining neurofibrillary tangle (NFT) staging by the method of Braak and Braak and by quantification of the abundance of diffuse, cored, and neuritic plaque burden using the scheme developed by the Consortium to Establish a Registry for Alzheimer Disease (CERAD). Vascular, Lewy body, and argyrophilic grain pathology were also assessed. We found 34 subjects (87%) with a Braak stage <IV; 32 subjects (82%) with less than moderate numbers of cored plaques and 37 subjects (95%) with less than moderate numbers of tau-positive neuritic plaques. Many subjects had moderate or frequent diffuse plaques (n = 19, 49%). By the National Institute on Aging-Reagan Institute (NIA-RI) criteria, none of our cases met criteria for high "likelihood" of AD. Four met NIA-RI criteria for intermediate "likelihood." Seven cases met CERAD criteria for possible AD. Nineteen met Khachaturian criteria for AD. Only 1 subject had neocortical Lewy bodies. Small, old infarcts were common, but no subjects had more than 2 of these and none had a single large infarction. Thus, the majority of individuals who are cognitively normal near the time of their death have minimal amounts of tau-positive neuritic pathology (Braak stage <IV and neuritic plaques <6 per x100 field in the most affected neocortical region). The few subjects with more severe AD pathology can be expected based on incidence rates of AD in the very elderly.

Aged↗
PubMed2002

Degeneration of the external cuneate nucleus in spinocerebellar ataxia type 3 (Machado-Joseph disease).

Owing to its anatomical connections, the external cuneate nucleus (ECU) plays a crucial role in processing proprioceptive input from the upper trunk and upper limbs. Here, we studied this dorsal column nucleus post-mortem in five individuals with clinically diagnosed and genetically confirmed spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, who had manifested upper trunk and upper limb ataxia. Polyethylene glycol-embedded 100-microm sections stained for lipofuscin pigment and Nissl material, as well as paraffin-embedded Nissl-stained thin sections, revealed serious neuronal loss in the ECU of all five SCA3 patients. As observed in other affected central nervous system structures, the ECU of these individuals displayed an astrogliosis, and some of the few surviving neurons harbored one or even two ataxin-3-immunopositive intranuclear inclusion bodies. The findings of the present study suggest that (1) the ECU is among the consistent targets of the degenerative process underlying SCA3 and (2) interruption of the proprioceptive pathway at the level of the ECU contributes significantly to upper limb and trunk ataxia in SCA3 patients.

Adult↗
PubMed2002

Interstitial cells subjacent to the entorhinal region expressing somatostatin-28 immunoreactivity are susceptible to development of Alzheimer's disease-related cytoskeletal changes.

Interstitial cells are isolated neurons located in the infracortical white matter that are known to express neuropeptides. Twenty-four cases selected for the absence, slight (Braak stages I-II), moderate (Braak stages III-IV), or serious degree (Braak stages V-VI) of cortical neurofibrillary pathology were studied for the presence of Alzheimer's disease-related abnormal tau in interstitial cells of the entorhinal region. AT8-immunoreactive white matter neurons were observed in all Braak stages of cortical neurofibrillary pathology. Both normal-appearing neurons and neurons with degenerative changes in the cellular processes were observed. Normal-appearing cells were predominantly found in stages I and II, whereas degenerative interstitial cells numerically increased from stage I onwards. The normal-appearing cells were medium-sized (10-25 micro m), with ovoid, fusiform, triangular or multipolar cell bodies, and showed an extensive dendritic field, which was oriented perpendicular to the direction of the perforant pathway. Since the morphology of the AT8-immunopositive normal-appearing cells was similar to that reported on somatostatinergic interstitial cells subjacent to the entorhinal region, double-labeling with AT8 and anti-somatostatin-28 (S309) was performed. All AT8-immunoreactive normal-appearing interstitial cells revealed co-staining with somatostatin-28 antiserum, whereas some of the AT8-immunopositive cells with degenerative processes reacted positively and others negatively with S309. In summary, a distinctive interstitial cell type characterized by extensive arborization oriented perpendicular to the course of the perforant pathway and showing somatostatin expression is susceptible to developing the Alzheimer's disease-related cytoskeletal changes. Progression in cytoskeleton change is accompanied by loss of somatostatin.

Adult↗
PubMed2002

Current state of stem cell research for the treatment of Parkinson's disease.

Current findings suggest that multipotent stem cells may be suitable for cell replacement therapies in the treatment of neurodegenerative disorders. Embryonic stem (ES) cells are pluripotent cells isolated from the inner cell mass of the preimplantation blastocyst, which give rise to all cells in the organism. Similarly, multipotent stem cells are also able to regenerate, but are believed to have a more restricted potential than ES cells, and are often defined by the organ from which they are derived. Neural stem cells have been categorized as multipotent stem cells derived from the nervous system with the capacity to regenerate and to give rise to cells belonging to all three cell lineages in the nervous system: neurons, oligodendrocytes, and astrocytes. It is hoped that research on stem cells may reveal methods for producing an infinite supply of dopamine neurons for transplant into Parkinson's disease (PD) patients. The problem is controlling cell growth and differentiation. We will briefly review the current state of stem cell research and will critically discuss the potential of stem cells for the treatment of PD.

Brain Tissue Transplantation↗
PubMed2002

The intralaminar nuclei assigned to the medial pain system and other components of this system are early and progressively affected by the Alzheimer's disease-related cytoskeletal pathology.

The intralaminar nuclei of the human thalamus are integrated into the ascending reticular activating system and into limbic, oculomotor and somatomotor loops. In addition, some of them also represent important components of the medial pain system. We examined the occurrence and severity of the Alzheimer's disease (AD)-related cytoskeletal pathology and beta-amyloidosis in the seven intralaminar nuclei (central lateral nucleus, CL; central medial nucleus, CEM; centromedian nucleus, CM; cucullar nucleus, CU; paracentral nucleus, PC; parafascicular nucleus, PF; subparafascicular nucleus, SPF) in 27 autopsy cases at different stages of the cortical neurofibrillary pathology (cortical NFT/NT-stages I-VI) and beta-amyloidosis (cortical phases 1-4). The CEM, CL, PF, and SPF are slightly affected at stage II (corresponding to preclinical AD). They are markedly involved at stages III and IV (i.e. incipient AD) and severely affected at stages V and VI (i.e. clinical AD). In the PC and CU, the cytoskeletal pathology is mild at stage III, marked at stage IV, and severe at stages V-VI, whereas the CM is only mildly affected at stages IV-VI. In all of the intralaminar nuclei, deposits of the protein beta-amyloid occur for the first time during the final phase of cortical beta-amyloidosis. Functionally, the cytoskeletal pathology encountered in the intralaminar nuclei may contribute to the memory and affective symptoms, attention deficits, and dysfunctions related to horizontal saccades and smooth pursuits seen in AD patients. Equally important, however, are the findings that the cytoskeletal pathology developing within the intralaminar nuclei assigned to the medial pain system (CEM, CL, CU, PC, PF) as well as within other components of this system begins already during the preclinical or incipient phases of AD. Given this fact, the question arises as to whether non-discriminative aspects mediated by the medial pain system could be employed to identify individuals in the very earliest stages of AD.

Aged↗
PubMed2002

Progressive supranuclear palsy: neuronal and glial cytoskeletal pathology in the higher order processing autonomic nuclei of the lower brainstem.

The medial and lateral parabrachial nuclei (MPB, LPB), the gigantocellular reticular nucleus (GI), the raphes magnus (RMG) and raphes obscurus nuclei (ROB), as well as the intermediate reticular zone (IRZ) represent pivotal subordinate brainstem centres, all of which control autonomic functions. In this study, we investigated the occurrence and severity of the neuronal and glial cytoskeletal pathology in these six brainstem nuclei from 17 individuals with clinically diagnosed and neuropathologically confirmed progressive supranuclear palsy (PSP). The association between the severity of the pathology and the duration of the disease was investigated by means of correlation analysis. The brainstem nuclei in all of the PSP cases were affected by the neuronal cytoskeletal pathology, with the IRZ and GI regularly showing severe involvement, the MPB, RMG, and ROB marked involvement, and the LPB mild involvement. In the six nuclear greys studied, glial cells undergo alterations of their cytoskeleton on an irregular basis, whereby diseased oligodendrocytes predominantly presented as coiled bodies and affected astrocytes as thorn-shaped astrocytes. In all six nuclei, the severity of the neuronal or glial cytoskeletal pathology showed no correlation with the duration of PSP. In view of their functional role, the neuronal pathology in the nuclei studied offers a possible explanation for the autonomic dysfunctions that eventually develop in the course of PSP.

Aged↗
PubMed2002

Genetic association of argyrophilic grain disease with polymorphisms in alpha-2 macroglobulin and low-density lipoprotein receptor-related protein genes.

Argyrophilic grain disease (AGD) is a neurodegenerative disorder of the aged human brain associated with the formation of abnormal tau protein in specific neurones and macroglial cells. Previously, we reported the association between AGD and the epsilon2 allele of apolipoprotein E (ApoE). Here, the polymorphisms of the alpha-2 macroglobulin gene (A2M) and those of the low-density lipoprotein receptor-related protein gene (LRP) were assessed in 115 AGD cases and compared with 170 controls. The results reveal an association between AGD and the C766T polymorphism of LRP (P=0.001). In addition, the present study shows that the valine to isoleucine (Val1000Ile) polymorphism of A2M is linked with AGD (P=0.03). By comparison, no relationship between AGD and the intronic 5-bp deletion/insertion polymorphism of A2M is demonstrable (P=0.8). Finally, this report corroborates and extends our earlier finding in that the frequency of the epsilon2 allele of ApoE is higher in AGD cases than in controls (17.4% vs. 8.5%, P=0.003), whereas the epsilon4 allele frequency approximates that in control cases (13.9% vs. 13.2%, P=0.93). This association, however, is only apparent in the presence of the LRP CC genotype. In conclusion, the present study shows that AGD is associated with the LRP, A2M and ApoE genes.

Aged↗
PubMed2002

Spinocerebellar ataxia type 3 (Machado-Joseph disease): severe destruction of the lateral reticular nucleus.

The lateral reticular nucleus (LRT) of the medulla oblongata is a precerebellar nucleus involved in proprioception and somatomotor automatisms. We investigated this nucleus in five individuals with clinically diagnosed and genetically confirmed spinocerebellar ataxia type 3 (SCA3, Machado-Joseph disease). Polyethylene glycol-embedded 100 micro m thick sections stained for lipofuscin granules and Nissl material as well as Nissl-stained paraffin-embedded sections revealed severe destruction of the LRT in all SCA3 brains examined. Some of the few surviving neurones contained ataxin-3-immunopositive intranuclear inclusion bodies, as noted in other affected brain regions in SCA3. Along with the severe neuronal depletion, obvious astrogliosis was seen in the LRT of all SCA3 patients. The findings suggest that the LRT is a consistent target of the pathological process underlying SCA3. In view of its afferent and efferent connections, destruction of the LRT probably contributes to gait ataxia in individuals suffering from SCA3.

Adult↗
PubMed2001

Early involvement of the tegmentopontine reticular nucleus during the evolution of Alzheimer's disease-related cytoskeletal pathology.

The tegmentopontine reticular nucleus (nucleus of Bechterew) plays a crucial role in the generation of horizontal saccades and smooth pursuit movement of the eyes. The evolution of Alzheimer's disease-related cytoskeletal pathology was studied of this nucleus was studied in 27 autopsy cases at different stages of the cortical neurofibrillary pathology (NFT/NT stages I--VI). The first cytoskeletal changes were seen at stages I and II (preclinical Alzheimer's disease). At stages III and IV (incipient Alzheimer's disease), the nucleus exhibited a marked pathology, and it was severely involved at stages V and VI (clinically overt Alzheimer's disease). Damage to the tegmentopontine reticular nucleus most probably contributes to the hypometrie of horizontal saccades and the slowing of smooth pursuits that characteristically develop in patients suffering from Alzheimer's disease. Given the fact that pathological alterations of the tegmentopontine reticular nucleus begin early during the evolution of the underlying process, the question arises as to whether dysfunctional horizontal saccades and abnormal smooth pursuits could be employed as means of screening or diagnosing Alzheimer's patients in the very earliest stages of the disease.

Aged↗
PubMed2001

Gender and age modify the association between APOE and AD-related neuropathology.

OBJECTIVE: To assess the impact of apolipoprotein E (APOE) polymorphism on AD-related neurofibrillary tangle (NFT) formation and senile plaques (SP). METHODS: A sample of 729 routine autopsy brains (359 men, 370 women; age range, 60 to 99 years) was investigated. All brains were classified neuropathologically according to a procedure permitting differentiation of six NFT stages and three SP stages. APOE genotyping was performed on all cases. RESULTS: The epsilon4 allele of APOE was associated not only with SP (p < 0.0001) but also with NFT formation (p < 0.0001). The effect of the epsilon4 allele on NFT formation was noted at ages > or =80 years (p < 0.0001) but not between ages 60 and 79 years (p = 0.12). An association between the epsilon4 allele and SP for women was found at ages 60 to 79 years (p < 0.0001) but not at > or =80 years of age (p = 0.063). By comparison, men showed an association in both age categories (p = 0.001 and p = 0.001). CONCLUSION: The results confirm the association between the epsilon4 allele and both types of AD-related lesions and show that this association is differentially modified by age and gender.

Age Factors↗
PubMed2001

alpha-synuclein immunopositive Parkinson's disease-related inclusion bodies in lower brain stem nuclei.

Advanced silver stains and immunohistochemical reactions against alpha-synuclein were used to detect Parkinson's disease-related cytoskeletal abnormalities in select lower brain stem nuclei. Various types of inclusion bodies including inconspicuous and heretofore unnoted granular particles and thread-like Lewy neurites were visualized. Of the nuclei investigated (gigantocellular reticular nucleus, bulbar raphe nuclei, coeruleus-subcoeruleus area), only lipofuscin- or neuromelanin-laden neuronal types showed a propensity to develop the pathological changes. Neuronal types devoid of pigment deposits remained free of the cytoskeletal abnormalities. Fine, dust-like particles and small globular Lewy bodies were encountered solely within the limits of intraneuronal lipofuscin or neuromelanin deposits.

Aged↗
PubMed2001

The autonomic higher order processing nuclei of the lower brain stem are among the early targets of the Alzheimer's disease-related cytoskeletal pathology.

The nuclei of the pontine parabrachial region (medial parabrachial nucleus, MPB; lateral parabrachial nucleus, LPB; subpeduncular nucleus, SPP) together with the intermediate zone of the medullary reticular formation (IRZ) are pivotal relay stations within central autonomic regulatory feedback systems. This study was undertaken to investigate the evolution of the Alzheimer's disease-related cytoskeletal pathology in these four sites of the lower brain stem. We examined the MPB, LPB, SPP and IRZ in 27 autopsy cases and classified the cortical Alzheimer-related cytoskeletal anomalies according to an established staging system (neurofibrillary tangle/neuropil threads [NFT/NT] stages I-VI). The lesions were visualized either with the antibody AT8, which is immunospecific for the abnormally phosphorylated form of the cytoskeletal protein tau, or with a modified Gallyas silver iodide stain. The MPB, SPB, and IRZ display cytoskeletal pathology in stage I and the LPB in stage II, whereby bothstages correspond to the preclinical phase of Alzheimer's disease (AD). In stages III-IV (incipient AD), the MPB and SPP are severely affected. In all of the stage III-IV cases, the lesions in the LPB and IRZ are well developed. In stages V and VI (clinical phase of AD), the MPB and SPP are filled with the abnormal intraneuronal material. At stages V-VI, the LPB is moderately involved and the IRZ shows severe damage. The pathogenesis of the AD-related cytoskeletal lesions in the nuclei of the pontine parabrachial region and in the IRZ conforms with the cortical NFT/NT staging sequence I-VI. In the event that the cytoskeletal pathology observed in this study impairs the function of the nerve cells involved, it is conceivable that autonomic mechanisms progressively deteriorate with advancing cortical NFT/NT stages. This relationship remains to be established, but it could provide insights into the illusive correlation between the AD-related cytoskeletal pathology and the function of affected neurons.

Aged↗
PubMed2001

Nerve cells expressing heat-shock proteins in Parkinson's disease.

A distinctive histopathological feature of several neurodegenerative diseases, including corticobasal degeneration, argyrophilic grain disease, progressive supranuclear palsy, and Pick's disease, are achromatic nerve cells that express small heat-shock proteins, such as alphaB-crystallin or hsp-27, and develop in specific telencephalic cortical areas and subcortical nuclei. Here, we point to the consistent presence of such cells in Parkinson's disease. In this disorder, the neurons under consideration remain immunonegative for phosphorylated neurofilaments or for ubiquitin, thus exhibiting an immunocytochemical profile different from that shown by alphaB-crystallin-positive neurons in other neurodegenerative disorders. In severe cases of Parkinson's disease, the alphaB-crystallin-positive neurons are dispersed throughout the cerebral cortex, amygdala, and ventral claustrum. In cases showing relatively mild involvement of the telecephalon, these neurons occur chiefly within the reaches of the anterior temporal and insular mesocortex. These telencephalic predilection sites are nearly identical with those of the alpha-synuclein pathology. Nevertheless, most of the telencephalic alphaB-crystallin-immunopositive neurons refrain from developing Lewy bodies and Lewy neurites and, vice versa, most of the nerve cells containing Lewy bodies do not accumulate alphaB-crystallin.

Aged↗
PubMed2001

The premotor region essential for rapid vertical eye movements shows early involvement in Alzheimer's disease-related cytoskeletal pathology.

The rostral interstitial nucleus of the medial longitudinal fascicle (riMLF) contains premotor neurons essential for the generation of rapid vertical eye movements. The Alzheimer's disease (AD)-related cytoskeletal changes and beta-amyloid deposits in this nucleus were examined in 30 autopsy cases and compared to the involvement of three associated nuclei - Edinger-Westphal nucleus, nucleus of Darkschewitsch and interstitial nucleus of Cajal. The riMLF displays slight cytoskeletal alterations already in the early stages in the development of the cortical cytoskeletal pathology (cortical NFT/NT-stages I-II, representing the preclinical phase of AD). In the cortical NFT/NT-stages III-IV (i.e. incipient phase of AD), the cytoskeletal pathology in the riMLF is pronounced and in stages V-VI (i.e. clinical phase of AD) it is severe. The progression of the cytoskeletal pathology in the riMLF correlates significantly with the cortical NFT/NT-stages I-VI that reflect the clinical course of AD. Isolated beta-amyloid deposits appear in the riMLF for the first time in the final beta-amyloid stage. In the Edinger-Westphal nucleus, in the nucleus of Darkschewitsch and most markedly in the interstitial nucleus of Cajal, the pathological changes were significantly less severe than those in the riMLF. In the event that the cytoskeletal pathology impairs the function of the premotor neurons of the riMLF, one would predict a progressive slowing of vertical saccades corresponding to the advancing cortical NFT/NT-stages.

Aged↗
PubMed2000

Pathoanatomy of Parkinson's disease.

Parkinson's disease is a widespread degenerative illness affecting the human central, peripheral, and enteric nervous systems. The underlying pathological process progresses slowly but relentlessly and involves multiple neuronal systems. The disease is the consequence of changes in the neuronal cytoskeleton developing in only a few susceptible types of nerve cells. Afflicted neurons eventually produce Lewy bodies in their perikarya and Lewy neurites in their neuronal processes. Immunoreactions against the presynaptic protein alpha-synuclein have revealed many kinds of inclusion bodies ranging from inconspicuous dot- or thread-like forms to particularly voluminous types. The selective vulnerability of nerve cells induces a distinctive distribution pattern of lesions which remains remarkably consistent across cases. Components of the limbic system and the motor system have been shown to be particularly vulnerable to severe destruction. Some subnuclei of the substantia nigra also undergo major changes. This damage is consistently accompanied by extranigral alterations, with predilection sites including the entorhinal region, the second sector of the Ammon's horn, and important subnuclei of the amygdala. In addition, the nucleus of the stria terminalis, components of the hypothalamus, all of the non-thalamic nuclei with diffuse projections to the cerebral cortex, and most of the centers regulating autonomic functions exhibit severe lesions.

Brain↗
PubMed2000

[Clinical aspects of "argyrophilic grain disease"].

Argyrophilic grain disease (AGD) is a frequently occurring degenerative illness of the aging human brain. It is accompanied by progressive pathological alterations of the cytsokeleton which are traceable to an abnormal phosphorylation of the microtubule associated tau protein. Histologically, it is possible with the help of suitable staining techniques to identify pathognomonic spindle-shaped cellular inclusions (argyrophilic grains). These cellular inclusions display a typical cortical as well as subcortical distribution pattern. The goal of the present study is the retrospective evaluation of the clinical findings from 53 individuals with neuropathologically demonstrable AGD-related changes of the brain. Nearly one-half of the cases (49%) was classifiable as demented in accordance with DSM IV-criteria. Moreover, the frequency of the dementia increased significantly in relation to the growing severity of the AGD-associated pathological cytoskeletal degeneration. These results confirm the assumption that AGD can cause degenerative changes ranging from cognitive impairment all the way to dementia. They also underscore the necessity of further prospective studies pertaining to the clinical aspects of this still enigmatic disease.

Aged↗
PubMed2000

[Neuroanatomy of Parkinson disease. Changes in the neuronal cytoskeleton of a few disease-susceptible types of neurons lead to progressive destruction of circumscribed areas in the limbic and motor systems].

Morbus Parkinson is a progressive degenerative disease of the human central, peripheral, and enteric nervous systems. In the course of the disease, not only the substantia nigra, but also extranigral components of the motor system, as well as numerous limbic system and autonomic centers undergo serious damage. Accordingly, Parkinson's disease is a multisystem disorder. Only specific types of projection neurons fall victim to it. The first manifestation of the pathological process which causes the disease are abnormalities of the neuronal cytoskeleton. Intracytoplasmic inclusions evolving in the form of Lewy bodies in perikarya and Lewy neurites in the neuronal processes result in premature cell death of the affected neurons. On the basis of this selective neuronal vulnerability, a categorization emerges of the pathological changes within the nervous system and corresponding functional impairments.

Apoptosis↗