S. M. Gentleman

Beta amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer's disease.

In a recent preliminary study it was reported that a severe head injury resulted in the deposition of beta amyloid protein (beta AP) in the cortical ribbon of 30% of patients who survived for less than two weeks. Multiple cortical areas have now been examined from 152 patients (age range 8 weeks-81 years) after a severe head injury with a survival time of between four hours and 2.5 years. This series was compared with a group of 44 neurologically normal controls (age range 51 to 80 years). Immunostaining with an antibody to beta AP confirmed the original findings that 30% of cases of head injury have beta AP deposits in one or more cortical areas. Increasing age seemed to accentuate the extent of beta AP deposition and potential correlations with other pathological changes associated with head injury were also investigated. In addition, beta amyloid precursor protein (beta APP) immunoreactivity was increased in the perikarya of neurons in the vicinity of beta AP deposits. The data from this study support proposals that increased expression of beta APP is part of an acute phase response to neuronal injury in the human brain, that extensive overexpression of beta APP can lead to deposition of beta AP and the initiation of an Alzheimer disease-type process within days, and that head injury may be an important aetiological factor in Alzheimers disease.

The dorsal motor nucleus of the vagus is not an obligatory trigger site of Parkinson's disease: a critical analysis of α-synuclein staging

Aims: It has been proposed that alpha‐synuclein (αSyn) pathology in Parkinsons disease (PD) spreads in a predictable caudo‐rostral way with the earliest changes seen in the dorsal motor nucleus of the vagus nerve (DMV). However, the reliability of this stereotypical spread of αSyn pathology has been questioned. In addition, the comparative occurrence of αSyn pathology in the spinal cord and brain has not been closely studied. Methods: In order to address these issues, we have examined 71 cases of PD from the UK Parkinsons Disease Society Tissue Bank at Imperial College, London. The incidence and topographic distribution of αSyn pathology in several brain regions and the spinal cord were assessed. Results: The most affected regions were the substantia nigra (SN; in 100% of cases) followed by the Nucleus Basalis of Meynert (NBM) in 98.5%. Fifty‐three per cent of cases showed a distribution pattern of αSyn compatible with a caudo‐rostral spread of αSyn through the PD brain. However, 47% of the cases did not fit the predicted spread of αSyn pathology and in 7% the DMV was not affected even though αSyn inclusions were found in SN and cortical regions. We also observed a high incidence of αSyn in the spinal cord with concomitant affection of the DMV and in a few cases in the absence of DMV involvement. Conclusions: Our results demonstrate a predominant involvement of the SN and NBM in PD but do not support the existence of a medullary induction site of αSyn pathology in all PD brains.

Distribution of β‐amyloid protein in the brain following severe head injury

Deposits of β‐amyloid protein (PAP) can be found in the brains of 30% of fatally head‐injured patients: they have been found in children and after survival times of only 4 h. The principal aims of this study were to map the distribution of βAP in 14 patients aged 65 years or less in whom it was known that the protein had been deposited, and to correlate its distribution with the pathologies of traumatic brain injury. The results show that βAP is widely distributed, and that there is no correlation between its presence and cerebral contusions, intracranial haematoma, axonal injury, ischaemic brain damage, brain swelling or the pathology of raised intracranial pressure. These findings suggest that the deposition of βAP is a consequence of the acute phase response of nerve cells to stress in susceptible individuals. Further studies will be required to establish the possible relationship between the deposition of βAP following head injury and the molecular neuropathology of Alzheimers disease.

The neuroinflammatory response in humans after traumatic brain injury.

Traumatic brain injury is a significant cause of morbidity and mortality worldwide. An epidemiological association between head injury and long‐term cognitive decline has been described for many years and recent clinical studies have highlighted functional impairment within 12 months of a mild head injury. In addition chronic traumatic encephalopathy is a recently described condition in cases of repetitive head injury. There are shared mechanisms between traumatic brain injury and Alzheimers disease, and it has been hypothesized that neuroinflammation, in the form of microglial activation, may be a mechanism underlying chronic neurodegenerative processes after traumatic brain injury.

Management of a twenty-first century brain bank: experience in the BrainNet Europe consortium

Collections of human postmortem brains gathered in brain banks have underpinned many significant developments in the understanding of central nervous system (CNS) disorders and continue to support current research. Unfortunately, the worldwide decline in postmortem examinations has had an adverse effect on research tissue procurement, particularly from control cases (non-diseased brains). Recruitment to brain donor programmes partially addresses this problem and has been successful for dementing and neurodegenerative conditions. However, the collection of brains from control subjects, particularly from younger individuals, and from CNS disorders of sudden onset, remains a problem. Brain banks need to adopt additional strategies to circumvent such shortages. The establishment of brain bank networks allows data on, and access to, control cases and unusual CNS disorders to be shared, providing a larger resource for potential users. For the brain banks themselves, inclusion in a network fosters the sharing of protocols and development of best practice and quality control. One aspect of this collective experience concerns brain bank management, excellence in which is a prerequisite not only for gaining the trust of potential donors and of society in general, but also for ensuring equitable distribution to researchers of high quality tissue samples. This review addresses the legal, ethical and governance issues, tissue quality, and health and safety aspects of brain bank management and data management in a network, as well as the needs of users, brain bank staffing, donor programs, funding issues and public relations. Recent developments in research methodology present new opportunities for researchers who use brain tissue samples, but will require brain banks to adopt more complex protocols for tissue collection, preparation and storage, with inevitable cost implications for the future.

Striatal Aβ peptide deposition mirrors dementia and differentiates DLB and PDD from other Parkinsonian syndromes

Recent neuropathological studies have described widespread amyloid-β peptide (Aβ) deposition in the striatum of patients with Lewy body disorders, particularly in Parkinsons disease with dementia (PDD) and dementia with Lewy bodies (DLB). However, positron emission tomography (PET) studies using the [(11)C]PIB ligand, binding to Aβ deposits, detects significant striatal pathology only in DLB and not in PDD. Employing immunohistochemistry, we examined striatal Aβ deposition in the caudate nucleus and putamen of 52 PD, 41 PDD, 14 DLB, 7 multiple system atrophy (MSA) and 14 progressive supranuclear palsy (PSP) cases in relation to the presence of dementia. PD, MSA and PSP cases showed little or no Aβ pathology in the striatum. In contrast, both PDD and DLB cases demonstrated significantly greater Aβ deposition in the striatum when compared to PD, MSA and PSP groups. We conclude that striatal Aβ pathology is common in both PDD and DLB and may reflect the development of dementia in these conditions. More detailed examination of the morphology of the Aβ pathology suggests that it is the presence of cored amyloid plaques in DLB, but not PDD, that underlies the differences seen in PET imaging.

Amyloid beta peptide causes chronic glial cell activation and neuro-degeneration after intravitreal injection.

We have previously demonstrated that amyloid beta (Aβ) peptide is acutely toxic to retinal neurones in vivo and that this toxicity is mediated by an indirect mechanism. We have now extended these studies to look at the chronic effect of intravitreal injection of Aβ peptides on retinal ganglion cells (RGC), the projection neurones of the retina and the glial cell response. 5 months after injection of Aβ1−42 or Aβ42−1 there was no significant reduction in RGC densities but there was a significant reduction in the retinal surface area after both peptides. Phosphate‐buffered saline (PBS) injection had no effect on retinal size or RGC density. There was a pronounced reduction in the number of large RGCs with a concomitant significant increase in medium and small RGCs. There was no change in cell sizes 5 months after injection with PBS. At 5 months after injection of both peptides, there was marked activation of Muller glial cells and microglia. There was also expression of the major histocompatibility complex (MHC) class II molecule on some of the microglial cells but we saw no evidence of T‐cell infiltration into the injected retinas. In order to elucidate potential toxic mechanisms, we have looked at levels of glutamine synthetase and nitric oxide synthase. As early as 2 days after injection we noted that activation of Muller glia was associated with a decrease in glutamine synthetase immuno‐reactivity but there was no detectable expression of inducible nitric oxide synthase in any retinal cells. These results suggest that chronic activation of glial cells induced by Aβ peptides may result in chronic atrophy of projection neurones in the rat retina.

Extensive grey matter pathology in the cerebellum in multiple sclerosis is linked to inflammation in the subarachnoid space

Multiple sclerosis (MS) is a progressive inflammatory neurological disease affecting myelin, neurons and glia. Demyelination and neurodegeneration of cortical grey matter contribute to a more severe disease, and inflammation of the forebrain meninges associates with pathology of the underlying neocortical grey matter, particularly in deep sulci. We assessed the extent of meningeal inflammation of the cerebellum, another structure with a deeply folded anatomy, to better understand the association between subarachnoid inflammation and grey matter pathology in progressive MS.

Cerebral amyloid angiopathy in traumatic brain injury: association with apolipoprotein E genotype

Objective: In view of the association of the apolipoprotein E (APOE) ε4 allele with poor outcome after traumatic brain injury we determined the frequency of cerebral amyloid angiopathy (CAA) and the extent of haemorrhagic pathology in relation to APOE genotype in an autopsy series of 88 head injured cases. Methods: Tissue sections from the frontal and temporal lobes were immunostained for amyloid-β peptide (Aβ) and stained for Congo red to identify vascular amyloid pathology. A semiquantitative assessment of contusions, the total contusion index, was used to estimate the severity of the haemorrhagic pathology. APOE genotypes were determined by polymerase chain reaction of genomic DNA extracted from paraffin embedded tissue sections. Results: CAA was present in 7/40 (18%) ε4 carriers compared with 1/48 (2%) non-ε4 carriers (p = 0.021, 95% confidence interval (CI) for difference in proportions with CAA 3% to 29%) with 6/40 (4 with CAA) ε4 carriers being homozygotes. Thus the risk of having CAA for ε4 carriers was 8.4 times that for the non-ε4 carriers. However, there was no clear tendency for patients with CAA to have more severe or more numerous contusions (median contusion index 19 (CAA) v 14.5, p = 0.23, 95% CI for difference in medians −5 to 14). Conclusions: Presence of CAA in head injured cases was significantly associated with possession of an APOE ε4 allele but not with the severity of contusions.

Disturbed sleep in Parkinson's disease: anatomical and pathological correlates.

Abnormal sleep is a common feature of Parkinsons disease (PD) and prodromal disorders of sleep are frequent (e.g. restless legs syndrome and rapid eye movement sleep behaviour disorder). However, the exact pathological basis of disturbed sleep remains as yet undefined.