Assessment of Alzheimer’s disease (AD)-related neurofibrillary pathology requires a procedure that permits a sufficient differentiation between initial, intermediate, and late stages. The gradual deposition of a hyperphosphorylated tau protein within select neuronal types in specific nuclei or areas is central to the disease process. The staging of AD-related neurofibrillary pathology originally described in 1991 was performed on unconventionally thick sections (100 μm) using a modern silver technique and reflected the progress of the disease process based chiefly on the topographic expansion of the lesions. To better meet the demands of routine laboratories this procedure is revised here by adapting tissue selection and processing to the needs of paraffin-embedded sections (5–15 μm) and by introducing a robust immunoreaction (AT8) for hyperphosphorylated tau protein that can be processed on an automated basis. It is anticipated that this revised methodological protocol will enable a more uniform application of the staging procedure.

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Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry.

Wernicke's encephalopathy is an acute neuropsychiatric syndrome resulting from thiamine deficiency, which is associated with significant morbidity and mortality. According to autopsy-based studies, the disorder is still greatly underdiagnosed in both adults and children. In this review, we provide an update on the factors and clinical settings that predispose to Wernicke's encephalopathy, and discuss the most recent insights into epidemiology, pathophysiology, genetics, diagnosis, and treatment. To facilitate the diagnosis, we classify the common and rare symptoms at presentation and the late-stage symptoms. We emphasise the optimum dose of parenteral thiamine required for prophylaxis and treatment of Wernicke's encephalopathy and prevention of Korsakoff's syndrome associated with alcohol misuse. A systematic approach helps to ensure that patients receive a prompt diagnosis and adequate treatment.

http://unmhospitalist.pbworks.com/f/Wernickes+encephalopathy.pdf

Wernicke's encephalopathy: new clinical settings and recent advances in diagnosis and management

The intralaminar and midline nuclei of the thalamus. Anatomical and functional evidence for participation in processes of arousal and awareness

The pace of nigrostriatal degeneration, both with regards to striatal denervation and loss of melanin and tyrosine hydroxylase-positive neurons, is poorly understood especially early in the Parkinson's disease process. This study investigated the extent of nigrostriatal degeneration in patients with Parkinson's disease at different disease durations from time of diagnosis. Brains of patients with Parkinson's disease (n=28) with post-diagnostic intervals of 1-27 years and normal elderly control subjects (n=9) were examined. Sections of the post-commissural putamen and substantia nigra pars compacta were processed for tyrosine hydroxylase and dopamine transporter immunohistochemistry. The post-commissural putamen was selected due to tissue availability and the fact that dopamine loss in this region is associated with motor disability in Parkinson's disease. Quantitative assessments of putaminal dopaminergic fibre density and stereological estimates of the number of melanin-containing and tyrosine hydroxylase-immunoreactive neurons in the substantia nigra pars compacta (both in total and in subregions) were performed by blinded investigators in cases where suitable material was available (n=17). Dopaminergic markers in the dorsal putamen showed a modest loss at 1 year after diagnosis in the single case available for study. There was variable (moderate to marked) loss, at 3 years. At 4 years post-diagnosis and thereafter, there was virtually complete loss of staining in the dorsal putamen with only an occasional abnormal dopaminergic fibre detected. In the substantia nigra pars compacta, there was a 50-90% loss of tyrosine hydroxylase-positive neurons from the earliest time points studied with only marginal additional loss thereafter. There was only a ∼10% loss of melanized neurons in the one case evaluated 1 year post-diagnosis, and variable (30 to 60%) loss during the first several years post-diagnosis with more gradual and subtle loss in the second decade. At all time points, there were more melanin-containing than tyrosine hydroxylase-positive cells. Loss of dopaminergic markers in the dorsal putamen occurs rapidly and is virtually complete by 4 years post-diagnosis. Loss of melanized nigral neurons lags behind the loss of dopamine markers. These findings have important implications for understanding the nature of Parkinson's disease neurodegeneration and for studies of putative neuroprotective/restorative therapies.

Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease

10·5 million children worldwide are estimated to have active epilepsy. Over the past 15 years, syndrome-oriented clinical and EEG diagnosis, and better aetiological diagnosis, especially supported by neuroimaging, has helped to clarify the diversity of epilepsy in children, and has improved management. Perinatal and postinfective encephalopathy, cortical dysplasia, and hippocampal sclerosis account for the most severe symptomatic epilepsies. Ion channel defects can underlie both benign age-related disorders and severe epileptic encephalopathies with a progressive disturbance in cerebral function. However, the reasons for age-related expression in children are not understood. Neither are the mechanisms whereby an epileptic encephalopathy originates. Several new drugs have been recently introduced but have provided limited therapeutic benefits. However, treatment and quality of life have improved because the syndrome-specific efficacy profile of drugs is better known, and there is heightened awareness that compounds with severe cognitive side-effects and heavy polytherapies should be avoided. Epilepsy surgery is an important option for a few well-selected individuals, but should be considered with great caution when there is no apparent underlying brain lesion.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(06)68182-8.pdf

Epilepsy in Children

The cerebral cortex is damaged in chronic alcoholics

α-Synucleinopathy phenotypes.

Whilst many reports mention neurofibrillary tangle pathology in the thalamus in progressive supranuclear palsy, there has been little detailed regional analysis of the distribution and density of thalamic pathology in this disease or in other parkinsonian syndromes. The caudal intralaminar thalamic nuclei are the major thalamic regulators of the caudate nucleus and putamen, areas known to be dysfunctional in progressive supranuclear palsy and Parkinson's disease. We investigated whether these thalamic nuclei degenerate in patients with these disorders compared with age-matched, neurologically normal controls. Neurofibrillary tangle and Lewy body pathology was assessed and unbiased optical disector methods were used to quantify total neuronal number. Despite different thalamic pathology, there was a dramatic reduction in the total neuronal number in the caudal intralaminar nuclei in both progressive supranuclear palsy and Parkinson's disease (40-55% loss). In contrast, there was no loss of volume or total neuronal number in the limbic thalamic nuclei in either disease group, indicating selective degeneration of the caudal intralaminar nuclei. In Parkinson's disease, Lewy bodies were found in these regions, while in progressive supranuclear palsy abundant intracellular neurofibrillary tangles and glial tangles concentrated in the caudal intralaminar nuclei. However, tangle formation accounted for only a small proportion of cell loss (</=10%) in the thalamus in progressive supranuclear palsy. These findings have several implications. The caudal intralaminar thalamus appears to be one of three basal ganglia sites commonly affected in both progressive supranuclear palsy and Parkinson's disease. These sites are the dopaminergic substantia nigra, the cholinergic pedunculopontine tegmental nucleus and, from our results, the glutamatergic caudal intralaminar thalamus. In both diseases these sites contain characteristic but different pathologies, indicating disease-specific mechanisms of neurodegeneration. Interestingly, the proportion of remaining neurons affected by these pathologies is low. This may indicate additional (possibly common) cellular mechanisms responsible for the degeneration in these regions. Both the dopaminergic nigra and the glutamatergic caudal intralaminar thalamus are the major regulators of basal ganglia function via the caudate nucleus and putamen. The pedunculopontine tegmental nucleus has major projections to both of these regulators. These findings indicate that dysregulation of two neurotransmitter systems within the basal ganglia may underlie common parkinsonian symptoms in these disorders. For patients with Parkinson's disease, this loss of glutamate regulation may help explain some problems with dopamine replacement therapies, particularly over time. For patients with progressive supranuclear palsy, more widespread degeneration of basal ganglia structures would contribute to poor treatment outcomes.

Loss of thalamic intralaminar nuclei in progressive supranuclear palsy and Parkinson's disease: clinical and therapeutic implications.

Two major noncortical inputs to the striatum originate from the substantia nigra and the thalamic centre median-parafascicular complex. Although it is established that in Parkinson's disease there is degeneration of the nigral dopaminergic neurons, there has been little analysis of the glutamatergic centre median-parafascicular complex. We therefore evaluated these and neighboring thalamic nuclei (for specificity of any changes) in 9 Parkinson's disease patients and 8 age-matched controls. Degeneration in the substantia nigra and centre median-parafascicular complex was estimated by using quantitative neuronal counts. On average, 70% of the pigmented nigral neurons degenerated and there was 30% to 40% neuronal loss in the centre median-parafascicular complex in Parkinson's disease. Thalamic degeneration was marked in neuronal subpopulations (50% loss of parvalbumin-positive neurons in the parafascicular, and 70% loss of non-parvalbumin-positive neurons in the centre median nuclei). In contrast, adjacent thalamic nuclei did not degenerate, which supports a selective neurodegeneration of the centre median-parafascicular complex. Our results show that the thalamic centre median-parafascicular complex is an additional nondopaminergic site of neurodegeneration in Parkinson's disease. Because this thalamic region provides important sensorimotor feedback to the striatum, degeneration of this region is likely to exacerbate the clinical signs and symptoms of Parkinson's disease.

H. Cartwright

Papers

The cerebral cortex is damaged in chronic alcoholics

α-Synucleinopathy phenotypes.

Loss of thalamic intralaminar nuclei in progressive supranuclear palsy and Parkinson's disease: clinical and therapeutic implications.

Degeneration of the centré median-parafascicular complex in Parkinson's disease.

Specific A10 dopaminergic nuclei in the midbrain degenerate in Parkinson's disease.