Environmental perception, public participation and urban planning in the London borough of Camden

Summary: p.ix

Size frequency distribution of the β-amyloid (aβ) deposits in dementia with Lewy bodies with associated Alzheimer’s disease pathology

The objective is to study β-amyloid (Aβ) deposition in dementia with Lewy bodies (DLB) with Alzheimer’s disease (AD) pathology (DLB/AD). The size frequency distributions of the Aβ deposits were studied and fitted by log-normal and power-law models. Patients were ten clinically and pathologically diagnosed DLB/AD cases. Size distributions had a single peak and were positively skewed and similar to those described in AD and Down’s syndrome. Size distributions had smaller means in DLB/AD than in AD. Log-normal and power-law models were fitted to the size distributions of the classic and diffuse deposits, respectively. Size distributions of Aβ deposits were similar in DLB/AD and AD. Size distributions of the diffuse deposits were fitted by a power-law model suggesting that aggregation/disaggregation of Aβ was the predominant factor, whereas the classic deposits were fitted by a log-normal distribution suggesting that surface diffusion was important in the pathogenesis of the classic deposits

Comparative quantitative study of ‘signature’ pathological lesions in the hippocampus and adjacent gyri of 12 neurodegenerative disorders

The hippocampus (HC) and adjacent gyri are implicated in dementia in several neurodegenerative disorders. To compare HC pathology among disorders, densities of ‘signature’ pathological lesions were measured at a standard location in eight brain regions of 12 disorders. Principal components analysis of the data suggested that the disorders could be divided into three groups: (1) Alzheimer’s disease (AD), Down’s syndrome (DS), sporadic Creutzfeldt–Jakob disease, and variant Creutzfeldt–Jakob disease in which either β-amyloid (Aβ) or prion protein deposits were distributed in all sectors of the HC and adjacent gyri, with high densities being recorded in the parahippocampal gyrus and subiculum; (2) Pick’s disease, sporadic frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions, and neuronal intermediate filament inclusion disease in which relatively high densities of neuronal cytoplasmic inclusions were present in the dentate gyrus (DG) granule cells; and (3) Parkinson’s disease dementia, dementia with Lewy bodies, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy in which densities of signature lesions were relatively low. Variation in density of signature lesions in DG granule cells and CA1 were the most important sources of neuropathological variation among disorders. Hence, HC and adjacent gyri are differentially affected in dementia reflecting either variation in vulnerability of hippocampal neurons to specific molecular pathologies or in the spread of pathological proteins to the HC. Information regarding the distribution of pathology could ultimately help to explain variations in different cognitive domains, such as memory, observed in various disorders

Different molecular pathologies result in similar spatial patterns of cellular inclusions in neurodegenerative disease:a comparative study of eight disorders

Recent research suggests cell-to-cell transfer of pathogenic proteins such as tau and α-synuclein may play a role in neurodegeneration. Pathogenic spread along neural pathways may give rise to specific spatial patterns of the neuronal cytoplasmic inclusions (NCI) characteristic of these disorders. Hence, the spatial patterns of NCI were compared in four tauopathies, viz., Alzheimer's disease, Pick's disease, corticobasal degeneration, and progressive supranuclear palsy, two synucleinopathies, viz., dementia with Lewy bodies and multiple system atrophy, the 'fused in sarcoma' (FUS)-immunoreactive inclusions in neuronal intermediate filament inclusion disease, and the transactive response DNA-binding protein (TDP-43)-immunoreactive inclusions in frontotemporal lobar degeneration, a TDP-43 proteinopathy (FTLD-TDP). Regardless of molecular group or morphology, NCI were most frequently aggregated into clusters, the clusters being regularly distributed parallel to the pia mater. In a significant proportion of regions, the regularly distributed clusters were in the size range 400-800 μm, approximating to the dimension of cell columns associated with the cortico-cortical pathways. The data suggest that cortical NCI in different disorders exhibit a similar spatial pattern in the cortex consistent with pathogenic spread along anatomical pathways. Hence, treatments designed to protect the cortex from neurodegeneration may be applicable across several different disorders. © 2012 Springer-Verlag

The second NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder associated with exposure to head trauma. In 2015, a panel of neuropathologists funded by the NINDS/NIBIB defined preliminary consensus neuropathological criteria for CTE, including the pathognomonic lesion of CTE as an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern, based on review of 25 tauopathy cases. In 2016, the consensus panel met again to review and refine the preliminary criteria, with consideration around the minimum threshold for diagnosis and the reproducibility of a proposed pathological staging scheme. Eight neuropathologists evaluated 27 cases of tauopathies (17 CTE cases), blinded to clinical and demographic information. Generalized estimating equation analyses showed a statistically significant association between the raters and CTE diagnosis for both the blinded (OR = 72.11, 95% CI = 19.5-267.0) and unblinded rounds (OR = 256.91, 95% CI = 63.6-1558.6). Based on the challenges in assigning CTE stage, the panel proposed a working protocol including a minimum threshold for CTE diagnosis and an algorithm for the assessment of CTE severity as Low CTE or High CTE for use in future clinical, pathological, and molecular studies

Pathology of the superior colliculus in chronic traumatic encephalopathy

PURPOSE: To investigate neuropathological changes in the superior colliculus in chronic traumatic encephalopathy. METHODS: The densities of the tau-immunoreactive neurofibrillary tangles, neuropil threads, dot-like grains, astrocytic tangles, and neuritic plaques, together with abnormally enlarged neurons, typical neurons, vacuolation, and frequency of contacts with blood vessels, were studied across the superior colliculus from pia mater to the periaqueductal gray in eight chronic traumatic encephalopathy and six control cases. RESULTS: Tau-immunoreactive pathology was absent in the superior colliculus of controls but present in varying degrees in all chronic traumatic encephalopathy cases, significant densities of tau-immunoreactive neurofibrillary tangles, NT, or dot-like grains being present in three cases. No significant differences in overall density of the tau-immunoreactive neurofibrillary tangles, neuropil threads, dot-like grains, enlarged neurons, vacuoles, or contacts with blood vessels were observed in control and chronic traumatic encephalopathy cases, but chronic traumatic encephalopathy cases had significantly lower mean densities of neurons. The distribution of surviving neurons across the superior colliculus suggested greater neuronal loss in intermediate and lower laminae in chronic traumatic encephalopathy. Changes in density of the tau-immunoreactive pathology across the laminae were variable, but in six chronic traumatic encephalopathy cases, densities of tau-immunoreactive neurofibrillary tangles, neuropil threads, or dot-like grains were significantly greater in intermediate and lower laminae. Pathological changes were not correlated with the distribution of blood vessels. CONCLUSIONS: The data suggest significant pathology affecting the superior colliculus in a proportion of chronic traumatic encephalopathy cases with a laminar distribution which could compromise motor function rather than sensory analysis

A comprehensive resource for induced pluripotent stem cells from patients with primary tauopathies

Primary tauopathies are characterized neuropathologically by inclusions containing abnormal forms of the microtubule-associated protein tau (MAPT) and clinically by diverse neuropsychiatric, cognitive, and motor impairments. Autosomal dominant mutations in the MAPT gene cause heterogeneous forms of frontotemporal lobar degeneration with tauopathy (FTLD-Tau). Common and rare variants in the MAPT gene increase the risk for sporadic FTLD-Tau, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We generated a collection of fibroblasts from 140 MAPT mutation/risk variant carriers, PSP, CBD, and cognitively normal controls; 31 induced pluripotent stem cell (iPSC) lines from MAPT mutation carriers, non-carrier family members, and autopsy-confirmed PSP patients; 33 genome engineered iPSCs that were corrected or mutagenized; and forebrain neural progenitor cells (NPCs). Here, we present a resource of fibroblasts, iPSCs, and NPCs with comprehensive clinical histories that can be accessed by the scientific community for disease modeling and development of novel therapeutics for tauopathies

Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing of a cohort of 1118 Caucasian DLB patients, and focused on genes causative of monogenic neurodegenerative diseases. We analyzed variants in 60 genes implicated in DLB, Alzheimer\u27s disease, Parkinson\u27s disease, frontotemporal dementia, and atypical parkinsonian or dementia disorders, in order to determine their frequency in DLB. We focused on variants that have previously been reported as pathogenic, and also describe variants reported as pathogenic which remain of unknown clinical significance, as well as variants associated with strong risk. Rare missense variants of unknown significance were found in APP, CHCHD2, DCTN1, GRN, MAPT, NOTCH3, SQSTM1, TBK1 and TIA1. Additionally, we identified a pathogenic GRN p.Arg493* mutation, potentially adding to the diversity of phenotypes associated with this mutation. The rarity of previously reported pathogenic mutations in this cohort suggests that the genetic overlap of other neurodegenerative diseases with DLB is not substantial. Since it is now clear that genetics plays a role in DLB, these data suggest that other genetic loci play a role in this disease