MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in amyotrophic lateral sclerosis-frontotemporal dementia

Amyotrophic lateral sclerosis and frontotemporal dementia are overlapping diseases in which MRI reveals brain structural changes in advance of symptom onset. Recapitulating these changes in preclinical models would help to improve our understanding of the molecular causes underlying regionally selective brain atrophy in early disease. We therefore investigated the translational potential of the TDP-43Q331K knock-in mouse model of amyotrophic lateral sclerosis-frontotemporal dementia using MRI. We performed in vivo MRI of TDP-43Q331K knock-in mice. Regions of significant volume change were chosen for post-mortem brain tissue analyses. Ex vivo computed tomography was performed to investigate skull shape. Parvalbumin neuron density was quantified in post-mortem amyotrophic lateral sclerosis frontal cortex. Adult mutants demonstrated parenchymal volume reductions affecting the frontal lobe and entorhinal cortex in a manner reminiscent of amyotrophic lateral sclerosis-frontotemporal dementia. Subcortical, cerebellar and brain stem regions were also affected in line with observations in pre-symptomatic carriers of mutations in C9orf72, the commonest genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Volume loss was also observed in the dentate gyrus of the hippocampus, along with ventricular enlargement. Immunohistochemistry revealed reduced parvalbumin interneurons as a potential cellular correlate of MRI changes in mutant mice. By contrast, microglia was in a disease activated state even in the absence of brain volume loss. A reduction in immature neurons was found in the dentate gyrus, indicative of impaired adult neurogenesis, while a paucity of parvalbumin interneurons in P14 mutant mice suggests that TDP-43Q331K disrupts neurodevelopment. Computerized tomography imaging showed altered skull morphology in mutants, further suggesting a role for TDP-43Q331K in development. Finally, analysis of human post-mortem brains confirmed a paucity of parvalbumin interneurons in the prefrontal cortex in sporadic amyotrophic lateral sclerosis and amyotrophic lateral sclerosis linked to C9orf72 mutations. Regional brain MRI changes seen in human amyotrophic lateral sclerosis-frontotemporal dementia are recapitulated in TDP-43Q331K knock-in mice. By marrying in vivo imaging with targeted histology, we can unravel cellular and molecular processes underlying selective brain vulnerability in human disease. As well as helping to understand the earliest causes of disease, our MRI and histological markers will be valuable in assessing the efficacy of putative therapeutics in TDP-43Q331K knock-in mice

Elana Horowitz, Toronto Coalition for Active Transportation

There has been increasing interest in community-based walkability audits (CWA) which are, for the purposes of this paper, audits administered by community members without the need for formal training. Although there are many examples of CWAs, the literature pertaining to this subset of audit tools is limited. The purpose of this research is to address these gaps. While not intending to be comprehensive, this research is meant to begin painting a picture of what is currently done, and how, with respect to CWAs. The paper includes a review of literature and thirteen case studies of CWA tools that are compared using a framework based on the literature review. The framework addresses a variety of issues including the focus, type, format and geographic scale of the audit, as well as which environmental features are addressed and the context in which the audit tool is presented to the public. An analysis is conducted as per each item in the case study framework.

A longitudinal analysis of travel demand and its determinants in the Greater Toronto-Hamilton Area

This study provides a unique long-term investigation of regional travel demand that addresses several gaps in the existing longitudinal literature. Firstly, it investigates the development of travel demand in terms of both vehicle kilometres travelled (VKT) and passenger kilometres travelled (PKT), based on actual demand, congestion and equilibrium distances, using road and multi-modal transit networks in the Greater Toronto-Hamilton Area (GTHA). Secondly, it identifies influential travel demand determinants after testing an extensive set of variables including longitudinal gravity-based transport accessibility measures. Thirdly, it investigates to what extent the determinants’ influence changes over time and various locations within the study area, providing new insights into the temporal and intra-regional variations of travel demand and its determinants. The findings show that VKT and PKT have grown in absolute and per trip terms, mainly due to substantial population growth, especially in the suburban areas. Whilst average potential travel times by transit have decreased, they are substantially longer than auto travel times. Furthermore, travel demand determinants vary significantly across space by degrees of urbanity, especially for VKT. The findings call for area- and population segment-specific land use and transportation policies across the GTHA

Planning context and urban intensification outcomes: Sydney versus Toronto

There is a lack of knowledge about effective implementation of intensification policies. The paper concentrates on the intensification experience of Sydney, Australia, and Toronto, Canada. Historical narratives, which document intensification efforts and outcomes since the 1950s, paint different pictures. For much of the period, Sydney adopted a medium-density strategy sustained by public-sector incentives and regulations. In Toronto, in contrast, the focus has been on high-density developments driven mostly by market trends. Lately, however, the Sydney intensification strategy has shifted to high-density projects. The paper concludes by drawing out findings that are relevant to intensification policies in the selected metropolitan regions and elsewhere: the ubiquity of NIMBY reactions; the importance of senior government involvement because less sensitive to anti-density NIMBY reactions; the possibility of framing intensification strategies in ways that avoid political party confrontation; and the role of major environmental movements in raising public opinion support to intensification