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Sporadic Creutzfeldt-Jakob Disease (sCJD) is the most common form of human prion disease. It is a rapidly progressive dementia with other associated neurological abnormalities which is invariably fatal, usually within 4-6 months of first symptoms, and affects around 80-100 patients in the UK each year. It is caused by propagation around the central nervous system of PrPSc, an abnormal conformational form of the host PrPC protein, which causes the transformation of PrPC to PrPSc, essentially self-replicating. This process causes neuronal loss and other pathological abnormalities, explaining the clinical presentation. sCJD is believed to occur as a de novo convolutional change which seems to occur as an unfortunate chance event. The existence of other forms of CJD, including variant CJD (vCJD) and iatrogenic CJD (iCJD) highlight the fact that the abnormally folded forms of the prion protein are infective agents, which can be transmitted by diet (from bovine spongiform encephalopathy - BSE - in cattle to humans in vCJD), or by medical intervention (predominantly from contaminated dura mater grafts, and cadaveric pituitary derived growth hormone in iCJD). These two routes of transmission can be associated with long intervals (up to around 40 years has been described) between exposure to the infective agent and subsequent symptom onset. It is possible that some cases classified as sCJD may in fact be acquired through other means of transmission. As part of the UK National CJD Surveillance process, the NCJDRSU collect data on potential routes of CJD transmission. In this thesis, I describe and analyse the data concerning three potential such routes for the definite or probable cases of sCJD reviewed by the NCJDRSU between 2010 and 2015 inclusive: 1) Packed red cell blood transfusion has been associated with iatrogenic transmission of variant CJD. We found no evidence of such transmission in sporadic CJD. I also describe the first two reported cases of sCJD occurring in patients with clotting disorders who had received numerous transfusions and other blood products; there have been no further published cases since this report, and these two cases are considered likely both to represent the chance development of sCJD. 2) Tissue and organ transplantation is another recognised route, with iatrogenic transmission of CJD described in corneal transplantation. A small number of sCJD patients have undergone surgery involving transplantation of tissues or organs. Although a few cases of interest were identified as recipients of potentially infective materials, including three patients who are suspected to have received dura mater grafts and one patient who underwent definite corneal transplantation, it was not possible to confirm the exact nature and source of these materials, meaning it is not certain that these cases definitely represent iatrogenic transmission. Therefore, I found no evidence that tissue or organ transplantation is responsible for the development of cases of iCJD among this patient cohort. 3) Other surgical procedures may convey the risk of transmission of PrPSc through incomplete sterilisation of instruments. I assessed the potential for UK sCJD patients to have come into contact with instruments used on another CJD patient, looking at associations between surgical procedures occurring within the same year, at the same hospital, and within the same surgical domain. While some such associations were identified, interpreting these associations is extremely difficult, in large part due to the absence of a suitable control group, as well as incomplete data availability. Overall, this work has identified no definite transmission of iCJD masquerading among the sCJD 2010-2015 patient cohort. There are significant limitations to each aspect of this work, in large part pertaining to incomplete medical records; these limitations are addressed in the relevant chapters. Some of these limitations may be difficult to overcome if future these studies are repeated in the future with a new cohort.

Ageing is the greatest risk factor for most forms of dementia. Variant Creutzfeldt-Jakob Disease (vCJD) however is predominantly a disease of younger adults and sporadic CJD (sCJD), although a disease of the older population, mainly affects those under 80 years of age. The very low age-specific incidence of both vCJD and sCJD in the oldest age group may, in part, be due to case under ascertainment, perhaps due to a lack of familiarity with CJD, or atypical clinical presentation of CJD In the UK, suspect cases of CJD are referred by clinicians to the National CJD Research & Surveillance Unit (NCJDRSU) for clinical assessment and epidemiological review. Case ascertainment in CJD is important not only for appropriate clinical care but also, due to the potential for person-to-person transmission of the CJD agent through medical procedures, to help protect public health. In this thesis: 1) I describe the clinical and referral characteristics of CJD patients diagnosed later in their disease progression and determine if these characteristics differ in those diagnosed earlier. A retrospective review of CJD cases referred to the NCJDRSU, for vCJD between 1995 and 2015 (n = 177) and for sCJD between 2010 and 2015 (n = 584) was undertaken. Age was significantly associated with timing of diagnosis, with later diagnoses occurring in older patients, and differences in clinical and referral characteristics between these and younger patients. 2) I also pilot a study of enhanced CJD surveillance in the older population. Since January 2016, patients aged ≥65 years seen in NHS Lothian with a diagnosis of non-CJD dementia but with atypical features (e.g. rapid speed of progression or focal neurology) have been invited to participate in a study to investigate whether atypical CJD might underlie the diagnosis of some patients with dementia. For each participant, a clinical examination was undertaken, with consent, including Addenbrooke's Cognitive Examination-III, the frontal assessment battery, the hospital anxiety and depression scale, Barthel's Index, and the Edinburgh Motor Assessment Scale. In addition, MRI was undertaken (including DWI and FLAIR sequences), a blood sample was taken for codon-129 subtyping and patients were consented for donation of brain tissue in the event of their death. Ten patients were recruited during the initial 6 months of study. Although patients had individual features of CJD there was no evidence of CJD clinically. No patients however reached postmortem during this initial study period. Barriers to referral, including clinician time pressures, likely impacted study referral.