Brain–specific proteins (BSP) are each relatively specific for particular cell–types within the nervous system. The BSP studied were glial fibrillary acidic protein (GFAP) and S100B for the astrocyte, ferritin for microglia and neurofilaments (Nf) for the axon. BSP are released into the extracellular fluid (ECF) following cellular destruction and during phases of high cellular activity such as astrocytic or microglial activation. ECF BSP equilibrate with those in the cerebrospinal fluid (CSF). This allows us to quantify BSP from the CSF and estimate the overall average of axonal damage (CSF Nf), astrocytic and microglia activation (respectively CSF S100B, CSF ferritin) and astrogliosis (CSF GFAP). New enzyme linked immunoabsorbant assays (ELISA) have been developed for measuring Nf and GFAP in the CSF. Previously established ELISAs have been used to measure S100B and ferritin. It has been shown that spinal cord atrophy in a mouse model of autoimmune encephalomyelitis (EAE) was paralleled by a decrease of Nf indicating loss of axons, and an increase in GFAP indicating astrogliosis. These findings have been confirmed and extended in a human post–mortem study where BSP levels were quantified in multiple sclerosis (MS) lesions of different age and activity. S100B and Nf were associated with acute lesions, ferritin was elevated in all lesion types, while GFAP was increased in both acute and chronic lesions. CSF BSP levels were then quantified in a cross–sectional study of MS patients with the aim of distinguishing clinical subgroups, such as relapsing remitting (RR), primary progressive (PP) and secondary progressive (SP) disease. In addition an attempt was made to relate CSF BSP levels to grades of disability using clinical scales including Kurtzke’s EDSS, an ambulation index (AI) and the 9–hole PEG test (9HPT). It was shown that CSF S100B was higher in RR MS while CSF ferritin was elevated in PP MS patients. The S100B:ferritin ratio emphasised the distinction between the MS subtypes. CSF GFAP was higher in poorly ambulating (AI) and severely disabled (EDSS) patients. CSF GFAP correlated with the EDSS in SP MS patients. This suggests that gliosis is an important feature in SP MS. CSF Nf levels were quantified in a longitudinal study at baseline and at 3–year follow–up. It was shown that more SP/PP than RR MS patients experienced an increase in CSF Nf levels over this time, suggesting cumulative axonal damage in this subgroup. RR MS patients who had elevated CSF Nf levels at baseline had a worse clinical course, suggesting that initial high CSF Nf levels in RR MS patients are a poor prognostic sign. CSF Nf levels at follow–up correlated with the EDSS, AI and 9HPT suggesting that axonal pathology in MS is a dynamic process possibly balancing features of de- and regenerative activities.

Study 1. Using a cognitive-process approach, 25 schizophrenic patients were matched with 25 healthy volunteers and compared on tests of memory and executive function. The schizophrenia group was found to have a significant impairment in immediate memory with relatively spared long-delay and recognition memory. Memory deficits were irrespective of the encoding strategies used and were unrelated to chronicity. In addition, the schizophrenic patients performed worse than controls on tests of executive function which was supported by some significant correlations between aspects of memory and executive function. The pattern of performance resembled that found in patients with subcortical or frontal lesions. Study 2. To examine further executive aspects of memory, an attempt to demonstrate confabulation in schizophrenia was made. Twelve schizophrenic patients were matched with 12 volunteers, 8 of whom were normal healthy subjects, with the remained being depressed patients. The subjects were asked to recall a set of experimental narratives, with confabulation being defined as the recall of ideas not present in the narrative. Subjects were also examined on a number of neuropsychological tests and the patients were assessed on the Krawiecka scale. Variable amounts of confabulation were observed in all the schizophrenic patients while only one control subject confabulated. The form of confabulation differed from those observed in other patients in that the original ideas were spontaneously rearranged to produce new ones. Confabulation was found to be related to difficulties in suppressing inappropriate responses and formal thought disorder. Study 3. Three schizophrenic patients previously identified as confabulators, were intensively studied to establish the mechanisms of narrative confabulation in schizophrenia. Patients were administered experimental tasks as well as standard neuropsychological tests of memory and executive function. Assessment of current symptoms was made using the SANS and SAPS scales. The severity of cognitive impairment was found to reflect the severity of confabulation, but memory impairment was neither nor sufficient to account for confabulation. Within the spectrum of executive deficits, impairments in response suppression and response monitoring, but not planning or generation were consistently associated with confabulation. The findings from the experimental tasks suggest that faults occur at both input and output. At the input stage, narrative material is encoded in a disorganised manner while at the output stage, this disorganisation is compounded by faulty editing processes. Study 4. Four schizophrenic patients who were known confabulators with narrative material, were subjected to an experimental autobiographical questionnaire designed to establish whether schizophrenic patients confabulate in response to questions calling on the recollection of personal facts and events. In addition, a number of neuropsychological tests were administered and current symptoms was assessed with the SANS and SAPS scales. All patients were observed to confabulate to varying degrees, particularly in response to questions relating to personal episodes rather than facts. For two patients, personal delusional systems were found to play a role in confabulation by providing a framework on which to base certain confabulatory recollections. Memory impairment was not found to be a necessary component to autobiographical confabulation but deficits in response suppression and response monitoring were observed to be related to the verification process performed during this task. Study 5. In an attempt to establish which anatomical regions may be at fault in schizophrenia when patients are engaged in response suppression tasks, six normal subjects were studied using positron emission tomography (PET) to identify anatomical regions involved when performing the Hayling Test. Subjects were also required to perform a control condition in which they had to read out the last word of given sentences. Compared to the control task, response initiation was associated with left sided activation of the frontal operculum, inferior frontal gyrus, middle temporal gyrus and right anterior cingulate gyrus, whereas response suppression was associated with left frontal operculum, inferior frontal gyrus and right anterior cingulate gyrus activation only. The difference between the two parts of the Hayling Test was in the increased activation of the left middle temporal gyrus and the left inferior frontal region (Brodmann's area 44/6) during response initiation.