Alzheimer Disease: Walker Z

Okello A, Edison P, Archer HA, Turkheimer FE, Kennedy J, Bullock R, Walker Z, Kennedy A, Fox N, Rossor M, Brooks DJ. · Division of Neuroscience and Mental Health, Faculty of Medicine, Imperial College London, London, UK. · Neurology. · Pubmed #19122031 No free full text.

Abstract: BACKGROUND: Activated microglia may play a role in the pathogenesis of Alzheimer disease (AD) as they cluster around beta-amyloid (Abeta) plaques. They are, therefore, a potential therapeutic target in both AD and its prodrome amnestic mild cognitive impairment (MCI). OBJECTIVE: To characterize in vivo with (11)C-(R)-PK11195 and (11)C-PIB PET the distribution of microglial activation and amyloid deposition in patients with amnestic MCI. METHODS: Fourteen subjects with MCI had (11)C-(R)-PK11195 and (11)C-PIB PET with psychometric tests. RESULTS: Seven out of 14 (50%) patients with MCI had increased cortical (11)C-PIB retention (p < 0.001) while 5 out of 13 (38%) subjects with MCI showed increased (11)C-(R)-PK11195 uptake. The MCI subgroup with increased (11)C-PIB retention also showed increased cortical (11)C-(R)-PK11195 binding (p < 0.036) though this increase only remained significant in frontal cortex after a correction for multiple comparisons. There was no correlation between regional levels of (11)C-(R)-PK11195 and (11)C-PIB binding in individual patients with MCI: only three of the five MCI cases with increased (11)C-(R)-PK11195 binding had increased levels of (11)C-PIB retention. CONCLUSIONS: Our findings indicate that, while amyloid deposition and microglial activation can be detected in vivo in around 50% of patients with mild cognitive impairment (MCI), these pathologies can occur independently. The detection of microglial activation in patients with MCI suggests that anti-inflammatory therapies may be relevant to the prevention of AD.

Walker Z, Jaros E, Walker RW, Lee L, Costa DC, Livingston G, Ince PG, Perry R, McKeith I, Katona CL. · University College London and Royal Free Hospitals, London, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #17353255 links to  free full text

Abstract: BACKGROUND: Dementia with Lewy bodies (DLB) is a common form of dementia. The presence of Alzheimer's disease (AD) pathology modifies the clinical features of DLB, making it harder to distinguish DLB from AD clinically during life. Clinical diagnostic criteria for DLB applied at presentation can fail to identify up to 50% of cases. Our aim was to determine, in a series of patients with dementia in whom autopsy confirmation of diagnosis was available, whether functional imaging of the nigrostriatal pathway improves the accuracy of diagnosis compared with diagnosis by means of clinical criteria alone. METHODS: A single photon emission computed tomography (SPECT) scan was carried out with a dopaminergic presynaptic ligand [123I]-2beta-carbometoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (FP-CIT; ioflupane) on a group of patients with a clinical diagnosis of DLB or other dementia. An abnormal scan was defined as one in which right and left posterior putamen binding, measured semiquantitatively, was more than 2 SDs below the mean of the controls. RESULTS: Over a 10 year period it was possible to collect 20 patients who had been followed from the time of first assessment and time of scan through to death and subsequent detailed neuropathological autopsy. Eight patients fulfilled neuropathological diagnostic criteria for DLB. Nine patients had AD, mostly with coexisting cerebrovascular disease. Three patients had other diagnoses. The sensitivity of an initial clinical diagnosis of DLB was 75% and specificity was 42%. The sensitivity of the FP-CIT scan for the diagnosis of DLB was 88% and specificity was 100%. CONCLUSION: FP-CIT SPECT scans substantially enhanced the accuracy of diagnosis of DLB by comparison with clinical criteria alone.

Sáez-Fonseca JA, Lee L, Walker Z. · Specialist Registrar North Essex Mental Heath Partnership NHS Trust, UK. · J Affect Disord. · Pubmed #17184844 No free full text.

Abstract: BACKGROUND: The term depressive pseudodementia has proved to be a popular clinical concept. Little is known about the long-term outcome of this syndrome. AIMS: To compare depressed elderly patients with reversible cognitive impairment and cognitively intact depressed elderly patients. METHODS: All patients suffering from moderate or severe depression admitted to St Margaret's Hospital, UK as inpatients or day hospital outpatients between January 1 1997 and December 31 1999 (n=182) were screened for entry into the study. Eligible patients were divided into those presenting with pseudodementia and those who were cognitively intact and followed up for 5 to 7 years. RESULTS: Seventy-one point four percent of those suffering from pseudodementia had converted into dementia at follow-up compared to only 18.2% in the cognitively intact group. The relative risk was 3.929 (95% CI: 1.985 to 7.775) and the 'number needed to harm' 1.88. CONCLUSIONS: Reversible cognitive impairment in late-life moderate to severe depression appears to be a strong predictor of dementia. Inpatients and day hospital outpatients with depressive pseudodementia should probably have a full dementia screening, comprehensive cognitive testing and ongoing monitoring of their cognitive function.

Regan C, Katona C, Walker Z, Hooper J, Donovan J, Livingston G. · Royal Free & University College Medical School, UCL, Department of Mental Health Sciences, Holborn Union Building, Archway Campus, Highgate Hill, London N19 5LW UK. · Neurology. · Pubmed #17060560 No free full text.

Abstract: OBJECTIVE: To test the hypothesis that patients with Alzheimer disease (AD) who have vascular risk factors have a worse prognosis over 18 months vs those without such risk factors. METHODS: A sample of 224 people with AD and their caregivers were recruited purposively to be representative of people with dementia in terms of cognition, sex, and living situations in a longitudinal study of AD. Standardized instruments measuring cognition, functional status, and neuropsychiatric symptoms were used to collect data. Physical examination and relevant blood tests were performed. RESULT: There was no difference in rate of deterioration between people with and without vascular risk factors, except in those who had a cerebrovascular accident (CVA) during the 18-month follow-up (p < 0.001). We considered possible confounders of outcome: sex, age, years of education, severity of dementia, depression, taking cholinesterase inhibitors (AChEIs), and whether those with vascular risk factors were more likely to die, but the results remained unchanged. Stopping AChEIs during the study was associated with cognitive and functional decline (p < 0.001). CONCLUSIONS: Vascular risk factors as measured clinically and biochemically do not significantly increase deterioration at 18 months in people with Alzheimer disease who have a low burden of cerebrovascular risk factors. However, cerebrovascular events are associated with more rapid decline. Vascular risk factors may contribute to the expression of Alzheimer disease initially but are not part of the underlying etiologic process.

Regan C, Katona C, Walker Z, Livingston G. · Department of Psychiatry and Behavioural Sciences, University College London, London, UK. · Int J Geriatr Psychiatry. · Pubmed #15717340 No free full text.

Abstract: BACKGROUND: Depression is common in Alzheimer's disease (AD; 5-35%). It is associated with increased disability, cost of care and carer burden. Exercise is known to be associated with a lower prevalence of depression across the age range but little is known about its relationship to depression in AD. AIMS: To investigate exercise and putative risk factors for depression in a community based sample of people with AD representative of the range of cognitive impairment found in the population with dementia. METHODS: Information was collected from 224 people with AD and their caregiver using standardised cognitive, psychological and behavioural instruments. Exercise levels were classified into three categories: absent, moderate, and vigorous, using the previous two weeks exercise levels to confirm regularity and recency. RESULTS: 9/51 (17.6%) depressed participants took exercise compared with 76/173 (43.9%) non-depressed [odds ratio (OR)=2.9, confidence interval (CI)=1.5-5.6, p=0.001]. Not taking part in other activities (hobbies and interests) was associated with depression but less so than lack of exercise. Independent predictors of depression were: lack of exercise (p <0.001, OR=3.4, CI = 1.7-7.2), taking cholinesterase inhibitors (p <0.05, OR=2.4, CI = 1.2-4.9) and having less involvement in hobbies or interests (p <0.05, OR = 1.2, CI = 1.0-1.5). CONCLUSION: None of the traditional risk factors for depression in older people were associated with depression in AD. Taking regular exercise may protect against depression in AD.

Dannhauser TM, Walker Z, Stevens T, Lee L, Seal M, Shergill SS. · Institute of Psychiatry, King's College London, UK. · Brain. · Pubmed #15705612 links to  free full text

Abstract: Recent neuroimaging studies have demonstrated changes in brain function in cognitively normal subjects at increased risk of developing Alzheimer's disease. Amnestic mild cognitive impairment (AMCI) carries a high risk of developing into Alzheimer's disease. In AMCI altered cortical activation has been demonstrated during memory tasks, using functional MRI (fMRI). Memory and attention are closely related cognitive functions. It is unclear whether the memory impairment of AMCI is associated with attentional deficits of the sort likely to be revealed by tasks requiring divided attention. Ten older adults (mean age 72 years, range 57-81 years) with AMCI were compared with healthy matched controls on divided attention and passive sensory processing tasks using fMRI. During the divided attention task both groups activated similar regions of left hemispheric prefrontal and extrastriate visual cortex. However, the AMCI group had attenuated prefrontal activation compared with age matched controls. On the passive sensory processing task there was no difference between the AMCI and control groups. We conclude that there are changes in the functional network subserving divided attention in patients with AMCI as reflected in the attenuation of prefrontal cortical activation. These findings have implications for evaluating cognition in AMCI and also for monitoring the effects of future treatments in AMCI.

Costa DC, Walker Z, Walker RW, Fontes FR. · University College, London, United Kingdom. · Mov Disord. · Pubmed #14531044 No free full text.

Abstract: Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) are the common forms of dementia at post-mortem, but distinguishing between these two types of dementia is often very difficult during life. Ioflupane significantly improves the differentiation during life between DLB and AD patients. However, there is a trend for lower caudate uptake in DLB than PD and lower posterior/caudal putamen uptake in PD than in DLB. Further research is needed to test the hypothesis that dopaminergic degeneration may be different, at least regarding anatomical distribution, in DLB and PD. Furthermore, it is important to consider and discuss the potential for ioflupane in the diagnostic workup of patients with DLB.

Tabet N, Walker Z, Mantle D, Costa D, Orrell M. · Postgraduate Medical School, Faculty of Health, University of Brighton, Falmer, Brighton BN1 9PH, UK. · Dement Geriatr Cogn Disord. · Pubmed #12714800 No free full text.

Abstract: The degeneration of dopaminergic cells in dementia with Lewy bodies (DLB) may provide an important source of additional free radical generation. As a result, the oxidative stress status in DLB could be significantly enhanced. Subsequently, the levels of endogenous antioxidants, which are an indirect measure of free radical activities, may be different in DLB patients when compared with Alzheimer's disease (AD) patients and controls. In this preliminary study, we measured the activities of superoxide dismutase (SOD), catalase (CAT), glutathione (GLU) and total antioxidant capacity in the blood of DLB, AD and control subjects. The state of nigrostriatal dopaminergic system was also assessed in vivo by using a radioactive ligand with an affinity for the dopamine pre-synaptic receptors and by imaging with single-photon emission tomography. Data obtained showed a decrease in dopamine pre-synaptic receptors in all the brain regions of DLB patients. The levels of SOD did not differ significantly between DLB, AD and control subjects. However, GLU levels were significantly higher in the DLB patients when compared with AD patients (p < 0.05) and controls (p < 0.01). CAT blood levels were also higher in DLB when compared with AD, but this did not reach statistical significance. The results suggest that a different oxidative stress state may exist in DLB. This may occur due to increased free radical production from the degeneration of dopaminergic cells and auto-oxidation of dopamine, the availability of which may be maintained in early-stage DLB disease as a result of the compensatory increase in its turnover from the remaining dopaminergic cells.

Carbonell J, Allen R, Kalsi G, McQuillin A, Livingston G, Katona C, Walker Z, Katz A, Rands G, Stevens T, Crossan I, Curtis D, Gurling H. · Molecular Psychiatry Laboratory, Windeyer Institute of Medical Sciences, Department of Psychiatry and Behavioural Sciences, Royal Free and University College Medical School, University College London, London, UK. · Psychiatr Genet. · Pubmed #12605101 No free full text.

Abstract: OBJECTIVES: To attempt to replicate previous reports that polymorphic variation in the DCP1 gene causes increased susceptibility to the development of Alzheimer's disease, either on its own or in interaction with the effects of the gene for apolipoprotein E (APOE). METHOD: Subjects older than 65 years of age consisting of 81 dementia patients diagnosed as having possible or probable Alzheimer's disease and 68 controls were obtained from Camden, Islington and Harlow psychiatric services. Subjects were genotyped for APOE alleles e2, e3 and e4, and the common insertion/deletion polymorphisms for DCP1* I/D were genotyped. RESULTS: There was no statistically significant difference in the frequency of the DCP1* insertion/deletion alleles between the cases and controls (X2 =0.04, 1 degree of freedom, not significant). When subjects were subdivided according to whether they possessed at least one copy of the APOE e4 allele, there were still no differences in DCP1 allele frequencies between cases and controls. CONCLUSIONS: Further research is needed to elucidate any role that the DCP1 polymorphism may play in relation to Alzheimer's disease. Previous studies may be false positive, or inconsistency in replication may be due to heterogeneity.

Walker Z, Costa DC, Walker RW, Shaw K, Gacinovic S, Stevens T, Livingston G, Ince P, McKeith IG, Katona CL. · University College London, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #12122169 links to  free full text

Abstract: BACKGROUND: Dementia with Lewy bodies (DLB) is one of the main differential diagnoses of Alzheimer's disease (AD). Key pathological features of patients with DLB are not only the presence of cerebral cortical neuronal loss, with Lewy bodies in surviving neurones, but also loss of nigrostriatal dopaminergic neurones, similar to that of Parkinson's disease (PD). In DLB there is 40-70% loss of striatal dopamine. OBJECTIVE: To determine if detection of this dopaminergic degeneration can help to distinguish DLB from AD during life. METHODS: The integrity of the nigrostriatal metabolism in 27 patients with DLB, 17 with AD, 19 drug naive patients with PD, and 16 controls was assessed using a dopaminergic presynaptic ligand, (123)I-labelled 2beta-carbomethoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl)nortropane (FP-CIT), and single photon emission tomography (SPET). A SPET scan was carried out with a single slice, brain dedicated tomograph (SME 810) 3.5 hours after intravenous injection of 185 MBq FP-CIT. With occipital cortex used as a radioactivity uptake reference, ratios for the caudate nucleus and the anterior and posterior putamen of both hemispheres were calculated. All scans were also rated by a simple visual method. RESULTS: Both DLB and PD patients had significantly lower uptake of radioactivity than patients with AD (p<0.001) and controls (p<0.001) in the caudate nucleus and the anterior and posterior putamen. CONCLUSION: FP-CIT SPET provides a means of distinguishing DLB from AD during life.

Stevens T, Livingston G, Kitchen G, Manela M, Walker Z, Katona C. · Department of Psychiatry and Behavioural Sciences, Royal Free and University College Medical School, London, UK. · Br J Psychiatry. · Pubmed #11872521 links to  free full text

Abstract: BACKGROUND: Epidemiological studies of dementia subtypes have revealed widely varying distribution rates. There are almost no published community prevalence data for dementia with Lewy bodies (DLB) or the frontal lobe dementias (FLD). AIMS: To identify the distribution of dementia subtypes in a representative community population of older people. METHOD: People aged > or = 65 years in randomised enumeration districts in Islington, north London, were screened using a reliable and valid questionnaire. People screened as having dementia were assessed in detail and diagnoses were made according to standard diagnostic criteria. RESULTS: Of 1085 people interviewed, 107 (9.86%) met screening criteria for dementia. Diagnoses were made for 72 people (67.3%). Distribution of subtypes varied according to the criteria used; the best-validated criteria yielding: Alzheimer's disease 31.3%; vascular dementia 21.9%; DLB 10.9%; and FLD 7.8%. CONCLUSIONS: Alzheimer's disease is confirmed as the most common cause of dementia in older people, followed by vascular dementia. However, DLB and FLD occur sufficiently often to be seen frequently in clinical practice and should be incorporated into future editions of standard diagnostic criteria.

Strydom A, Hassiotis A, Walker Z. · No affiliation provided · J Intellect Disabil Res. · Pubmed #15494067 No free full text.

This publication has no abstract.

Walker Z, Costa DC, Ince P, McKeith IG, Katona CL. · No affiliation provided · Lancet. · Pubmed #10466669 No free full text.

Abstract: With the dopaminergic presynaptic ligand FP-CIT and single photon emission tomography we have shown a severe dopaminergic degeneration in a patient with a necropsy confirmed diagnosis of dementia with Lewy bodies (DLB). We suggest that functional imaging of the nigrostriatal dopamine pathway helps to distinguish DLB from Alzheimer's disease during life.