Alzheimer Disease: Holmes C

Aalten P, Verhey FR, Boziki M, Brugnolo A, Bullock R, Byrne EJ, Camus V, Caputo M, Collins D, De Deyn PP, Elina K, Frisoni G, Holmes C, Hurt C, Marriott A, Mecocci P, Nobili F, Ousset PJ, Reynish E, Salmon E, Tsolaki M, Vellas B, Robert PH. · Department of Psychiatry and Neuropsychology, Alzheimer Centre Limburg, Maastricht University Hospital, Maastricht, The Netherlands. · Dement Geriatr Cogn Disord. · Pubmed #18025783 links to  free full text

Abstract: BACKGROUND/AIMS: The aim of this study was to determine the consistency of neuropsychiatric subsyndromes of the Neuropsychiatric Inventory across several clinical and demographic subgroups (e.g. dementia subtypes, dementia severity, medication use, age and gender) in a large sample of outpatients with dementia. METHODS: Cross-sectional data of 2,808 patients with dementia from 12 centres from the European Alzheimer's Disease Consortium were collected. Principal component analysis was used for factor analysis. Subanalyses were performed for dementia subtypes, dementia severity, medication use, age and gender. RESULTS: The results showed the relatively consistent presence of the 4 neuropsychiatric subsyndromes 'hyperactivity', 'psychosis', 'affective symptoms' and 'apathy' across the subanalyses. The factor structure was not dependent on dementia subtypes, age and gender but was dependent on dementia severity and cholinesterase use. The factors hyperactivity and affective symptoms were present in all subanalyses, but the presence of the factors apathy and psychosis was dependent on use of cholinesterase inhibitors and dementia severity, respectively. CONCLUSION: The present study provided evidence of the relative consistency of neuropsychiatric subsyndromes across dementia subtypes, age and gender, thereby stressing the importance of thinking about neuropsychiatric subsyndromes instead of separate symptoms. However, the subsyndromes apathy and psychosis were dependent on use of cholinesterase inhibitors and dementia severity.

Aalten P, Verhey FR, Boziki M, Bullock R, Byrne EJ, Camus V, Caputo M, Collins D, De Deyn PP, Elina K, Frisoni G, Girtler N, Holmes C, Hurt C, Marriott A, Mecocci P, Nobili F, Ousset PJ, Reynish E, Salmon E, Tsolaki M, Vellas B, Robert PH. · Department of Psychiatry and Neuropsychology, Alzheimer Centre Limburg, Maastricht University Hospital, Maastricht, The Netherlands. · Dement Geriatr Cogn Disord. · Pubmed #17986816 links to  free full text

Abstract: BACKGROUND/AIMS: The aim of this study was to identify neuropsychiatric subsyndromes of the Neuropsychiatric Inventory in a large sample of outpatients with Alzheimer's disease (AD). METHODS: Cross-sectional data of 2,354 patients with AD from 12 centres from the European Alzheimer's Disease Consortium were collected. Principal component analysis was used for factor analysis. RESULTS: The results showed the presence of 4 neuropsychiatric subsyndromes: hyperactivity, psychosis, affective symptoms and apathy. The subsyndrome apathy was the most common, occurring in almost 65% of the patients. CONCLUSION: This large study has provided additional robust evidence for the existence of neuropsychiatric subsyndromes in AD.

Holmes C. · Thornhill Research Unit, University of Southampton, Moorgreen Hospital, Botley Road, West End, Southampton SO30 3JB, UK. · Br J Psychiatry. · Pubmed #11823322 links to  free full text

Abstract: BACKGROUND: Patients with Alzheimer's disease show a wide variation in clinical phenotype. Genetic research has been largely concerned with the role of mutations or common variants as risk factors for the disease. Do genetic factors also influence clinical phenotype? AIMS: To examine the evidence that genetic factors influence the clinical expression of the disease in addition to influencing risk. METHOD: A selective review was made of the key literature. RESULTS: Mutations in three genes, coding for amyloid precursor protein, presenilin-1 and presenilin-2, and a common variation (epsilon4) in another gene, APOE, have been shown to lead to an earlier development of the disease. More recently, genetic association and twin studies have suggested a role for genetic factors in the development of other aspects of clinical phenotype, notably the appearance of non-cognitive symptoms. CONCLUSIONS: In Alzheimer's disease genetic variation influences a number of aspects of clinical phenotype.

Boche D, Zotova E, Weller RO, Love S, Neal JW, Pickering RM, Wilkinson D, Holmes C, Nicoll JA. · Division of Clinical Neurosciences, University of Southampton, Southampton General Hospital, Southampton, UK. · Brain. · Pubmed #18953056 No free full text.

Abstract: A major feature of Alzheimer's disease is the accumulation of amyloid-beta peptide (Abeta) in the brain both in the form of plaques in the cerebral cortex and in blood vessel as cerebral amyloid angiopathy (CAA). Experimental models and human clinical trials have shown that accumulation of Abeta plaques can be reversed by immunotherapy. In this study, we hypothesized that Abeta in plaques is solubilized by antibodies generated by immunization and drains via the perivascular pathway, detectable as an increase in cerebrovascular Abeta. We have performed a follow up study of Alzheimer's disease patients immunized against Abeta42. Neuropathological examination was performed on nine patients who died between four months and five years after their first immunization. Immunostaining for Abeta40 and Abeta42 was quantified and compared with that in unimmunized Alzheimer's disease controls (n = 11). Overall, compared with these controls, the group of immunized patients had approximately 14 times as many blood vessels containing Abeta42 in the cerebral cortex (P<0.001) and seven times more in the leptomeninges (P = 0.013); among the affected blood vessels in the immunized cases, most of them had full thickness and full circumference involvement of the vessel wall in the cortex (P = 0.001), and in the leptomeninges (P = 0.015). There was also a significantly higher level of cerebrovascular Abeta40 in the immunized cases than in the unimmunized cases (cortex: P = 0.009 and leptomeninges: P = 0.002). In addition, the immunized patients showed a higher density of cortical microhaemorrhages and microvascular lesions than the unimmunized controls, though none had major CAA-related intracerebral haemorrhages. The changes in cerebral vascular Abeta load did not appear to substantially influence the structural proteins of the blood vessels. Unlike most of the immunized patients, two of the longest survivors, four to five years after first immunization, had virtually complete absence of both plaques and CAA, raising the possibility that, given time, Abeta is eventually cleared from the cerebral vasculature. The findings are consistent with the hypothesis that Abeta immunization results in solubilization of plaque Abeta42 which, at least in part, exits the brain via the perivascular pathway, causing a transient increase in the severity of CAA. The extent to which these vascular alterations following Abeta immunization in Alzheimer's disease are reflected in changes in cognitive function remains to be determined.

Holmes C, Wilkinson D, Dean C, Vethanayagam S, Olivieri S, Langley A, Pandita-Gunawardena ND, Hogg F, Clare C, Damms J. · Memory Assessment and Research Centre, University of Southampton, Clinical Neurosciences Research Division, Moorgreen Hospital, Botley Rd., Southampton, UK. · Neurology. · Pubmed #15277611 No free full text.

Abstract: OBJECTIVE: To determine the efficacy of donepezil in the treatment of neuropsychiatric symptoms in patients with Alzheimer disease (AD) in a randomized withdrawal study. METHOD: Patients with mild to moderate AD with marked neuropsychiatric symptoms at baseline (Neuropsychiatric Inventory [NPI] > 11 points) were treated openly with donepezil 5 mg daily for 6 weeks followed by 10 mg daily for a further 6 weeks. Patients were then randomized (60:40) to either placebo or 10 mg donepezil daily. All patients were assessed at 6 weeks and provided there was no marked cognitive deterioration their blinded treatment was continued for a further 6 weeks. NPI and carer distress were assessed at 6 weekly intervals throughout the study. RESULTS: A total of 134 patients participated. Following randomization patients who continued on donepezil 10 mg for 12 weeks had improvements in NPI compared with the placebo group (mean change -2.9 vs 3.3 points; ITT-LOCF p = 0.02) and in NPI-Distress scores (median change -2.0 vs 1.0 points; ITT-LOCF p = 0.01). During the open-label phase the total NPI and NPI-Distress scores were lower after 12 weeks treatment with open label donepezil compared with baseline (total NPI 22 points vs13 points; ITT-LOCF p < 0.0001; NPI-Distress 13.5 vs 7.9 points; ITT-LOCF p < 0.0001). In the open-label phase all domains of the NPI (with the exception of elation) were improved (all p < 0.05 after Bonferroni correction). CONCLUSIONS: Donepezil has significant efficacy in the treatment of neuropsychiatric symptoms in patients with mild to moderate AD.

Kemp PM, Holmes C, Hoffmann S, Wilkinson S, Zivanovic M, Thom J, Bolt L, Fleming J, Wilkinson DG. · Department of Nuclear Medicine, Southampton University Hospitals Trust, Southampton, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #14617718 links to  free full text

Abstract: OBJECTIVE: To determine the effects of cholinergic treatment on the muscarinic receptor in patients with Alzheimer's disease. METHODS: 12 patients with mild to moderate Alzheimer's disease and six controls were studied. The patients underwent ADAS-COG psychometric assessment and SPECT brain imaging with (123)I quinuclidinyl benzilate (QNB), to demonstrate the postsynaptic muscarinic M1 receptor, before being randomised in a double blind study to receive either an acetylcholinesterase inhibitor (donepezil) or placebo for four months. Following this, the ADAS-COG and the (123)I-QNB receptor scan were repeated. The controls were imaged on one occasion only. All image analyses were undertaken using SPM99. RESULTS: (123)I-QNB imaging showed a significant relation between baseline psychometric impairment and deficits on scanning. Both placebo and actively treated groups had reductions in (123)I-QNB uptake. Greater reductions in receptor binding were demonstrated in the placebo group than in those receiving active treatment. Intraindividual reproducibility of the (123)I-QNB imaging technique appeared highly robust. CONCLUSIONS: The results suggest that (123)I-QNB uptake is better preserved in Alzheimer's disease patients on cholinergic treatment than on placebo. Cholinergic treatment may play a neuroprotective role. Sequential (123)I-QNB imaging seems to be a powerful tool in monitoring the response of these receptors to disease modifying treatments.

Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA. · Division of Clinical Neurosciences, University of Southampton, Southampton, UK; Moorgreen Hospital, Hampshire Partnership Trust, Southampton, UK. · Lancet. · Pubmed #18640458 No free full text.

Abstract: BACKGROUND: Immunisation of patients with Alzheimer's disease with full-length amyloid-beta peptide (Abeta(42)) can clear amyloid plaques from the brain. Our aim was to assess the relation between Abeta(42) immune response, degree of plaque removal, and long-term clinical outcomes. METHODS: In June, 2003, consent for long-term clinical follow-up, post-mortem neuropathological examination, or both, was sought from 80 patients (or their carers) who had entered a phase I randomised, placebo-controlled trial of immunisation with Abeta(42) (AN1792, Elan Pharmaceuticals) in September, 2000. The follow-up study was completed in September, 2006. Plaques were assessed in terms of the percentage area of the cortex with Abeta immunostaining (Abeta load) and in terms of characteristic histological features reflecting plaque removal. Survival of all 80 individuals until severe dementia or death was assessed with a Cox proportional hazard model. FINDINGS: 20 participants--15 in the AN1792 group, five in the placebo group--died before follow-up started. A further 22 patients--19 in the AN1792 group, three in the placebo group--died during follow-up. Nine of the deceased patients, all in the AN1792 group, had given consent for post-mortem analysis; one of these who did not die with Alzheimer's disease was excluded. In the remaining eight participants who received immunisation and who were examined neuropathologically, mean Abeta load was lower than in an unimmunised control group that was matched for age at death (2.1% [SE 0.7] in treated participants vs 5.1% [0.9] in controls; mean difference 3.0%, 95% CI 0.6-5.4; p=0.02). Although there was considerable variation in Abeta load and degree of plaque removal among immunised participants, the degree of plaque removal varied significantly with mean antibody response attained during the treatment study period (Kruskal-Wallis p=0.02). Seven of the eight immunised patients who underwent post-mortem assessment, including those with virtually complete plaque removal, had severe end stage dementia before death. In the whole cohort, there was no evidence of improved survival (hazard ratio 0.93, 95% CI 0.43-3.11; p=0.86) or of an improvement in the time to severe dementia (1.18, 0.45-3.11; p=0.73) in the AN1792 group versus the placebo group. INTERPRETATION: Although immunisation with Abeta(42) resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not prevent progressive neurodegeneration.

Howard RJ, Juszczak E, Ballard CG, Bentham P, Brown RG, Bullock R, Burns AS, Holmes C, Jacoby R, Johnson T, Knapp M, Lindesay J, O'Brien JT, Wilcock G, Katona C, Jones RW, DeCesare J, Rodger M, Anonymous00016. · Medical Research Council Neurogeneration Research Centre, Institute of Psychiatry, King's College London, London, United Kingdom. · N Engl J Med. · Pubmed #17914039 links to  free full text

Abstract: BACKGROUND: Agitation is a common and distressing symptom in patients with Alzheimer's disease. Cholinesterase inhibitors improve cognitive outcomes in such patients, but the benefits of these drugs for behavioral disturbances are unclear. METHODS: We randomly assigned 272 patients with Alzheimer's disease who had clinically significant agitation and no response to a brief psychosocial treatment program to receive 10 mg of donepezil per day (128 patients) or placebo (131 patients) for 12 weeks. The primary outcome was a change in the score on the Cohen-Mansfield Agitation Inventory (CMAI) (on a scale of 29 to 203, with higher scores indicating more agitation) at 12 weeks. RESULTS: There was no significant difference between the effects of donepezil and those of placebo on the basis of the change in CMAI scores from baseline to 12 weeks (estimated mean difference in change [the value for donepezil minus that for placebo], -0.06; 95% confidence interval [CI], -4.35 to 4.22). Twenty-two of 108 patients (20.4%) in the placebo group and 22 of 113 (19.5%) in the donepezil group had a reduction of 30% or greater in the CMAI score (the value for donepezil minus that for placebo, -0.9 percentage point; 95% CI, -11.4 to 9.6). There were also no significant differences between the placebo and donepezil groups in scores for the Neuropsychiatric Inventory, the Neuropsychiatric Inventory Caregiver Distress Scale, or the Clinician's Global Impression of Change. CONCLUSIONS: In this 12-week trial, donepezil was not more effective than placebo in treating agitation in patients with Alzheimer's disease. (ClinicalTrials.gov number, NCT00142324 [ClinicalTrials.gov].).

Piggott MA, Ballard CG, Rowan E, Holmes C, McKeith IG, Jaros E, Perry RH, Perry EK. · Institute for Ageing and Health, Wolfson Research Centre, Newcastle General Hospital, Newcastle-upon-Tyne NE4 6BE, United Kingdom. · Synapse. · Pubmed #17663455 No free full text.

Abstract: Dementia with Lewy bodies (DLB) is a progressive dementia frequently accompanied by psychotic symptoms. Similar symptoms can occur in Alzheimer's disease (AD) to a lesser extent. The use of neuroleptic medication to treat psychosis in both diseases is of modest efficacy and can induce severe adverse reactions in DLB. Dopamine D2 receptors in the cerebral cortex are the putative target for the antipsychotic action of these drugs, but the status of these receptors in DLB is unknown. Autoradiography was used to examine the density D2 receptors in postmortem temporal cortex tissue from prospectively assessed patients with neuropathologically confirmed DLB and AD. D2 receptors were substantially (over 40%) and significantly (P < 0.001) reduced in temporal cortex in DLB, and in DLB with concomitant Alzheimer pathology, but was not significantly changed in AD. This reduction correlated with greater cognitive decline (P < 0.01), but was not significantly related to visual or auditory hallucinations or delusions. D2 receptor density was inversely correlated with cortical Lewy body pathology in the neocortex (P < 0.001). The specific loss of D2 receptors associated with Lewy body pathology, in conjunction with our previous finding of low D2 receptors in striatum in DLB, provides a possible explanation for neuroleptic intolerance. That the reduction of D2 receptors correlated with cognitive decline suggests that neuroleptics, as dopamine D2 receptor antagonists, may have a deleterious effect on cognition in DLB.

Smith T, Gildeh N, Holmes C. · University of Southampton, England. · Can J Psychiatry. · Pubmed #17542384 No free full text.

Abstract: OBJECTIVE: To prospectively validate the Montreal Cognitive Assessment (MoCA) in a UK memory clinic. METHOD: We administered the MoCA and Mini-Mental State Examination (MMSE) to 32 subjects fulfilling diagnostic criteria for dementia, to 23 subjects fulfilling diagnostic criteria for mild cognitive impairment (MCI), and to 12 memory clinic comparison subjects, at baseline and then at 6-month follow-up. Clinical diagnoses for dementia and MCI were made according to ICD-10 and Petersen criteria. The sensitivity and specificity of both measures were assessed for detection of MCI and dementia. RESULTS: With a cut-off score of 26, the MMSE had a sensitivity of 17% to detect subjects with MCI, whereas the MoCA detected 83%. The MMSE had a sensitivity of 25% to detect subjects with dementia, whereas the MoCA detected 94%. Specificity for the MMSE was 100%, and specificity for the MoCA was 50%. Of subjects with MCI, 35% developed dementia within 6 months, and all scored less than 26 points on the MoCA at baseline. CONCLUSIONS: The MoCA is a useful brief screening tool for the detection of mild dementia or MCI in subjects scoring over 25 points on the MMSE. In patients already diagnosed with MCI, the MoCA helps identify those at risk of developing dementia at 6-month follow-up.

Holmes C, McCulley M, Nicoll JA, Alder JT, Chen CP, Francis PT. · University of Southampton, Clinical Neurosciences Research Division, Memory Assessment and Research Centre, Moorgreen Hospital, Botley Rd., Southampton, United Kingdom. · Neurosci Lett. · Pubmed #17481814 No free full text.

Abstract: A common intronic single nucleotide polymorphism (T102C) in the 5-HT2A receptor gene is associated with the development of different neuropsychiatric symptoms, including hallucinations and depressive symptoms in Alzheimer's disease (AD). Differential 5-HT2A receptor binding has also been associated with the development of these symptoms in AD. However, the relationship between 5-HT2A (T102C) genotype and 5-HT2A receptor binding in AD and control human brains has not been examined. We examined the association between different 5-HT2A (T102C) genotypes and [(3)H] ketanserin binding in the temporal and frontal cortex of 20 AD and 14 control human brains. In homozygotes, but not heterozygotes, there was a significant reduction in B(max) values for [(3)H] ketanserin binding in both areas of cortex in AD compared with control subjects. This study suggests a mechanism for the generation of different neuropsychiatric symptoms in AD from a single nucleotide polymorphism with reduced receptor binding in T102C 5-HT2A receptor gene homozygotes correlating with susceptibility to depressive symptoms, whereas the relative preservation of receptor binding in heterozygotes with AD correlating with susceptibility to hallucinations.

Holmes C, Wilkinson D, Dean C, Clare C, El-Okl M, Hensford C, Moghul S. · No affiliation provided · Int J Geriatr Psychiatry. · Pubmed #17380475 No free full text.

This publication has no abstract.

Nicoll JA, Barton E, Boche D, Neal JW, Ferrer I, Thompson P, Vlachouli C, Wilkinson D, Bayer A, Games D, Seubert P, Schenk D, Holmes C. · Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, UK. · J Neuropathol Exp Neurol. · Pubmed #17086100 No free full text.

Abstract: Neuropathologic examination of 3 patients with Alzheimer disease in the Elan Pharmaceuticals trial using antibodies specific for different Abeta species showed in one case, 4 months after the immunization, evidence of a stage of active plaque clearance with "moth-eaten" plaques and abundant Abeta phagocytosis by microglia. At 1 to 2 years after immunization, 2 cases showed extensive areas cleared of plaques (69% and 86% of the temporal cortex was plaque-free). Cortex cleared of plaques in all 3 cases had a characteristic constellation of features, including a very low plaque burden, sparse residual dense plaque cores, and phagocytosed Abeta within microglia. There was resolution of tau-containing dystrophic neurites, although other features of tau pathology (tangles and neuropil threads) remained and cerebral amyloid angiopathy persisted. Although most antibodies generated by Abeta42 immunization in humans bind the intact N-terminus, immunohistochemistry with specific antibodies showed clearance of all major species of Abeta (Abeta40, Abeta42, and N-terminus truncated Abeta). Abeta immunotherapy can clear all Abeta species from the cortex. However, if it is to be used for treatment of established Alzheimer disease, then the residual tau pathology and cerebral amyloid angiopathy require further study.

Holmes C, Knights A, Dean C, Hodkinson S, Hopkins V. · School of Medicine, University of Southampton, UK. · Int Psychogeriatr. · Pubmed #16805928 No free full text.

Abstract: BACKGROUND: A recent Cochrane report concluded that more and better quality research is required to investigate the effectiveness of music therapy in reducing problems in behavioral, social, emotional and cognitive domains in patients with dementia. This randomized placebo-controlled trial with blinded observer rater aimed to explore whether music, live or pre-recorded, is effective in the treatment of apathy in subjects with moderate to severe dementia. METHODS: Thirty-two subjects meeting ICD-10 diagnostic criteria for moderate to severe dementia and fulfilling diagnostic criteria for apathy were exposed to live interactive music, passive pre-recorded music or silence for 30 minutes. Each subject was randomized to 30-minute music or silent periods and was video recorded and the muted recording analyzed every 3 minutes using dementia care mapping to assess the quality of engagement to the blinded music intervention. RESULTS: Compared to low baseline levels of positive engagement (12.5%) in the silent placebo period, the majority of subjects (69%), regardless of dementia severity, showed a significant and positive engagement to live music. Engagement to pre-recorded music was non-significant, with just 25% of all subjects showing positive engagement. No subjects showed any evidence of experiencing a state of ill-being during either the live or pre-recorded music sessions. CONCLUSIONS: During the intervention, live interactive music has immediate and positive engagement effects in dementia subjects with apathy, regardless of the severity of their dementia. Pre-recorded music is non-harmful but less clearly beneficial.

Kemp PM, Hoffmann SA, Holmes C, Bolt L, Ward T, Holmes RB, Fleming JS. · Department of Nuclear Medicine, Southampton University Hospitals Trust, Southampton, UK. · Nucl Med Commun. · Pubmed #16264357 No free full text.

Abstract: AIM: To assess the role of 99mTc-hexamethylpropyleneamine oxime single-photon emission computed tomography (99mTc-HMPAO SPECT) imaging of the precuneus and medial temporal lobe in the individual patient with mild Alzheimer's disease and dementia with Lewy bodies (DLB) using statistical parametric mapping and visual image interpretation. METHODS: Thirty-four patients with mild late-onset Alzheimer's disease, 20 patients with early-onset Alzheimer's disease, 15 patients with DLB and 31 healthy controls were studied. All patients fulfilled appropriate clinical criteria; the DLB patients also had evidence of dopaminergic presynaptic terminal loss on 123I-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl)-tropane imaging. 99mTc-HMPAO SPECT brain scans were acquired on a multidetector gamma camera and images were assessed separately by visual interpretation and with SPM99. RESULTS: Statistical parametric maps were significantly more accurate than visual image interpretation in all disease categories. In patients with mild late-onset Alzheimer's disease, statistical parametric mapping demonstrated significant hypoperfusion to the precuneus in 59% and to the medial temporal lobe in 53%. Seventy-six per cent of these patients had a defect in either location. No controls had precuneal or medial temporal lobe hypoperfusion (specificity, 100%). Statistical parametric mapping also demonstrated 73% of patients with DLB to have precuneal abnormalities, but only 6% had medial temporal lobe involvement. CONCLUSION: These findings illustrate the capability of statistical parametric mapping to demonstrate reliable abnormalities in the majority, but not all, patients with either mild Alzheimer's disease or DLB. Precuneal hypoperfusion is not specific to Alzheimer's disease and is equally likely to be found in DLB. In this study, medial temporal hypoperfusion was significantly more common in Alzheimer's disease than in DLB. Statistical parametric maps appear to be considerably more reliable than simple visual interpretation of 99mTc-HMPAO images for these regions.

Holmes C, Ballard C, Lehmann D, David Smith A, Beaumont H, Day IN, Nadeem Khan M, Lovestone S, McCulley M, Morris CM, Munoz DG, O'Brien K, Russ C, Del Ser T, Warden D. · University of Southampton, Clinical Neurosciences Research Division, Memory Assessment and Research Centre, Moorgreen Hospital, Botley Road, Southampton, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #15834019 links to  free full text

Abstract: OBJECTIVE: To determine whether individuals with Alzheimer's disease (AD) and the K variant allele of butyrylcholinesterase have a slower rate of cognitive decline than those without the K variant allele of butyrylcholinesterase. METHOD: The cognitive status of 339 community based subjects with AD was assessed with the Mini Mental State Examination at baseline and yearly over a three year follow up period. The rates of cognitive decline of subjects with and without the K variant allele were compared. RESULT: Presence of the K allele was associated with a slower average rate of cognitive decline in subjects with severe AD. CONCLUSIONS: This finding is consistent with the suggestion that the K variant of butyrylcholinesterase has an important role in disease progression in AD, and this may have implications for treatment.

Dunn N, Holmes C, Mullee M. · Primary Medical Care, University of Southampton, Southampton, UK. · Alzheimer Dis Assoc Disord. · Pubmed #15764867 No free full text.

Abstract: Lithium compounds might theoretically play a role in preventing dementia by inhibiting formation both of beta amyloid and hyper phosphorylated tau protein. We carried out a case-control study to assess any possible clinical effects of lithium therapy on the diagnosis of dementia, using data from the General Practice Research Database, which collects routine data from primary care patients in the UK. Patients who received lithium had a higher risk of a diagnosis of dementia compared with those who did not (adjusted odds ratio 1.8, 95% CI 1.1-2.8). There was a trend toward increasing risk with increasing numbers of lithium prescriptions. This evidence does not support the use of lithium for preventing dementia.

Engelborghs S, Holmes C, McCulley M, De Deyn PP. · Department of Neurology and Memory Clinic, Middelheim General Hospital, ZNA, and Laboratory of Neurochemistry and Behaviour, Born-Bunge Foundation, University of Antwerp, Antwerp, Belgium. · Int J Geriatr Psychiatry. · Pubmed #15497194 No free full text.

This publication has no abstract.

Ballard CG, Jacoby R, Del Ser T, Khan MN, Munoz DG, Holmes C, Nagy Z, Perry EK, Joachim C, Jaros E, O'Brien JT, Perry RH, McKeith IG. · Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK. · Am J Psychiatry. · Pubmed #15121649 links to  free full text

Abstract: OBJECTIVE: This investigation was undertaken to clarify the neuropathological substrates of key psychiatric symptoms in dementia with Lewy bodies. METHOD: The authors studied 112 autopsy-confirmed cases of dementia with Lewy bodies in patients who had had annual standardized clinical evaluations until their death. The relationships of persistent psychiatric symptoms (visual hallucinations, delusions, depression) to plaques (Consortium to Establish a Registry for Alzheimer's Disease protocol), tangles (Braak staging), and Lewy bodies (consensus Lewy body staging) were evaluated. In addition, symptom frequency and persistent symptoms were compared in the patients with Lewy body dementia and 90 patients with autopsy-confirmed Alzheimer's disease studied prospectively during life. RESULTS: The main neuropathological correlate of persistent visual hallucinations was the presence of less severe tangle pathology, but there was no significant association between tangle pathology and persistent delusions. Lewy body staging was associated with the presence of persistent visual hallucinations and persistent delusions. All baseline psychiatric features were significantly more frequent in dementia with Lewy bodies than in Alzheimer's disease, as were persistent visual hallucinations, but patients who had dementia with Lewy bodies and severe tangle pathology had a clinical symptom profile more similar to that of Alzheimer's disease patients and were less likely to have neocortical Lewy bodies. CONCLUSIONS: The modest proportion of patients with Lewy body dementia and more severe tangle pathology resembled Alzheimer's disease patients clinically. Unlike Alzheimer's disease, dementia with Lewy bodies showed a significant inverse association between tangle burden and psychosis.

McCulley MC, Day IN, Holmes C. · University of Southampton, Human Genetics Division, School of Medicine, Duthie Building (MP808), Southampton General Hospital, Tremona Road, Southampton, United Kingdom. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #14681913 No free full text.

Abstract: Depressive symptoms have been associated with raised interleukin 1-beta (IL-1beta) plasma levels. The presence of behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease, including depressive symptoms, have been shown to be influenced by common genetic polymorphisms. A common polymorphism in the promoter region of IL-1beta has been linked to altered synthesis of IL-1beta. We hypothesize that this common genetic polymorphism is a risk factor for the appearance of depressive symptoms in AD. A total of 133 subjects, diagnosed as probable AD and 156 controls were genotyped for the -511 variant of IL-1beta. Neither genotype or allele frequencies differed between the AD and control group. However, an allelic association was found between the T variant and the symptoms of depression in AD subjects. Genotypic analysis showed that heterozygotes were three times more likely to develop depressive symptoms than CC homozygotes.

Holmes C, El-Okl M, Williams AL, Cunningham C, Wilcockson D, Perry VH. · School of Medicine and Biological Sciences, University of Southampton, Southampton, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #12754353 links to  free full text

Abstract: Activated microglia, the resident macrophages of the brain, are a feature of Alzheimer's disease. Animal models suggest that when activated microglia are further activated by a subsequent systemic infection this results in significantly raised levels of interleukin 1beta within the CNS, which may in turn potentiate neurodegeneration. This prospective pilot study in Alzheimer's disease subjects showed that cognitive function can be impaired for at least two months after the resolution of a systemic infection and that cognitive impairment is preceded by raised serum levels of interleukin 1beta. These relations were not confounded by the presence of any subsequent systemic infection or by baseline cognitive scores. Further research is needed to determine whether recurrent systemic infections drive cognitive decline in Alzheimer's disease subjects through a cytokine mediated pathway.

Kemp PM, Holmes C, Hoffmann SM, Bolt L, Holmes R, Rowden J, Fleming JS. · Department of Nuclear Medicine, Southampton University Hospitals Trust, Southampton, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #12754337 links to  free full text

Abstract: OBJECTIVE: To compare the HMPAO SPECT cerebral perfusion patterns in early and late onset Alzheimer's disease. METHODS: Twenty patients with early onset disease (<65 years) and 44 patients with late onset disease (>65 years) were studied. All patients fulfilled NINCDS-ADRDA clinical criteria and had details of disease severity and length of history at the time of imaging. Technetium-99m HMPAO SPECT brain scans were acquired on a multi-detector gammacamera and analysed visually and with statistical parametric mapping (SPM99). RESULTS: Patients with early onset disease had significantly greater posterior cortical association area involvement whereas those with late onset disease had significantly greater medial temporal hypoperfusion. These findings were unchanged after controlling for disease severity and length of illness. DISCUSSION: These functional imaging findings of the differences between early and late onset Alzheimer's disease are supported by published findings that include histopathological and clinical evidence; namely late onset patients tend to present with the characteristic involvement of the medial temporal lobes producing marked memory loss whereas early onset patients present with predominant posterior cortical association area involvement. These age related findings should be borne in mind when clinically diagnosing, and interpreting functional brain imaging studies in, patients with suspected Alzheimer's disease.

Holmes C, Arranz M, Collier D, Powell J, Lovestone S. · University of Southampton, Clinical Neurosciences Research Division, Memory Assessment and Research Centre, Moorgreen Hospital, Southampton, United Kingdom. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #12707936 No free full text.

Abstract: This study investigated possible associations between selected polymorphisms in the serotonin receptor genes, 5-HT2A and 5-HT2C, with the presence of co-morbid depressive illness at baseline in a community based cohort of 158 patients with late onset patients with Alzheimer's disease (AD). An association was found between the presence of major depressive illness at baseline and both the 5-HT2A and 5-HT2C polymorphisms. Specifically, homozygous carriers of the 5-HT2A C102 allele were five times more likely to have major depressive illness than heterozygotes. In addition, homozygous or hemizygous carriers of the 5-HT2C Ser allele were 12 times more likely to have major depressive illness than homozygous or hemizygous carriers of the 5-HT2C Cys allele.

Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. · Division of Clinical Neurosciences, University of Southampton, Southampton, UK. · Nat Med. · Pubmed #12640446 No free full text.

Abstract: Amyloid-beta peptide (Abeta) has a key role in the pathogenesis of Alzheimer disease (AD). Immunization with Abeta in a transgenic mouse model of AD reduces both age-related accumulation of Abeta in the brain and associated cognitive impairment. Here we present the first analysis of human neuropathology after immunization with Abeta (AN-1792). Comparison with unimmunized cases of AD (n = 7) revealed the following unusual features in the immunized case, despite diagnostic neuropathological features of AD: (i) there were extensive areas of neocortex with very few Abeta plaques; (ii) those areas of cortex that were devoid of Abeta plaques contained densities of tangles, neuropil threads and cerebral amyloid angiopathy (CAA) similar to unimmunized AD, but lacked plaque-associated dystrophic neurites and astrocyte clusters; (iii) in some regions devoid of plaques, Abeta-immunoreactivity was associated with microglia; (iv) T-lymphocyte meningoencephalitis was present; and (v) cerebral white matter showed infiltration by macrophages. Findings (i)-(iii) strongly resemble the changes seen after Abeta immunotherapy in mouse models of AD and suggest that the immune response generated against the peptide elicited clearance of Abeta plaques in this patient. The T-lymphocyte meningoencephalitis is likely to correspond to the side effect seen in some other patients who received AN-1792 (refs. 7-9).

Holmes C, Lovestone S. · University of Southampton, Clinical Neurosciences Research Division, Memory Assessment and Research Centre, Moorgreen Hospital, Botley Road, Southampton SO30 3JB, UK. · Age Ageing. · Pubmed #12615565 links to  free full text

Abstract: BACKGROUND: National Institute of Clinical Excellence guidelines advocate the use of the Mini-Mental Test Examination and a functional assessment as a means of measuring treatment response. However, there is little knowledge of the change expected in those with Alzheimer's disease in clinical practice. OBJECTIVE: to describe the long-term variability of the Mini-Mental Test Examination and Blessed Dementia Rating Scale. METHOD: 374 Alzheimer's disease patients referred to psychiatric services in southeast London were followed annually over a 3-year period. RESULTS: the mean Mini-Mental Test Examination score for the total group at baseline was 9.9 points. Individual variability in the rate of cognitive and functional decline is large and around 40% of patients after 1 year, and up to one-quarter of patients after 3 years who survived, show no change or an improvement in scores compared with baseline measures. CONCLUSIONS: in the evaluation of individual treatment response the rate of change, as measured by the Mini-Mental Test Examination and Blessed Dementia Rating Scale, is of limited value.