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Clive Holmes

Publications and source records attributed to Clive Holmes.

At least 19 recordsLinked to original sources
PubMed2025

Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer's disease.

BACKGROUND: Protein truncating variants (PTVs) in SORL1 are observed almost exclusively in Alzheimer’s Disease (AD) cases, but the effect of rare SORL1 missense variants is unclear. METHODS: To identify high-priority missense variants (HPVs), we applied ‘domain mapping of disease mutations’ for the 637 unique coding SORL1 variants detected in 18,959 AD-cases and 21,893 non-demented controls. RESULTS: In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and APOE-genotype contributed to AAO-variability. The median AAO of PTV- and HPV-carriers is ~8–10 years earlier than wild-type SORL1 carriers, matched for APOE-genotype. Specific HPVs are highly penetrant and lead to earlier AAOs than PTVs, suggesting possible dominant negative effects. CONCLUSION: Our results justify a debate on whether HPV carriers should be considered for clinical counseling.

Humans↗
PubMed2011

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).

ATP-Binding Cassette Transporters↗
PubMed2007

Systemic infections and inflammation affect chronic neurodegeneration.

It is well known that systemic infections cause flare-ups of disease in individuals with asthma and rheumatoid arthritis, and that relapses in multiple sclerosis can often be associated with upper respiratory-tract infections. Here we review evidence to support our hypothesis that in chronic neurodegenerative diseases such as Alzheimer's disease, with an ongoing innate immune response in the brain, systemic infections and inflammation can cause acute exacerbations of symptoms and drive the progression of neurodegeneration.

Aging↗
PubMed2006

Keep music live: music and the alleviation of apathy in dementia subjects.

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.

Aged↗
PubMed2006

Abeta species removal after abeta42 immunization.

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.

Alzheimer Disease↗
PubMed2005

The contribution of statistical parametric mapping in the assessment of precuneal and medial temporal lobe perfusion by 99mTc-HMPAO SPECT in mild Alzheimer's and Lewy body dementia.

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.

Adult↗
PubMed2004

Association between interleukin 1-beta promoter (-511) polymorphism and depressive symptoms in Alzheimer's disease.

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.

Aged↗
PubMed2004

Neuropathological substrates of psychiatric symptoms in prospectively studied patients with autopsy-confirmed dementia with lewy bodies.

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.

Aged↗
PubMed2003

Depression in Alzheimer's disease: the effect of serotonin receptor gene variation.

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.

Age of Onset↗
PubMed2003

Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report.

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).

Aged↗
PubMed2003

Long-term cognitive and functional decline in late onset Alzheimer's disease: therapeutic implications.

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.

Aged↗
PubMed2002

The clinical phenotype of familial and sporadic late onset Alzheimer's disease.

BACKGROUND: Familial factors are clearly associated with an increased risk of developing late onset Alzheimer's disease (LOAD). However, there is emerging evidence to suggest that familial factors may also influence clinical phenotype. To date, most studies have focussed on familial influences upon age of onset or duration of illness and few studies have compared the frequency of non-cognitive symptoms between familial and sporadic LOAD. OBJECTIVE: To describe the clinical phenotype, with an emphasis on non-cognitive symptoms, of patients with LOAD and to explore familial differences. METHOD: 374 patients with LOAD were recruited from the community based Camberwell Dementia Case Register and a comparison made of the clinical phenotype of patients with and without a first degree family history of dementia. RESULTS: A first degree family history of dementia was found in 27% of fully ascertained cases. An earlier age of onset was found in familial cases (77.2 years compared to 78.3 years, p<0.05). However, no other differences in clinical phenotype, including the rate of cognitive decline, duration or the frequency of non-cognitive symptoms, were found between familial and sporadic cases. CONCLUSIONS: Apart from an earlier age of onset, patients with familial LOAD, as a group, do not have major differences in their clinical phenotype compared to patients with sporadic LOAD.

Age Factors↗
PubMed2002

Lavender oil as a treatment for agitated behaviour in severe dementia: a placebo controlled study.

OBJECTIVE: To determine whether aromatherapy with lavender oil is effective in the treatment of agitated behaviour in patients with severe dementia. DESIGN: A placebo controlled trial with blinded observer rater. SETTING: A long-stay psychogeriatric ward. PATIENTS: Fifteen patients meeting ICD-10 diagnostic criteria for severe dementia and suffering from agitated behaviour defined as a minimum score of three points on the Pittsburgh Agitation Scale (PAS). INTERVENTION: A 2% lavender oil aromatherapy stream was administered on the ward for a two hour period alternated with placebo (water) every other day for a total of ten treatment sessions. ASSESSMENTS: For each subject 10 total PAS scores were obtained. Five during treatment and five during placebo periods. RESULTS: Nine patients (60%) showed an improvement, five (33%) showed no change and one patient (7%) showed a worsening of agitated behaviour during aromatherapy compared with placebo. A comparison of the group median PAS scores during aromatherapy showed a significant improvement in agitated behaviour during aromatherapy compared with placebo (median PAS scores 3 c.f. 4; Wilcoxon Signed-Ranks test p = 0.016 (one-tailed)). CONCLUSIONS: Lavender oil administered in an aroma stream shows modest efficacy in the treatment of agitated behaviour in patients with severe dementia.

Aged↗
PubMed2002

Prophylactic therapy with lithium in elderly patients with unipolar major depression.

OBJECTIVES: To compare the relapse rate of elderly depressed patients taking low dose lithium as an additional therapy with antidepressant medication to those receiving antidepressant medication alone. METHODS: Fifty elderly subjects recovering from a major depressive illness taking continuation antidepressants were randomised, in a double blind study, to receive additional lithium carbonate or placebo and followed up over a two year period for evidence of relapse. RESULTS: Relapse rate was significantly greater in those subjects taking antidepressant medication alone compared to subjects taking additional lithium therapy. After six months four (17%) subjects taking antidepressant medication alone had relapsed, whereas none of the subjects taking additional lithium had relapsed. After two years eight (33%) subjects taking antidepressant medication alone had relapsed, whereas only one (4%) of the subjects taking additional lithium had relapsed. CONCLUSION: This preliminary study suggests that long-term low dose lithium therapy is well tolerated and protects elderly patients from a relapse of depressive illness.

Aged↗
PubMed2002

A positive association between 5HT re-uptake binding sites and depression in dementia with Lewy bodies.

BACKGROUND: Depression is a common and distressing problem in the context of dementia, and is significantly more common in Dementia with Lewy bodies (DLB) than in Alzheimer's disease. The neurochemical basis for depression in DLB has not been investigated. AIM: To investigate the association between depression and 5HT transporter re-uptake binding in DLB patients. METHOD: A representative cohort of dementia patients received annual assessments, which included a standardised evaluation of depression until death. At post-mortem, (3H) cyanoimipramine autoradiography was used to quantify 5HT transporter re-uptake sites in the hippocampus and adjacent temporal cortex (Brodmann Area-BA 36, and 20); and parietal neocortex (BA 7a). RESULTS: Twenty-one cases were evaluated neurochemically, of whom seven had experienced a major depressive disorder. Major depression was associated with a significant preservation of 5HT transporter re-uptake sites in the parietal neocortex compared with non-affected cases (BA 7a area 1 t = 3.3, P = 0.004; BA 7a area 3 t = 3.8, P = 0.001). CONCLUSION: This preliminary report is important in challenging some of the assumptions about cortical monoamine functioning in depressed dementia.

Aged↗
PubMed2002

Disturbances of consciousness in dementia with Lewy bodies associated with alteration in nicotinic receptor binding in the temporal cortex.

Disturbances of consciousness, including fluctuations in attention and awareness, are a common and clinically important symptom in dementia with Lewy bodies (DLB). In the present study we investigate potential mechanisms of such disturbances of consciousness (DOC) in a clinicopathological study evaluating specific components of the cholinergic system. [3H]Epibatidine binding to the high-affinity nicotinic receptor in the temporal cortex (Brodmann's areas 20 and 36) differentiated DLB cases with and without DOC, being 62-66% higher in those with DOC (F=4.5,p=.025). The were no differences between DLB patients with or without DOC in 125I-labeled alpha-bungaratoxin binding to the low-affinity nicotinic receptor, [3H]pirenzepine binding to the muscarinic M1 receptor, or in choline acetyltransferase activity. These findings provide support for the hypothesis that cholinergic activity is an important neural correlate if consciousness and suggest a mechanism of DOC in DLB involving alterations in the nicotinic receptor, composed of predominantly alpha4 and beta2 subunits.

Aged↗