Sally I. Sharp

Association of Plasma Clusterin Concentration With Severity, Pathology, and Progression in Alzheimer Disease

CONTEXT Blood-based analytes may be indicators of pathological processes in Alzheimer disease (AD). OBJECTIVE To identify plasma proteins associated with AD pathology using a combined proteomic and neuroimaging approach. DESIGN Discovery-phase proteomics to identify plasma proteins associated with correlates of AD pathology. Confirmation and validation using immunodetection in a replication set and an animal model. SETTING A multicenter European study (AddNeuroMed) and the Baltimore Longitudinal Study of Aging. PARTICIPANTS Patients with AD, subjects with mild cognitive impairment, and healthy controls with standardized clinical assessments and structural neuroimaging. MAIN OUTCOME MEASURES Association of plasma proteins with brain atrophy, disease severity, and rate of clinical progression. Extension studies in humans and transgenic mice tested the association between plasma proteins and brain amyloid. RESULTS Clusterin/apolipoprotein J was associated with atrophy of the entorhinal cortex, baseline disease severity, and rapid clinical progression in AD. Increased plasma concentration of clusterin was predictive of greater fibrillar amyloid-beta burden in the medial temporal lobe. Subjects with AD had increased clusterin messenger RNA in blood, but there was no effect of single-nucleotide polymorphisms in the gene encoding clusterin with gene or protein expression. APP/PS1 transgenic mice showed increased plasma clusterin, age-dependent increase in brain clusterin, as well as amyloid and clusterin colocalization in plaques. CONCLUSIONS These results demonstrate an important role of clusterin in the pathogenesis of AD and suggest that alterations in amyloid chaperone proteins may be a biologically relevant peripheral signature of AD.

Hypertension is a potential risk factor for vascular dementia: systematic review.

The aim of the study was to conduct a meta‐analysis of epidemiological and case control studies to determine whether arterial hypertension is specifically associated with an increased risk of vascular dementia (VaD).

Genetics of attention-deficit hyperactivity disorder (ADHD)

Attention-deficit hyperactivity disorder (ADHD) is a clinically and genetically heterogeneous syndrome which is comorbid with childhood conduct disorder, alcoholism, substance abuse, dis-social personality disorder, and affective disorders. A small but consistent overlap with autistic symptoms has also been established. Twin and family studies of ADHD show a substantial genetic heritability with little or no family environmental effect. Linkage and association studies have conclusively implicated the dopamine transporter gene (DAT1). DAT1 has also been confirmed as being associated with bipolar disorder. Remarkably, and for the first time in psychiatry, genetic markers at the DAT1 locus appear to be able to predict clinical heterogeneity because the non-conduct disordered subgroup of ADHD is associated with DAT1 whereas other subgroups do not appear to be associated. The second most well replicated susceptibility gene encodes the DRD4 dopamine receptor and many other dopamine related genes appear to be implicated. It is becoming increasingly clear that genes causing bipolar mania overlap with genes for a subtype of ADHD. The key to understanding the genetics of ADHD is to accept very considerable heterogeneity with different genes having effects in different families and in different individuals. It is too early to interpret the new wave of genome-wide association and copy number variant studies but preliminary data support the overlap with affective disorder genes and also with CNS connectivity genes likely to be involved in autism and affective disorders.

Neuropsychiatric symptoms in dementia: Importance and treatment considerations

Neuropsychiatric symptoms are frequent in people with dementia, result in distress for the people experiencing them and their caregivers, and are a common precipitant of institutional care. The safe and effective treatment of these symptoms is a key clinical priority, but is a long way from being achieved. Psychological interventions are recommended as the first line treatment strategy in most good practice guidelines, and there is emerging evidence of efficacy for agitation and depression. Neuroleptics remain the mainstay of pharmacological treatment, although meta-analyses indicate that they are mainly of benefit for the short-term (up to 12 weeks) treatment of aggression in people with Alzheimers disease, and there have been increasing concerns about serious adverse effects including mortality. The evidence is limited for other pharmacological approaches for the treatment of agitation, and psychosis in people with Alzheimers disease is limited, but post-hoc analyses do indicate that memantine may be a promising therapy and aromatherapy may be a useful alternative. Autopsy studies indicate that the adrenergic system may be an important therapeutic target. Clinical experience suggests that antidepressants are effective in people with severe depression in the context of dementia, but the evidence base regarding the broader value of antidepressants is far from clear. There are very few trials specifically focusing upon the treatment of neuropsychiatric symptoms in common non-Alzheimer dementias, which is a major limitation and urgently needs to be addressed to provide an evidence base to enable the safe and effective treatment of these individuals.

Alcohol consumption and risk of type 2 diabetes in European men and women: influence of beverage type and body size The EPIC-InterAct study

Abstract.  Beulens JWJ, van der Schouw YT, Bergmann MM, Rohrmann S, B Schulze M, Buijsse B, Grobbee DE, Arriola L, Cauchi S, Tormo M‐J, Allen NE, van der A DL, Balkau B, Boeing H, Clavel‐Chapelon F, de Lauzon‐Guillan B, Franks P, Froguel P, Gonzales C, Halkjær J, Huerta JM, Kaaks R, Key TJ, Khaw KT, Krogh V, Molina‐Montes E, Nilsson P, Overvad K, Palli D, Panico S, Ramón Quirós J, Ronaldsson O, Romieu I, Romaguera D, Sacerdote C, Sánchez M‐J, Spijkerman AMW, Teucher B, Tjonneland A, Tumino R, Sharp S, Forouhi NG, Langenberg C, Feskens EJM, Riboli E, Wareham NJ (University Medical Center Utrecht, The Netherlands; German Institute of Human Nutrition, Potsdam‐Rehbrücke, Germany; German Cancer Research Centre, Heidelberg, Germany; Basque Government, San Sebastian, CIBERESP, Spain; Institut de Biologie de Lille, Lille, France; Murcia Regional Health Council, Murcia, Spain; CIBER Epidemiologia y Salud Publica (CIBERESP), Spain; University of Oxford, Oxford, UK; National Institute of Public Health and the Environment, Bilthoven, The Netherlands; Inserm, CESP Centre for Research in Epidemiology and Population Health, Villejuif Cedex, France; Lund University, Malmö, Sweden; Imperial College, London, UK; Department of Epidemiology, Barcelona, Spain; Danish Cancer Society, Copenhagen, Denmark; University of Cambridge, Cambridge, UK; Fondazione IRCCS Istituto Nazionale Tumori Milan, Milan, Italy; Andalusian School of Public Health, Granada, Spain; School of Public Health, Aarhus, Denmark; Cancer Research and Prevention Institute (ISPO), Florence, Italy; Università Federico II, Napoli, Italy; Consejeria de Salud y Servicios Sanitarios, Oviedo‐Asturias, Spain; Umea University, Umea, Sweden; International Agency for Research of Cancer, Lyon, France; Center for Cancer Prevention (CPO‐Piemonte), Torino, Italy; “Civile ‐ M.P. Arezzo” Hospital, Ragusa, Italy; Addenbrooke’s Hospital, Cambridge, UK; and Wageningen University, Wageningen, The Netherlands). Alcohol consumption and risk of type 2 diabetes in European men and women: influence of beverage type and body size. The EPIC–InterAct study. J Intern Med 2012; 272: 358–370.

Cortical serotonin 1A receptor levels are associated with depression in patients with dementia with Lewy bodies and Parkinson's disease dementia.

Background: Serotonin 1A receptors (5-HT1A) have not been studied in dementia with Lewy bodies (DLB) or Parkinson’s disease dementia (PDD) patients with depression. Aim: To examine 5-HT1A in DLB and PDD postmortem in relation to depression. Methods: [3H]8-hydroxy-2-dipropylaminotetralin binding to 5-HT1A was determined in temporal cortex (Brodmann areas, BA20 and BA36) from 10 DLB patients, 17 PDD patients and 9 controls. Results: 5-HT1A density was significantly higher in BA36 in combined DLB/PDD patients with depression, but was unaltered in BA20. Conclusion: Higher BA36 5-HT1A density in PDD and DLB patients than in control is dependent on whether the patient had experienced depression during life, not DLB/PDD diagnosis. A 5-HT1A antagonist adjuvant may improve treatment of depression in dementia.

Genetic association of the tachykinin receptor 1 TACR1 gene in bipolar disorder, attention deficit hyperactivity disorder, and the alcohol dependence syndrome.

Single nucleotide polymorphisms (SNPs) in the tachykinin receptor 1 gene (TACR1) are nominally associated with bipolar affective disorder (BPAD) in a genome‐wide association study and in several case‐control samples of BPAD, alcohol dependence syndrome (ADS) and attention‐deficit hyperactivity disorder (ADHD). Eighteen TACR1 SNPs were associated with BPAD in a sample (506 subjects) from University College London (UCL1), the most significant being rs3771829, previously associated with ADHD. To further elucidate the role of TACR1 in affective disorders, rs3771829 was genotyped in a second BPAD sample of 593 subjects (UCL2), in 997 subjects with ADS, and a subsample of 143 individuals diagnosed with BPAD and comorbid alcohol dependence (BPALC). rs3771829 was associated with BPAD (UCL1 and UCL2 combined: P = 2.0 × 10−3), ADS (P = 2.0 × 10−3) and BPALC (P = 6.0 × 10−4) compared with controls screened for the absence of mental illness and alcohol dependence. DNA sequencing in selected cases of BPAD and ADHD who had inherited TACR1‐susceptibility haplotypes identified 19 SNPs in the promoter region, 5′ UTR, exons, intron/exon junctions and 3′ UTR of TACR1 that could increase vulnerability to BPAD, ADS, ADHD, and BPALC. Alternative splicing of TACR1 excludes intron 4 and exon 5, giving rise to two variants of the neurokinin 1 receptor (NK1R) that differ in binding affinity of substance P by 10‐fold. A mutation in intron four, rs1106854, was associated with BPAD, although a regulatory role for rs1106854 is unclear. The association with TACR1 and BPAD, ADS, and ADHD suggests a shared molecular pathophysiology between these affective disorders.

Choline Acetyltransferase Activity in Vascular Dementia and Stroke

Background/Aim: Alterations in cholinergic activity have not been systematically studied in types of cerebrovascular disease. We examined cholinergic function at postmortem, focussing on stroke and vascular dementia (VaD). Methods: Post-mortem brain tissue was studied from 61 patients with stroke or VaD (13 infarct dementia; 8 stroke/no dementia; 11 sub-cortical ischaemic VaD, SIVD; 29 VaD and concurrent Alzheimer’s disease, AD), 12 patients with AD and 23 controls. Choline acetyltransferase (ChAT) was measured in Brodmann areas (BA) 9 and 20/21. Results: There were significant reductions in ChAT activity in patients with VaD and concurrent AD compared to age-matched controls (BA9: t = 2.7, p = 0.009; BA20/21: t = 4.67, p = 0.000). In patients with infarct dementia, there was a significant 27% increase in ChAT activity in BA9 (t = 2.1, p = 0.047), but not in BA20/21 (t = 1.67, p = 0.106), compared to the age-matched control group. There was no relationship between ChAT activity and cognition in the VaD patients. Conclusions: Loss of cholinergic function is only evident in VaD patients with concurrent AD. A novel increase in cholinergic activity was identified in patients with infarct dementia, which may create important new treatment opportunities.

The functional GRM3 Kozak sequence variant rs148754219 affects the risk of schizophrenia and alcohol dependence as well as bipolar disorder

We previously reported that a Kozak sequence variant in the metabotropic glutamate receptor 3 gene (GRM3), rs148754219, is associated with bipolar disorder (BP) and affects gene transcription and translation (Kandaswamy et al., 2013). A marker near GRM3, rs12704290, is one of the top hits and reached genome-wide significance in a recently reported genome-wide association study of schizophrenia (SZ) (Ripke et al., 2014), and markers for GRM3 have also been reported to demonstrate association with alcohol dependence syndrome (ADS) (Levey et al., 2014). In our original sample, considering patients successfully genotyped for rs148754219, 19 out of 1062 BP cases and only four out of 932 controls were heterozygous [odds ratio (OR)=4.2 (1.4–12.3), P=0.005]. We have genotyped this variant in additional controls and cases diagnosed with BP, SZ and ADS with the same ancestry. Patients were assessed by trained clinicians as described previously (Kandaswamy et al., 2013; Way et al., 2014). Allele counts were compared and significance was tested using Fisher’s exact test. Thirteen out of 934 additional BP cases and three out of 377 additional controls were heterozygous [OR=1.8 (0.49–6.2), P=not significant]. Combined with the originally reported results (Kandaswamy et al., 2013), 32 out of 1964 BP cases and seven out of 1309 controls were heterozygous [OR=3.0 (1.3–6.8), P=0.003]. Out of 1235 SZ cases 16 were heterozygous and were compared with the total control sample [OR=2.4 (0.99–5.8), P=0.03]. Out of 1514 ADS cases 18 were heterozygous and one was homozygous for the variant allele [OR=2.5 (1.0–5.9), P=0.03]. If all case cohorts (BP, SZ and ADS) are combined together, there would be one homozygote and 66 heterozygotes out of 4971 cases compared with the seven heterozygotes out of 1309 controls [OR=2.7 (1.2–5.8), P=0.004]. Previous work has supported the view that some genetic risk factors may be common to different psychiatric diagnoses (Lydall et al., 2011; Lee et al., 2013). Although the individual results are of questionable significance, the magnitude and direction of effect are consistent across all the cohorts and thus suggest the possibility that this rare variant may have a direct, functional effect on the risk of developing any of these three disorders. Because of its rarity, large sample sizes would be needed to confirm these results. Doing this would be worthwhile because if this finding is confirmed it could provide molecular insight into a mechanism involving GRM3 leading to increased risk of mental disorders and could provide a basis for further functional and therapeutic studies.

Genetic association, mutation screening, and functional analysis of a Kozak sequence variant in the metabotropic glutamate receptor 3 gene in bipolar disorder.

IMPORTANCE Genetic markers at the gene encoding the metabotropic glutamate receptor 3 (GRM3) showed allelic association with bipolar disorder. OBJECTIVE To screen the GRM3 gene and adjacent control regions of genomic DNA in volunteers with bipolar affective disorder for mutations increasing susceptibility to bipolar disorder. DESIGN Sequencing and high-resolution melting curve analysis of DNA followed by genotyping was carried out in 1099 patients with bipolar affective disorder and 1152 healthy comparator individuals. SETTING Participants with bipolar disorder were recruited from National Health Service psychiatric services and from patient organizations. PARTICIPANTS Individuals were included if they had Research Diagnostic Criteria diagnoses of bipolar I and bipolar II disorder and were of British or Irish ancestry. MAIN OUTCOMES AND MEASURES Identification of base pair changes in the GRM3 gene that affected expression or function of the GRM3 receptor that also showed an allelic association with bipolar disorder. RESULTS A base pair variant (rs148754219) was found in the Kozak sequence of exon 1 of the GRM3 gene, 2 bases before the translation start codon of one of the receptor isoforms, in 23 of 2251 people who were screened and genotyped. Nineteen of the 1099 bipolar cases (1.7%) were mutation carriers compared with 4 of 1152 healthy comparators (0.3%). The variant was associated with bipolar disorder (P = .005; odds ratio, 4.20). Bioinformatic, electrophoretic mobility shift assay, and gene expression analysis found that the variant created a new transcription factor protein binding site and had a strong effect on gene transcription and translation. CONCLUSIONS AND RELEVANCE Confirmation of these findings is needed before the Kozak sequence variant can be accepted as a potential marker for personalized treatment of affective disorders with drugs targeting the metabotropic glutamate receptor 3.