Emma L. Jones

Drug repositioning for Alzheimer's disease

Existing drugs for Alzheimers disease provide symptomatic benefit for up to 12 months, but there are no approved disease-modifying therapies. Given the recent failures of various novel disease-modifying therapies in clinical trials, a complementary strategy based on repositioning drugs that are approved for other indications could be attractive. Indeed, a substantial body of preclinical work indicates that several classes of such drugs have potentially beneficial effects on Alzheimers-like brain pathology, and for some drugs the evidence is also supported by epidemiological data or preliminary clinical trials. Here, we present a formal consensus evaluation of these opportunities, based on a systematic review of published literature. We highlight several compounds for which sufficient evidence is available to encourage further investigation to clarify an optimal dose and consider progression to clinical trials in patients with Alzheimers disease.

Optimised anaesthesia to reduce post operative cognitive decline (POCD) in older patients undergoing elective surgery, a randomised controlled trial.

Background The study determined the one year incidence of post operative cognitive decline (POCD) and evaluated the effectiveness of an intra-operative anaesthetic intervention in reducing post-operative cognitive impairment in older adults (over 60 years of age) undergoing elective orthopaedic or abdominal surgery. Methods and Trial Design The design was a prospective cohort study with a nested randomised, controlled intervention trial, using intra-operative BiSpectral index and cerebral oxygen saturation monitoring to enable optimisation of anaesthesia depth and cerebral oxygen saturation in older adults undergoing surgery. Results In the 52 week prospective cohort study (192 surgical patients and 138 controls), mild (χ2 = 17.9 p<0.0001), moderate (χ2 = 7.8 p = 0.005) and severe (χ2 = 5.1 p = 0.02) POCD were all significantly higher after 52 weeks in the surgical patients than among the age matched controls. In the nested RCT, 81 patients were randomized, 73 contributing to the data analysis (34 intervention, 39 control). In the intervention group mild POCD was significantly reduced at 1, 12 and 52 weeks (Fisher’s Exact Test p = 0.018, χ2 = 5.1 p = 0.02 and χ2 = 5.9 p = 0.015), and moderate POCD was reduced at 1 and 52 weeks (χ2 = 4.4 p = 0·037 and χ2 = 5.4 p = 0.02). In addition there was significant improvement in reaction time at all time-points (Vigilance Reaction Time MWU Z =  −2.1 p = 0.03, MWU Z = −2.7 p = 0.004, MWU Z = −3.0 p = 0.005), in MMSE at one and 52 weeks (MWU Z = −2.9 p = 0.003, MWU Z = −3.3 p = 0.001), and in executive function at 12 and 52 weeks (Trail Making MWU Z = −2.4 p = .0.018, MWU Z = −2.4 p = 0.019). Conclusion POCD is common and persistent in older adults following surgery. The results of the nested RCT indicate the potential benefits of intra-operative monitoring of anaesthetic depth and cerebral oxygenation as a pragmatic intervention to reduce post-operative cognitive impairment. Trial Registration Controlled-Trials.com ISRCTN39503939

Memantine for dementia in adults older than 40 years with Down's syndrome (MEADOWS): a randomised, double-blind, placebo-controlled trial

BACKGROUND Prevalence of Alzheimers disease in people with Downs syndrome is very high, and many such individuals who are older than 40 years have pathological changes characteristic of Alzheimers disease. Evidence to support treatment with Alzheimers drugs is inadequate, although memantine is beneficial in transgenic mice. We aimed to assess safety and efficacy of memantine on cognition and function in individuals with Downs syndrome. METHODS In our prospective randomised double-blind trial, we enrolled adults (>40 years) with karyotypic or clinically diagnosed Downs syndrome, with and without dementia, at four learning disability centres in the UK and Norway. We randomly allocated participants (1:1) to receive memantine or placebo for 52 weeks by use of a computer-generated sequence and a minimisation algorithm to ensure balanced allocation for five prognostic factors (sex, dementia, age group, total Downs syndrome attention, memory, and executive function scales [DAMES] score, and centre). The primary outcome was change in cognition and function, measured with DAMES scores and the adaptive behaviour scale (ABS) parts I and II. We analysed differences in DAMES and ABS scores between groups with analyses of covariance or quantile regression in all patients who completed the 52 week assessment and had available follow-up data. This study is registered, number ISRCTN47562898. FINDINGS We randomly allocated 88 patients to receive memantine (72 [82%] had DAMES data and 75 [85%] had ABS data at 52 weeks) and 85 to receive placebo (74 [87%] and 73 [86%]). Both groups declined in cognition and function but rates did not differ between groups for any outcomes. After adjustment for baseline score, there were non-significant differences between groups of -4·1 (95% CI -13·1 to 4·8) in DAMES scores, -8·5 (-20·1 to 3·1) in ABS I scores, and 2·0 (-7·2 to 11·3) in ABS II scores, all in favour of controls. 10 (11%) of 88 participants in the memantine group and six (7%) of 85 controls had serious adverse events (p=0·33). Five participants in the memantine group and four controls died from serious adverse events (p=0·77). INTERPRETATION There is a striking absence of evidence about pharmacological treatment of cognitive impairment and dementia in people older than 40 years with Downs syndrome. Despite promising indications, memantine is not an effective treatment. Therapies that are effective for Alzheimers disease are not necessarily effective in this group of patients. FUNDING Lundbeck.

Evidence that PICALM affects age at onset of Alzheimer's dementia in Down syndrome

It is known that individuals with Down syndrome develop Alzheimer’s disease with an early age at onset, although associated genetic risk factors have not been widely studied. We tested whether genes that increase the risk of late-onset Alzheimer’s disease influence the age at onset in Down syndrome using genome-wide association data for age at onset of dementia in a small sample of individuals (N = 67) with Down syndrome. We tested for association with loci previously associated with Alzheimer’s disease risk and, despite the small size of the study, we detected associations with age at onset of Alzheimer’s disease in Down syndrome with PICALM (β = 3.31, p = 0.011) and the APOE loci (β = 3.58, p = 0.014). As dementia in people with Down syndrome is relatively understudied, we make all of these data publicly available to encourage further analyses of the problem of Alzheimer’s disease in Down syndrome.

Association of a polymorphism in mitochondrial transcription factor A (TFAM) with Parkinson's disease dementia but not dementia with Lewy bodies

The single nucleotide polymorphism (SNP) A>G rs2306604 in the gene encoding mitochondrial transcription factor A (TFAM) has been associated with Alzheimers disease, with the A allele being recognised as a risk factor, but has not been studied in other types of dementia. We hypothesised that TFAM SNP rs2306604 might also be associated with Lewy body dementias. To test this hypothesis rs2306604 genotype was determined in 141 controls and 135 patients with dementia with Lewy bodies (DLB) or Parkinsons disease dementia (PDD). rs2306604 genotype frequencies were significantly different to controls in PDD (p=0.042), but not in DLB (p=0.529). The A allele was also associated with PDD (p=0.024, OR=2.092), but not DLB (p=0.429, OR=1.308). Moreover, the A allele was strongly associated with PDD in males (p=0.001, OR=5.570), but not in females (p=0.832, OR=1.100). Mitochondrial DNA copy number in the prefrontal cortex was also significantly reduced in PDD patients, but this reduction was not associated with rs2306604 genotype. These data show that the TFAM SNP rs2306604 A allele may be a risk factor for PDD, particularly in males, but not for DLB. Therefore, the genetic factors that predispose individuals to develop dementia may differ in PDD and DLB.

The extended tau haplotype and the age of onset of dementia in Down syndrome.

Background/Aims: Most people with Down syndrome (DS) develop Alzheimer’s disease (AD). The extended tau haplotype has been linked to AD. In this study, we examined the haplotype’s effect on the age of onset of AD in DS. Methods: People with DS were assessed for dementia. Genotyping was performed for the extended tau haplotype, APOE anda polymorphism in APP, attt5–8. Results: Haplotype frequencies vary between those developing AD before 45 and those developing dementia after this age (p = 0.03). H1/H2 individuals are more likely to develop dementia before 45 than H1/H1 individuals (OR = 3, 95% CI = 1.01–8.91). Conclusion: Even in a condition driven by excess amyloid pathology, factors affecting tau are also important and should be considered as potential treatment targets.

Genetic associations of autopsy-confirmed vascular dementia subtypes.

Background/Aims: Genetic risk factors have not been clearly established for vascular dementias (VaD) related to stroke and cerebrovascular disease. Methods: Samples were genotyped for APOE, MTHFR and ICAM. Aβ levels and choline acetyltransferase (ChAT) activities were assayed in controls and individuals with VaD. Results: Associations were found between the APOE-Ε4 allele and mixed dementia, infarct/stroke dementia and subcortical ischemic vascular dementia (SIVD), and higher Aβ1-42 levels and decreased ChAT activity. MTHFR was more associated with SIVD, mixed dementia, and lower ChAT activity. Conclusions: The study demonstrates important differences in the genetic associations of VaD and begins to clarify the genetic basis of key pathological substrates.

Polymorphisms in BACE2 may affect the age of onset Alzheimer's dementia in Down syndrome

It is known that Alzheimers disease (AD) presents at an early age in people with Down syndrome (DS). The trisomy 21 in DS provides an opportunity to study the effect of duplicated genes in AD. APP and BACE2 are 2 genes located in chromosome 21 and related to AD. We looked into our cohort of 67 DS cases with dementia for the effect of BACE2 variants in age of onset of dementia. Of the 83 single-nucleotide polymorphisms (SNPs), 6 were associated with age of onset and another 8 SNPs were borderline associated. Our finding also replicated a previous study showing association of rs2252576 with AD.

Determining the Association of the 5HTTLPR Polymorphism with Delusions and Hallucinations in Lewy Body Dementias

OBJECTIVES To determine whether the 5HTTLPR serotonin transporter polymorphism is associated with delusions and hallucinations in people with dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD). DESIGN Prospective cohort study. PARTICIPANTS A total of 187 individuals, recruited from centres in Norway, Sweden, and the United Kingdom were included in this study; 97 with clinically or neuropathologically diagnosed DLB/PDD and 90 cognitively normal individuals as a comparison group. MEASUREMENTS All participants with dementia underwent serial evaluation of neuropsychiatric symptoms to assess the presence of persistent delusions and hallucinations using the Columbia University Scale for Psychopathology in Alzheimer disease, the Neuropsychiatric Inventory, or the Present Behavioural Examination. Severity of cognitive impairment was measured using the Mini Mental State Examination (MMSE). Individuals were genotyped for the 5HTTLPR polymorphism. RESULTS Logistic regression demonstrated that homozygosity for the L/L genotype and lower MMSE were associated with an increased risk for delusions (odds ratio: 11.5 and 1.16, respectively). Neither was significantly associated with hallucinations. CONCLUSIONS This study is the first to demonstrate the 5HTTLPR polymorphism is associated with delusions in Lewy body dementias, with important implications regarding the mechanisms underlying this symptom across the AD/DLB/PDD spectrum. Further studies are warranted to investigate this relationship further and examine treatment opportunities.

CSF α-synuclein as a diagnostic biomarker for Parkinson disease and related dementias.

Parkinson disease (PD), PD dementia (PDD), and dementia with Lewy bodies (DLB) are neurodegenerative diseases with a shared pathologic substrate, intraneuronal inclusions of Lewy bodies and Lewy neurites incorporating abnormal aggregates of α-synuclein. Neuroimaging biomarkers, particularly PET and SPECT ligands binding to the dopamine transporter, combined with operationalized clinical criteria can achieve good sensitivity and specificity for the diagnosis of PD, PDD, and DLB.1 However, a CSF biomarker linked to disease pathology may further contribute to diagnostic accuracy, and would be particularly valuable in settings where sophisticated neuroimaging is not available. Perhaps more importantly, a biomarker more closely related to α-synuclein pathology would be invaluable for the development and evaluation of putative disease-modifying therapies in clinical trials. Encouragingly, preliminary results indicate that α-synuclein can be measured in CSF2,–,4 but not all available antibodies are specific to α-synuclein; furthermore, it is not conclusive whether there are consistent PD or DLB-associated changes in total α-synuclein compared to age-matched controls. Of particular note, changes in total α-synuclein have also been reported in Alzheimer disease (AD) compared …