The APPLE Tree programme: Active Prevention in People at risk of dementia through Lifestyle, bEhaviour change and Technology to build REsiliEnce-randomised controlled trial.

BACKGROUND: Large-scale trials of multidomain interventions show that modifying lifestyle and psychological risk factors can slow cognitive decline. We aim to determine if a lower intensity, personally tailored secondary dementia prevention programme for older people with subjective or mild objective memory decline, informed by behaviour change theory, reduces cognitive decline over 2 years. METHODS: A multi-site, single-blind randomised controlled trial recruiting 704 older adults at high dementia risk due to mild cognitive impairment (MCI) or subjective cognitive decline (SCD). Participants are randomised using 1:1 allocation ratio to the APPLE Tree intervention versus control arm (dementia prevention information), stratified by site. The intervention explores and implements strategies to promote healthy lifestyle, increase pleasurable activities and social connections and improve long-term condition self-management. Two facilitators trained and supervised by a clinical psychologist deliver ten, 1-h group video call sessions over 6 months (approximately every fortnight), video-call 'tea breaks' (less structured, facilitated social sessions) in intervening weeks and individual goal-setting phone calls every 2 weeks. From 6 to 12 months, participants meet monthly for 'tea breaks', with those not attending receiving monthly goal-setting phone calls. Participants receive a food delivery, pedometer and website access to cognitive training and information about lifestyle modification. Follow-ups for all outcome measures are at 12 and 24 months. The primary outcome is cognition (Neuropsychological Test Battery (NTB) score) at 24 months. Secondary outcomes are quality of life, cost per quality-adjusted life year (QALY) and wellbeing and lifestyle factors the intervention targets (diet, vascular risk, body weight, activity, sleep, anxiety, depression, social networks and loneliness, alcohol intake and smoking). Participants from purposively selected sites participate in qualitative process evaluation interviews, which will be analysed using thematic analytic methods. DISCUSSION: If effective, the intervention design, involving remote delivery and non-clinical facilitators, would facilitate intervention roll-out to older people with memory concerns. TRIAL REGISTRATION: ISRCTN17325135 . Registration date 27 November 2019.

Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series.

Next-generation genetic sequencing (NGS) technologies facilitate the screening of multiple genes linked to neurodegenerative dementia, but there are few reports about their use in clinical practice. Which patients would most profit from testing, and information on the likelihood of discovery of a causal variant in a clinical syndrome, are conspicuously absent from the literature, mostly for a lack of large-scale studies. We applied a validated NGS dementia panel to 3241 patients with dementia and healthy aged controls; 13,152 variants were classified by likelihood of pathogenicity. We identified 354 deleterious variants (DV, 12.6% of patients); 39 were novel DVs. Age at clinical onset, clinical syndrome and family history each strongly predict the likelihood of finding a DV, but healthcare setting and gender did not. DVs were frequently found in genes not usually associated with the clinical syndrome. Patients recruited from primary referral centres were compared with those seen at higher-level research centres and a national clinical neurogenetic laboratory; rates of discovery were comparable, making selection bias unlikely and the results generalisable to clinical practice. We estimated penetrance of DVs using large-scale online genomic population databases and found 71 with evidence of reduced penetrance. Two DVs in the same patient were found more frequently than expected. These data should provide a basis for more informed counselling and clinical decision making.

European Association of Nuclear Medicine and European Academy of Neurology recommendations for the use of brain 18 F-fluorodeoxyglucose positron emission tomography in neurodegenerative cognitive impairment and dementia: Delphi consensus.

BACKGROUND AND PURPOSE: Recommendations for using fluorodeoxyglucose positron emission tomography (FDG-PET) to support the diagnosis of dementing neurodegenerative disorders are sparse and poorly structured. METHODS: Twenty-one questions on diagnostic issues and on semi-automated analysis to assist visual reading were defined. Literature was reviewed to assess study design, risk of bias, inconsistency, imprecision, indirectness and effect size. Critical outcomes were sensitivity, specificity, accuracy, positive/negative predictive value, area under the receiver operating characteristic curve, and positive/negative likelihood ratio of FDG-PET in detecting the target conditions. Using the Delphi method, an expert panel voted for/against the use of FDG-PET based on published evidence and expert opinion. RESULTS: Of the 1435 papers, 58 papers provided proper quantitative assessment of test performance. The panel agreed on recommending FDG-PET for 14 questions: diagnosing mild cognitive impairment due to Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) or dementia with Lewy bodies (DLB); diagnosing atypical AD and pseudo-dementia; differentiating between AD and DLB, FTLD or vascular dementia, between DLB and FTLD, and between Parkinson's disease and progressive supranuclear palsy; suggesting underlying pathophysiology in corticobasal degeneration and progressive primary aphasia, and cortical dysfunction in Parkinson's disease; using semi-automated assessment to assist visual reading. Panellists did not support FDG-PET use for pre-clinical stages of neurodegenerative disorders, for amyotrophic lateral sclerosis and Huntington disease diagnoses, and for amyotrophic lateral sclerosis or Huntington-disease-related cognitive decline. CONCLUSIONS: Despite limited formal evidence, panellists deemed FDG-PET useful in the early and differential diagnosis of the main neurodegenerative disorders, and semi-automated assessment helpful to assist visual reading. These decisions are proposed as interim recommendations.

Identification of biomarkers in Lewy-body disorders.

Dementia with Lewy bodies (DLB) may account for up to 30% of all dementia cases. The symptoms of DLB can be difficult to disentangle from other dementia subtypes, particularly Alzheimer's disease (AD). AD and DLB pathologies often overlap within individuals. Like DLB, Parkinson's disease dementia (PDD) also shares common features with DLB. Currently, whether an individual is diagnosed with PDD or DLB depends solely on the timing of symptom onset. Early, accurate diagnosis is needed for optimal management and treatment. It is hoped that the development of existing and new Lewy body disorders biomarkers will facilitate more accurate diagnosis. Reduced dopamine transporter levels in DLB as shown with [123I]FP-CIT-SPECT currently appears to be the most reliable and valid biomarker, although other (predominantly imaging-based) methods also appear to have the high sensitivity and specificity required for a good biomarker. This includes (in DLB compared to AD) reduced cardiac 123I-MIBG uptake, occipital hypometabolism on FDG-PET and preservation of medial temporal lobe structures on CT/MRI. Perfusion SPECT, cerebrospinal fluid protein levels (amyloid, tau and α-synuclein), electroencephalography, saccadic eye movement tracking and 11C-PiB amyloid imaging also hold promise as biomarkers in terms of differentiating DLB, AD, PDD and other neurodegenerative disorders, although findings are less consistent. Studies utilising a combination approach in which two or more potential biomarkers are compared seem to provide very good sensitivity and specificity. In general, longitudinal studies, pathological confirmation of diagnosis and the combined approach may hold the most promise for the identification of biomarkers.

Subjective cognitive impairment: functional MRI during a divided attention task.

BACKGROUND: Individuals with subjective cognitive impairment (SCI) have persistent memory complaints but normal neurocognitive performance. For some, this may represent a pre-mild cognitive impairment (MCI) stage of Alzheimer's disease (AD). Given that attentional deficits and associated brain activation changes are present early in the course of AD, we aimed to determine whether SCI is associated with brain activation changes during attentional processing. METHODS: Eleven SCI subjects and 10 controls completed a divided attention task during functional magnetic resonance imaging. RESULTS: SCI and control groups did not differ in sociodemographic, neurocognitive or behavioural measures. When group activation during the divided attention task was compared, the SCI group demonstrated increased activation in left medial temporal lobe, bilateral thalamus, posterior cingulate and caudate. CONCLUSION: This pattern of increased activation is similar to the pattern of decreased activation reported during divided attention in AD and may indicate compensatory changes. These findings suggest the presence of early functional changes in SCI; longitudinal studies will help to further elucidate the relationship between SCI and AD.

(11)C-PIB PET in subjective cognitive impairment.

People with Subjective Cognitive Impairment (SCI) may be at increased risk of dementia. In this study we examined amyloid load in 5 SCI subjects and 14 controls using PIB PET scanning. One SCI subject had significantly increased PIB retention in the cortical areas of interest. Larger, longitudinal studies are indicated.

The determinants of family carers' abusive behaviour to people with dementia: results of the CARD study.

BACKGROUND: Although dementia and elder abuse prevention are political priorities, there are no evidence-based interventions to reduce abuse by family carers. We have limited understanding of why some family carers, but not others in similar circumstances, behave abusively. We aimed to test our hypothesis, that more anxious dementia carers report more abusive behaviours, and dysfunctional coping strategies and carer burden mediate this relationship. METHOD: We interviewed 220 family/friend dementia carers from Essex and London Community Mental Health Teams. We used the revised Modified Conflict Tactics Scale to measure abuse. RESULTS: More anxious and depressed carers reported more abuse; this relationship was mediated by using dysfunctional coping strategies and higher burden. Abuse was predicted by: spending more hours caring, experiencing more abusive behaviour from care recipients and higher burden. LIMITATIONS: This was a cross-sectional study so we cannot confirm directions of causality. While many carers were willing to report abusive actions, some may not have been and our numbers may be an underestimate. CONCLUSION: Anxious and depressed carers are particularly likely to report abusive behaviour when asked. Testing interventions directed at reducing carer anxiety, depression or changing unhelpful coping strategies, and/or reducing care recipient aggression where possible, is a logical and urgent next step.

Conversion of amyloid positive and negative MCI to AD over 3 years: an 11C-PIB PET study.

BACKGROUND: Patients with amnestic mild cognitive impairment (MCI) represent an important clinical group as they are at increased risk of developing Alzheimer disease (AD). (11)C-PIB PET is an in vivo marker of brain amyloid load. OBJECTIVE: To assess the rates of conversion of MCI to AD during a 3-year follow-up period and to compare levels of amyloid deposition between MCI converters and nonconverters. METHODS: Thirty-one subjects with MCI with baseline (11)C-PIB PET, MRI, and neuropsychometry have been clinically followed up for 1 to 3 years (2.68 +/- 0.6 years). Raised cortical (11)C-PIB binding in subjects with MCI was detected with region of interest analysis and statistical parametric mapping. RESULTS: Seventeen of 31 (55%) subjects with MCI had increased (11)C-PIB retention at baseline and 14 of these 17 (82%) clinically converted to AD during follow-up. Only one of the 14 PIB-negative MCI cases converted to AD. Of the PIB-positive subjects with MCI, half (47%) converted to AD within 1 year of baseline PIB PET, these faster converters having higher tracer-retention values than slower converters in the anterior cingulate (p = 0.027) and frontal cortex (p = 0.031). Seven of 17 (41%) subjects with MCI with known APOE status were epsilon4 allele carriers, this genotype being associated with faster conversion rates in PIB-positive subjects with MCI (p = 0.035). CONCLUSIONS: PIB-positive subjects with mild cognitive impairment (MCI) are significantly more likely to convert to AD than PIB-negative patients, faster converters having higher PIB retention levels at baseline than slower converters. In vivo detection of amyloid deposition in MCI with PIB PET provides useful prognostic information.

Microglial activation and amyloid deposition in mild cognitive impairment: a PET study.

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.

Cerebral white matter changes and rate of progression of dementia during cholinesterase inhibitor treatment: a retrospective cohort study.

BACKGROUND: Cerebral white matter changes (WMC) represent cerebrovascular disease (CVD) and are common in dementia. Cholinesterase inhibitors (ChEIs) are effective in Alzheimer's Disease (AD) with or without CVD, and in Dementia with Lewy Bodies (DLB). Predictors of treatment response are controversial. OBJECTIVE: To investigate the effect of WMC severity on rate of progression of dementia during treatment with ChEIs. METHODS: CT or MRI brain scans were rated for WMC severity in 243 patients taking ChEIs for dementia. Raters were blind to patients' clinical risk factors, dementia subtype and course of illness. Effects of WMC severity on rates of decline in cognition, function and behaviour were analysed for 140 patients treated for 9 months or longer. Analysis was performed for this group as a whole and within diagnostic subgroups AD and DLB. The main outcome measure was rate of change in Mini Mental State Examination (MMSE) score. Secondary measures were rates of change in scores on the Cambridge Cognitive Examination (CAMCOG), Instrumental Activities of Daily Living (IADL) and Clifton Assessment Procedures for the Elderly - Behaviour Rating Scale (CAPE-BRS). RESULTS: There was no significant association between severity of WMC and any specified outcome variable for the cohort as a whole or for patients with AD. In patients with DLB, higher WMC scores were associated with more rapid cognitive decline. CONCLUSIONS: Increased WMC severity does not influence clinical response to ChEI treatment in AD, but may hasten deterioration in ChEI-treated patients with DLB.

Relationship of vascular risk to the progression of Alzheimer disease.

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.

Striatal dopamine transporter in dementia with Lewy bodies and Parkinson disease: a comparison.

OBJECTIVE: To study the nigrostriatal pathways in 21 patients with dementia with Lewy bodies (DLB), 19 drug naive Parkinson disease (PD) patients, and 16 controls using a dopaminergic presynaptic ligand [123I]-2beta-carbometoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (FP-CIT) and SPECT in order to assess similarities or differences between DLB and PD. METHODS: A SPECT scan was carried out 3 to 4 hours after administration of 185 MBq (IV) of FP-CIT. Using occipital cortex as a radioactivity uptake reference, ratios for the caudate nuclei and the anterior and posterior putamina of both hemispheres were calculated. From the FP-CIT binding measurements, asymmetry indices and caudate:putamen ratios were derived. RESULTS: The DLB and PD groups had lower FP-CIT binding in all striatal areas than controls (analysis of variance: p < 0.001 in all measures). DLB patients also had significantly lower binding in the caudate nucleus than the PD patients. There was greater asymmetry of uptake in the posterior putamina of PD patients than DLB patients (p < 0.04) and controls (p < 0.01). The mean caudate:putamen ratio for the DLB group was not significantly different from that of the controls, while the mean caudate:putamen ratio of the PD group was higher than that of the control group (p < 0.001) and the DLB group (p < 0.001). CONCLUSION: This study showed differences between PD and DLB in the pattern of striatal dopaminergic dysfunction. DLB patients do not have the characteristic selective degeneration of ventrolateral nigral neurons seen in PD. This could explain some of the clinical differences between DLB and PD.

Dopamine transporter binding in Gilles de la Tourette syndrome: a [123I]FP-CIT/SPECT study.

OBJECTIVE: To investigate dopamine transporter binding in Gilles de la Tourette syndrome (GTS) with SPECT and [123I]FP-CIT. METHOD: Ten neuroleptic naïve/free patients with GTS, and 10 age- and gender-matched normal volunteers were studied. Subjects were clinically evaluated. GTS severity and affective symptoms were measured and the presence of GTS-related behaviours were recorded. RESULTS: The GTS group showed significantly higher binding in both caudate and putamen nuclei than the controls. No associations were found between striatal binding ratios and measures of affect or GTS-related behaviours. CONCLUSION: Patients with GTS show higher striatal binding of FP-CIT to the striatum in comparison with age- and gender-matched control subjects, indicating that dopamine transporter abnormalities are involved in the pathophysiology of GTS. These abnormalities appear to be distributed across both caudate and putamen.

A memory clinic for older people with intellectual disabilities.

Cognitive decline in older people with intellectual disabilities (ID) is often under-recognized. Following the publication of the National Service Framework for Older People and the white paper Valuing People, older people with intellectual disabilities of all aetiologies should have access to a systematic assessment of their cognitive function in order to detect decline in cognition and adaptive skills and implement appropriate treatments as early as possible. The development of a memory clinic for older people with ID is described, including instruments used and characteristics of attendees. Such projects are in line with current UK government policies and can contribute to the improvement of standards of care and support research in this vulnerable group of people.

Variation in the DCP1 gene, encoding the angiotensin converting enzyme ACE, is not associated with increased susceptibility to Alzheimer's disease.

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.

Differentiation of dementia with Lewy bodies from Alzheimer's disease using a dopaminergic presynaptic ligand.

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.

Clinical presentations in monozygotic twins with dementia with Lewy bodies.

BACKGROUND: Dementia with Lewy bodies (DLB) is widely recognized as the second most common neurodegenerative cause of dementia in patients over the age of 65. The clinical distinction between DLB and Alzheimers's disease (AD) can be difficult due to the significant clinical overlap between the two disorders. Although the specificity of current consensus criteria is high, the sensitivity of case detection is lower and more variable. In some cases, the diagnosis is only made at postmortem examination. CASE REPORT: Monozygotic twins with the neuropathological diagnosis of Lewy body disease are presented in this report. Despite a very similar presentation and a comparable course of illness, the twins received different clinical diagnoses during life, one DLB and the other AD. This highlights the difficulty of making a clinical diagnosis of DLB, which very much depends on recognizing the features of fluctuation in level of awareness, hallucinations, delusions and the occurrence of falls, and the interpretation of the importance of these signs and symptoms. Pathological examination was virtually identical for the two cases showing the classic neuropathological features of Lewy Body disease.

Long-Term use of rivastigmine in patients with dementia with Lewy bodies: an open-label trial.

Patients with dementia with Lewy bodies (DLB) have progressive deficits in cognition, parkinsonism, and neuropsychiatric symptoms. Cholinesterase inhibitors have been used to ameliorate cognitive decline and neuropsychiatric symptoms in short-term trials. In this study, patients with DLB were treated with rivastigmine up to 96 weeks. Improvement from baseline was seen in cognitive function as measured by the Mini-Mental State Examination (MMSE), and neuropsychiatric symptoms as measured by the Neuropsychiatric Inventory (NPI) over the first 24 weeks of treatment. By 96 weeks, neither the MMSE scores nor the NPI scores were significantly worse than at baseline.

Eligibility criteria for elderly mentally ill continuing-care National Health Service patients: are they being met and do they need revision?

BACKGROUND: in 1996, the British government directed health authorities to draw up local eligibility criteria for National Health Service continuing health care. OBJECTIVES: to examine whether elderly mentally ill continuing-care National Health Service patients fulfilled a variety of eligibility criteria for their placement, and to identify the characteristics of patients who met local eligibility criteria. DESIGN: descriptive study. SETTING: four continuing-care units for elderly mentally ill patients in and around London. SUBJECTS: 67 continuing-care inpatients. METHODS: interview with nurse carer and, where possible, the patient with the use of standard global, functional, behavioural and cognitive rating scales. We determined fulfillment of Royal College of Psychiatrists' guideline criteria and three local eligibility criteria for elderly mentally ill continuing care. We identified clinical differences between those eligible and ineligible. RESULTS: although there were wide variations between local eligibility criteria, their effects were the same. In total, 58% of patients fulfilled all local eligibility criteria; 42% fulfilled none. Patients who fulfilled local eligibility criteria scored much higher on ratings of aggression, activity disturbance (wandering, and purposeless and inappropriate activity) and paranoid and delusional ideation. Ten percent of patients fulfilled Royal College of Psychiatrists' criteria but not local eligibility criteria. CONCLUSIONS: comprehensive and unambiguous national eligibility criteria should be introduced to reflect clinical needs and provide equity of access.