Gordon Wilcock

Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB) Report of the consortium on DLB international workshop

Recent neuropathologic autopsy studies found that 15 to 25% of elderly demented patients have Lewy bodies (LB) in their brainstem and cortex, and in hospital series this may constitute the most common pathologic subgroup after pure Alzheimers disease (AD).The Consortium on Dementia with Lewy bodies met to establish consensus guidelines for the clinical diagnosis of dementia with Lewy bodies (DLB) and to establish a common framework for the assessment and characterization of pathologic lesions at autopsy. The importance of accurate antemortem diagnosis of DLB includes a characteristic and often rapidly progressive clinical syndrome, a need for particular caution with neuroleptic medication, and the possibility that DLB patients may be particularly responsive to cholinesterase inhibitors. We identified progressive disabling mental impairment progressing to dementia as the central feature of DLB. Attentional impairments and disproportionate problem solving and visuospatial difficulties are often early and prominent. Fluctuation in cognitive function, persistent well-formed visual hallucinations, and spontaneous motor features of parkinsonism are core features with diagnostic significance in discriminating DLB from AD and other dementias. Appropriate clinical methods for eliciting these key symptoms are described. Brainstem or cortical LB are the only features considered essential for a pathologic diagnosis of DLB, although Lewy-related neurites, Alzheimer pathology, and spongiform change may also be seen. We identified optimal staining methods for each of these and devised a protocol for the evaluation of cortical LB frequency based on a brain sampling procedure consistent with CERAD. This allows cases to be classified into brainstem predominant, limbic (transitional), and neocortical subtypes, using a simple scoring system based on the relative distribution of semiquantitative LB counts. Alzheimer pathology is also frequently present in DLB, usually as diffuse or neuritic plaques, neocortical neurofibrillary tangles being much less common. The precise nosological relationship between DLB and AD remains uncertain, as does that between DLB and patients with Parkinsons disease who subsequently develop neuropsychiatric features. Finally, we recommend procedures for the selective sampling and storage of frozen tissue for a variety of neurochemical assays, which together with developments in molecular genetics, should assist future refinements of diagnosis and classification. NEUROLOGY 1996;47: 1113-1124

The cholinergic hypothesis of Alzheimer’s disease: a review of progress

Alzheimer’s disease is one of the most common causes of mental deterioration in elderly people, accounting for around 50%-60% of the overall cases of dementia among persons over 65 years of age. The past two decades have witnessed a considerable research effort directed towards discovering the cause of Alzheimer’s disease with the ultimate hope of developing safe and effective pharmacological treatments. This article examines the existing scientific applicability of the original cholinergic hypothesis of Alzheimer’s disease by describing the biochemical and histopathological changes of neurotransmitter markers that occur in the brains of patients with Alzheimer’s disease both at postmortem and neurosurgical cerebral biopsy and the behavioural consequences of cholinomimetic drugs and cholinergic lesions. Such studies have resulted in the discovery of an association between a decline in learning and memory, and a deficit in excitatory amino acid (EAA) neurotransmission, together with important roles for the cholinergic system in attentional processing and as a modulator of EAA neurotransmission. Accordingly, although there is presently no “cure” for Alzheimer’s disease, a large number of potential therapeutic interventions have emerged that are designed to correct loss of presynaptic cholinergic function. A few of these compounds have confirmed efficacy in delaying the deterioration of symptoms of Alzheimer’s disease, a valuable treatment target considering the progressive nature of the disease. Indeed, three compounds have received European approval for the treatment of the cognitive symptoms of Alzheimer’s disease, first tacrine and more recently, donepezil and rivastigmine, all of which are cholinesterase inhibitors.

Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: multicentre randomised controlled trial

Abstract Objective: To evaluate the efficacy and safety of galantamine in the treatment of Alzheimers disease. Design: Randomised, double blind, parallel group, placebo controlled trial. Setting: 86 outpatient clinics in Europe and Canada. Participants: 653 patients with mild to moderate Alzheimers disease. Intervention: Patients randomly assigned to galantamine had their daily dose escalated over three to four weeks to maintenance doses of 24 or 32 mg. Main outcome measures: Scores on the 11 item cognitive subscale of the Alzheimers disease assessment scale, the clinicians interview based impression of change plus caregiver input, and the disability assessment for dementia scale. The effect of apolipoprotein E4 genotype on reponse to treatment was also assessed. Results: At six months, patients who received galantamine had a significantly better outcome on the 11 item cognitive subscale of the Alzheimers disease assessment scale than patients in the placebo group (mean treatment effect 2.9 points for lower dose and 3.1 for higher dose, intention to treat analysis, P<0.001 for both doses). Galantamine was more effective than placebo on the clinicians interview based impression of change plus caregiver input (P<0.05 for both doses v placebo). At six months, patients in the higher dose galantamine group had significantly better scores on the disability assessment for dementia scale than patients in the placebo group (mean treatment effect 3.4 points, P<0.05). Apolipoprotein E genotype had no effect on the efficacy of galantamine. 80% (525) of patients completed the study. Conclusion: Galantamine is effective and well tolerated in Alzheimers disease. As galantamine slowed the decline of functional ability as well as cognition, its effects are likely to be clinically relevant.

Effect of Tarenflurbil on Cognitive Decline and Activities of Daily Living in Patients With Mild Alzheimer Disease: A Randomized Controlled Trial

CONTEXT Amyloid-beta peptide (Abeta(42)) has been implicated in the pathogenesis of Alzheimer disease (AD). Tarenflurbil, a selective Abeta(42)-lowering agent, demonstrated encouraging results on cognitive and functional outcomes among mildly affected patients in an earlier phase 2 trial. OBJECTIVE To determine the efficacy, safety, and tolerability of tarenflurbil. DESIGN, SETTING, AND PATIENTS A multicenter, randomized, double-blind, placebo-controlled trial enrolling patients with mild AD was conducted at 133 trial sites in the United States between February 21, 2005, and April 30, 2008. Concomitant treatment with cholinesterase inhibitors or memantine was permitted. INTERVENTION Tarenflurbil, 800 mg, or placebo, administered twice a day. MAIN OUTCOME MEASURES Co-primary efficacy end points were the change from baseline to month 18 in total score on the subscale of the Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog, 80-point version) and Alzheimer Disease Cooperative Studies-activities of daily living (ADCS-ADL) scale. Additional prespecified slope analyses explored the possibility of disease modification. RESULTS Of the 1684 participants randomized, 1649 were included in the analysis, and 1046 completed the trial. Tarenflurbil had no beneficial effect on the co-primary outcomes (difference in change from baseline to month 18 vs placebo, based on least squares means: 0.1 for ADAS-Cog; 95% CI, -0.9 to 1.1; P = .86 and -0.5 for ADCS-ADL; 95% CI, -1.9 to 0.9; P = .48) using an intent-to-treat analysis. No significant differences occurred in the secondary outcomes. The ADAS-Cog score decreased by 7.1 points over 18 months. The tarenflurbil group had a small increase in frequency of dizziness, anemia, and infections. CONCLUSION Tarenflurbil did not slow cognitive decline or the loss of activities of daily living in patients with mild AD. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00105547.

Neuropathological assessment of the lesions of significance in vascular dementia

OBJECTIVES To better define the neuropathology of vascular dementia. METHODS The neuropathological findings in 18 elderly, undemented subjects free of cerebrovascular disease were compared with 19 elderly undemented subjects who had cerebrovascular disease (many of whom had had a “stroke”) and 24 elderly demented subjects who had cerebrovascular disease, but no other pathology to account for dementia. Cases in all groups were selected for absence or no more than very mild Alzheimer type pathology. RESULTS Microvascular brain damage in the form of severe cribriform change and associated subcortical white matter damage and microinfarction were correlated with a history of dementia. Severe cribriform change was much more common and microinfarction somewhat more common in the demented group with vascular disease than the undemented group with vascular disease (P=0.0006 and P=0.031 respectively). Other findings of note were that congophilic angiopathy had a greater prevalence in the vascular dementia group than the control group, single cerebral infarcts were more common in the group who were undemented with vascular disease than in the group with dementia and vascular disease (P=0.0028), and the last group lacked evidence of macroscopic infarction more often than the first (P=0.034). There was a non-significant trend for the ratio of infarcted:uninfarcted tissue in one cerebral hemisphere to be higher in the group with dementia and vascular disease than in the group with vascular disease but no dementia. CONCLUSIONS Microvascular disease, not macroscopic infarction, was the chief substrate of vascular dementia in this series of cases.

Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease

Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimers disease (LOAD). These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low-frequency coding variants with large effects on LOAD risk, we carried out whole-exome sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large LOAD case–control data sets. A rare variant in PLD3 (phospholipase D3; Val232Met) segregated with disease status in two independent families and doubled risk for Alzheimer’s disease in seven independent case–control series with a total of more than 11,000 cases and controls of European descent. Gene-based burden analyses in 4,387 cases and controls of European descent and 302 African American cases and controls, with complete sequence data for PLD3, reveal that several variants in this gene increase risk for Alzheimer’s disease in both populations. PLD3 is highly expressed in brain regions that are vulnerable to Alzheimer’s disease pathology, including hippocampus and cortex, and is expressed at significantly lower levels in neurons from Alzheimer’s disease brains compared to control brains. Overexpression of PLD3 leads to a significant decrease in intracellular amyloid-β precursor protein (APP) and extracellular Aβ42 and Aβ40 (the 42- and 40-residue isoforms of the amyloid-β peptide), and knockdown of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a twofold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may help to identify rare variants with large effects on risk for disease or other complex traits.

Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II trial

BACKGROUND The amyloid-beta peptide Abeta(42) has been implicated in the pathogenesis of Alzheimers disease (AD). We aimed to test the effects of tarenflurbil, a selective Abeta(42)-lowering agent (SALA), on cognition and function in patients with mild to moderate AD. METHODS 210 patients living in the community who had a mini-mental state examination (MMSE) score of 15-26 were randomly assigned to receive tarenflurbil twice per day (400 mg [n=69] or 800 mg [n=70]) or placebo (n=71) for 12 months in a phase II, multicentre, double-blind study. Primary efficacy outcomes were the AD assessment scale cognitive subscale (ADAS-cog), the Alzheimers Disease Cooperative Study activities of daily living scale (ADCS-ADL), and the clinical dementia rating sum of boxes (CDR-sb). In a 12-month extended treatment phase, patients who had received tarenflurbil continued to receive the same dose, and patients who had received placebo were randomly assigned to tarenflurbil at 800 mg or 400 mg twice per day. Primary efficacy analyses were done by intention to treat. This trial is registered with Health Canada (084527) and the Medicines and Healthcare products Regulatory Agency in the UK (20365/0001/A 69316). FINDINGS A prespecified interaction analysis revealed that patients with mild AD (baseline MMSE 20-26) and moderate AD (baseline MMSE 15-19) responded differently to tarenflurbil in the ADAS-cog and the ADCS-ADL (p>or=0.10); therefore, these groups were analysed separately. Patients with mild AD in the 800 mg tarenflurbil group had lower rates of decline than did those in the placebo group in activities of daily living (ADCS-ADL difference in slope 3.98 [95% CI 0.33 to 7.62] points per year, effect size [reduction from placebo decline rate] 46.4%, Cohens d 0.45; p=0.033) and global function (CDR-sb difference -0.80 [-1.57 to -0.03] points per year, effect size 35.7%, Cohens d 0.42; p=0.042); slowing of cognitive decline did not differ significantly (ADAS-cog difference -1.36 [-4.07 to 1.36] points per year, effect size 33.7%, Cohens d 0.20; p=0.327). In patients with moderate AD, 800 mg tarenflurbil twice per day had no significant effects on ADCS-ADL and ADAS-cog and had a negative effect on CDR-sb (-52%, Cohens d -1.08; p=0.003). The most common adverse events were diarrhoea (in seven, nine, and five patients in the 800 mg, 400 mg, and placebo groups, respectively), nausea (in seven, seven, and four patients), and dizziness (in five, nine, and four patients). Patients with mild AD who were in the 800 mg tarenflurbil group for 24 months had lower rates of decline for all three primary outcomes than did patients who were in the placebo group for months 0-12 and a tarenflurbil group for months 12-24 (all p<0.001), and had better outcomes than did patients who were in the placebo group for months 0-12 and the 800 mg tarenflurbil group for months 12-24 (all p<0.05). INTERPRETATION 800 mg tarenflurbil twice per day was well tolerated for up to 24 months of treatment, with evidence of a dose-related effect on measures of daily activities and global function in patients with mild AD. FUNDING Myriad Pharmaceuticals.

Monoaminergic innervation of the frontal and temporal lobes in Alzheimer's disease

Seven markers of ascending (corticopetal) dopaminergic, noradrenergic and serotonergic neurones and choline acetyltransferase activity have been studied postmortem in frontal and temporal cortex from subjects with Alzheimers disease and compared with a matched group of controls. Dopaminergic neurones (concentrations of dopamine, dihydroxyphenylacetic acid and homovanillic acid) were not deficient but some markers of the other neurones were affected. Noradrenaline and serotonin concentrations were reduced whereas the concentrations of their metabolites were either unaltered (5-hydroxyindoleacetic acid) or increased (3-methoxy-4-hydroxyphenylglycol). All deficits were most pronounced in the temporal cortex. Severely demented subjects had evidence of generalized neuronal loss, whereas those with moderate dementia showed significant loss of only choline acetyltransferase activity. In Alzheimer subjects, a significant relationship (inverse) was found between 5-hydroxyindoleacetic acid concentration and the number of neurofibrillary tangles.

THE NUCLEUS BASALIS IN ALZHEIMER'S DISEASE: CELL COUNTS AND CORTICAL BIOCHEMISTRY

The cell density in the Nucleus Basalis in six patients with clinical and histological evidence of Alzheimers disease and reduced choline acetyltransferase activity in frontal and temporal cortex was found to be in approximately 50% of the cell count in five control subjects.

Is inhibition of the renin–angiotensin system a new treatment option for Alzheimer's disease?

Findings from longitudinal and cross-sectional studies suggest an association between high blood pressure and dementia, and in turn the use of antihypertensives has been suggested to reduce incidence of dementia. Alzheimers disease, the most common cause of dementia, is characterised in part by the deposition of amyloid beta protein (Abeta) in the brain. Reduction of Abeta load is now a major therapeutic strategy. In recent years the renin-angiotensin system, already of recognised importance in the pathogenesis of hypertension, has become a source of interest in the pathogenesis of Alzheimers disease. This review explores molecular, genetic, and clinical studies that might help explain the relation between the renin-angiotensin system, hypertension, and Alzheimers disease and whether treatment with angiotensin converting enzyme (ACE) inhibitors and similar treatment strategies have a part to play in the management of the disease.