The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in ∼50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Diagnosis and management of dementia with Lewy bodies: Third report of the DLB Consortium

The NINCDS-ADRDA and the DSM-IV-TR criteria for Alzheimer's disease (AD) are the prevailing diagnostic standards in research; however, they have now fallen behind the unprecedented growth of scientific knowledge. Distinctive and reliable biomarkers of AD are now available through structural MRI, molecular neuroimaging with PET, and cerebrospinal fluid analyses. This progress provides the impetus for our proposal of revised diagnostic criteria for AD. Our framework was developed to capture both the earliest stages, before full-blown dementia, as well as the full spectrum of the illness. These new criteria are centred on a clinical core of early and significant episodic memory impairment. They stipulate that there must also be at least one or more abnormal biomarkers among structural neuroimaging with MRI, molecular neuroimaging with PET, and cerebrospinal fluid analysis of amyloid beta or tau proteins. The timeliness of these criteria is highlighted by the many drugs in development that are directed at changing pathogenesis, particularly at the production and clearance of amyloid beta as well as at the hyperphosphorylation state of tau. Validation studies in existing and prospective cohorts are needed to advance these criteria and optimise their sensitivity, specificity, and accuracy.

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Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS–ADRDA criteria

The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.

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Diagnosis and management of dementia with Lewy bodies Fourth consensus report of the DLB Consortium

The demographics of aging suggest a great need for the early diagnosis of dementia and the development of preventive strategies. Neuropathology and structural MRI studies have pointed to the medial temporal lobe (MTL) as the brain region earliest affected in Alzheimer’s disease (AD). MRI findings provide strong evidence that in mild cognitive impairments (MCI), AD-related volume losses can be reproducibly detected in the hippocampus, the entorhinal cortex (EC) and, to a lesser extent, the parahippocampal gyrus; they also indicate that lateral temporal lobe changes are becoming increasingly useful in predicting the transition to dementia. Fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) imaging has revealed glucose metabolic reductions in the parieto-temporal, frontal and posterior cingulate cortices to be the hallmark of AD. Overall, the pattern of cortical metabolic changes has been useful for the prediction of future AD as well as in distinguishing AD from other neurodegenerative diseases. FDG-PET on average achieves 90% sensitivity in identifying AD, although specificity in differentiating AD from other dementias is lower. Moreover, recent MRI-guided FDG-PET studies have shown that MTL hypometabolism is the most specific and sensitive measure for the identification of MCI, while the utility of cortical deficits is controversial. This review highlights cross-sectional, prediction and longitudinal FDG-PET studies and attempts to put into perspective the value of FDG-PET in diagnosing AD-like changes, particularly at an early stage, and in providing diagnostic specificity. The examination of MTL structures, which has so far been exclusive to MRI protocols, is then examined as a possible strategy to improve diagnostic specificity. All told, there is considerable promise that early and specific diagnosis is feasible through a combination of imaging modalities.

Brain glucose metabolism in the early and specific diagnosis of Alzheimer's disease. FDG-PET studies in MCI and AD.

Dementia with Lewy bodies is relatively common cause of degenerative dementia in older people. This debilitating disorder is comprised of core features including dementia, fluctuating cognition, motor parkinsonism, and visual hallucinations, as well as other symptoms such as rapid eye movement sleep behavior disorder, olfactory dysfunction, autonomic dysfunction, sensitivity to neuroleptics, anxiety, depression, and delusions. Pharmacotherapy, so far exclusively symptomatic, should be implemented with caution and only when symptoms are disturbing and after non-pharmacological interventions fail. Treatment with acetylcholinesterase inhibitors (AChEi), such as donepezil and rivastimine, is considered a first line therapy. There is substantial evidence that AChEi address cognitive as well as behavioral symptoms without substantially increasing parkinsonism. Dopaminergic treatment for motor symptoms requires balancing risk of worsened psychosis and is consider only moderately beneficial.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(03)00619-7.pdf

Dementia With Lewy Bodies

Glucose Hypometabolism and Neuropathological Correlates in Brains of Dementia with Lewy Bodies

Alcohol use disorder is a common and complex disorder with a well-documented highly hereditary nature (Higuchi et al., 2006; Roh et al., 2008). Subjective response to alcohol is also known to be a genetically influenced characteristic (Schuckit et al., 2007; Viken et al., 2003). This suggests that genetic influences on individual variation in subjective response to alcohol may underlie the effects of genes on alcohol-related disorders. A low level of response to the acute effects of alcohol has been associated with an increased risk of both excessive alcohol intake (Hinckers et al., 2006; Schuckit et al., 2007) and alcohol dependence (Schuckit, 1994; Schuckit and Smith, 1996; Schuckit et al., 2004), which are well known to be highly heritable (Kendler, 2001).

There is consistent evidence that the GABAA receptor regulates the alcohol self-administration in animal models, probably by stimulating reward circuitry in the mesolimbic system (Chester and Cunningham, 2002; Eiler and June, 2007; Harvey et al., 2002; June et al., 2003). Several GABAA receptor subunits have been implicated in alcohol effects, so that the specific subunit composition of the receptor may be an important determinant of alcohol’s CNS effects. The α2 subunit of the GABAA receptor mediates the anxiolytic effects of benzodiazepines (Low et al., 2000; Rudolph et al., 1999) and enhances the hypnotic, but not the sedative, effects of combined exposure to alcohol and benzodiazepines (Tauber et al., 2003). Two genome-wide scans in humans have provided evidence of linkage of alcohol dependence to a region of chromosome 4p that includes a cluster of 4 genes encoding γ-aminobutyric acid A (GABAA) receptor subunits (Long et al., 1998; Reich et al., 1998). A previous study (Edenberg et al., 2004) found that 31 single nucleotide polymorphisms (SNPs) in GABAA receptor α2 subunit gene (GABRA2), but only 1 of the 20 SNPs in the flanking genes, showed significant association with alcohol dependence. Additional studies have provided the replication of this association in a region of GABRA2 among various ethnic groups (Covault et al., 2004; Fehr et al., 2006; Lappalainen et al., 2005; Soyka et al., 2008); though, there is a negative association study between GABRA2 and alcohol dependence (Matthews et al., 2007). Previous studies have also provided evidence that GABAA receptors mediate several behavioral effects of alcohol such as ethanol self-administration and motor impairment (Davies, 2003; Grobin et al., 1998; Hanchar et al., 2005). GABRA2 gene was associated with the differences in the subjective effects of alcohol including blushing sensations, stimulant and sedative effects (Pierucci-Lagha et al., 2005), and the variance in drinking behavior (Bauer et al., 2007). In the former study (Pierucci-Lagha et al., 2005), the more common A allele of the rs279858 SNP within the GABRA2 gene showed greater subjective effects of alcohol than did individuals with 1 or 2 copies of the alcohol dependence–associated G allele. These findings underscore the potential contributions of variation at GABRA2 to the differences in the subjective responses to alcohol, the variance of drinking behavior, and the risk for alcohol dependence.

This study examined the moderating effects of GABRA2 alleles on subjective and physiologic effects of alcohol in healthy social drinkers. We used the alcohol clamp method for alcohol administration, which uses an intravenous infusion of alcohol at rates adjusted online to close the gap between measurements of breath alcohol concentration (BrAC) and the target concentration. The clamp method reduces experimental variance in BrAC (O’Connor et al., 1998) which can be caused by the substantial pharmacokinetic variability following oral alcohol administration. Therefore, the alcohol clamp used in this study is a more exhaustive objective measure than the oral loading of alcohol that was used in the previous study of the effects of GABRA2 on the subjective effects of alcohol assessed only during the ascending limb of the BrAC (Pierucci-Lagha et al., 2005). Our method allowed the evaluation of the initial response to alcohol following the ascending limb of the BrAC as well as the adaptive response to alcohol during the clamped BrAC interval. Based on the previous studies, we hypothesized that GABRA2 alleles would moderate the subjective responses to alcohol measured during not only the ascending limb of BrAC curve but also the clamped BrAC interval. As we expected, subjects with ALDH2*1/*2 showed higher initial response than those with ALDH2*1/*1 (Matsushita et al., manuscript in preparation). Therefore, we divided subjects by ALDH2 genotype and performed further analyses separately in each ALDH2 genotypic group.

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Role of GABRA2 in Moderating Subjective Responses to Alcohol

Alcohol-related diseases have multiple and varied associations with acetaldehyde, a highly toxic product of ethanol oxidation that accumulates in the absence of active aldehyde dehydrogenase (ALDH). This study was designed to clarify the role of acetaldehyde in liver injury, specifically in vivo and in vitro effects on Kupffer cell release of the inflammatory cytokine tumor necrosis factor-alpha (TNF-Α).

Acetaldehyde accumulation suppresses Kupffer cell release of TNF-α and modifies acute hepatic inflammation in rats

Telomere shortening in alcohol dependence: Roles of alcohol and acetaldehyde.

Genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B; rs1229984, His48Arg) and aldehyde dehydrogenase-2 (ALDH2; rs671, Glu504Lys) affect body weight, body fat, and lipid metabolism in individuals with alcohol dependence, and the aim of this study was to identify their determinants in relation to the development of fatty liver. We evaluated associations between the presence of fatty liver and ADH1B and ALDH2 genotypes and other factors in 1604 Japanese men who had been admitted for treatment of alcohol dependence. Fatty liver was diagnosed when ultrasonography showed both hepatorenal contrast and liver brightness. Age-adjusted usual alcohol intake did not differ according to ADH1B or ALDH2 genotypes. A multivariate analysis showed that the adjusted odds ratio (OR, 95% confidence interval) of slow-metabolizing ADH1B Arg/Arg carriers was 1.61 (1.27–2.03) for fatty liver and 1.82 (1.37–2.41) for fatty liver with deep attenuation in comparison with the ADH1B His/Arg or His/His carriers, and that the OR of inactive heterozygous ALDH2 Glu/Lys carriers was 1.43 (1.08–1.91) for fatty liver and 1.84 (1.31–2.59) for fatty liver with deep attenuation in comparison with the ALDH2 Glu/Glu carriers. Younger age, shorter interval between the last drink and the ultrasound examination, larger body mass index, and absence of cirrhosis were identified as other positive determinants for fatty liver. The ADH1B Arg/Arg genotype and the ALDH2 Glu/Lys genotype were positive determinants of fatty liver in the subjects. These results suggest that slow ethanol and acetaldehyde metabolism accelerates the development of alcoholic fatty liver in heavy drinkers.

Sachiko Hara

Papers

Glucose Hypometabolism and Neuropathological Correlates in Brains of Dementia with Lewy Bodies

Role of GABRA2 in Moderating Subjective Responses to Alcohol

Acetaldehyde accumulation suppresses Kupffer cell release of TNF-α and modifies acute hepatic inflammation in rats

Telomere shortening in alcohol dependence: Roles of alcohol and acetaldehyde.

Slow-metabolizing ADH1B and inactive heterozygous ALDH2 increase vulnerability to fatty liver in Japanese men with alcohol dependence.