J.A. Edwardson

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

Nicotinic receptor abnormalities in Alzheimer's and Parkinson's diseases.

The status of cholinergic receptors in dementia is related to the question of potential cholinergic therapy. Whilst muscarinic receptor binding is generally reported to be normal or near normal, findings are reported which indicate substantial reductions of hippocampal nicotinic (high affinity nicotine) binding (occurring in conjunction with decreased choline acetyltransferase) in both Alzheimers and Parkinsons but not Huntingtons disease. A further indication that nicotinic receptor function may be abnormal in Alzheimers disease is the extensive loss of an endogenous compound, detected for the first time in human brain, which inhibits normal nicotinic binding. Both receptor binding and the inhibitor are also substantially decreased with increasing age in the normal hippocampus.

Cholinergic Receptors in Cognitive Disorders

Cholinergic receptors (muscarinic subtypes M1 and M2, and putative nicotinic binding) have been examined in the hippocampus obtained at autopsy from a variety of patients with cognitive disorders (Alzheimers, Parkinsons, and Huntingtons diseases, Downs Syndrome and alcoholic dementia) and compared with neurologically normal controls and cases of Motor Neuron disease. In all of the disorders associated with a pre-synaptic cortical cholinergic deficit reflected by an extensive loss of choline acetyltransferase (Alzheimers disease, Parkinsons disease and Downs Syndrome) there was a substantial reduction in the binding of (3H) nicotine to the nicotinic receptor. By contrast reductions in both muscarinic subtypes (M1 and M2) were apparent to only a moderate extent in Alzheimers disease, whereas in Parkinsons disease binding was significantly increased (apparently not in relation to anti-cholinergic drug treatment) in the non-demented but not demented cases. A further abnormality detected in Alzheimers disease but not the other disorders investigated was a decrease in an endogenous inhibitor of nicotinic binding, the identity of which is as yet unknown but which may be a candidate for a possible endogenous modulator of the nicotinic receptor. These observations suggest that in Alzheimers disease not only muscarinic but also nicotinic receptor function should be considered in relation both to future therapeutic strategies and, in the search for a clinical marker which might be of diagnostic value, to potential probes of the cortical cholinergic system.

Topography, extent, and clinical relevance of neurochemical deficits in dementia of Lewy body type, Parkinson's disease, and Alzheimer's disease

Cholinergic and monoaminergic (dopaminergic and serotonergic) activities have been examined in postmortem brain tissue in senile dementia of Lewy body type, Parkinsons disease, and Alzheimers disease. Quantitative data suggest that although extrapyramidal symptoms relate to striatal levels of dopamine, cognitive impairment is most closely associated with cholinergic (but not monoaminergic) deficits in temporal and archicortical areas. Hallucinations, which are most frequent in Lewy body dementia, appear to be related to an extensive cholinergic deficit in temporal neocortex and the resulting imbalance between decreased cholinergic and relatively preserved serotonergic activities. Topographic analyses such as these including consideration of quantitative threshold effects, may be relevant to the future anatomic focus of neurochemical investigations in dementia and to the development of appropriate experimental models.

Uptake and distribution of iron and transferrin in the adult rat brain

Brain uptake of iron‐59 and iodine‐125‐labelled transferrin from blood in the adult rat has been investigated using graphical analysis to determine the blood‐brain barrier permeability to these tracers in experiments that lasted between 5 min and 8 days. The blood‐brain barrier permeability (Kin) to 59Fe was 89 ± 10−5 ml/min/g compared to the value of 7 ± 10−5 ml/min/g for 125I‐transferrin, which is similar to that of albumin, a plasma marker. The autoradiographic distribution of these tracers in brain was also studied to determine any regional variation in brain uptake after the tracers had been administered either system‐ically or applied in vitro. No regional uptake was seen for 125I‐transferrin even after 24 h of circulation. In contrast, 59Fe showed selective regional uptake by the choroid plexus and extra‐blood‐brain barrier structures 4 h after administration. After 24 h of circulation, 59Fe distribution in brain was similar to the transferrin receptor distribution, as determined in vitro, but was unlike the distribution of non‐haem iron determined histochemically. The data suggest that brain iron uptake does not involve any significant transcytotic pathway of transferrin‐bound iron into brain. It is proposed that the uptake of iron into brain involves the entry of iron‐loaded transferrin to the cerebral capillaries, deposition of iron within the endothelial cells, followed by recycling of apotransferrin to the circulation. The deposited iron is then delivered to brain‐derived transferrin for extracellular transport within the brain, and subsequently taken up via transferrin receptors on neurones and glia for usage or storage.

Mitochondrial DNA haplogroups and susceptibility to AD and dementia with Lewy bodies

Article abstract The authors analyzed the relationship between nuclear genetic risk factors (apolipoprotein E genotype) and mitochondrial DNA (mtDNA) sequence variants in pathologically proved cases of AD (n = 185), dementia with Lewy bodies (DLB; n = 84), and control subjects (n = 179). Specific European mtDNA haplogroups and the A4336G mutation were not associated with an increased risk of AD. mtDNA haplogroup H was overrepresented in the DLB patients when compared with control subjects. Additional studies are needed to clarify the significance of the association.

Does the mitochondrial genome play a role in the etiology of Alzheimer’s disease?

We report here the analyses of complete mtDNA coding region sequences from more than 270 Alzheimer’s disease (AD) patients and normal controls to determine if inherited mtDNA mutations contribute to the etiology of AD. The AD patients and normal individuals were carefully screened and drawn from two populations of European descent in an effort to avoid spurious effects due to local population anomalies. Overall, there were no significant haplogroup associations in the combined AD and normal control sequence sets. Reduced median network analysis revealed that the AD mtDNA sequences contained a higher number of substitutions in tRNA genes, and that there was an elevated frequency of replacement substitutions in the complex I genes of the control sequences. Analysis of the replacement substitutions indicated that those arising in the AD mtDNAs were no more deleterious, on average, than those in the control mtDNAs. The only evidence for the synergistic action of mutations was the presence of both a rare non-conservative replacement substitution and a tRNA mutation in 2 AD mtDNAs, from a total of 145, whereas such a combination of mutations was not observed in the control sequences. Overall, the results reported here indicate that pathogenic inherited mtDNA mutations do not constitute a major etiological factor in sporadic AD. At most, a small proportion of AD patients carry a pathogenic mtDNA mutation and a small proportion of cognitively normal aged individuals carry a mtDNA mutation that reduces the risk of AD.

Regulation of attention and response to therapy in dementia by butyrylcholinesterase.

OBJECTIVESnTo determine the response of patients with different butyrylcholinesterase genotypes to therapy, and the influence of butyrylcholinesterase on cognition. Acetylcholine plays a key role in attention and memory and reduced cortical acetylcholine is associated with the severity of dementia. Inhibitors of the enzyme acetylcholinesterase are an effective dementia treatment, though the role of the related enzyme butyrylcholinesterase is less well understood.nnnMETHODSnWe examined the response of a cohort of dementia patients enrolled in a trial of a cholinesterase inhibitor who had been genotyped at the butyrylcholinesterase locus. Additionally a prospectively assessed cohort of dementia patients was genotyped and rate of cognitive decline examined, along with baseline cognitive performance in a group of elderly non-demented individuals. We identified that the presence of reduced-activity butyrylcholinesterase variants correlates with preserved attentional performance and reduced rate of cognitive decline. During cholinesterase inhibitor therapy, patients with normal butyrylcholinesterase show improved attention, though patients carrying reduced-activity enzyme do not, possibly due to being at ceiling performance. Butyrylcholinesterase did not however affect attentional performance in non-demented individuals with mild cognitive impairment.nnnCONCLUSIONSnThese findings indicate that the butyrylcholinesterase enzyme is a major regulator of attention especially in cholinergic deficiency states through its ability to hydrolyse acetylcholine. Pharmacologic manipulation of this enzyme may be a viable strategy in dementia treatment and, with butyrylcholinesterase genotyping, may provide pharmacogenomic treatment of dementia.

Quantification and Characterisation of Fluctuating Cognition in Dementia with Lewy Bodies and Alzheimer’s Disease

Fluctuating cognition (FC) is a common and important symptom in dementia, particularly dementia with Lewy bodies (DLB), although it has not been empirically quantified or characterised. Forty subjects (15 DLB, 15 AD, 10 elderly controls) were evaluated using a clinical FC severity scale, as well as receiving measures of variability in attentional performance and slow EEG rhythms across 90 s, 1 h and 1 week. DLB patients had significantly more severe FC and more severe variability in attentional and slow electrocortical measures than either AD patients or normal controls in all time frames. Attentional and EEG variability also correlated significantly with independent clinical ratings of FC. Clinical quantification and measures of attention and EEG variability can therefore make an important and standardised contribution to the assessment of FC in dementia, facilitating future treatment studies with important implications for the potential causative mechanisms and differential diagnosis.

N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) affects locomotor activity without producing a nigrostriatal lesion in the rat

Drug addicts abusing heroin substitutes contaminated with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and perhaps those who work with this substance, may develop symptoms similar to those seen in Parkinsons disease [7, 12, 13]. We describe the results of a study in which rats were given daily injections of MPTP for two weeks. A progressive suppression of activity was seen, but the subjects rapidly recovered when treatment ceased. The animals were then injected with D-amphetamine or apomorphine; the former drug enhanced activity, to levels seen in control (non-MPTP treated) subjects. Apomorphine had no effect, either on control or MPTP-treated subjects. The effects of acute (0, 2.5, 5.0 and 10.0 mg per rat) administration of MPTP were also studied. The two lower doses significantly decreased activity, but the highest dose did not. Histological examination showed that 2 weeks treatment with MPTP did not produce neuronal degeneration in the pars compacta of the substantia nigra (SN). In these animals, there were no changes in levels of dopamine, 5-hydroxytryptamine, or their metabolites in either the SN or the caudate nucleus. MPTP had no effect on the levels of neurotensin, somatostatin and substance P in several brain areas. It is concluded that MPTP has reliable effects on locomotor activity in rats without producing measurable histological or neurochemical changes in the nigrostriatal dopaminergic system.