Neuropathology of cognitively normal elderly

Despite general agreement about the boundaries of Alzheimer disease (AD), establishing a maximum limit for Alzheimer-type pathology in cognitively intact individuals might aid in defining more precisely the point at which Alzheimer pathology becomes clinically relevant. In this study, we examined the neuropathological changes in the brains of 39 longitudinally followed. cognitively normal elderly individuals (24 women, 15 men; age range 74-95, median 85 years). Neuropathological changes of the Alzheimer type were quantified by determining neurofibrillary tangle (NFT) staging by the method of Braak and Braak and by quantification of the abundance of diffuse, cored, and neuritic plaque burden using the scheme developed by the Consortium to Establish a Registry for Alzheimer Disease (CERAD). Vascular, Lewy body, and argyrophilic grain pathology were also assessed. We found 34 subjects (87%) with a Braak stage 相似文献   

Clinical neuropathology practice news 3-2012: the "ABC" in AD-revised and updated guideline for the neuropathologic assessment of Alzheimer's disease

The two major approaches for the neuropathological assessment of Alzheimer's disease (AD) related pathology have been based on the assessment of neuritic plaques (CERAD) and neurofibrillary pathology (Braak and Braak). In 1997 these two approaches were integrated in the criteria and recommendations of the National Institute on Aging and the Reagan Institute Working group. Recently a new guideline has been published by the National Institute on Aging-Alzheimer's Association. This new guideline recognizes the existence of a pre-clinical stage of AD as part of continuous neuropathological changes in the background of the disease process, and it fosters the assessment of amyloid-beta phases in addition to neurofibrillary degeneration and neuritic plaques following an "ABC" score. Further, it suggests protocols for the neuropathological assessment of additional/concomitant neurodegenerative and vascular pathologies. Altogether, the new guideline responds to the need for an update of the existing "1997 criteria" for AD. Continued studies will have to assess the added value of the new approach and the influence of interlaboratory and/or methodological differences on the implementation of these new recommendations.     

Impact of coexistent Alzheimer pathology on the natural history of Parkinson's disease

Summary. Objective: To assess the impact of coexisting Alzheimer (AD) pathology on the natural history of Parkinson's disease (PD). Background: AD changes are frequently present in brains of demented PD patients. Assessing the relative contribution of AD pathology to the natural history of PD is difficult and the impact of both AD and cortical Lewy body (LB) pathologies on cognitive dysfunction is still under discussion. From clinical experience, dementia in PD patients, mainly related to AD pathology, is associated with a poor outcome, but the impact of AD pathology on the natural history of PD has not been studied systematically. Material and methods: In 200 consecutive autopsy cases of PD (sex (m/f) ratio 1 : 1.1), age at death 58–98 (mean 77.0 ± 9.5) years, from a specialized Austrian brain bank, retrospectively assessed major initial clinical symptoms (tremor, akinesia), moderate/severe dementia, and duration of illness were correlated with associated AD pathologies using CERAD, Braak and NIA-Reagan criteria. Mann-Whitney U-test, Cox-regression were used for statistical analysis. Results: While gender had no influence on the clinical motor symptoms and outcome, tremor dominant type had a significantly better outcome than akinetic forms (p = 0.022), even after adjustment with age at onset and associated AD pathology (CERAD and Braak criteria). Patients with late onset showed significantly shorter duration of illness irrespective of dementia. Moderate to severe dementia, reported in 33% of the sample, was significantly correlated with AD pathology (all 3 criteria) that showed significantly negative correlation with survival: between CERAD 0-A vs. B and C there was a significant difference of odd ratios (p < 0.001), as was between Braak stages 0–2, 3–4.5, and 5, but not between Braak stages 3–4 and 5. Conclusions: The present data confirm previous studies suggesting better outcome of tremor-dominant than akinetic-rigid type of PD, significantly worse outcome in PD with late onset and dementia that is significantly correlated with coexistent neuritic Alzheimer pathology, particularly when using the CERAD and NIA-R criteria for the diagnosis of AD. Further studies are needed to elucidate the relative impact of cortical LB and AD pathologies on the natural history of PD. Received February 9, 2001; accepted September 10, 2001     

Cytokine gene expression as a function of the clinical progression of Alzheimer disease dementia

BACKGROUND: Inflammatory cytokines have been linked to Alzheimer disease (AD) neurodegeneration, but little is known about the temporal control of their expression in relationship to clinical measurements of AD dementia progression. DESIGN AND MAIN OUTCOME MEASURES: We measured inflammatory cytokine messenger RNA (mRNA) expression in postmortem brain specimens of elderly subjects at different clinical stages of dementia and neuropathological dysfunction. SETTING AND PATIENTS: Postmortem study of nursing home patients. RESULTS: In brains of cognitively normal control subjects, higher interleukin 6 (IL-6) and transforming growth factor beta1 (TGF-beta1) mRNA expression was observed in the entorhinal cortex and superior temporal gyrus compared with the occipital cortex. Compared with age-matched controls, subjects with severe/terminal dementia, but not subjects at earlier disease stages, had higher IL-6 and TGF-beta1 mRNA expression in the entorhinal cortex (P<.01) and superior temporal gyrus (P<.01). When stratified by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropathological criteria, IL-6 mRNA expression in both the entorhinal cortex (P<.05) and superior temporal gyrus (P<.01) correlated with the level of neurofibrillary tangles but not neuritic plaques. However, in the entorhinal cortex, TGF-beta1 mRNA did not correlate with the level of either neurofibrillary tangles or neuritic plaques. Interestingly, in the superior temporal gyrus, TGF-beta1 mRNA expression negatively correlated with neurofibrillary tangles (P<.01) and showed no relationship to the pathological features of neuritic plaques. CONCLUSIONS: The data are consistent with the hypothesis that cytokine expression may differentially contribute to the vulnerability of independent cortical regions during the clinical progression of AD and suggest that an inflammatory cytokine response to the pathological effects of AD does not occur until the late stages of the disease. These findings have implications for the design of anti-inflammatory treatment strategies. Arch Neurol. 2000;57:1153-1160     

Cortical inflammation in Alzheimer disease but not dementia with Lewy bodies

BACKGROUND: There have been no previous studies on the role of inflammation in the brain for the second most common dementing disorder, dementia with Lewy bodies. OBJECTIVE: To investigate the degree of cortical inflammation in dementia with Lewy bodies (DLB) compared with Alzheimer disease (AD) and control brains. DESIGN AND MAIN OUTCOME MEASURES: Post-mortem tissue collection from a brain donor program using standardized diagnostic criteria. Brains collected from January 1, 1993, through December 31, 1996, were screened and selected only for the presence or absence of tau neuritic plaques. Results of immunohistochemistry for HLA-DR were quantified using area fraction counts. Counts were performed by investigators who were unaware of the diagnosis. Results were compared across groups using analysis of variance and posthoc testing. SETTING: A medical research institute in Sydney, Australia. PATIENTS: Eight brains with DLB and without the tau neuritic plaques typical of AD, 10 brains with AD and no Lewy bodies, and 11 nondemented controls without significant neuropathological features were selected from a consecutive sample. RESULTS: Compared with AD, DLB demonstrated significantly less inflammation in the form of HLA-DR-reactive microglia in all cortical regions (P<.001, posthoc). The level of inflammation in DLB was comparable to that seen in controls (P=.54, post hoc). CONCLUSIONS: Inflammation appears related to the tau neuritic plaques of AD. Despite similar clinical presentations, therapeutic anti-inflammatory strategies are not likely to be effective for pure DLB. Arch Neurol. 2000.     

Olfactory tau pathology in Alzheimer disease and mild cognitive impairment

OBJECTIVE: To examine the occurrence of tau pathology in the olfactory system in aged subjects and its relation to the severity of Alzheimer disease (AD) pathology. MATERIAL AND METHODS: 273 autopsy cases (167 female, 106 male, aged 61-102, mean 83.2+/-4.5 SD years) underwent a standard neuropathological assessment with immuno-histochemical study of tau and Abeta amyloid in the olfactory bulb and nerve, and diagnosis of AD using established consensus criteria including Braak staging of neuritic AD pathology. RESULTS: All cases of definite AD (Braak stages 5 and 6, n = 96) showed large numbers of neuropil threads and neurofibrillary tangles, with amyloid deposits in 50%, and neuritic plaques only in two cases. Braak stage 4 (n = 73) was associated with tau pathology in the olfactory system in 90.4 and amyloid deposits in 9%, Braak stage 3 (n = 56) with mainly mild to moderate olfactory tau lesions in 44.6 and Abeta deposits in 9%. Braak stage 2 (n = 22) showed olfactory tau pathology in 36.4% without amyloid deposits, whereas Braak stages 0 and 1 (n = 25) were all negative. Olfactory tau pathology showed highly significant correlation with neuritic Braak staging in the brain, while both scores showed significant but low correlation with age. CONCLUSIONS: These data confirm previous studies demonstrating considerable tau pathology in the olfactory system in all definite AD cases, in more than 2/3 of limbic AD and in more than 1/3 of elderly individuals with or without mild cognitive impairment associated with Braak stage 2. Clinical dementia correlated with both Braak and olfactory tau scores, indicating that both are associated with a high risk of cognitive decline.     

Alzheimer neuropathologic alterations in aged cognitively normal subjects

The histopathologic changes distinguishing early Alzheimer disease (AD) from normal or pathologic aging are not clearly defined. This report describes the autopsy findings of 59 elderly, well-educated, volunteers. They were examined longitudinally with mental status testing, some for up to 8 years, as part of our normal aging study. This study reveals that (1) the brains of many subjects who did not show cognitive impairment on neuropsychologic testing contain abundant senile plaques (SP) and/or neurofibrillary tangles (NFT); (2) 29 subjects met Khachaturian criteria for AD, 15 met CERAD and 7 met National Institute on Aging-Reagan Institute guidelines; (3) Braak and Braak staging method included 9 in stage IV subjects, 4 in stage V, and 1 in stage VI; (4) there was a progression of NFT from entorhinal cortex to hippocampus and amygdala as a function of age; (5) 2 subjects met criteria for a diagnosis of dementia with Lewy bodies but were not demented; (6) cerebral amyloid angiopathy was present in leptomeningeal vessels in 75% of subjects and in parenchymal vessels in 62% of subjects; (7) only 10 of 59 subjects (17%) had no or few degenerative brain changes. Our study demonstrates that the brains of a large percentage of cognitively normal, relatively well-educated individuals contain numerous degenerative changes and only a small percentage are relatively free of these changes.     

Does striatal pathology distinguish Parkinson disease with dementia and dementia with Lewy bodies?

The morphological differentiation of Parkinson disease with dementia (PDD) and dementia with Lewy bodies (DLB) is a matter of discussion. The objective of this study was to investigate the regional distribution of beta-amyloid (Abeta) plaques, alpha-synuclein (AS), and pathology in both disorders. The basal ganglia from 17 age-matched patients of PDD and DLB each were immunohistochemically examined with variable degrees of associated Alzheimer pathology using antibodies to Abeta, AS, and tau. DLB brains showed a significantly higher burden of (diffuse) amyloid plaques in the putamen and caudate nucleus and slightly more severe tau pathology than PDD brains despite similar neuritic Braak stages. Phases of Abeta development in DLB brains often, but inconsistently, correlated with both neuritic Braak stages and severity of striatal Abeta load, while these correlations were almost never seen in PDD cases with Alzheimer lesions. They also revealed a higher burden of AS-lesions (both Lewy neurites and Lewy bodies) than PDD cases that commonly had a paucity of all three types of lesion. The globus pallidus was virtually spared in both phenotypes. Differences in AS and Abeta pathologies and much less of tau lesions in the striatum support a morphologic distinction between PDD and DLB, which may be of pathophysiologic importance, but the causes of these differences are unclear.     

Clinicopathologic correlates in temporal cortex in dementia with Lewy bodies

OBJECTIVE: To address the relationship between dementia and neuropathologic findings in dementia with Lewy bodies (DLB) in comparison with AD. METHODS: We evaluated the clinical presentation of autopsy-confirmed DLB in comparison with AD according to new Consortium on DLB criteria and compared the two conditions using quantitative neuropathologic techniques. This clinicopathologic series included 81 individuals with AD, 20 with DLB (7 "pure" DLB and 13 "DLB/AD"), and 33 controls. We counted number of LB, neurons, senile plaques (SP), and neurofibrillary tangles (NFT) in a high order association cortex, the superior temporal sulcus (STS), using stereologic counting techniques. RESULTS: The sensitivity and specificity of Consortium on DLB clinical criteria in this series for dementia, hallucinations, and parkinsonism are 53% and 83%, respectively, at the patient's initial visit and 90% and 68%, respectively, if data from all clinic visits are considered. In pathologically confirmed DLB brains, LB formation in an association cortical area does not significantly correlate with duration of illness, neuronal loss, or concomitant AD-type pathology. Unlike AD, there is no significant neuronal loss in the STS of DLB brains unless there is concomitant AD pathology (neuritic SP and NFT). CONCLUSIONS: The evaluation of new Consortium on DLB criteria in this series highlights their utility and applicability in clinicopathologic studies but suggests that sensitivity and specificity, especially at the time of the first clinical evaluation, are modest. The lack of a relationship of LB formation to the amount of Alzheimer-type changes in this series suggests that DLB is a distinct pathology rather than a variant of AD.     

"Preclinical" AD revisited: neuropathology of cognitively normal older adults

OBJECTIVE: To classify neuropathologic alterations in the brains of nondemented older adults using current sets of criteria for AD. BACKGROUND: AD neuropathologic alterations are found in the brains of some nondemented elderly subjects and suggest the possibility of presymptomatic AD. Three sets of guidelines have been developed to classify AD using senile plaques, neuritic plaques, and neurofibrillary tangles (NFT). METHODS: Neuropathologic changes in 59 older adults followed longitudinally with a standard battery of mental status measures were investigated using Khachaturian, Consortium to Establish a Registry for Alzheimer's Disease (CERAD), and National Institute on Aging-Reagan Institute (NIA-RI) guidelines. AD neuropathologic markers were evaluated in neocortical and allocortical regions. Cases were categorized as neuropathologically "normal" or "AD-like" and compared for possible mental status differences. RESULTS: Between 11 and 49% of cases met one or more of the three classifications of AD. With adjustments for multiple comparisons, only NFT in hippocampal CA1 region were associated with autopsy age, suggesting that this may represent a pathologic process associated with normal brain aging. Using the NIA-RI guidelines, subjects in the AD-like group performed less well on the immediate paragraph recall and word-list delayed recall than their counterparts who did not meet these guidelines. CONCLUSIONS: These data indicate that the prevalence of "preclinical" AD in our population is relatively low based on the NIA-RI classification. Although many subjects had AD-like changes based on CERAD and Khachaturian guidelines, they exhibited no differences in mental performance, suggesting that the aging brain may be able to withstand such structural changes without meaningful impact on mental functioning.     

Increased neurofibrillary tangles in the brains of older pedestrians killed in traffic accidents

BACKGROUND/AIMS: Older people are over-represented in pedestrian fatalities, and it has been suggested that the presence of cognitive impairment or dementia in these individuals may contribute to their accidents. Using neuropathological methods, we aimed to compare the prevalence of dementia pathology in fatally injured older pedestrians with similarly aged ambulatory subjects who died from other causes. METHODS: The brains of 52 pedestrians (65-93 years) and 52 controls (65-92 years) were assessed for neurofibrillary tangles (NFT), neuritic plaques, Lewy bodies and vascular lesions using established neuropathological criteria. RESULTS: The examination for Alzheimer's disease (AD) pathology showed that 43% of the pedestrians had NFT scores of III-VI using Braak and Braak staging, compared with 23% of the controls (p < 0.05, Fisher's exact test), indicating incipient, possible or probable AD. There were no differences in the prevalence of pathology for vascular dementia or dementia with Lewy bodies. CONCLUSION: These results suggest that cognitive decline associated with AD, even in the earliest stages of the disease, may be a factor in fatal traffic accidents for older pedestrians. Special measures for pedestrian safety are necessary in areas with high densities of older citizens and especially for those diagnosed as having a mild cognitive impairment or AD.     

AD lesions and infarcts in demented and non-demented Japanese-American men

Neocortical neuritic plaques and neurofibrillary tangles are hallmark neuropathological lesions of dementia. Concomitant cerebrovascular lesions increase dementia severity in patients meeting neuropathological criteria for Alzheimer's disease and contribute to cognitive impairment in persons with mild entorhinal Alzheimer lesions. This study investigates whether individuals with sparse neocortical neuritic plaques experience increased odds of crossing the threshold to clinical dementia when they have coexistent cerebrovascular lesions. Dementia examinations were given to 3,734 men during the 1991-1993 Honolulu-Asia Aging Study examination and to 2,603 men during the 1994-1996 examination. Lesion quantification was done without clinical data. Among 333 autopsied men, 120 had dementia, 115 had marginal results, and 98 had normal cognition. In men with neurofibrillary tangles, dementia frequency increased with increasing neuritic plaque density, and increased further in the presence of cerebrovascular lesions. The association was strongest in men with sparse neuritic plaques (1-3/mm(2)) where dementia frequency more than doubled with coexistent cerebrovascular lesions (45 vs 20%). Among all dementia cases, 24% were linked to cerebrovascular lesions. Findings suggest cerebrovascular lesions are associated with a marked excess of dementia in cases with low neuritic plaque frequency. Prevention of cerebrovascular lesions may be critically important in preserving late-life cognitive function.     

Pathologic and nicotinic receptor binding differences between mild cognitive impairment, Alzheimer disease, and normal aging

BACKGROUND: Neurochemical and pathologic studies show that mild cognitive impairment (MCI) is frequently a transitional state between normal aging and Alzheimer disease (AD). Neuropathologic sample sizes have been limited because relatively few individuals with MCI die before dementia develops. Decreased neocortical nicotinic receptor binding is characteristic of AD but has not been investigated in subjects with MCI. OBJECTIVE: To assess nicotinic receptor binding and pathologic differences in control subjects with no dementia (ND) and in subjects with clinically and pathologically described MCI or Alzheimer disease. DESIGN: This was a clinicopathologic analysis. Subjects with ND had no demonstrable cognitive or functional impairment. Subjects with MCI met Petersen clinical criteria for single- or multiple-domain amnestic MCI and died before the disorder progressed to AD. Subjects with AD met National Institute for Neurological Diseases and Stroke/Alzheimer's Disease and Related Disorders Association clinical criteria for AD. All subjects underwent a complete diagnostic and semiquantitative neuropathologic examination. Data were examined after both clinical and histopathologic classification of subjects. SETTING: Sun Health Research Institute Brain Donation Program, and Arizona Alzheimer Disease Center. PARTICIPANTS: Twenty-one control subjects with ND, 8 subjects with MCI, and 70 subjects with AD, prospectively followed up to autopsy. MAIN OUTCOME MEASURES: Nicotinic acetylcholine receptor binding value, total tangle density, total plaque density, and Braak stage. RESULTS: At the last examination before death, subjects with AD were significantly younger, less educated, and more cognitively and globally impaired compared with subjects with ND. When categorized by clinical diagnosis, MCI was always intermediate between ND and AD. On the whole, MCI was pathologically intermediate between ND and AD for senile plaque density, neurofibrillary tangle density, and Braak stage, but some subjects with MCI lacked neuritic plaques entirely. Binding for nicotinic acetylcholine receptors did not differ between the ND and MCI groups, but it was significantly less in the AD group. CONCLUSIONS: Most MCI may be considered a transitional state between ND and AD clinically and neuropathologically, but in some MCI cases there is lack of neuritic plaques, and, therefore, it cannot be considered early AD. Nicotinic receptor binding seems to be lost during the transition from MCI to AD.     

Cognitive burden and excess Lewy-body pathology in the Lewy-body variant of Alzheimer disease.

OBJECTIVES: Authors compared the degrees of cognitive deficit among individuals with Alzheimer disease (AD), the Lewy-body variant of AD (LBV), and "pure" dementia with Lewy bodies (DLB); and compared cortical Lewy body (LB) counts in LBV versus DLB and neuritic plaque and neurofibrillary tangle severity in LBV versus AD. METHODS: Authors examined brain specimens from consecutive autopsies of elderly nursing home subjects. Numbers and densities of plaques, Lewy bodies, and tangle severity were determined in multiple cortical regions, and demographic and clinical variables were compared among the three groups. RESULTS: The three groups did not differ in demographic or clinical variables. The LBV group was significantly more impaired than the other groups. Cortical LB counts were significantly higher in LBV than in DLB. There was no evidence of increased plaque or tangle severity in LBV than in AD. CONCLUSION: The co-occurrence of AD and LB pathology is associated with higher numbers of LBs and more severe dementia than when classical AD or LB lesions occur alone.     

Prevalence and impact of vascular and Alzheimer pathologies in Lewy body disease

Whereas the prevalence and impact of vascular pathology in Alzheimer diease (AD) are well established, the role of vascular and Alzheimer pathologies in the progression of neurodegeneration and cognitive impairment in Parkinson disease (PD) is under discussion. A retrospective clinico-pathologic study of 100 patients with autopsy proven PD (including 44 cases with dementia/PDD) and 20 cases of dementia with Lewy bodies (DLB) confirmed essential clinical (duration of illness, Mini-Mental State Examination/MMSE, age at death) and morphologic differences between these groups; Lewy body Braak scores and Alzheimer pathologies (neuritic Braak stage, cortical Aβ plaque load, and generalized cerebral amyloid angiopathy or CAA) were significantly higher/more severe in DLB and PDD than in PD without dementia. Duration of illness showed no association to any of the examined pathologic parameters, while there was a moderate association between LB scores and neuritic Braak stages, the latter significantly increasing with age. Significant association between cerebrovascular lesions and neuritic Braak stage was seen in PDD but not in PD subjects without dementia. These data suggest an influence of Alzheimer-related lesions on the progression of the neurodegenerative process and, in particular, on cognitive decline in both PDD and DLB. On the other hand, both these factors in PD and DLB appear to be largely independent from coexistent vascular pathology, except in cases with severe cerebrovascular lesions or those related to neuritic AD pathology. Assessment of ApoE genotype in a small number of cases showed no significant differences in the severity of Aβ plaque load and CAA except for much lower intensities in non-demented ε3/3 patients. Despite increasing evidence suggesting synergistic reactions between α-synuclein (αSyn), tau and Aβ-peptides, the major protein markers of both AD and Lewy body diseases, and of both vascular pathology and AD, the molecular background and pathophysiological impact of these pathologies on the progression of neurodegeneration and development of cognitive decline in PD await further elucidation. Dedicated to the memory of Professor Dr. Franz Seitelberger, a pioneer of modern neuropathology and neurosciences.     

Validation of the neuropathologic criteria of the third consortium for dementia with Lewy bodies for prospectively diagnosed cases

There is limited information on the validity of the pathologic criteria of the Third Consortium on Dementia with Lewy bodies (CDLB), and none are based on prospectively diagnosed cases. In this study, the core clinical features of dementia with Lewy bodies (DLB) and the suggestive clinical feature of rapid eye movement sleep behavior disorder were assessed using a battery of standardized clinical instruments in 76 patients with the clinical diagnosis of either DLB or Alzheimer disease. At autopsy, 29 patients had high-likelihood, 17 had intermediate-likelihood, and 6 had low-likelihood DLB pathology. The frequency of core clinical features and the accuracy of the clinical diagnosis of probable DLB were significantly greater in high-likelihood than in low-likelihood cases. This is consistent with the concept that the DLB clinical syndrome is directly related to Lewy body pathology and inversely related to Alzheimer pathology. Thus, the Third Consortium on DLB neuropathologic criteria scheme performed reasonably well and are useful for estimating the likelihood of the premortem DLB syndrome based on postmortem findings. In view of differences in the frequency of clinically probable DLB in cases with Braak neurofibrillary tangle stages V (90%) and VI (20%) and diffuse cortical Lewy bodies, a possible modification of the scheme is to consider cases with neurofibrillary tangle stage VI to be low-likelihood DLB.     

Neurofibrillary pathology in Alzheimer disease with Lewy bodies: two subgroups

BACKGROUND: While NFT frequency is reportedly reduced in AD+DLB, we often encounter abundant neocortical NFTs in such cases and decided to investigate this discrepancy. OBJECTIVE: To compare neurofibrillary tangle (NFT) frequency in Alzheimer disease with concomitant dementia with Lewy bodies (AD+DLB) with NFT frequency in "pure" AD. METHODS: Neurofibrillary tangle frequency, as well as regional staging of neurofibrillary degeneration modified from Braak, was scored in 160 autopsy cases of primary dementia (80 AD+DLB cases and 80 pure AD cases). RESULTS: Neurofibrillary tangle and modified Braak scores were lower in AD+DLB, as reported previously. Yet, neocortical NFT scores assumed markedly different patterns in the 2 groups (P = .001). In pure AD, NFT scores of "frequent" were predominant: more cases exhibited frequent than moderate or sparse NFTs. In AD+DLB, the distribution of NFT scores was bimodal: NFTs were either frequent or few to absent. Neocortical NFT scores in the AD+DLB group tended to parallel the severity of other types of tau cytopathology (neuropil threads and tau-positive plaque neurites). CONCLUSIONS: Cases of AD+DLB may be divided into 2 subgroups based on the extent of neocortical neurofibrillary pathology. These findings could have implications for disease pathogenesis and treatment.     

Neuropathological investigation of the hypometabolic regions on positron emission tomography with [18F] fluorodeoxyglucose in patients with dementia with Lewy bodies

We performed a quantitative neuropathological examination of the hypometabolic regions on FDG PET in dementia with Lewy bodies (DLB), Alzheimer's disease (AD) and control cases. When the DLB cases were divided into two groups according to concomitant AD pathology (ADP), neuronal loss in the temporo-parietal association area was milder in the DLB groups than in the AD group, although there were no differences between the two DLB groups. Tau and Aβ immunoreactivities were observed in the AD group and the DLB group with ADP, but were rare in the DLB group without ADP. Tau and Aβ immunoreactivities as well as numbers of neurofibrillary tangles (NFTs) and neuritic plaques (NPs) were more common in the AD group than in the DLB group with ADP. There was no difference in neuronal loss in the occipital area among the three groups. α-Synuclein immunoreactivity was observed in the DLB groups but not in the AD group. There were no differences in α-synuclein immunoreactivity and number of Lewy bodies (LBs) between the two DLB groups. These findings indicate that the neuropathological bases of the hypometabolic regions in the temporo-parietal association and occipital area in DLB may be AD pathology and Lewy pathology, respectively.     

Neuropathological diagnostic criteria for Alzheimer's disease

Neuropathological diagnostic criteria for Alzheimer's disease (AD) are based on tau‐related pathology: NFT or neuritic plaques (NP). The Consortium to Establish a Registry for Alzheimer's disease (CERAD) criterion evaluates the highest density of neocortical NP from 0 (none) to C (abundant). Clinical documentation of dementia and NP stage A in younger cases, B in young old cases and C in older cases fulfils the criterion of AD. The CERAD criterion is most frequently used in clinical outcome studies because of its inclusion of clinical information. Braak and Braak's criterion evaluates the density and distribution of NFT and classifies them into: I/II, entorhinal; III/IV, limbic; and V/VI, neocortical stage. These three stages correspond to normal cognition, cognitive impairment and dementia, respectively. As Braak's criterion is based on morphological evaluation of the brain alone, this criterion is usually adopted in the research setting. The National Institute for Aging and Ronald and Nancy Reagan Institute of the Alzheimer's Association criterion combines these two criteria and categorizes cases into NFT V/VI and NP C, NFT III/IV and NP B, and NFT I/II and NP A, corresponding to high, middle and low probability of AD, respectively. As most AD cases in the aged population are categorized into Braak tangle stage IV and CERAD stage C, the usefulness of this criterion has not yet been determined. The combination of Braak's NFT stage equal to or above IV and Braak's senile plaque Stage C provides, arguably, the highest sensitivity and specificity. In future, the criteria should include in vivo dynamic neuropathological data, including 3D MRI, PET scan and CSF biomarkers, as well as more sensitive and specific immunohistochemical and immunochemical grading of AD.     

Rapid eye movement sleep behavior disorder and subtypes in autopsy-confirmed dementia with Lewy bodies

The purpose of this study was to determine whether dementia with Lewy bodies with and without probable rapid eye movement sleep behavior disorder differ clinically or pathologically. Patients with dementia with Lewy bodies (DLB) with probable rapid eye movement sleep behavior sleep disorder (n = 71) were compared with those without it (n = 19) on demographics, clinical variables (core features of dementia with Lewy bodies, dementia duration, rate of cognitive/motor changes), and pathologic indices (Lewy body distribution, neuritic plaque score, Braak neurofibrillary tangle stage). Individuals with probable rapid eye movement sleep behavior disorder were predominantly male (82% vs 47%) and had a shorter duration of dementia (mean, 8 vs 10 years), earlier onset of parkinsonism (mean, 2 vs 5 years), and earlier onset of visual hallucinations (mean, 3 vs 6 years). These patients also had a lower Braak neurofibrillary tangle stage (stage IV vs stage VI) and lower neuritic plaque scores (18% vs 85% frequency), but no difference in Lewy body distribution. When probable rapid eye movement sleep behavior disorder developed early (at or before dementia onset), the onset of parkinsonism and hallucinations was earlier and Braak neurofibrillary tangle stage was lower compared with those who developed the sleep disorder after dementia onset. Women with autopsy-confirmed DLB without a history of dream enactment behavior during sleep had a later onset of hallucinations and parkinsonism and a higher Braak NFT stage. Probable rapid eye movement sleep behavior disorder is associated with distinct clinical and pathologic characteristics of dementia with Lewy bodies.