The cellular pathology associated with Alzheimer β-amyloid deposits in non-demented aged individuals

In this study, we have compared the cellular pathology associated with β-amyloid (βA) deposits which characterize Alzheimer's disease (AD) in demented patients with pathologically confirmed AD, with that in non-demented aged individuals. Brain sections from two severely demented AD cases, six non-demented individuals with βA deposits, and six age-matched controls devoid of βA deposits were double-immunostained with antibodies against βA, and antibody markers for neurofibrillary tangles (NFT), astrocytes and microglial cells. We found that the severely demented patients displayed numerous plaques of variable morphology, most of which were associated with NFT, hypertrophied astrocytes and reactive microglial cells. In contrast, non-demented patients showed fewer plaques, few or no NFT and less astroglial and microglial reaction. The number of plaques with associated abnormal cellular elements were much lower in non-demented than in demented cases. Furthermore, classical plaques were more likely to be associated with abnormal cellular elements than diffuse plaques, which were most often devoid of any associated cellular change. These findings suggest that: (i) βA plaques in non-demented individuals may represent an early stage of AD; (ii) βA deposition is the first recognizable pathological abnormality of AD; and (iii) NFT, and astro-and microglial proliferation are later features, possibly secondary to the known dystrophic effects of the βA peptide and other fragments of its precursor protein.     

Activated microglial cells and complement factors are unrelated to cortical Lewy bodies

Inflammatory mechanisms have been demonstrated in Alzheimer’s disease (AD) but their presence in other neurodegenerative disorders is not well documented. Complement factors and activated microglia have been reported in the substantia nigra of Parkinson’s disease (PD). In the present study we investigated the cingulate gyrus of 25 autopsied patients with clinically and neuropathologically well-documented PD, with or without dementia, for the presence of (activated) microglial cells and their relation with Lewy body (LB)-bearing neurons. In addition, we studied the presence of complement factors in LBs. Of the 25 patient, 15 were clinically demented, fulfilling criteria for dementia with LBs (DLB); 7 also fulfilled CERAD morphological criteria for probable or definite Alzheimer type of dementia. Microglia clustering was seen around congophilic plaques with or without tau pathology. Microglial cells were not associated with LB-bearing neurons or noncongophilic plaques. The cortex of DLB patients without AD plaques did not show more microglial cells than the cortex of non-demented controls. The number of microglia was the lowest in young control patients who died immediately after trauma. Complement factor C3d was occasionally seen in diffusely ubiquinated neurons but late complement factors were not detected in these neurons. Double staining for complement and α-synuclein was negative, suggesting the absence of complement in LBs. In contrast, AD plaques in the same sections showed complement factors C3c, C3d, C1q and C5–9. In conclusion, we have found no evidence that inflammatory mechanism are involved in LB formation in cerebral cortex. Received: 17 June 1999 / Revised: 20 December 1999 / Accepted: 15 February 2000     

Can Alzheimer's type pathology influence the clinical phenotype of Parkinson's disease?

OBJECTIVES: Patients with clinical and pathological diagnosis of Parkinson's disease (PD) may, at death, also be found to have the pathological changes of Alzheimer's disease (AD). With this study we aim to determine the influence of AD pathology on the clinical phenotype of PD. METHODS: We studied 64 patients who donated their brains to the University of Miami Brain Endowment Bank(TM) and fulfilled the clinical and pathological criteria for PD. For the evaluation of AD pathology we used the CERAD criteria. Dementia was diagnosed, in life, also using standard criteria. Case histories were abstracted and reviewed by one investigator (SP) who then made comparisons between patients. RESULTS: Patients with AD pathology (PD-AD) were older both at the time of diagnosis and death. The presence of AD pathology did not seem to influence disease duration in our cohort of PD patients. As expected there was a clear relation between AD pathology and dementia but not all PD-AD patients were demented. Psychosis and depression were also found to be more prevalent in the PD-AD patients. In the comparison between demented and non-demented PD-AD patients dementia was more likely to appear in patients with PD and definite criteria for AD. CONCLUSION: Apart from dementia AD pathology seems to be associated with a number of other clinical characteristics of PD.     

Somatostatin immunoreactivity is reduced in Parkinson''s disease dementia with Alzheimer''s changes

Somatostatin-like immunoreactivity (SLI) was measured in postmortem brain tissue from 15 control patients, 7 non-demented parkinsonian patients and 7 demented parkinsonian patients who had Alzheimer-type cortical pathology. The non-demented parkinsonian patients had normal concentrations of SLI in the cerebral cortex, hippocampus, amygdala, putamen, caudate or globus pallidus. Demented parkinsonian patients with Alzheimer-type cortical pathology had significantly reduced (approximately 40%) levels of SLI in both the frontal (Brodmann area 6) and temporal (Brodmann area 21) cortex. These findings suggest that parkinsonian dementia with Alzheimer-type pathology like Alzheimer's disease itself, is associated with reduced concentrations of cortical somatostatin.     

Alzheimer-type lesions in Huntington's disease

Summary. Cognitive changes in Huntington's disease (HD) are variously related to diffuse cortical atrophy with neuron loss and dystrophic neurites leading to disruption of striato-frontal or limbic circuitries, while recent studies suggest an increasing prevalence of Alzheimer-like lesions in HD brain. A comparative morphological study of 27 autopsy cases of HD (age 34 to 75 years) and of 26 age- and sex-matched non-demented controls was performed. Absence of Alzheimer-type lesions was seen in 33% of HD brains (mean age 49 years); 48% showed early non-neuritic tau pathology in limbic areas (Braak stages I and II) without amyloid deposits occurring as early as age 34 years (mean age 54 years), while Braak stages II and Ill with amyloid plaques were present in 19%, the youngest such HD patient being 42 years (mean age 54 years). In controls, similar tau pathology changes with later onset (age 45 years) and occurrence of amyloid plaques in 26% – all aged over 60 years – were observed. No probable or definite cases of Alzheimer disease (AD) according to CERAD criteria were seen in both cohorts. Those data confirm previous studies on the rare coexistence of HD and AD, although initial stages of Alzheimer-like lesions develop rather early in HD patients, but obviously show less rapid progress even in advanced age. The reasons for the early onset but mild progress of Alzheimer-like lesions in HD and their contribution to cognitive decline await further elucidation. Received January 13, 1998; accepted February 17, 1998     

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   

Histopathological criteria for progressive dementia disorders: clinical-pathological correlation and classification by multivariate data analysis

Summary Autopsied brains from 55 patients with dementia between 59–95 years of age (mean age 77.9±8.1 years) and 19 non-demented individuals between 46–91 years of age (mean age 74.3±10.5 years) were examined to establish histopathological criteria for normal ageing, primary degenerative [Alzheimer's disease (AD)/senile dementia of Alzheimer type (SDAT)] and vascular (multi-infarct) dementia (MID) disorders. Senile/neuritic plaques, neurofibrillary tangles, microscopic infarcts and perivascular serum protein deposits were quantified in the frontal lobe (Brodmann area 10) and in the hippocampus. The demented patients were classified according to the DSM-III criteria into AD/SDAT and MID. Operationally defined histopathological criteria for dementias, based on the degree/amount of the histopathological changes seen in aged non-demented patients, were postulated. The demented patients were clearly separable into three histopathological types, namely AD/SDAT, MID and AD-MID, the dementia type where both the degenerative and the vascular changes are coexistent in greater extent than are seen in the non-demented individuals. Using general clinical, gross neuroanatomical and histopathological data three separate dementia classes, namely AD/SDAT, MID and AD-MID, were visualized in two-dimensional space by multivariate data analysis. This analysis revealed that the pathology in the AD-MID patients was not merely a linear combination of the pathology in AD/SDAT and MID, indicating that AD-MID might represent a dementia type of its own. The clinical diagnosis for AD/SDAT and MID was certain in only half of the AD/SDAT and one third of the MID cases when evaluated histopathologically and by multivariate data analysis. AD/SDAT, MID and AD-MID were histopathologically diagnosed in 49%, 24% and 27%, respectively, of all the dementia cases studied. Opposite correlation between the number of tangles, plaques and the patient age in non-demented and AD/SDAT cases were observed, indicating that the pathogenesis of tangles and plaques in the two groups of patients might be different and that AD/SDAT might not be a form of an exaggerated ageing process.     

Cortical Lewy bodies and Alzheimer-type changes in patients with Parkinson’s disease

We investigated the role of cortical Lewy bodies (LB) and Alzheimer-type changes in cognitive impairment in patients with idiopathic Parkinson’s disease (PD). We evaluated 44 cases for the extent of neuropathological lesions with a CERAD neuropathological assessment battery and the stage of dementia using Reisberg’s global deterioration scale (GDS). Substantia nigra, amygdala, hippocampus and cerebral cortex were examined for LB and Alzheimer-type changes. For detection of LB, the cortical areas were stained with polyclonal antibodies against ubiquitin and tau. We found at least one cortical LB in 93% of cases. Furthermore, 43% of the cases had histological findings of definite Alzheimer’s disease (AD). The association between cognitive impairment and the number of cortical LB and Alzheimer-type changes in the amygdala, hippocampus and six selected gyri from cerebral cortex were analyzed using stepwise linear regression. In this analysis the total number of cortical LB, and the amount of neurofibrillary tangles in the temporal cortex remained statistically significant. When the cases with neuropathological changes consistent with a diagnosis of AD were excluded, the correlation between the total number of cortical LB and cognitive impairment was more obvious. A stepwise linear regression analysis in these cases found the total number of cortical LB to be the statistically significant predictor of cognitive impairment. This study revealed that LB densities in the cortex, especially in the temporal neocortex, correlated significantly with the cognitive impairment in PD independent of or in addition to Alzheimer-type pathology. Received: 18 August 1997 / Revised, accepted: 2 December 1997     

Different CSF β-amyloid processing in Alzheimer’s and Creutzfeldt–Jakob disease

Decreased levels of β-amyloid (Aβ) 1-42 in cerebrospinal fluid (CSF) are characteristic for Alzheimer’s disease (AD) and are also evident in Creutzfeldt–Jakob disease (CJD). Aβ plaques are thought to be responsible for this decrease in AD patients, whereas such Aβ plaques are rarely seen in CJD. To investigate the Aβ pattern in brain and CSF of neuropathologically confirmed CJD and AD patients we used an electrophoretic method to investigate Aβ peptide fractions which are not accessible to ELISA and immunohistochemistry. We analyzed Aβ peptides in the CSF of autopsy-confirmed CJD and AD patients and the corresponding brain homogenates using a quantitative urea-based Aβ electrophoresis immunoblot (Aβ-SDS-PAGE/immunoblot).The CSF Aβ1-42 decrease correlated with the brain Aβ load in AD, but not in CJD. There was no difference in the soluble fractions of brain homogenate in AD and CJD. We therefore conclude that different mechanisms in AD and CJD are responsible for the Aβ1-42 decrease in the CSF.     

Application of the National Institute on Aging (NIA)-Reagan Institute criteria for the neuropathological diagnosis of Alzheimer disease

The Khachaturian criteria and the Consortium to Establish a Registry for Alzheimer Disease (CERAD) criteria for the neuropathological assessment of Alzheimer disease (AD) emphasize senile or neuritic plaques, age, and clinical history. A new scheme stressing topographic staging of neurofibrillary changes in addition to neuritic plaques has been proposed by the National Institute on Aging (NIA)-Reagan Institute Consensus Conference. This scheme assigns cases to high, intermediate, or low likelihood categories that the dementia is due to AD. We applied this method to 84 brains from subjects with clinical and neuropathological diagnoses of AD (n = 33), non-AD dementing illnesses (n = 34), including dementia with Lewy bodies (DLB) and progressive supranuclear palsy (PSP), and no neurological disease (n = 17). We also used Khachaturian and CERAD criteria. Neurofibrillary tangle and neuropil thread densities were assessed on 6-micrometer-thick modified Bielschowsky-stained paraffin sections from entorhinal-perirhinal cortex, CA1 of hippocampus, and neocortex including inferior temporal, visual association, and primary visual cortices. Each case was assigned a Braak and Braak stage. Using the NIA-Reagan criteria, we found excellent agreement between clinical history of AD dementia and brains assigned to the high likelihood category that dementia was due to AD. Among brains diagnosed neuropathologically with other degenerative diseases, NIA-Reagan criteria were more conservative than previous criteria, and these cases were likely to be categorized as intermediate or low likelihood that dementia was due to AD. All brains from nondemented subjects were assigned to the low (81%) or intermediate (19%) categories. In summary, we found good correlation between the NIA-Reagan criteria and clinical dementia, and there was generally good agreement between these criteria and existing neuropathological methods, Khachaturian and CERAD, in diagnosing AD. In studying several other neurodegenerative diseases, such as DLB, which shows neuropathological and clinical overlap with AD, the staging of neurofibrillary changes offered potential diagnostic refinement.     

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     

β-Protein/A4 deposits are not associated with hyperphosphorylated tau in somatostatin neurons in the hypothalamus of Alzheimer’s disease patients

With respect to the pathogenesis of Alzheimer’s disease (AD), it has been hypothesized that amorphous plaques containing β-protein/A4 (Aβ) would locally induce cytoskeletal changes, and that neurons affected by neurofibrillary tangles (NFTs) lose their neuropeptide concentration and eventually die. To test this presumed cascade of events, the hypothalami of 14 non-demented subjects (Braak 0–III) and 28 AD patients (Braak IV–VI) aged 40–98 years were selected. The subject of our study was the nucleus tuberalis lateralis (NTL), which harbors a subpopulation of somatostatinergic neurons with extensive intrinsic interconnectivity. We used Gallyas silver staining, Congo staining, single- and double-staining with monoclonal antibody AT8 and polyclonal antibody anti-Aβ, and double-immunolabeling with AT8 and anti-somatostatin_1–12 with the following results: (1) Significant amounts of silver-staining NFTs were present in only three AD patients. (2) High densities of AT8-stained cytoskeletal changes were mainly found in aged, demented patients. (3) In contrast, large amounts of Aβ deposits were mainly observed in young and middle-aged (40–59 years) AD patients, and were very low or absent mainly in the older non-demented subjects and in AD patients. (4) Reduced anti-somatostatin staining was observed in the NTL of most AD patients, but anti-somatostatin/AT8 double-stained neurons were found virtually exclusively in aged AD patients. Thus, the occurrence of Aβ deposits and hyperphosphorylated tau formation in somatostatin cells are basically independent events, while decreased somatostatin staining only partly goes together with cytoskeletal changes in somatostatin cells in the NTL of AD patients. These observations cannot be explained by the amyloid cascade hypothesis.     

Cerebrovascular P-glycoprotein expression is decreased in Creutzfeldt–Jakob disease

The abnormal conformation and assembly of proteins in the central nervous system is increasingly thought to be a critical pathogenic mechanism in neurodegenerative disorders such as Creutzfeldt–Jakob disease (CJD) and Alzheimer’s disease (AD). CJD is marked primarily by the buildup of misfolded prion protein (PrP^Sc) in brain, whereas the accrual of β-amyloid protein (Aβ) and tau protein are characteristic for AD. Prior studies have shown that the ATP-binding cassette transporter P-glycoprotein (P-gp) is a cellular efflux pump for Aβ, and that age-associated deficits in P-gp may be involved in the pathogenesis of Alzheimer’s disease. In the present study, we investigated the relationship between P-gp and idiopathic CJD, and found that CJD, like AD, is associated with a decrease in the expression of cerebrovascular P-gp. In some instances, Aβ and PrP deposits coexist in cases of CJD, suggesting the possibility of pathogenic interactions. Since there is, to date, no evidence that PrP itself is a substrate for P-gp, we hypothesize that the age-related deficits in P-gp could promote the accumulation of PrP^Sc either by promoting the buildup of Aβ (which could act as a seed for the aggregation of PrP^Sc), or by overloading the ubiquitin-proteasomal catabolic system, and thereby facilitating the accumulation of PrP. Alternatively, the loss of P-gp could be a non-specific response to neurodegenerative changes in the central nervous system. In either case, dysfunction of this critical toxin-elimination pathway in CJD and AD suggests that selectively increasing cerebrovascular P-gp function could open new therapeutic pathways for the prevention and/or treatment of a number of proteopathic disorders of the central nervous system.     

Microglial activation in early stages of amyloid β protein deposition

The present study was undertaken to investigate the relationship of microglial activation to amyloid β protein (Aβ) deposition, particularly at the early stage. Using single and double immunostaining methods with a panel of microglia markers and antibodies against Aβ and amyloid β protein precursor (APP), we examined the cerebrum and cerebella of both Alzheimer’s disease (AD) and non-demented subjects obtained at autopsy. In non-demented, middle-aged subjects that had small amounts of cerebral Aβ deposits, approximately 70% of the diffuse plaques contained ramified microglia. However, no evidence of microglial activation was found in diffuse plaques in any of the non-demented subjects. Dual immunostaining of sections of cerebral cortex using antibodies against Aβ and major histocompatibility complex class II antigen showed that in AD subjects, approximately 20% of total diffuse plaques contained a few, activated microglia. Most of these plaques were defined as a transitional form between diffuse and primitive plaques. Both primitive and classic plaques in the cerebral cortex of AD subjects consistently contained clusters of activated microglia. Subpial Aβ deposits without neuritic changes lacked microglial activation. In the cerebellum, all of the diffuse plaques lacked microglial activation, and activated microglia in the compact plaques were not as hypertrophic as those in cerebral primitive/classic plaques. Our findings indicate that microglial reactions are absent in the early stages of Aβ deposition, and it occurs during the transition from diffuse to primitive plaques, when amounts of Aβ deposits and the degree of neuritic changes increase. Received: 17 January 1997 / Revised, accepted: 7 April 1997     

Association of apolipoprotein ɛ4 allele and neuropathologic findings in patients with dementia

Apolipoprotein E (APOE) is a lipoprotein expressed in liver and brain as one of three isoforms (APOE 2, APOE 3 and APOE 4). Recent findings suggest that the presence of APOE 4 is associated with an increased risk for both familial Alzheimer's disease and late-onset Alzheimer's disease. We extended these observations by determining the frequency of APOE alleles in patients with pathologically confirmed Alzheimer's Disease (AD), Parkinson's disease (PD), diffuse Lewy Body disease (DLBD), AD with concomitant PD pathology, demented PD patients without or with concomitant AD pathology and in schizophrenics with a progressive dementia (SCHIZ+DEM). The APOE genotype was determined by restriction digestion of polymerase chain reaction-amplified DNA isolated from frozen brain samples. The frequency of the APOE 4 allele was highest among sporadic AD and DLBD patients (0.30 and 0.38, respectively) and lowest in the SCHIZ+DEM and non-demented PD patients (0.06 and 0.1, respectively). Thus, the APOE 4 allele is over-represented selectively in patients with dementias associated with plaques and tangles and/or cortical Lewy bodies, but not in demented schizophrenics or non-demented PD patients.     

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease

The Neuropathology Task Force of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) has developed a practical and standardized neuropathology protocol for the postmortem assessment of dementia and control subjects. The protocol provides neuropathologic definitions of such terms as "definite Alzheimer's disease" (AD), "probable AD," "possible AD," and "normal brain" to indicate levels of diagnostic certainty, reduce subjective interpretation, and assure common language. To pretest the protocol, neuropathologists from 15 participating centers entered information on autopsy brains from 142 demented patients clinically diagnosed as probable AD and on eight nondemented patients. Eighty-four percent of the dementia cases fulfilled CERAD neuropathologic criteria for definite AD. As increasingly large numbers of prospectively studied dementia and control subjects are autopsied, the CERAD neuropathology protocol will help to refine diagnostic criteria, assess overlapping pathology, and lead to a better understanding of early subclinical changes of AD and normal aging.     

Prion protein immunocytochemistry: reliable protocols for the investigation of Creutzfeldt–Jakob disease

Current criteria for the histological diagnosis of Creutzfeldt–Jakob disease (CJD) include features such as spongiform change, neuronal loss and reactive gliosis which are shared to a varying extent with other neurodegenerative disorders. Reliable visualization of prion protein (PrP) has substantial potential value in diagnostic practice and as a research tool, since accumulation of the disease–associated isoform of this protein is apparently specific for spongiform encephalopathies. A number of antisera against PrP have previously been employed in conjunction with a range of pre–treatments designed to optimize the specificity of immunostaining; such varied usage makes the comparison and interpretation of results difficult. This study was undertaken to identify optimal combinations of each of three PrP antisera and five pre–treatments designed to specifically demonstrate disease–specific PrP in a series of seven CJD cases, six cases of Alzheimer–type dementia and six non–demented control cases. Specific staining of amyloid plaques, spongiform neuropil, neurons and, occasionally, astrocytes was achieved in CJD cases. Alzheimer and control cases were unstained. Use of formic acid with guanidine thiocyanate, and hydrolytic autoclaving with IB 3 and SP30 antisera proved most effective and can be recommended for future immunocytochemical studies. PrP immunocytochemistry revealed a greater extent of subcortical neural involvement than routine histological techniques in CJD; the relationship between classical neuropathology in CJD and PrP accumulation as revealed by immunocytochemistry is not clear cut and requires further investigation. These findings may help to broaden our understanding of human spongiform encephalopathies, and have implications for diagnostic practices in neuropathology.     

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.     

Immunohistochemical localization of 14.3.3 ζ protein in amyloid plaques in human spongiform encephalopathies

The localization of 14.3.3 proteins was studied in different subtypes of brain amyloid plaques. We examined paraffin-embedded brain sections of sporadic MV2 Creutzfeldt-Jakob disease (sCJD) with Kuru plaques, sporadic VV2 CJD with plaque-like PrP(sc) (the abnornal form of prion protein) deposits, variant CJD (vCJD) with florid plaques, Gerstmann-Straüssler-Scheinker (GSS) with multicentric plaques and of Alzheimer's disease (AD) with senile plaques. Adjacent immunostaining revealed PrP(sc) and 14.3.3 zeta deposits in the same amyloid plaques in all cases of sporadic CJD and vCJD, whereas 14.3.3 zeta was not seen in amyloid plaques of GSS with A117V, P102L and D202N mutations. The same immunostaining method using anti-betaA4 and anti-14.3.3 zeta antibodies revealed no colocalization in patients with AD. Our data suggest that 14.3.3 zeta protein could interact either with PrP or with other components of PrP(sc) deposits in CJD.