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1.  Neuropathologic correlates of cognition in a population-based sample 
Many cognitively normal older adults have underlying neuropathologic changes of Alzheimer’s disease (AD), vascular brain injury (VBI), or Lewy body disease (LBD), which confer an increased risk of dementia. The current study focused on the association between multiple neuropathologic indices and performance on specific cognitive domains in a community sample of older adults. Of 438 participants in the Adult Changes in Thought population-based study of brain aging who were autopsied, 363 subjects had cognitive testing at their final study visit and were included. Associations were measured between performance on the Cognitive Abilities Screening Instrument prior to death and neuropathologic endpoints, including AD neuropathologic changes, LBD, cerebral amyloid angiopathy, and measures of VBI. Braak stage for neurofibrillary tangles, lower brain weight, and VBI as measured by cerebral cortical microvascular lesions (μVBI) explained a significant proportion of the variance associated with global cognitive test performance (R2=0.31, p< 0.0001) both in the entire sample and when analysis was restricted to non-demented subjects (R2= 0.23, p< 0.0001). Specific cognitive domains were differentially related to neuropathologic lesion type: memory and executive function with AD pathologic changes and cortical μVBI, executive function with subcortical μVBI, and visuospatial construction with LBD. Thus, neuropathologic lesions of LBD and μVBI are associated with poorer cognitive performance over and above AD neuropathologic changes in subjects without dementia in this cohort. These findings underscore that cognitive impairment is a complex convergent trait that has important implications for clinical investigation and medical management of older adults.
doi:10.3233/JAD-130281
PMCID: PMC3737376  PMID: 23666176
Alzheimer’s disease; brain; cerebrovascular disorders; cognition; dementia; Lewy bodies; pathologic processes
2.  Pathologic correlates of dementia in individuals with Lewy body disease 
Cognitive impairment and dementia are more common in patients with Parkinson disease (PD) than age-matched controls, and appear to become more frequent as PD progresses. However, estimates of dementia in patients with PD have varied widely, likely due in part to differences in case definition, case ascertainment, and methodology. First, we review investigations of usual pathologic correlates of dementia in patients with brainstem (b) Lewy Body Disease (LBD) and report our findings from the initial 266 brain autopsies from a population-based study of brain aging and incident dementia. Our results showed that 2.6% of subjects were diagnosed with PD during life but that 20% had bLBD at autopsy. Seventy percent of individuals with bLBD had high-level of one or more cerebral pathologic changes significantly associated with dementia: Alzheimer's disease (AD), cerebral (c) LBD, or microvascular brain injury (μVBI); these were commonly co-morbid. Next we consider proposed contributors to cognitive impairment and dementia in the approximately 30% of patients with only bLBD, including regionally selective dendritic degeneration of neostriatal medium spiny neurons. Diseases contributing to cognitive impairment and dementia in patients with bLBD are heterogeneous, providing diagnostic challenges as well as multiple opportunities for successful intervention in patients with PD.
doi:10.1111/j.1750-3639.2009.00371.x
PMCID: PMC2881486  PMID: 20522091
3.  Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias 
PLoS Genetics  2014;10(9):e1004606.
Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4,914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD (neuritic plaques, NPs; neurofibrillary tangles, NFTs), and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), hippocampal sclerosis of the elderly (HS), and vascular brain injury (VBI). Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene (APOE). GalNAc transferase 7 (GALNT7), ATP-Binding Cassette, Sub-Family G (WHITE), Member 1 (ABCG1), and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (KCNMB2) was strongly associated with HS. Twelve of the 21 non-APOE genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4 with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related dementias.
Author Summary
Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study (GWAS), as well as an analysis of known genetic risk loci for AD dementia, using data from 4,914 brain autopsies. Genome-wide significance was observed for 7 genes and pathologic features of AD and related diseases. Twelve of the 22 genetic risk loci for clinically-defined AD dementia were confirmed in our pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for hallmark pathologic features of AD were strongly positive and linear. Our study discovered new genetic associations with specific pathologic features and aligned known genetic risk for AD dementia with specific pathologic changes in a large brain autopsy study of AD and related dementias.
doi:10.1371/journal.pgen.1004606
PMCID: PMC4154667  PMID: 25188341
4.  STRIATAL AMYLOID PLAQUE DENSITY PREDICTS BRAAK NEUROFIBRILLARY STAGE AND CLINICOPATHOLOGICAL ALZHEIMER’S DISEASE: IMPLICATIONS FOR AMYLOID IMAGING 
Amyloid imaging may revolutionize Alzheimer’s disease (AD) research and clinical practice but is critically limited by an inadequate correlation between cerebral cortex amyloid plaques and dementia. Also, amyloid imaging does not indicate the extent of neurofibrillary tangle (NFT) spread throughout the brain. Currently, the presence of dementia as well as a minimal brain load of both plaques and NFTs is required for the diagnosis of AD. Autopsy studies suggest that striatal amyloid plaques may be mainly restricted to subjects in higher Braak NFT stages that meet clinicopathological diagnostic criteria for AD. Striatal plaques, which are readily identified by amyloid imaging, might therefore be used to predict the presence of a higher Braak NFT stage and clinicopathological AD in living subjects. This study determined the sensitivity and specificity of striatal plaques for predicting a higher Braak NFT stage and clinicopathological AD in a postmortem series of 211 elderly subjects. Subjects included 87 clinicopathologically classified as non-demented elderly controls and 124 with AD. A higher striatal plaque density score (moderate or frequent) had 95.8% sensitivity, 75.7% specificity for Braak NFT stage V or VI and 85.6% sensitivity, 86.2% specificity for the presence of dementia and clinicopathological AD (National Institute on Aging – Reagan Institute “intermediate” or “high”). Amyloid imaging of the striatum may be useful as a predictor, in living subjects, of Braak NFT stage and the presence or absence of dementia and clinicopathological AD. Validation of this hypothesis will require autopsy studies of subjects that had amyloid imaging during life.
doi:10.3233/JAD-2011-111340
PMCID: PMC3760731  PMID: 22112552
Alzheimer’s disease; amyloid imaging; striatum; amyloid plaques; diagnosis; therapy; asymptomatic; preclinical; autopsy
5.  Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts 
Acta Neuropathologica  2011;123(3):381-394.
Cortical microinfarcts (CMIs) observed in brains of patients with Alzheimer’s disease tend to be located close to vessels afflicted with cerebral amyloid angiopathy (CAA). CMIs in Alzheimer’s disease are preferentially distributed in the arterial borderzone, an area most vulnerable to hypoperfusion. However, the causal association between CAA and CMIs remains to be elucidated. This study consists of two parts: (1) an observational study using postmortem human brains (n = 31) to determine the association between CAA and CMIs, and (2) an experimental study to determine whether hypoperfusion worsens CAA and induces CMIs in a CAA mouse model. In postmortem human brains, the density of CMIs was 0.113/cm2 in mild, 0.584/cm2 in moderate, and 4.370/cm2 in severe CAA groups with a positive linear correlation (r = 0.6736, p < 0.0001). Multivariate analysis revealed that, among seven variables (age, disease, senile plaques, neurofibrillary tangles, CAA, atherosclerosis and white matter damage), only the severity of CAA was a significant multivariate predictor of CMIs (p = 0.0022). Consistent with the data from human brains, CAA model mice following chronic cerebral hypoperfusion due to bilateral common carotid artery stenosis induced with 0.18-mm diameter microcoils showed accelerated deposition of leptomeningeal amyloid β (Aβ) with a subset of them developing microinfarcts. In contrast, the CAA mice without hypoperfusion exhibited very few leptomeningeal Aβ depositions and no microinfarcts by 32 weeks of age. Following 12 weeks of hypoperfusion, cerebral blood flow decreased by 26% in CAA mice and by 15% in wild-type mice, suggesting impaired microvascular function due to perivascular Aβ accumulation after hypoperfusion. Our results suggest that cerebral hypoperfusion accelerates CAA, and thus promotes CMIs.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-011-0925-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s00401-011-0925-9
PMCID: PMC3282897  PMID: 22170742
Cerebral amyloid angiopathy; Cortical microinfarcts; Tg-SwDI; Bilateral common carotid artery stenosis
6.  “End-Stage” Neurofibrillary Tangle Pathology in Preclinical Alzheimer's Disease: Fact or Fiction? 
Among individuals who were cognitively intact before death, autopsies may reveal some Alzheimer's disease-type pathology. The presence of end-stage pathology in cognitively intact persons would support the hypothesis that pathological markers are epiphenomena. We assessed advanced neurofibrillary (Braak stages V and VI) pathology focusing on nondemented individuals. Data from the National Alzheimer's Coordinating Center database (n = 4,690 included initially) and from the Nun Study (n = 526 included initially) were analyzed, with antemortem information about global cognition and careful postmortem studies available from each case. Global cognition (final Mini-Mental State Examination scores [MMSE] and clinical ‘dementia’ status) was correlated with neuropathology, including the severity of neurofibrillary pathology (Braak stages and neurofibrillary tangle counts in cerebral neocortex). Analyses support three major findings: 1. Braak stage V cases and Braak VI cases are significantly different from each other in terms of associated antemortem cognition; 2. There is an appreciable range of pathology within the category of Braak stage VI based on tangle counts such that brains with the most neurofibrillary tangles in neocortex always had profound antemortem cognitive impairment; and 3. There was no nondemented case with final MMSE score of 30 within a year of life and Braak stage VI pathology. It may be inappropriate to combine Braak stages V and VI cases, particularly in patients with early cognitive dysfunction, since the two pathological stages appear to differ dramatically in terms of both pathological severity and antemortem cognitive status. There is no documented example of truly end-stage neurofibrillary pathology coexisting with intact cognition.
doi:10.3233/JAD-2011-101980
PMCID: PMC3171001  PMID: 21471646
GRN; miRNA; microRNA; neurofibrillary tangles; neuropathology
7.  MRI correlates of neurofibrillary tangle pathology at autopsy 
Neurology  2008;71(10):743-749.
Background:
Neurofibrillary tangles (NFTs), composed of hyperphosphorylated tau proteins, are one of the pathologic hallmarks of Alzheimer disease (AD). We aimed to determine whether patterns of gray matter atrophy from antemortem MRI correlate with Braak staging of NFT pathology.
Methods:
Eighty-three subjects with Braak stage III through VI, a pathologic diagnosis of low- to high-probability AD, and MRI within 4 years of death were identified. Voxel-based morphometry assessed gray matter atrophy in each Braak stage compared with 20 pathologic control subjects (Braak stages 0 through II).
Results:
In pairwise comparisons with Braak stages 0 through II, a graded response was observed across Braak stages V and VI, with more severe and widespread loss identified at Braak stage VI. No regions of loss were identified in Braak stage III or IV compared with Braak stages 0 through II. The lack of findings in Braak stages III and IV could be because Braak stage is based on the presence of any NFT pathology regardless of severity. Actual NFT burden may vary by Braak stage. Therefore, tau burden was assessed in subjects with Braak stages 0 through IV. Those with high tau burden showed greater gray matter loss in medial and lateral temporal lobes than those with low tau burden.
Conclusions:
Patterns of gray matter loss are associated with neurofibrillary tangle (NFT) pathology, specifically with NFT burden at Braak stages III and IV and with Braak stage itself at higher stages. This validates three-dimensional patterns of atrophy on MRI as an approximate in vivo surrogate indicator of the full brain topographic representation of the neurodegenerative aspect of Alzheimer disease pathology.
GLOSSARY
= Alzheimer disease;
= argyrophilic grains disease;
= amnestic mild cognitive impairment;
= Clinical Dementia Rating scale sum of boxes;
= dementia with Lewy bodies;
= false-discovery rate;
= Mini-Mental State Examination;
= neurofibrillary tangle;
= National Institute on Aging;
= spoiled gradient echo;
= voxel-based morphometry.
doi:10.1212/01.wnl.0000324924.91351.7d
PMCID: PMC2676950  PMID: 18765650
8.  Incidental Lewy Body Disease: Do some cases represent a preclinical stage of Dementia with Lewy Bodies? 
Neurobiology of Aging  2009;32(5):857-863.
Lewy pathology occurs in 8–17% of neurologically-normal people >age 60, termed incidental Lewy body disease, (iLBD). It is often assumed to represent preclinical Parkinson disease (PD). However, some iLBD cases have diffuse pathology inconsistent with preclinical PD. We analyzed iLBD cases (α-synuclein immunohistochemistry) using the Braak PD staging scheme and determined if some had a neuropathological pattern suggestive of preclinical Dementia with Lewy bodies (DLB). Of the 235 brains examined, 34 had iLBD (14.5%) and all but one could be assigned a Braak PD stage. The distribution of α-synuclein pathology in the 33 cases fell into three patterns: (1) Diffuse cortical and subcortical α-synuclein pathology; (2) No cortical a-synuclein pathology, but a caudal-to-rostral ascending pattern, primarily involving brainstem; (3) Intermediate between these two categories. Also, 6/33 cases failed to follow the pattern of contiguous spread proposed by Braak. These findings suggest dichotomy in the distribution of iLBD: some cases fit the Braak ascending scheme, conceptually consistent with preclinical PD, whereas others displayed prominent cortical involvement that might represent preclinical DLB.
doi:10.1016/j.neurobiolaging.2009.05.019
PMCID: PMC3366193  PMID: 19560232
incidental Lewy body disease; parkinson disease; dementia with Lewy bodies
9.  Immunohistochemical analysis of ubiquilin-1 in the human hippocampus: Association with neurofibrillary tangle pathology 
This postmortem immunohistochemical study examined the localization and distribution of ubiquilin-1 (UBL), a shuttle protein which interacts with ubiquitin and the proteasome, in the hippocampus from Alzheimer’s disease (AD) dementia cases, and age-matched cases without dementia. Cases were stratified neuropathologically based on Braak staging for neurofibrillary tangles (NFT); cases without dementia were Braak stages 0-I-II (n=5), and AD cases were either Braak stages III–IV (n=7) or V–VI (n=11). In Braak stage 0-I-II cases, UBL immunoreactivity was detected in a dense fiber network in the neuropil, and in the cell cytoplasm and nucleoplasm of pyramidal neurons in CA fields and dentate gyrus granular neurons. In Braak stages III–IV and V–VI cases, UBL immunoreactivity was reduced in the neuropil and in the cytoplasm of the majority of CA1 neurons. In contrast, some CA1 pyramidal neurons and the majority of CA2/3 pyramidal, CA4 multipolar, and dentate granular neurons in Braak III–IV and Braak V–VI cases had markedly increased UBL immunoreactivity in the nucleoplasm. Dual immunofluorescence analysis of UBL and antibody clone AT8 revealed co-localization most frequently in CA1 pyramidal neurons in the Braak stage III–IV and V–VI cases. Further processing using the pan-amyloid marker X-34 revealed prominent UBL/X-34 dual labeling of extracellular NFT confined to the CA1/subiculum in the Braak stage V–VI cases. Our results demonstrate that in AD hippocampus, early NFT changes are associated with neuronal up-regulation of UBL in nucleoplasm, or its translocation from the cytoplasm to the nucleus. The perseverance of UBL changes in CA2/3. CA4, and DG, generally considered as more resistant to NFT pathology, but not in the CA1, may mark a compensatory, potentially protective response to increased tau phosphorylation in hippocampal neurons; the failure of such a response may contribute to neuronal degeneration in end-stage AD.
doi:10.1111/neup.12055
PMCID: PMC4000263  PMID: 23869942
Alzheimer; amyloid; Plic-1; ubiquilin; tau
10.  Adult Changes in Thought Study: Dementia is an Individually Varying Convergent Syndrome with Prevalent Clinically Silent Diseases that may be Modified by Some Commonly Used Therapeutics 
Current Alzheimer research  2012;9(6):718-723.
The Adult Changes in Thought (ACT) study is a longitudinal population-based prospective cohort study of brain aging and incident dementia in the Seattle metropolitan area. Observational studies using autopsies from ACT indicate that dementia is a convergent syndrome that commonly derives from Alzheimer’s disease (AD), microvascular brain injury (μVBI), and Lewy body disease (LBD), and that these diseases have prevalent subclinical forms that also are commonly co-morbid. The existence of subclinical diseases highlights potential opportunities to intervene before the development of clinically apparent impairments. Our observations suggest that some such interventions already may exist to suppress processes of AD (statin therapy) or μVBI (treatment of hypertension). Reduced burden of LBD is associated with cigarette smoking; although smoking is not recommended as an intervention, these exposure data may provide clues to alternative neuroprotective mechanisms. Self reported anti-oxidant supplementation was without apparent effect in this cohort on indices of AD, μVBI, or LBD. Continued observational studies of brain aging will provide further insight into the convergent complexity of the dementia syndrome and its subclinical forms as well as highlight potential interventions that will require validation in clinical trials.
PMCID: PMC3409333  PMID: 22471861
11.  Thinking outside the box: Alzheimer-type neuropathology that does not map directly onto current consensus recommendations 
Many cognitively impaired patients’ brains fall into neuropathologic diagnostic categories that cannot be defined explicitly by the National Institute on Aging and Reagan Institute (NIA-RI) guidelines. Two specific case categories are considered: “tangle-intensive” patients with the highest density of neurofibrillary tangles (NFTs, as graded by the Braak staging system) but only moderate density of neuritic amyloid plaques (NPs, as graded by CERAD); and conversely “plaque-intensive” patients with intermediate severity NFTs and high density of NPs. To better understand these technically unclassifiable cases, we analyzed NACC Registry data, which includes both clinical and pathological information from the National Institute on Aging-funded Alzheimer Disease Centers (ADCs). 1,672 cases with antemortem diagnoses of dementia were included. To evaluate the diagnostic tendencies of ADC neuropathologists, we assessed how the plaque-intensive and tangle-intensive cases were diagnosed ultimately. Tangle-intensive cases were more likely to be designated “High likelihood” that the dementia was due to AD, whereas plaque-intensive cases were typically designated “Intermediate likelihood”. Only the Braak stage VI “tangle-intensive” cases had lower final MMSE scores than the “plaque-intensive” cases (P<0.02). We conclude that more explicit diagnostic categories, along with better understanding of pathology in earlier phases of the disease, may be helpful to better guide neuropathologists.
doi:10.1097/NEN.0b013e3181d8db07
PMCID: PMC2892786  PMID: 20418781
12.  Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics: A retrospective study 
Lancet neurology  2011;10(9):785-796.
Objective
Neurofibrillary pathology has a stereotypic progression in Alzheimer's disease (AD) that is encapsulated in the Braak staging scheme. Some AD cases do not fit the Braak staging scheme and are considered atypical. The purpose of this study was to compare clinical and pathological features of typical AD with atypical AD that had either hippocampal sparing (HpSp) and limbic-predominant (LP) neurofibrillary pathology.
Methods
A mathematical algorithm was devised to classify AD cases into typical, HpSp and LP according to the density and distribution of neurofibrillary tangle (NFT) counts from thioflavin S fluorescent microscopy in three cortical regions and two Hp sectors. The algorithm was applied to NFT counts of 889 cases of AD (409 men and 480 women; age at death: 37-103 years). Cases so classified were compared on clinical, demographic, pathological and genetic grounds. An independent series of 113 cases of AD were similarly evaluated to validate findings from the initial cohort.
Findings
In comparison to typical AD, HpSp (n=97) had higher NFT densities in cortical areas and lower NFT densities in hippocampus, while LP (n=127) had lower NFT densities in cortical areas and higher NFT densities in the Hp. HpSp had less Hp atrophy than typical AD (11%) and LP (14%). HpSp were younger, with a higher proportion of men, whereas LP was older, with a higher proportion of women. MAPT H1H1 genotype was more frequent in LP compared with HpSp, but not between LP and typical AD. APOE ε4 allele status differed among AD subtypes only when age of onset was considered. Clinical presentation, age of onset, disease duration, and rate of decline differed among the AD subtypes. The findings were confirmed in a replication cohort.
Interpretation
Our data supports the hypothesis of distinct clinicopathologic subtypes of AD. HpSp and LP AD account for about 25% of AD and are important to consider in clinical, genetic, biomarker and treatment studies.
doi:10.1016/S1474-4422(11)70156-9
PMCID: PMC3175379  PMID: 21802369
Alzheimer disease; APOE; digital microscopy; hippocampus; MAPT; neurofibrillary tangles; thioflavin S fluorescent microscopy
13.  Relation of neuropathology with cognitive decline among older persons without dementia 
Objective: Although it is now widely accepted that dementia has a long preclinical phase during which neuropathology accumulates and cognition declines, little is known about the relation of neuropathology with the longitudinal rate of change in cognition among older persons without dementia. We quantified the burden of the neuropathologies of the three most common causes of dementia [i.e., Alzheimer’s disease (AD), cerebrovascular disease (CVD), and Lewy body disease (LBD)] and examined their relation with cognitive decline in a large cohort of persons without dementia proximate to death.
Methods: A total of 467 deceased participants without dementia from two longitudinal clinical-pathologic studies, Rush Memory and Aging Project and Religious Orders Study, completed a mean of 7 annual evaluations including 17 cognitive tests. Neuropathologic examinations provided quantitative measures of AD (i.e., amyloid load, tangle density), CVD (i.e., macroscopic infarcts, microinfarcts), and neocortical Lewy bodies. Random coefficient models were used to examine the relation of the neuropathologies with rates of global cognitive decline as well as decline in four specific cognitive systems.
Results: At autopsy, 82% of persons without dementia had amyloid, 100% had tangles, 29% had macroscopic infarcts, 25% had microinfarcts, and 6% had neocortical Lewy bodies. Global cognition declined a mean of 0.034 unit per year (SE = 0.003, p < 0.001). In separate analyses, amyloid, tangles (p-values <0.001) and neocortical Lewy bodies (p = 0.015) were associated with an increased rate of global cognitive decline; macroscopic infarcts and microinfarcts were not. Further, when analyzed simultaneously, amyloid, tangles, and neocortical Lewy bodies remained associated with global cognitive decline (p-values <0.024). Finally, measures of AD were associated with decline in three of four systems, including episodic memory (i.e., tangles), semantic memory (i.e., amyloid and tangles), and working memory (i.e., amyloid). Lewy bodies also were associated with decline in three of four systems (i.e., semantic memory, working memory, and perceptual speed).
Interpretation: The neuropathologies of the common causes of dementia, particularly AD and neocortical LBD, are associated with decline in multiple cognitive abilities among older persons without dementia.
doi:10.3389/fnagi.2013.00050
PMCID: PMC3766823  PMID: 24058343
cognitive aging; Alzheimer’s disease; neuropathology; vascular disease; Lewy bodies
14.  Brains with Medial Temporal Lobe Neurofibrillary Tangles But No Neuritic Amyloid Plaques Are a Diagnostic Dilemma But May Have Pathogenetic Aspects Distinct from Alzheimer Disease 
Brains that have many neurofibrillary tangles (NFTs) in medial temporal lobe structures (Braak Stages III or IV) but no cortical neuritic plaques (NPs) may be a diagnostic dilemma; they also raise questions about the “amyloid cascade hypothesis” of Alzheimer disease (AD) in which NFT development is thought to occur downstream of the development of amyloid plaques. To determine the clinical, demographic, and biological factors related to NFT+/NP− cases, we analyzed 26 NFT+/NP− patient brains identified from the University of Kentucky AD Center autopsy cohort (n = 502); most of these patients were at least 85 years old and lacked profound antemortem cognitive impairment. A subset of the cases had neurofibrillary tangles in the medulla oblongata. Aberrant TAR-DNA binding protein-43 immunohistochemical staining was seen in 5 of the 26 cases with the clinical diagnoses of AD or mild cognitive impairment. We also queried cases in the National Alzheimer’s Coordinating Center Registry (n = 5,108) and found 219 NFT+/NP− cases. Those patients had a relatively high likelihood of belonging to a birth cohort with the highest incidence of influenza infection during the 1918–1919 pandemic. This observation may link the pathogenesis in NFT+/NP− cases to encephalitis during childhood. We conclude that NFT+/NP- cases comprise approximately 5% of aged individuals in multiple data sets; these cases are not necessarily within the spectrum of AD.
doi:10.1097/NEN.0b013e3181aacbe9
PMCID: PMC2725359  PMID: 19535994
Alzheimer disease; Amyloid; CERAD; Neurofibrillary tangle, Postencephalitic; tau
15.  Microglial phenotypes and toll-like receptor 2 in the substantia nigra and hippocampus of incidental Lewy body disease cases and Parkinson’s disease patients 
Next to α-synuclein deposition, microglial activation is a prominent pathological feature in the substantia nigra (SN) of Parkinson’s disease (PD) patients. Little is known, however, about the different phenotypes of microglia and how they change during disease progression, in the SN or in another brain region, like the hippocampus (HC), which is implicated in dementia and depression, important non-motor symptoms in PD.
We studied phenotypes and activation of microglia in the SN and HC of established PD patients (Braak PD stage 4–6), matched controls (Braak PD stage 0) and of incidental Lewy Body disease (iLBD) cases (Braak PD stage 1–3) that are considered a prodromal state of PD. As recent experimental studies suggested that toll-like receptor 2 (TLR2) mediates α-synuclein triggered microglial activation, we also studied whether TLR2 expression is indeed related to pathology in iLBD and PD patients.
A clear α-synuclein pathology-related increase in amoeboid microglia was present in the HC and SN in PD. Also, morphologically primed/reactive microglial cells, and a profound increase in microglial TLR2 expression were apparent in iLBD, but not PD, cases, indicative of an early activational response to PD pathology. Moreover, TLR2 was differentially expressed between the SN and HC, consistent with a region-specific pattern of microglial activation.
In conclusion, the regional changes in microglial phenotype and TLR2 expression in primed/reactive microglia in the SN and HC of iLBD cases indicate that TLR2 may play a prominent role in the microglial-mediated responses that could be important for PD progression.
doi:10.1186/s40478-014-0090-1
PMCID: PMC4224021  PMID: 25099483
Parkinson’s disease; Substantia nigra; Hippocampus; Incidental Lewy body disease; Microglia; Toll-like receptor 2
16.  Nonsteroidal anti-inflammatory drugs are associated with increased neuritic plaques(e–Pub ahead of print) 
Neurology  2010;75(13):1203-1210.
Objectives:
Observational and experimental studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer disease (AD); however, clinical trials and other observational studies, including the Adult Changes in Thought (ACT) study, show no protection or promotion of AD. The objective of this study is to determine the relationship between common dementia-associated pathologies and mid- to late-life NSAID exposure.
Methods:
We examined the association of mid- to late-life NSAID use with neuropathologic findings on 257 autopsies from ACT, a population-based study of brain aging and incident dementia. Cumulative standard daily doses (SDD) of nonselective NSAIDs were determined from ≥10 years of computerized pharmacy dispensing data. Analyses were adjusted for selection bias to broaden generalizability of results to 3,026 eligible participants in the ACT cohort. Seven pathologic indices were evaluated: intermediate or frequent score for neuritic plaques, Braak stages V or VI for neurofibrillary tangles, >2 cerebral microinfarcts, the presence of any neocortical Lewy bodies, any macroscopic infarcts, any amyloid angiopathy, and moderate or severe atherosclerosis.
Results:
Of the neuropathologic indices evaluated, only neuritic plaque score was significantly increased in participants with greater use of nonselective NSAIDs (p = 0.065), specifically in those with high levels of cumulative use: 1,000–2,000 SDD (adjusted relative risk [RR] 2.16, 95% confidence interval [CI] 1.02–4.25, compared to light/nonuse [<60 SDD]) and >2,000 SDD (adjusted RR 2.37, 95% CI 1.24–4.67).
Conclusions:
Increased neuritic plaque accumulation may explain the association between heavy use of nonselective NSAIDs and increased risk of dementia among ACT participants.
GLOSSARY
= amyloid angiopathy;
= Adult Changes in Thought;
= Alzheimer disease;
= Consortium to Establish a Registry for Alzheimer's Disease;
= confidence interval;
= cerebral microinfarct;
= Diagnostic and Statistical Manual of Mental Disorders, 4th edition;
= Group Health Cooperative;
= Lewy body disease;
= neurofibrillary tangle;
= neuritic plaque;
= nonsteroidal anti-inflammatory drug;
= over-the-counter;
= relative risk;
= standard daily dose;
= vascular brain injury.
doi:10.1212/WNL.0b013e3181f52db1
PMCID: PMC3013492  PMID: 20811000
17.  Lewy body disease and dementia with Lewy bodies 
In 1976 we reported our first autopsied case with diffuse Lewy body disease (DLBD), the term of which we proposed in 1984. We also proposed the term “Lewy body disease” (LBD) in1980. Subsequently, we classified LBD into three types according to the distribution pattern of Lewy bodies: a brain stem type, a transitional type and a diffuse type. Later, we added the cerebral type. As we have proposed since 1980, LBD has recently been used as a generic term to include Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB), which was proposed in 1996 on the basis of our reports of DLBD.
DLB is now known to be the second most frequent dementia following Alzheimer’s disease (AD).
In this paper we introduce our studies of DLBD and LBD.
doi:10.2183/pjab.90.301
PMCID: PMC4275567  PMID: 25311140
Lewy body disease (LBD); diffuse Lewy body disease (DLBD); dementia with Lewy bodies (DLB); Parkinson’s disease (PD); Parkinson’s disease with dementia (PDD)
18.  Modeling the Association between 43 Different Clinical and Pathological Variables and the Severity of Cognitive Impairment in a Large Autopsy Cohort of Elderly Persons 
We evaluated the association between mini-mental status examination (MMSE) scores proximal to death and the values of 43 different clinical and pathological parameters. Studies were performed using data from 334 elderly, longitudinally evaluated research subjects who had undergone autopsy and satisfied inclusion criteria from an initial study group of 501. Interindividual variance in MMSE scores was used as a surrogate for the severity of cognitive impairment linked to aging (CILA). A statistical linear regression-based model provided a framework for assessing the parameters with significant, direct impact on CILA severity. Strong association between CILA and Alzheimer’s disease (AD) pathology, especially isocortical neurofibrillary tangles, was evident. The pattern of association between AD lesion densities with cognitive impairment severity was biologically informative, with neuritic plaques having more impact in relatively high-functioning individuals. Abundant isocortical Lewy bodies tended to be an additive pathology correlating with final MMSE scores approximately 10 points lower. In a subset of cases we found evidence for association between TDP-43-related pathology and CILA severity, independent of AD or hippocampal sclerosis. There was no support for independent association between CILA severity and most evaluated indices including diffuse plaques, argyrophilic grains, heart disease, education level, apolipoprotein E alleles or diabetes.
doi:10.1111/j.1750-3639.2008.00244.x
PMCID: PMC2864342  PMID: 19021630
ApoE; cognition; human; stroke; DLB; hippocampal sclerosis
19.  Association of brain pathology with the progression of frailty in older adults 
Neurology  2013;80(22):2055-2061.
Objective:
We tested the hypothesis that brain pathology is associated with the rate of progression of physical frailty in older adults.
Methods:
A total of 791 older adults participating in the Religious Orders Study and Memory and Aging Project had annual clinical evaluations from which a previously established composite measure of physical frailty was derived and brain autopsy after death. A uniform neuropathologic examination included the assessment of macroinfarcts, microinfarcts, atherosclerosis, arteriolosclerosis, Alzheimer disease and Lewy body pathology, and nigral neuronal loss.
Results:
Mean follow-up before death was 6.4 years and age at death was 88.5 years. More than 95% of cases had evidence of one or more brain pathologies. In a linear mixed-effect model controlling for age, sex, and education, frailty increased at approximately 0.12 unit/year (estimate 0.117, SE 0.035, p < 0.001). The rate of progression of frailty was accelerated with increasing age (estimate 0.002, SE 0.001, p = 0.012). In separate models, the presence of macroinfarcts, Alzheimer disease and Lewy body pathology, and nigral neuronal loss was associated with a more rapid progression of frailty (all p values ≤0.010). When these 4 brain pathologies were considered together in a single model, Alzheimer disease pathology, macroinfarcts, and nigral neuronal loss showed independent associations with the rate of progression of frailty and accounted for more than 8% of the variance unexplained by demographic variables alone.
Conclusion:
The accumulation of common brain pathologies contributes to progressive physical frailty in old age.
doi:10.1212/WNL.0b013e318294b462
PMCID: PMC3716398  PMID: 23635961
20.  Interhemispheric distribution of Alzheimer disease and vascular pathology in brain aging 
Background and purpose
Most of the neuropathological studies in brain aging were based on the assumption of a symmetric right-left hemisphere distribution of both Alzheimer's disease (AD) and vascular pathology. To explore the impact of asymmetric lesion formation on cognition, we performed a clinicopathological analysis of 153 cases with mixed pathology except macroinfarcts.
Methods
Cognitive status was assessed prospectively using the Clinical Dementia Rating (CDR) scale; neuropathological evaluation included assessment of Braak neurofibrillary tangle (NFT) and Aß-deposition staging, microvascular pathology and lacunes. The right-left hemisphere differences in neuropathological scores were evaluated using the Wilcoxon signed rank test. The relationship between the interhemispheric distribution of lesions and CDR scores was assessed using ordered logistic regression.
Results
Unlike Braak NFT and Aß deposition staging, vascular scores were significantly higher in the left hemisphere for all CDR scores. A negative relationship was found between Braak NFT, but not Aß, staging and vascular scores in cases with moderate to severe dementia. In both hemispheres, Braak NFT staging was the main determinant of cognitive decline followed by vascular scores and Aß deposition staging. The concomitant predominance of AD and vascular pathology in the right hemisphere was associated with significantly higher CDR scores.
Conclusions
Our data show that the cognitive impact of AD and vascular lesions in mixed cases may be assessed unilaterally without major information loss. However, interhemispheric differences and, in particular, increased vascular and AD burden in the right hemisphere may increase the risk for dementia in this group.
doi:10.1161/STROKEAHA.108.530337
PMCID: PMC2674266  PMID: 19118241
Alzheimer; cerebral infarct; cognition; white matter disease
21.  Lewy- and Alzheimer-type pathologies in Parkinson’s disease dementia: which is more important? 
Brain : a journal of neurology  2011;134(0 5):1493-1505.
Summary
The relative importance of Lewy- and Alzheimer-type pathologies to dementia in Parkinson’s disease remains unclear. We have examined the combined associations of α-synuclein, tau and amyloid-β accumulation in 56 pathologically confirmed Parkinson’s disease cases, 29 of whom had developed dementia. Cortical and subcortical amyloid-β scores were obtained, while tau and α-synuclein pathologies were rated according to the respective Braak stages. Additionally, cortical Lewy body and Lewy neurite scores were determined and Lewy body densities were generated using morphometry. Non-parametric statistics, together with regression models, receiver-operating characteristic curves and survival analyses were applied. Cortical and striatal amyloid-β scores, Braak tau stages, cortical Lewy body, Lewy neurite scores and Lewy body densities, but not Braak α-synuclein stages, were all significantly greater in the Parkinson’s disease-dementia group (P < 0.05), with all the pathologies showing a significant positive correlation to each other (P < 0.05). A combination of pathologies [area under the receiver-operating characteristic curve = 0.95 (0.88–1.00); P < 0.0001] was a better predictor of dementia than the severity of any single pathology. Additionally, cortical amyloid-β scores (r = −0.62; P = 0.043) and Braak tau stages (r = −0.52; P = 0.028), but not Lewy body scores (r = −0.25; P = 0.41) or Braak α-synuclein stages (r = −0.44; P = 0.13), significantly correlated with mini-mental state examination scores in the subset of cases with this information available within the last year of life (n = 15). High cortical amyloid-β score (P = 0.017) along with an older age at onset (P = 0.001) were associated with a shorter time-to-dementia period. A combination of Lewy- and Alzheimer-type pathologies is a robust pathological correlate of dementia in Parkinson’s disease, with quantitative and semi-quantitative assessment of Lewy pathology being more informative than Braak α-synuclein stages. Cortical amyloid-β and age at disease onset seem to determine the rate to dementia.
doi:10.1093/brain/awr031
PMCID: PMC4194668  PMID: 21596773
lewy bodies; amyloid-β; tau; Parkinson’s disease; dementia
22.  Limbic Lobe Microvacuolation is Minimal in Alzheimer's Disease in the Absence of Concurrent Lewy Body Disease 
Microvacuolation is relatively common in the limbic lobe in Lewy body disease (LBD). Similar pathology has also been reported in Alzheimer's disease (AD). Almost all of the studies of microvacuolation in AD, however, antedated the routine application of sensitive immunohistochemical methods to detect Lewy bodies. This raises the possibility that microvacuolation previously reported in AD may have been due to unrecognized LB pathology. To explore this issue, α-synuclein immunohistochemistry was used to evaluate a consecutive series of AD as well as cases with mixed AD and LBD (AD/LBD). Independently, the degree of microvacuolation was graded in the entorhinal cortex and the amygdala of the same cases. The results showed that microvacuolation was more common and more severe in AD/LBD than in pure AD cases. In pure AD cases microvacuolation was related to senile plaque density, especially in the amygdala, where many of the neuropil vacuoles were around dense-cored, neuritic plaques. In contrast, in AD/LBD microvacuolation correlated with LB density in the entorhinal cortex and amygdala. These results suggest that microvacuolation has a different pathogenesis in AD and in AD/LBD. Moreover, when prominent microvacuolation is detected in AD, it is imperative to exclude concurrent LBD.
PMCID: PMC2480549  PMID: 18787618
Alzheimer's disease; Lewy body disease; microvacuolation; spongiosis
23.  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 pathological criteria of the Third Consortium on Dementia with Lewy bodies (CDLB) and none based upon 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 CDLB neuropathological criteria scheme performed reasonably well and is useful for estimating the likelihood of the premortem DLB syndrome based upon postmortem findings. In view of differences in the frequency of clinically probable DLB in cases with Braak NFT stages V (90%) and VI (20%) and diffuse cortical Lewy bodies, a possible modification of the scheme considering cases with NFT stage VI to be low-likelihood DLB is suggested.
doi:10.1097/NEN.0b013e31817d7a1d
PMCID: PMC2745052  PMID: 18596548
Alzheimer disease; α-synuclein; Clinicopathologic correlation; Diagnostic criteria; Dementia with Lewy bodies; Prospective study; REM behavior disorder
24.  Neuropathologically defined subtypes of Alzheimer’s disease differ significantly from neurofibrillary tangle-predominant dementia 
Acta neuropathologica  2012;124(5):681-692.
Alzheimer’s disease (AD) can be classified based on the relative density of neurofibrillary tangles (NFTs) in the hippocampus and association cortices into three subtypes: typical AD, hippocampal-sparing AD (HpSp AD), and limbic-predominant AD (LP AD). AD subtypes not only have pathologic, but also demographic, clinical, and genetic differences. Neurofibrillary tangle-predominant dementia (NFTD), a disorder with NFTs relatively restricted to limbic structures, shares this feature with LP AD raising the possibility that NFTD is a variant of AD. The objective criteria for pathologic diagnosis of NFTD are not available. A goal of this study was to design a mathematical algorithm that could diagnose NFTD from NFT and senile plaque (SP) counts in hippocampus and association cortices, analogous to that used to subtype AD. Moreover, we aimed to compare pathologic, demographic, clinical, and genetic features of NFTD (n = 18) with LP AD (n = 19), as well as the other AD subtypes, typical AD (n = 52) and HpSp AD (n = 17). Using digital microscopy, we confirmed that burden of phospho-tau (CP13) and of an NFT conformational epitope (Ab39) correlated with NFT densities and showed expected patterns across AD subtypes. HpSp AD had the highest and LP AD had the lowest burden of cortical CP13 and Ab39 immunoreactivity. On the other hand, cortical β-amyloid burden did not significantly differ between AD subtypes. Semi-quantitative assessment of SPs in the basal ganglia did show HpSp AD to have significantly more frequent presence of SPs compared to typical AD, which was more frequent than LP AD. Compared to LP AD, NFTD had an older age at disease onset and shorter disease duration, as well as lower Braak NFT stage. NFTs and SPs on thioflavin-S fluorescent microscopy, as well as CP13, Ab39, and Aβ immunoreactivities were very low in the frontal cortex of NFTD, differentiating NFTD from AD subtypes, including LP AD. MAPT H1H1 genotype frequency was high (~70 %) in NFTD and LP AD, and similar to typical AD, while APOE ε4 carrier state was low in NFTD. While it shares clinical similarities with regard to female sex predominance, onset in advanced age, and a slow cognitive decline, NFTD has significant pathologic differences from LP AD, suggesting that it may not merely be a variant of AD.
doi:10.1007/s00401-012-1044-y
PMCID: PMC3483034  PMID: 22968369
Alzheimer disease; Neurofibrillary tangle-predominant dementia; APOE; Digital microscopy; MAPT; Neurofibrillary tangles; Amyloid plaques; Basal ganglia
25.  Alzheimer Disease Pathology in Subjects Without Dementia in Two Studies of Aging: The Nun Study and the Adult Changes in Thought Study 
Individuals with antemortem preservation of cognition who show autopsy evidence of at least moderate Alzheimer disease (AD) pathology suggest the possibility of brain reserve, that is, functional resistance to structural brain damage. This reserve would, however, only be relevant if the pathologic markers correlate well with dementia. Using data from the Nun Study (n = 498) and the Adult Changes in Thought (ACT) Study (n = 323), we show that Braak staging correlates strongly with dementia status. Moreover, participants with severe (Braak stage V–VI) AD pathology who remained not demented represent only 12% (Nun Study) and 8% (ACT study) of nondemented subjects. Comparison of these subjects to those who were demented revealed that the former group was often significantly memory impaired despite not being classified as demented. Most of these nondemented participants showed only stage V neurofibrillary pathology and frontal tangle counts that were slightly lower than a comparable (Braak stage V) dementia group. In summary, these data indicate that, in individuals with AD-type pathology who do not meet criteria for dementia, neocortical neurofibrillary tangles are somewhat reduced and incipient cognitive decline is present. Our data provide a foundation for helping to define additional factors that may impair, or be protective of, cognition in older adults.
doi:10.1097/NEN.0b013e31822e8ae9
PMCID: PMC3445265  PMID: 21937909
Adult Changes in Thought Study; Alzheimer disease; brain reserve; dementia; Nun Study; presymptomatic; preclinical

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