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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.  Hippocampal sclerosis in Lewy body disease is a TDP-43 proteinopathy similar to FTLD-TDP Type A 
Acta neuropathologica  2014;129(1):53-64.
Hippocampal sclerosis (HpScl) is frequent in frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), but it also occurs in dementia of the elderly with or without accompanying Alzheimer type pathology. HpScl has been hypothesized to be a neurodegenerative process given its association with TDP-43 pathology, but this is still controversial. TDP-43 pathology is found in Lewy body disease (LBD), but no study has focused on the pathologic and genetic characteristics of HpScl in LBD. We found HpScl in 5.2% of 669 LBD cases (289 transitional and 380 diffuse). Older age, higher Braak neurofibrillary tangle (NFT) stage, and presence of TDP-43 pathology were associated with HpScl. There was no difference in the frequency of HpScl between transitional and diffuse LBD, suggesting that Lewy related pathology appears to have no direct association with HpScl. All HpScl cases had TDP-43 pathology consistent with Type A pattern. HpScl cases harbored genetic variation in TMEM106B that has been previously associated with FTLD-TDP. Interestingly, the severity of TDP-43-positive fine neurites in CA1 sector, a possible pathologic precursor of HpScl, was associated with the TMEM106B variant. These results demonstrate HpScl in LBD is a TDP-43 proteinopathy and is similar to FTLD-TDP Type A. Furthermore, a subset of LBD cases without HpScl (“pre-HpScl”) had similar pathologic and genetic characteristics to typical HpScl, suggesting that the spectrum of HpScl pathology may be wider than previously thought. Some cases with many extracellular NFTs also had a similar profile. We suggest that HpScl is “masked” in these cases.
doi:10.1007/s00401-014-1358-z
PMCID: PMC4282950  PMID: 25367383
Hippocampal sclerosis; Lewy body disease; Neuropathology; TDP-43; TMEM106B
4.  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
5.  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
6.  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
7.  “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
8.  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
9.  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
10.  Neuropathological comparisons of amnestic and nonamnestic mild cognitive impairment 
BMC Neurology  2015;15:146.
Background
Although there are studies investigating the pathologic origins of mild cognitive impairment (MCI), they have revolved around comparisons to normal elderly individuals or those with Alzheimer’s disease (AD) or other dementias. There are few studies directly comparing the comprehensive neuropathology of amnestic (aMCI) and nonamnestic (naMCI) MCI.
Methods
The database of the Brain and Body Donation Program (www.brainandbodydonationprogram.org), a longitudinal clinicopathological study of normal aging and neurodegenerative disorders, was queried for subjects who were carrying a diagnosis of aMCI or naMCI at the time of autopsy. Neuropathological lesions, including neuritic plaques, neurofibrillary tangles (NFTs), Lewy bodies (LBs), infarcts, cerebral white matter rarefaction (CWMR), cerebral amyloid angiopathy (CAA), and concurrent major clinicopathological diagnoses, including Parkinson’s disease (PD) were analyzed.
Results
Thirty four subjects with aMCI and 15 naMCI met study criteria. Subjects with aMCI were older at death (88 vs. 83 years of age, p = 0.03). Individuals with naMCI had higher densities of LBs within the temporal lobe (p = 0.04) while subjects with aMCI had a propensity for increased NFTs in parietal and temporal lobes (p values = 0.07). After adjusting for age at death, the only significant difference was greater densities of temporal lobe NFTs within the aMCI group. Other regional pathology scores for plaques, NFTs, and LBs were similar between groups. Subjects met clinico-pathological criteria for co-existent PD in 24 % aMCI and 47 % naMCI while neuropathological criteria for AD were met in equal percentages of aMCI and of naMCI cases (53 %); these proportional differences were not significant (p values > 0.35). Furthermore, regardless of amnestic status, there was a greater presence of CAA (71 % of MCI with executive dysfunction vs. 39 % without p = 0.03) and a greater presence of CWMR (81 % of MCI with executive dysfunction and 54 % without p = 0.046) in MCI cases with executive dysfunction.
Conclusions
No single pathologic entity strongly dichotomized MCI groups, perhaps due to the pathologic heterogeneity found within both entities. However, these data suggest the possibility for naMCI to have a propensity for increased LBs and aMCI for increased NFTs in select anatomic regions.
doi:10.1186/s12883-015-0403-4
PMCID: PMC4545878  PMID: 26289075
11.  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
12.  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
13.  Alpha-synucleinopathy and neuropsychological symptoms in a population-based cohort of the elderly 
Introduction
Studies with strong selection biases propose that alpha-synucleinopathy (AS) spreads upwards and downwards in the neuraxis from the medulla, that amygdala-dominant AS is strongly associated with Alzheimer’s disease (AD), and that a more severe involvement of the cerebral cortex is correlated with increasing risk of dementia. This study examines the association of AS patterns and observed neuropsychological symptoms in brains of a population-representative donor cohort.
Methods
Brains donated in 2 out of 6 cognitive function and ageing study cohorts (Cambridgeshire and Nottingham) were examined. Over 80% were >80 years old at death. The respondents were evaluated prospectively in life for cognitive decline and dementia. Immunocytochemistry for tau and alpha-synuclein (using LB509 by Zymed Laboratories) was carried out in 208 brains to establish Braak stage and the pattern and severity of AS following the dementia with Lewy bodies (DLB) consensus recommendations. Dementia, specific neuropsychological measures as measured using the Cambridge cognitive examination, the presence of hallucinations and Parkinson’s disease were investigated.
Results
Four patterns of AS were observed: no AS pathology (n = 92), AS pathology following the DLB consensus guidelines (n = 33, of which five were ‘neocortical’), amygdala-predominant AS (n = 18), and other AS patterns (n = 33). Each group was subdivided according to high/low neurofibrillary tangles (NFT) Braak stage. Results showed no association between dementia and these patterns of AS, adjusting for the presence of NFT or not. The risk of visual hallucinations shows a weak association with AS in the substantia nigra (odds ratio (OR) = 3.2; 95% confidence interval (CI) 0.5 to 15.5; P = 0.09) and amygdala (OR = 3.0; 95% CI 0.7 to 12.3; P = 0.07). The analysis is similar for auditory hallucinations in subcortical regions.
Conclusions
Among the whole population of older people, AS does not increase the risks for dementia, irrespective of Braak stage of NFT pathology. There was no evidence that the pattern of AS pathology in cortical areas was relevant to the risk of hallucination. In general, the hypothesis that AS as measured using these methods per se is a key determinant of cognitive clinical phenotypes is not supported.
doi:10.1186/s13195-015-0101-x
PMCID: PMC4394405  PMID: 25870655
14.  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
15.  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
16.  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
17.  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
18.  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
19.  Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer’s disease spectrum 
Brain  2015;138(5):1370-1381.
Murray et al. examine the correspondence between Thal amyloid phase, tau pathology and clinical characteristics in a large Alzheimer’s disease autopsy series. They extrapolate their findings to an autopsy cohort for which Pittsburgh compound-B imaging data are available, and evaluate the neuropathological significance of a quantitative amyloid-β imaging cut-off point.
Murray et al. examine the correspondence between Thal amyloid phase, tau pathology and clinical characteristics in a large Alzheimer’s disease autopsy series. They extrapolate their findings to an autopsy cohort for which Pittsburgh compound-B imaging data are available, and evaluate the neuropathological significance of a quantitative amyloid-β imaging cut-off point.
Thal amyloid phase, which describes the pattern of progressive amyloid-β plaque deposition in Alzheimer’s disease, was incorporated into the latest National Institute of Ageing – Alzheimer’s Association neuropathologic assessment guidelines. Amyloid biomarkers (positron emission tomography and cerebrospinal fluid) were included in clinical diagnostic guidelines for Alzheimer’s disease dementia published by the National Institute of Ageing – Alzheimer’s Association and the International Work group. Our first goal was to evaluate the correspondence of Thal amyloid phase to Braak tangle stage and ante-mortem clinical characteristics in a large autopsy cohort. Second, we examined the relevance of Thal amyloid phase in a prospectively-followed autopsied cohort who underwent ante-mortem 11C-Pittsburgh compound B imaging; using the large autopsy cohort to broaden our perspective of 11C-Pittsburgh compound B results. The Mayo Clinic Jacksonville Brain Bank case series (n = 3618) was selected regardless of ante-mortem clinical diagnosis and neuropathologic co-morbidities, and all assigned Thal amyloid phase and Braak tangle stage using thioflavin-S fluorescent microscopy. 11C-Pittsburgh compound B studies from Mayo Clinic Rochester were available for 35 participants scanned within 2 years of death. Cortical 11C-Pittsburgh compound B values were calculated as a standard uptake value ratio normalized to cerebellum grey/white matter. In the high likelihood Alzheimer’s disease brain bank cohort (n = 1375), cases with lower Thal amyloid phases were older at death, had a lower Braak tangle stage, and were less frequently APOE-ε4 positive. Regression modelling in these Alzheimer’s disease cases, showed that Braak tangle stage, but not Thal amyloid phase predicted age at onset, disease duration, and final Mini-Mental State Examination score. In contrast, Thal amyloid phase, but not Braak tangle stage or cerebral amyloid angiopathy predicted 11C-Pittsburgh compound B standard uptake value ratio. In the 35 cases with ante-mortem amyloid imaging, a transition between Thal amyloid phases 1 to 2 seemed to correspond to 11C-Pittsburgh compound B standard uptake value ratio of 1.4, which when using our pipeline is the cut-off point for detection of clear amyloid-positivity regardless of clinical diagnosis. Alzheimer’s disease cases who were older and were APOE-ε4 negative tended to have lower amyloid phases. Although Thal amyloid phase predicted clinical characteristics of Alzheimer’s disease patients, the pre-mortem clinical status was driven by Braak tangle stage. Thal amyloid phase correlated best with 11C-Pittsburgh compound B values, but not Braak tangle stage or cerebral amyloid angiopathy. The 11C-Pittsburgh compound B cut-off point value of 1.4 was approximately equivalent to a Thal amyloid phase of 1–2.
doi:10.1093/brain/awv050
PMCID: PMC4407190  PMID: 25805643
Alzheimer’s disease; neuropathology; Thal amyloid phase; Pittsburgh compound B; Braak tangle stage
20.  Clinical and imaging features of mixed Alzheimer and vascular pathologies 
The co-occurrence of both Alzheimer disease (AD) pathology and vascular brain injury (VBI) is very common, especially amongst the oldest of old. In neuropathologic studies, the prevalence of AD, VBI, and mixed AD/VBI lesions ranks ahead of Lewy bodies and hippocampal sclerosis. In the modern era of structural magnetic resonance imaging (MRI) and amyloid positron emission tomography (PET) imaging, this review examines 1) the prevalence of mixed AD and VBI pathology, 2) the significance of these pathologies for cognitive impairment (AD and vascular cognitive impairment (VCI)), and 3) the diagnosis and treatment of mixed AD/VCI. Although epidemiologic studies report that vascular risk factors for arteriosclerosis increase the risk of incident AD, both autopsy and amyloid PET studies indicate that AD and VBI contribute additively, but independently, to the risk of dementia. The literature confirms the malignancy of AD and highlights the adverse effects of microinfarcts on cognitive function. For the clinical diagnosis of mixed AD/VCI, the presence of AD can be recognized by neuropsychological profile, structural imaging, cerebrospinal fluid biomarkers, and glucose PET and amyloid PET imaging. The diagnosis of VBI, however, still hinges predominantly on the structural MRI findings. Severe amnesia and atrophy of the hippocampus are characteristic of early AD, whereas the cognitive profile for VCI is highly variable and dependent on size and location of VBI. The cognitive profile of mixed AD/VBI is dominated by AD. With the notable exception of microinfarcts (which elude in vivo detection), infarcts, hemorrhages, and white matter hyperintensities on structural MRI currently represent the best markers for the presence VBI. Better markers that reflect the health and reactivity of intracerebral blood vessels are needed. For prevention and treatment, the type of underlying cerebrovascular disease (for example, arteriosclerosis or cerebral amyloid angiopathy) should be considered. It is likely that reduction of vascular risk factors for arteriosclerosis can significantly reduce vascular contributions to mixed dementia.
doi:10.1186/s13195-015-0104-7
PMCID: PMC4342006  PMID: 25722748
21.  Alzheimer pathology does not mediate the association between depressive symptoms and subsequent cognitive decline 
Background
Depressive symptoms in non-demented persons appear to hasten the conversion from Mild Cognitive Impairment (MCI) to clinical Alzheimer's disease (AD) and doubles the risk of incident AD. However, the mechanism(s) by which depression might effect this risk has not been well established. The purpose of this analysis is to test the hypothesis that progression of AD pathology mediates depression's apparent effect on the risk of dementia conversion using longitudinally collected psychometric testing and autopsy data from the Honolulu-Asia Aging Study (HAAS).
Methods
Latent factor variables representing AD, cortical Lewy body (CLB) and ischemic neuropathology were tested as potential mediators of the Centers for Epidemiological Studies depression scale (CES-D)'s significant association with the 10-year prospective rate of cognitive decline, adjusted for baseline cognition, age, education, total number of medications and brain weight at autopsy.
Results
CES-D scores, neurofibrillary tangle (NFT) counts, CLB counts and ischemic lesions each made significant independent contributions to cognitive decline. However, CES-D scores were not significantly associated with any pathological variable, which thus were not mediators of its effect.
Conclusions
We can confirm that subsyndromal depressive symptoms are significantly associated with subsequent cognitive decline. Although the effect is relatively modest, it is stronger than that of amyloid-related neuropathologies, and independent of that of NFT, CLB and ischemic lesions. Our results argue against AD-related neuropathology as a mediator of depression's effects on cognitive decline, but cannot rule out a significant mediation effect in a subset of cases, perhaps with greater baseline depressive symptoms.
doi:10.1016/j.jalz.2011.11.009
PMCID: PMC4459124  PMID: 23154050
aging; Alzheimer's; depression; dementia; longitudinal; neuropathology
22.  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
23.  Detection of hyperphosphorylated tau protein and α-synuclein in spinal cord of patients with Alzheimer’s disease 
The aim of this study was to investigate the neuropathological features of the spinal cord in patients suffering with Alzheimer’s disease (AD). Spinal cord tissue collected from three AD patients and eight controls was selected for the study. Data were collected at T2, T8, T10, L4, and S2 spinal levels. The sections were subjected to hematoxylin and eosin and Gallyas–Braak staining methods and then were immunostained with antibodies such as phosphorylated tau protein (AT8), α-synuclein, Aβ, amyloid precursor protein, ubiquitin, and TDP-43. Pathological changes exhibited by the biomarkers were detected by microscopy. Neurofibrillary tangles (NFTs) were detectable in spinal anterior horn motor neurons in two of the three AD patients. AT8-positive axons or axon-like structures and AT8 expression in glial cells were detected in all three AD cases. Hyperphosphorylation of tau protein was detected in spinal anterior horn cells, glial cells, and axons, and its severity was associated with NFTs in the brain tissue. α-Synuclein-positive Lewy bodies and scattered Lewy-like neuritis were detected in the medial horn of the thoracic spinal cord and ventral sacral gray matter, respectively, in one patient who had AD with Lewy bodies. Neither amyloid deposition nor amyloid precursor protein and TDP-43 expression was detected in the spinal cord of AD patients. Spinal cord of AD patients was observed to contain phosphorylated tau protein and α-synuclein immunoreactive structures, which may play a role in dyskinesia and autonomic dysfunction in advanced AD.
doi:10.2147/NDT.S90735
PMCID: PMC4777227  PMID: 27013875
Alzheimer’s disease; α-synuclein; tau protein; neurofibrillary tangles; histopathology
24.  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)
25.  Differential expression of galanin in the cholinergic basal forebrain of patients with Lewy body disorders 
Introduction
Depletion of cholinergic neurons within the nucleus basalis of Meynert (nbM) is thought to contribute to the development of cognitive impairments in both Alzheimer’s disease (AD) and Lewy body disorders (LBD). It has been reported that, in late stage AD, a network of fibres that contain the neuropeptide galanin displays significant hypertrophy and ‘hyperinnervates’ the surviving cholinergic neurons. Galanin is considered as a highly inducible neuroprotective factor and in AD this is assumed to be part of a protective tissue response. The aim of this study was to determine if a similar galanin upregulation is present in the nbM in post-mortem tissue from patients with LBD. Gallatin immunohistochemistry was carried out on anterior nbM sections from 76 LBD cases (27 PD, 15 PD with mild cognitive impairment (MCI), 34 PD with dementia (PDD) and 4 aged-matched controls. Galaninergic innervation of cholinergic neurons was assessed on a semi-quantitative scale.
Results
The LBD group had significantly higher galaninergic innervation scores (p = 0.016) compared to controls. However, this difference was due to increased innervation density only in a subgroup of LBD cases and this correlated positively with choline acetyltransferase–immunopositive neuron density.
Conclusion
Galanin upregulation within the basal forebrain cholinergic system in LBD, similar to that seen in AD, may represent an intrinsic adaptive response to neurodegeneration that is consistent with its proposed roles in neurogenesis and neuroprotection.
Electronic supplementary material
The online version of this article (doi:10.1186/s40478-015-0249-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s40478-015-0249-4
PMCID: PMC4666186  PMID: 26621352

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