The study investigates the effects of genetic factors on the pathology of Alzheimer’s disease (AD) and Lewy body (LB) diseases, including Parkinson’s disease and dementia with Lewy bodies. A multicenter autopsy series (762 brain samples) with AD, LB or vascular pathology was examined. We assessed the effects of the tau gene (MAPT) H1 haplotype, the H1-specific SNP rs242557, APOE and the α-synuclein gene (SNCA) 3′UTR SNP rs356165 on the burden of AD and LB pathology. We counted neurofibrillary tangles (NFTs) in four brain regions, senile plaques (SPs) in five and LBs in four. We also documented Braak NFT stage, brain weight and presence of vascular pathology. MAPT H1 associated with lower counts of NFTs in the middle frontal (P<0.001) and inferior parietal (P=0.005) cortices, and also with lower counts of SPs in the motor cortex (P=0.001). Associations of MAPT H1 with increased LB counts in the middle frontal cortex (P=0.011) and inferior parietal cortex (P=0.033) were observed but were not significant after multiple testing adjustment. The APOE ε4 allele was strongly associated with overall Alzheimer type pathology (all P≤0.001). SNCA rs356165 and the MAPT H1-specific SNP rs242557 did not associate with AD or LB pathology. This study shows for the first time that MAPT H1 is associated with reduced Alzheimer type pathology, which could have important implications for the understanding of disease mechanisms and their genetic determinants.
MAPT; SNCA; APOE; Alzheimer pathology; Lewy body
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.
Alzheimer’s disease; amyloid imaging; striatum; amyloid plaques; diagnosis; therapy; asymptomatic; preclinical; autopsy
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.
Although organochlorines have been reported more frequently in Parkinson’s disease (PD) brains than controls, the association with brain Lewy pathology is unknown. Honolulu-Asia Aging Study (HAAS) participants, exposed to organochlorines from a variety of sources during mid-life, represent a population well suited to determine the relationship of brain organochlorines with Lewy pathology in decedents from the longitudinal HAAS.
Study design included the measurement of 21 organochlorine levels in frozen occipital lobe samples from HAAS decedents. Alpha-synuclein immunostaining performed on 225 brains was used to identify Lewy bodies and Lewy neurites.
With the potential for spurious associations to appear between Lewy pathology and 17 organochlorine compounds found to be present in at least one brain, initial assessments identified heptachlor epoxide isomer b, methoxychlor, and benzene hexachloride b as being most important. Prevalence of Lewy pathology was 75% (6/8) among brains with any 2 of the 3 compounds, 48.8% (79/162) among those with 1, and 32.7% (18/55) for those with neither (P=0.007 test for trend). While findings persisted after removing cases with PD and dementia with Lewy bodies, and when adjustments were made for age at death, body mass index, pack-years of cigarette smoking, and coffee intake (p=0.013), results were insignificant when correcting for multiple testing.
While consistent with earlier accounts of an association between organochlorines and clinical PD, associations with Lewy pathology warrant further study.
Parkinson’s disease; epidemiology; Lewy body; organochlorines; pesticides
To assess the contribution of dementia-related neuropathologic lesions to age-related and disease-related change in cognitive function.
A total of 354 Catholic nuns, priests, and brothers had annual clinical evaluations for up to 13 years, died, and underwent brain autopsy. The clinical evaluations included detailed testing of cognitive function from which previously established composite measures of global cognition and specific cognitive functions were derived. As part of a uniform neuropathologic evaluation, the density of neurofibrillary tangles was summarized in a composite measure and the presence of Lewy bodies and gross and microscopic cerebral infarction was noted.
During follow-up, rate of global cognitive decline was gradual at first and then more than quadrupled in the last 4 to 5 years of life consistent with the onset of progressive dementia. Neurofibrillary tangles, cerebral infarction, and neocortical Lewy bodies all contributed to gradual age-related cognitive decline and little age-related decline was evident in the absence of these lesions. Neurofibrillary tangles and neocortical Lewy bodies contributed to precipitous disease-related cognitive decline, but substantial disease-related decline was evident even in the absence of these lesions.
Mild age-related decline in cognitive function is mainly due to the neuropathologic lesions traditionally associated with dementia.
= Alzheimer disease.
Neocortical neuritic plaques (NP) and neurofibrillary tangles (NFT) are hallmarks of Alzheimer’s disease (AD) and usually, both are present. The Honolulu-Asia Aging Study autopsy series includes a significant number of individuals with only one neocortical AD lesion type. These could represent an early phase of the AD process. If so, such individuals would be expected to share other clinical and pathological features of AD. We compared frequency of apolipoprotein epsilon E4 (APOE4) allele, average Braak stage, and burden of cerebral amyloid angiopathy (CAA) among the two single lesion type groups, a group without AD lesions, and groups with high and low frequencies of both AD lesions. Single AD lesion groups shared only the characteristics associated with their unique lesion type with the combined AD lesion group and did not have higher prevalence of dementia than the no AD lesion group. Only the NP+NFT group showed a “dose response” relationship with greater probability of dementia with higher neocortical frequencies of either AD lesion. The single neocortical AD lesion groups do not appear to represent early AD.
Alzheimer’s disease; Neocortical neuritic plaques; Neocortical neurofibrillary tangles; Braak stage; Apolipoprotein epsilon E4; Cerebral amyloid angiopathy
To study the association of microinfarcts (MBI) to ante-mortem global cognitive function (CF), and to investigate whether brain weight (BW), Alzheimer’s lesions (neurofibrillary tangles (NFT) or neuritic plaques (NP) mediate the association.
Subjects are 437 well-characterized male decedents from the Honolulu Asia Aging Autopsy Study. Brain pathology was ascertained with standardized methods, CF was measured by the Cognitive Abilities Screening Instrument (CASI)and data were analyzed using formal mediation analyses, adjusted for age at death, time between last CF measure and death, education, and head size. Based on ante-mortem diagnoses, demented and non-demented subjects were examined together and separately.
In those with no dementia, MBI were strongly associated with the last ante-mortem CF score; this was significantly mediated by BW, and not NFT or NP. In contrast, among those with an ante-mortem diagnosis of dementia, NFT had the strongest associations with BW and with CF, and MIB were modestly associated with CF.
This suggests microinfarct pathology is a significant and independent factor contributing to brain atrophy and cognitive impairment, particularly before dementia is clinically evident. The role of vascular damage as initiator, stimulator, or additive contributor to neurodegeneration may differ depending on when in the trajectory towards dementia the lesions develop.
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.
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.
GRN; miRNA; microRNA; neurofibrillary tangles; neuropathology
To test the hypothesis that use of antihypertensive medication is associated with lower Alzheimer disease (AD) neuropathology.
This was a postmortem study of 291 brains limited to those with normal neuropathology or with uncomplicated AD neuropathology (i.e., without other dementia-associated neuropathology) in persons with or without hypertension (HTN) who were and were not treated with antihypertensive medications. Neuritic plaque (NP) and neurofibrillary tangle (NFT) densities, quantified in selected brain regions according to the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropathologic criteria, with additional cortical NP counts, yielded 24 neuropathologic regional measures or summaries. Medicated hypertension (HTN-med; n = 77), nonmedicated HTN (HTN-nomed; n = 42), and non-HTN (no-HTN; n = 172) groups were compared by analyses of variance.
The HTN-med group had significantly less neuropathology than the no-HTN group. The no-HTN group averaged over 50% higher mean NP and NFT ratings, and double the mean NP count, of the HTN-med group. The HTN-nomed group had significantly more neuropathology than the HTN-med group, but not significantly less than the no-HTN group.
There was substantially less Alzheimer disease (AD) neuropathology in the medicated hypertension group than the nonhypertensive group, which may reflect a salutary effect of antihypertensive medication against AD-associated neuropathology.
= Alzheimer disease;
= analysis of covariance;
= analysis of variance;
= body mass index;
= calcium channel blockers;
= Clinical Dementia Rating scale;
= Consortium to Establish a Registry for Alzheimer’s Disease;
= diastolic blood pressure;
= entorhinal cortex;
= Honolulu Asia Aging Study;
= inferior parietal lobule;
= Jewish Home and Hospital;
= midfrontal gyrus;
= Mount Sinai School of Medicine;
= neurofibrillary tangle;
= nursing homes;
= neuritic plaque;
= occipital calcarine cortex;
= orbital frontal cortex;
= systolic blood pressure;
= superior temporal gyrus.
Basic lexical skills are hypotheseized to be relatively preserved in mild dementia but clinical studies have had inconsistent results.
More than 400 older Catholic nuns, priests, and brother recruited from groups across the United States completed annual evaluations for up to 15 years, died, and underwent brain autopsy. Each clinical evaluation included administration of a 20-item word reading test and a 15-item vocabulary test which were combined to form a composite measure of word knowledge. In a uniform neuropathologic examination, Alzheimer’s disease pathology was quantified with a composite index of plaques and tangles and the presence of gross and microscopic cerebral infarctions and Lewy bodies was recorded.
Postmortem pathologic level of Alzheimer’s disease was linearly related to rate of decline in word knowledge. Decline was nearly fourfold faster at a relatively high level of pathology (75th percentile) compared to a relatively low level (25th percentile). Effects for word reading and vocabulary were similar. Gross cerebral infarctions and Lewy bodies were associated with accelerated decline in vocabulary but not in word reading.
Common chronic neurodegenerative conditions impair word knowledge in old age.
Alzheimer’s disease; cerebrovascular disease; Lewy bodies; cognition; post mortem
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.
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.
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.
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.
Alzheimer; cerebral infarct; cognition; white matter 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.
Alzheimer disease; Amyloid; CERAD; Neurofibrillary tangle, Postencephalitic; tau
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.
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).
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.
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.
= 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.
To assess the distribution of dementia subtypes in Brazil using a population-based clinicopathological study.
Brains from deceased individuals aged ≥50 years old were collected after the next of kin signed an informed consent form and provided information through standardized questionnaires. Post-mortem clinical diagnoses were established in consensus meetings, and only cases with moderate or severe dementia or without cognitive impairment were included in the analysis. Immunohistochemical neuropathological examinations were performed following the universally accepted guidelines. A diagnosis of Alzheimer's disease was made when there were at least both a moderate density of neuritic plaques (Consortium to Establish a Register for Alzheimer's disease B or C) and Braak stage III for neurofibrillary tangle distribution. For the diagnosis of vascular dementia, at least three zones or strategic areas had to be affected by infarcts, lacunae, or microinfarcts.
From 1,291 subjects, 113 cases were classified as having moderate or severe dementia, and 972 cases were free of cognitive impairment. The neuropathological diagnoses of the dementia sub-group were Alzheimer's disease (35.4%), vascular dementia (21.2%), Alzheimer's disease plus vascular dementia (13.3%), and other causes of dementia (30.1%). Small-vessel disease, which alone was not considered sufficient for a vascular dementia diagnosis, was present in 38.9% of all of the dementia cases and in 16.8% of the group without cognitive impairment (odds ratio = 2.91; 95% confidence interval, 1.53-5.51), adjusted for age, sex, and education.
The relatively high frequencies of vascular dementia and small-vessel disease in the dementia sub-group constitute relevant findings for public health initiatives because control of vascular risk factors could decrease the prevalence of dementia in developing countries.
Dementia; Alzheimer's Disease; Vascular Dementia; Cerebrovascular Disease; Post-Mortem Diagnosis; Prevalence
We examined correlations between blood pressure and dementia-related pathologic brain changes in a community-based autopsy sample.
Prospective cohort study.
A large health maintenance organization in Seattle, Washington.
A cohort of 250 participants who were ≥ 65 years old and cognitively normal at time of enrollment in the Adult Changes in Thought (ACT) study, and who underwent autopsy.
Blood pressure and history of antihypertensive treatment were taken at enrollment. A linear regression model was used to examine the relationship between blood pressure (systolic and diastolic blood pressure) at enrollment and pathologic changes in cerebrum (cystic macroscopic infarcts, microinfarcts, neuritic plaques, neurofibrillary tangles, and cortical Lewy bodies).
The presence of more than 2 microinfarcts, but not any other pathologic change, was independently associated with systolic (SBP) in younger participants (age 65–80, n=137), but not in older participants (age >80, n=91). The relative risk (RR) for >2 microinfarcts with each 10 mmHg increase in SBP was 1.15 (95% confidence interval (CI): 1.00, 1.33) in the younger participants, adjusted for age-at-entry, gender, and time to death. This RR was particularly strong in younger participants not taking antihypertensive medications (RR: 1.48; 95% CI: 1.21, 1.81); significant associations were not observed in participants treated for hypertension. Findings for diastolic blood pressure were negative.
The association between elevated SBP and cerebrovascular damage in untreated older adults (age 65–80) suggests that adequate hypertension treatment may reduce dementia risk by minimizing microvascular injury to cerebrum.
dementia; blood pressure; hypertension; neuropathology; autopsy
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.
Cerebral amyloid angiopathy; Cortical microinfarcts; Tg-SwDI; Bilateral common carotid artery stenosis
Immunohistochemical characterization of the distribution of GABAA receptor subunits γ 1/3 and 2 in the hippocampus relative to neurofibrillary tangle (NFT) pathology staging was performed in cognitively normal subjects (Braak stage I/II, n=4) and two groups of Alzheimer’s disease (AD) patients (Braak stage III/IV, n=4; Braak stage V/VI, n=8). In both Braak groups of AD patients, neuronal γ1/3 and γ2 immunoreactivity was preserved in all hippocampal subfields. However, compared to normal controls neuronal γ1/3 immunoreactivity was more intense in several end-stage AD subjects. Despite increased NFT pathology in the Braak V/VI AD group, GABAAγ 1/3 and γ2 immunoreactivitydid not co-localize with markers of NFT. These results suggest that upregulating or preserving GABAAγ 1/3 and γ2 receptors may protect neurons against neurofibrillary pathology in AD.
Alzheimer’s disease; GABA; excitotoxicity; neurodegeneration; tau
Alzheimer’s disease (AD) manifests with progressive memory loss and decline of spatial awareness and motor skills. Neurofibrillary tangles (NFTs) represent one of the pathological hallmarks of AD. Previous studies suggest that the enzyme prolyl-peptidyl cis–trans isomerase PIN1 [protein interacting with NIMA (never in mitosis A)-1] recognizes hyperphosphorylated tau (in NFTs) and facilitates its dephosphorylation, thereby recovering its function. This study aims to determine the frequency, severity and distribution of PIN1 immunoreactivity and its relationship to NFTs and other neuropathological markers of neurodegeneration such as amyloid-β (Aβ) plaques and transcription-responsive DNA-binding protein of Mr 43 kDa (TDP-43). Immunohistochemical analysis of 194 patients (46 with AD, 43 with Parkinson’s disease/dementia with Lewy bodies, 12 with progressive supranuclear palsy/corticobasal degeneration, 36 with frontotemporal lobar degeneration, 21 with motor neuron disease and 34 non-demented (ND) individuals) revealed an increased frequency and severity of PIN1 immunoreactive inclusions in AD as compared to all diagnostic groups (P < 0.001). The hippocampal and cortical distribution of PIN1 granules was distinct from that of NFTs, Aβ and TDP-43 pathologies, though the frequency of neurons with PIN1 immunoreactivity increased with increasing NFT pathology. There was a progressive increase in PIN1 changes in ND individuals as the degree of AD-type pathological changes increased. Present findings indicate that PIN1 changes are a constant feature of AD pathology and could serve as a biomarker of the onset or spread of AD neuropathology independent of tau or Aβ.
Alzheimer’s disease; PIN1; Neurofibrillary tangles; Neurodegeneration; Dementia
is a common psychiatric disorder in late life and it may be associated
with vascular disease processes. Although there are clinical and
neuroimaging studies lending support to such a "vascular
depression" hypothesis there have been no neuropathological studies
to directly test this. Postmortem tissue was investigated to determine
whether late life depression was associated with atheromatous change in
large and medium vessels and microvascular disease in the brain.
tissue wae obtained from 20 patients with a history of at least one
episode of DSM-IV major depression and 20 control subjects. Standard
procedures were carried out to analyze and quantify Alzheimer type
pathology (plaques, tangles, Braak staging) and cortical Lewy bodies.
Coronary arteries, cerebral vessels, and aorta were rated for
atheromatous disease on a 0-3 scale and the four neocortical areas
were rated for microvascular disease.
RESULTS—The two groups
showed no significant differences in age, sex, or postmortem delay.
There was a significant increase in atheromatous disease in the
depressed group (p=0.023). No differences were found for microvascular
disease, either in the brain generally or locally in the frontal lobes.
No subject had any significant Alzheimer type or Lewy body pathology.
evidence was found for an excess of atheromatous disease, related to
the aortic and cerebral vessels, in late life depression. However,
there was no evidence of an increase in microvascular disease. The
findings broadly support the vascular depression hypothesis.
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.
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.
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.
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.
Alzheimer disease; APOE; digital microscopy; hippocampus; MAPT; neurofibrillary tangles; thioflavin S fluorescent microscopy
Background and Purpose
Little is known about the role of microinfarcts in dementia and cognition. We examined microinfarcts and dementia, global cognition, and five cognitive systems in community-dwelling older persons.
425 subjects enrolled in the Religious Orders Study underwent annual clinical evaluations, including 19 neuropsychological tests and assessment for dementia, and brain autopsy (39% men; mean age-at-death 87, MMSE 21). Neuropathologic examination documented the presence, number, and location of chronic microinfarcts on 6µm hematoxylin & eosin stained sections from cortical and subcortical regions. Multiple regression analyses adjusted for age-at-death, sex, education, macroscopic infarcts, Alzheimer’s disease (AD) pathology, and Lewy bodies.
Microinfarcts were present in 129/425 (30%) persons (54 cortical, 80 subcortical; 49 multiple). 58/129 (45%) of persons with microinfarcts did not exhibit macroscopic infarcts. Persons with microinfarcts had increased odds of dementia (OR=1.77; 95% CI:1.07, 2.92), especially those persons with multiple cortical microinfarcts. Microinfarcts were also associated with lower average global cognition (estimate=−0.287, SE=0.113, p=0.012), particularly for persons with multiple cortical microinfarcts. Microinfarcts were specifically associated with lower episodic memory (estimate=−0.279, SE=0.138, p=0.044), semantic memory (estimate=−0.391, SE=0.130, p=0.003), and perceptual speed (estimate=−0.400, SE=0.117, p<0.001). In addition, single, multiple, and cortical microinfarcts were associated with worse semantic memory and perceptual speed (all p<0.028). Neither macroscopic infarcts nor AD pathology modified these associations (all p>0.154).
Microinfarcts are common, and persons with multiple cortical microinfarcts have higher odds of dementia. Microinfarcts are also associated with lower cognition, specifically perceptual speed, semantic and episodic memory.
microinfarct; pathology; dementia; cognition
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.
Adult Changes in Thought Study; Alzheimer disease; brain reserve; dementia; Nun Study; presymptomatic; preclinical
Previous studies suggested a relationship between severity of symptoms and the degree of neurofibrillary tangles (NFTs) clustering in different areas of the cortex in Alzheimer’s disease (Lee et al.). The posterior inferior temporal cortex or Brodmann’s area (BA37) is involved in object naming and recognition memory. But the cellular architecture and connectivity and the NTF pathology of this cortex in AD received inadequate attention. In this report, we describe the laminar distribution and topography of NFT pathology of BA 37 in brains of AD patients by using thionin staining for Nissl substance, thioflavin-S staining for Neurofibrillary tangles (NFTs), and phosphorylated tau (AT8) immunohistochemistry. NFTs mostly occurred in cortical layers II, III, V and VI in the area 37 of AD brain. Moreover, NFTs appeared like a patch or in cluster pattern along the cortical layers III and V and within the columns of pyramidal cell layers. The abnormal, intensely labeled AT8 immunoreactive cells were clustered mainly in layers III and V. Based on previously published clinical correlations between cognitive abnormalities in AD and the patterns of laminar distributed NFT cluster pathology in other areas of the brain, we conclude that a similar NFT pathology that severely affected BA 37, may indicate disruption of some forms of naming and object recognition related circuits in AD.
Neurofibrillary tangles; posterior inferior temporal cortex; Brodmann’s area 37; phosphorylated tau; laminar distribution; memory impairment; object recognition
Alzheimer’s disease (AD) is associated with neuronal degeneration, synaptic loss, and deficits in multiple neurotransmitter systems. Alterations in the serotonin 1A (5-HT1A) receptor can contribute to impaired cognitive function in AD, and both in vitro binding and PET imaging studies have demonstrated that 5-HT1A receptors in the hippocampus/medial temporal cortex are affected early in AD. This neuropathological study examined the localization and immunoreaction intensity of 5-HT1A receptor protein in AD hippocampus with the goal to determine whether neuronal receptor levels are influenced by the severity of neurofibrillary tangles (NFT) severity defined by Braaks’ pathological staging and to provide immunohistochemical confirmation of the binding assays and PET imaging studies. Subjects included AD patients and non-AD controls (NC) stratified into three Braaks’ stages (Braak 0–II, NC; Braak III/IV and V/VI, AD). In the Braak 0–II group, 5-HT1A-immunoreactivity (ir) was prominent in the neuropil of the CA1 and subiculum, moderate in the dentate gyrus molecular layer (DGml), and low in the CA3 and CA4. No changes in 5-HT1A-ir were observed in the hippocampus of AD subjects in the Braak III/IV group. Hippocampal 5-HT1A-ir intensity was markedly decreased in the CA1 region in 6 out of 11 (54.5%) subjects in the Braak V/VI group. Across all three groups combined, there was a statistically significant association between reduced 5HT1A-ir and neuronal loss in the CA1, but not in the CA3. The present data demonstrate that hippocampal 5-HT1A receptors are mainly preserved until the end-stage of NFT progression in AD. Thus, the utility of PET imaging using a 5-HT1A specific radiolabeled probe as a marker of hippocampal neuronal loss may be limited to the CA1 field in advanced stage AD cases.
Alzheimer’s disease; hippocampus; immunohistochemistry; serotonin 1A receptor; neurofibrillary tangle