Alzheimer's Disease Neuropathologic Change Research Articles

Characterization of the 18 kDa translocator protein (TSPO) expression in post-mortem normal and Alzheimer's disease brains.

The 18 kDa translocator protein (TSPO) is a widely used target for microglial PET imaging radioligands, but its expression in post‐mortem normal and diseased human brain is not well described. We aimed at characterizing the TSPO expression in human control (CTRL) and Alzheimer's disease (AD) brains. Specifically, we sought to: (1) define the cell type(s) expressing TSPO; (2) compare tspo mRNA and TSPO levels between AD and CTRL brains; (3) correlate TSPO levels with quantitative neuropathological measures of reactive glia and AD neuropathological changes; and (4) investigate the effects of the TSPO rs6971 SNP on tspo mRNA and TSPO levels, glial responses and AD neuropathological changes. We performed quantitative immunohistochemistry and Western blot in post‐mortem brain samples from CTRL and AD subjects, as well as analysis of publicly available mouse and human brain RNA‐Seq datasets. We found that: (1) TSPO is expressed not just in microglia, but also in astrocytes, endothelial cells and vascular smooth muscle cells; (2) there is substantial overlap of tspo mRNA and TSPO levels between AD and CTRL subjects and in TSPO levels between temporal neocortex and white matter in both groups; (3) TSPO cortical burden does not correlate with the burden of activated microglia or reactive astrocytes, Aβ plaques or neurofibrillary tangles, or the cortical thickness; (4) the TSPO rs6971 SNP does not significantly impact tspo mRNA or TSPO levels, the magnitude of glial responses, the cortical thickness, or the burden of AD neuropathological changes. These results could inform ongoing efforts toward the development of reactive glia‐specific PET radioligands.

Spectrum of tau pathologies in Huntington's disease

Huntington's disease (HD) is an autosomal dominant disorder caused by a trinucleotide expansion in the huntingtin gene. Recently, a new role for tau has been implicated in the pathogenesis of HD, whereas others have argued that postmortem tau pathology findings are attributable to concurrent Alzheimer's disease pathology. The frequency of other well-defined common age-related tau pathologies in HD has not been examined in detail. In this single center, retrospective analysis, we screened seven cases of Huntington's disease (5 females, 2 males, age at death: 47–73 years) for neuronal and glial tau pathology using phospho-tau immunohistochemistry. All seven cases showed presence of neuronal tau pathology. Five cases met diagnostic criteria for primary age-related tauopathy (PART), with three cases classified as definite PART and two cases as possible PART, all with a Braak stage of I. One case was diagnosed with low level of Alzheimer's disease neuropathologic change. In the youngest case, rare perivascular aggregates of tau-positive neurons, astrocytes and processes were identified at sulcal depths, meeting current neuropathological criteria for stage 1 chronic traumatic encephalopathy (CTE). Although the patient had no history of playing contact sports, he experienced several falls, but no definitive concussions during his disease course. Three of the PART cases and the CTE-like case showed additional evidence of aging-related tau astrogliopathy. None of the cases showed significant tau pathology in the striatum. In conclusion, while we found evidence for tau hyperphosphorylation and aggregation in all seven of our HD cases, the tau pathology was readily classifiable into known diagnostic entities and most likely represents non-specific age- or perhaps trauma-related changes. As the tau pathology was very mild in all cases and not unexpected for a population of this age range, it does not appear that the underlying HD may have promoted or accelerated tau accumulation.

Luminex-based quantification of Alzheimer's disease neuropathologic change in formalin-fixed post-mortem human brain tissue

The vast majority of archived research and clinical pathological specimens are stored in the form of formalin fixed, paraffin-embedded (FFPE) tissues, but, unlike fresh frozen tissue samples, highly quantitative measures in FFPE tissues are limited to immunohistochemical and immunofluorescence thresholding image analysis studies, cell counting, and ordinal ranking systems. This poses a significant obstacle for clinical investigations that aim to correlate diagnostic markers of neurodegenerative diseases like Alzheimer's disease (AD) with parameters like age, gender, drug exposures, genotype, disease stage, co-morbidities, or environmental factors. To overcome this limitation, we have developed Luminex-based techniques and protocols for the quantification of amyloid β and hyperphosphorylated Tau in FFPE brain sections. We validated the Luminex assay in FFPE sections from prefrontal cortex, hippocampus, and neostriatum from 30 cases that underwent prior neuropathological diagnostic assessment of AD following the current NIA–AA recommendations for AD: 10 cases diagnosed as not or low, 10 cases as intermediate, and 10 cases as high AD neuropathologic change. Consistent with the neuropathologic assessment, Luminex assay detected high amounts of amyloid beta in the frontal cortex and striatum, and high amounts of hyperphosphorylated Tau in the frontal cortex and hippocampus, of cases with high AD neuropathologic change. This assay can be expanded to detect diverse antigenic targets of interest, as we show here with IBA1 and GFAP. This novel approach supports multiplexed highly quantitative, molecularly specific neuropathology measures to further explore mechanisms of neurodegeneration in AD.

Clinical significance of amyloid β positivity in patients with probable cerebral amyloid angiopathy markers.

We investigated the frequency and clinical significance of amyloid β (Aβ) positivity on PET in patients with cerebral amyloid angiopathy (CAA). We recruited 65 patients who met the modified Boston criteria for probable CAA. All underwent amyloid PET, MRI, APOE genotyping and neuropsychological testing, and we obtained information on MRI markers of CAA and ischemic cerebral small-vessel disease (CSVD). We investigated the CAA/ischemic CSVD burden and APOE genotypes in relation to Aβ positivity and investigated the effect of Aβ positivity on longitudinal cognitive decline. Among the 65 CAA patients, 43 (66.2%) showed Aβ PET positivity (Aβ+). Patients with Aβ+ CAA had more lobar microbleeds (median 9, interquartile range 2-41, vs. 3, 2-8; P = 0.045) and a higher frequency of cortical superficial siderosis (34.9% vs. 9.1%; P = 0.025), while patients with Aβ- CAA had more lacunes (1, 0-2, vs. 0, 0-1; P = 0.029) and a higher frequency of severe white matter hyperintensities (45.5% vs. 20.9%; P = 0.040). The frequency of ε4 carriers was higher in Aβ+ patients (57.1%) than in Aβ- patients (18.2%; P = 0.003), while the frequency of ε2 carriers did not differ between the two groups. Finally, Aβ positivity was associated with faster decline in multiple cognitive domains including language (P < 0.001), visuospatial function (P < 0.001), and verbal memory (P < 0.001) in linear mixed effects models. Our findings suggest that a significant proportion of patients with probable CAA in a memory clinic are Aβ- on PET. Aβ positivity in CAA patients is associated with a distinct pattern of CSVD biomarker expression, and a worse cognitive trajectory. Aβ positivity has clinical relevance in CAA and might represent either advanced CAA or additional Alzheimer's disease neuropathological changes.

Failure to detect an association between self-reported traumatic brain injury and Alzheimer's disease neuropathology and dementia

IntroductionRecent research with neuropathologic or biomarker evidence of Alzheimer's disease (AD) casts doubt on traumatic brain injury (TBI) as a risk factor for AD. We leveraged the National Alzheimer's Coordinating Center to examine the association between self-reported TBI with loss of consciousness and AD neuropathologic changes, and with baseline and longitudinal clinical status. MethodsThe sample included 4761 autopsy participants (453 with remote TBI with loss of consciousness; 2822 with AD neuropathologic changes) from National Alzheimer's Coordinating Center. ResultsSelf-reported TBI did not predict AD neuropathologic changes (P > .10). Reported TBI was not associated with baseline or change in dementia severity or cognitive function in participants with or without autopsy-confirmed AD. DiscussionSelf-reported TBI with loss of consciousness may not be an independent risk factor for clinical or pathological AD. Research that evaluates number and severity of TBIs is needed to clarify the neuropathological links between TBI and dementia documented in other large clinical databases.

Dementia in Down syndrome: unique insights for Alzheimer diseaseresearch.

Virtually all adults with Down syndrome (DS) show the neuropathological changes of Alzheimer disease (AD) by the age of 40 years. This association is partially due to overexpression of amyloid precursor protein, encoded by APP, as a result of the location of this gene on chromosome 21. Amyloid-β accumulates in the brain across the lifespan of people with DS, which provides a unique opportunity to understand the temporal progression of AD and the epigenetic factors that contribute to the age of dementia onset. This age dependency in the development of AD in DS can inform research into the presentation of AD in the general population, in whom a longitudinal perspective of the disease is not often available. Comparison of the risk profiles, biomarker profiles and genetic profiles of adults with DS with those of individuals with AD in the general population can help to determine common and distinct pathways as well as mechanisms underlying increased risk of dementia. This Review evaluates the similarities and differences between the pathological cascades and genetics underpinning DS and AD with the aim of providing a platform for common exploration of these disorders.

Amyloid pathology in the brain after ischemia.

As the population is aging all over the world, the economic burden of ischemic brain injuries is constantly increasing. Human brain ischemia is one of the leading causes of premature death, significant morbidity and physical and mental disabilities, resulting in a lower quality of life and unusually high costs of health and social care. One of the most difficult problems associated with the pathology of the brain after ischemia is progressive dementia observed in people who survived the stroke. More recently, brain ischemia has been shown to elicit Alzheimer's disease neuropathologic change, possibly facilitating the development of dementia due to the amyloidogenic processing of Alzheimer's disease-related amyloid protein precursor into amyloid. The main purpose of this review is to present the development of Alzheimer's disease neuropathologic change in the brain after human and experimental ischemia, with a particular emphasis on proteins and genes involved in the amyloidogenic processing of the amyloid protein precursor to amyloid.

Neurodegenerative Dementias: Improving Brain Health to Decrease Risk.

Neurodegenerative Dementias: Improving Brain Health to Decrease Risk.

Antemortem CSF Aβ42/Aβ40 ratio predicts Alzheimer's disease pathology better than Aβ42 in rapidly progressive dementias.

ObjectiveDespite the critical importance of pathologically confirmed samples for biomarker validation, only a few studies have correlated CSF Aβ42 values in vivo with postmortem Alzheimer's disease (AD) pathology, while none evaluated the CSF Aβ42/Aβ40 ratio. We compared CSF Aβ42 and Aβ42/Aβ40 ratio as biomarkers predicting AD neuropathological changes in patients with a short interval between lumbar puncture and death.MethodsWe measured CSF Aβ40 and Aβ42 and assessed AD pathology in 211 subjects with rapidly progressive dementia (RPD) and a definite postmortem diagnosis of Creutzfeldt‐Jakob disease (n = 159), AD (n = 12), dementia with Lewy bodies (DLB, n = 4), AD/DLB mixed pathologies (n = 5), and various other pathologies (n = 31).ResultsThe score reflecting the severity of Aβ pathology showed a better correlation with ln(Aβ42/Aβ40) (R 2 = 0.506, β = −0.713, P < 0.001) than with ln(Aβ42) (R 2 = 0.206, β = −0.458, P < 0.001), which was confirmed after adjusting for covariates. Aβ42/Aβ40 ratio showed significantly higher accuracy than Aβ42 in the distinction between cases with or without AD pathology (AUC 0.818 ± 0.028 vs. 0.643 ± 0.039), especially in patients with Aβ42 levels ≤495 pg/mL (AUC 0.888 ± 0.032 vs. 0.518 ± 0.064). Using a cut‐off value of 0.810, the analysis of Aβ42/Aβ40 ratio yielded 87.0% sensitivity, 88.2% specificity in the distinction between cases with an intermediate‐high level of AD pathology and those with low level or no AD pathology.InterpretationThe present data support the use of CSF Aβ42/Aβ40 ratio as a biomarker of AD pathophysiology and noninvasive screener for Aβ pathology burden, and its introduction in the research diagnostic criteria for AD.

Relative neuron loss in hippocampal sclerosis of aging and Alzheimer's disease.

To characterize the pattern of neuron loss in hippocampal sclerosis of aging (HS-Aging) and age-related diseases and to evaluate its contribution to cognitive impairment in the elderly. Participants (n = 1,361) came from longitudinal observational studies of aging at the Knight Alzheimer Disease Research Center, Washington University (St. Louis, MO). Relative neuron loss in the hippocampus of HS-Aging was measured using unbiased stereological methods. Transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy, a putative marker of HS-Aging, was assessed. Clinical and cognitive data were analyzed using parametric statistical methods. Ninety-three cases had HS-Aging (6.8%), 8 cases had "pure" HS-Aging, and 37 cases had comorbid intermediate or high Alzheimer's disease neuropathological change (i/h ADNC). Relative neuron loss (ratio of neuron number in hippocampal subfield CA1 to the neuron number in parahippocampal gyrus) was 0.15 for HS-Aging; this was significantly lower than 0.64 for i/h ADNC and 0.66 for control cases (Kruskal-Wallis test, p < 0.0001; p = 0.0003, respectively). TDP-43 proteinopathy was present in 92.4% of HS-Aging cases, higher than that in i/h ADNC (52%) and control (25%) cases. Pure HS-Aging cases were more likely to have cognitive impairment in the memory domain. Relative neuron loss in the hippocampus compared to the parahippocampus gyrus may be useful in distinguishing HS-Aging in the context of comorbid ADNC. HS-Aging contributes to cognitive impairment, which phenotypically resembles AD dementia. TDP proteinopathy is a frequent comorbidity in HS-Aging and may contribute to cognitive impairment to a modest degree. Ann Neurol 2018;84:749-761.

The role of myelin damage in Alzheimer's disease pathology.

Although Alois Alzheimer described myelin disruption in Alzheimer’s disease (AD) as early as in 1911, his observation has escaped the attention of researchers since that time. Alzheimer’s disease has been mainly considered as a grey matter disorder; nevertheless, recent evidence suggests that myelin impairment may play an important role in AD pathology. Classical neuropathological changes in AD, e.g. the accumulation of aggregated Aβ 42 and the presence of neurofibrillary tangles, are responsible for neuronal loss, but they may also induce death of oligodendrocytes and myelin damage. There is also evidence that myelin pathology may even precede Aβ and tau pathologies in AD. The state of the art does not allow us to determine whether myelin damage is a primary or a secondary injury in AD subjects. The article presents an overview of current knowledge on the role of myelin in AD pathology and its interactions with Aβ and tau pathologies.

Non-Alzheimer's contributions to dementia and cognitive resilience in The 90+ Study.

The diagnosis of Alzheimer's disease (AD) in the oldest-old is complicated by the increasing prevalence of age-related neurofibrillary tangles, plaques and non-AD pathologies such as cerebrovascular disease (CVD), hippocampal sclerosis (HS), aging-related tau astrogliopathy (ARTAG), as well as TDP-43 and Lewy pathology. The contribution of these non-AD pathologies to dementia and cognitive resilience is unclear. We assessed the level of AD neuropathologic change (ADNPC) and non-AD pathology in 185 participants enrolled in The 90+ Study with available cognitive assessments and brain tissue. Logistic regression models-adjusting for age, sex and education-determined the association between each pathology and dementia or between subgroups. 53% had dementia, primarily AD or mixed AD; 23% had cognitive impairment without dementia (CIND); 23% were not impaired. Both AD and non-AD pathology was prevalent. 100% had tangles, 81% had plaques, and both tangles and plaques associated with dementia. ARTAG distributed across limbic (70%), brainstem (39%) and cortical regions (24%). 49% had possible CVD and 26% had definite CVD, while HS was noted in 15%. Cortical ARTAG, CVD and HS were each associated with dementia, but limbic and brainstem ARTAGs were not. TDP-43 and Lewy pathologies were found in 36 and 17% and both associated with dementia. No pathology distinguished CIND and the not impaired. By NIA-AA criteria and dementia status, the cohort was subdivided into four groups: those with minimal ADNPC included the not dementia (ND) and Not AD dementia groups; and those with significant ADNPC included the Resilient without dementia and AD dementia groups. Compared to the ND group, the Not AD dementia group had more HS, cortical ARTAG, TDP-43, and Lewy pathology. Compared to the AD dementia group, the Resilient group had less CVD, no HS and less cortical ARTAG, TDP-43 and Lewy pathology. Our findings imply that reductions in non-AD pathologies including CVD contribute to cognitive resilience in the oldest-old.

Imbalance of Circulating Th17 and Regulatory T Cells in Alzheimer's Disease: A Case Control Study.

The neuropathological hallmarks of Alzheimer’s disease (AD), i.e., neuritic plaques and neurofibrillary tangles, consist of beta amyloid peptides (Aβ) and hyperphosphorylated Tau. These are accompanied by reactive microglia and astrocytes in the vicinity of the neuritic plaques and by changes to the peripheral immune system, e.g., an increase of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in the peripheral blood. To address a potential involvement of peripheral T helper cell (Th) subsets in AD, we conducted a case control study with 54 individuals with AD dementia (n = 14), with mild cognitive impairment (MCI) due to AD (MCIAD, n = 14), with MCI unlikely due to AD (MCIother, n = 13), and controls without cognitive impairment (controls, n = 13). The proportions of CD3+CD8−IL-17A+IFNγ− Th17 cells, CD3+CD8−IL-17A−IFNγ+ Th1 cells, and CD4+CD127lowCD25+ regulatory T cells (Tregs) were assessed by flow cytometry. In addition, the correlations of the proportions of Th subsets to cerebrospinal fluid biomarkers were studied. CD3+CD8−IL-17A+IFNγ− Th17 cells were significantly increased in subjects with MCIAD compared to age- and sex-matched subjects with MCIother and controls (MCIAD mean = 1.13, SD = 0.77; MCIother mean = 0.58, SD = 0.28; and controls mean = 0.52, SD = 0.22; p = 0.008). The proportion of CD4+CD127lowCD25+ Tregs was not altered between the different groups, but it significantly positively related with the levels of total Tau and pTau181 (rTreg|totalTau = 0.43, p = 0.021, n = 28; rTreg|pTau181 = 0.46; p = 0.024, n = 28) in subjects with AD but not in nonAD controls (rTreg|totalTau = −0.51, p = 0.007, n = 26). The increase of circulating CD3+CD8−IL-17A+IFNγ− Th17 cells in the early stages of AD and the association of CD4+CD127lowCD25+ Tregs with neurodegeneration marker Tau may indicate that the adaptive immune system relates to neuropathological changes in AD.

Selectively Impaired Vasodilation of Human White Matter Penetrating Cerebral Arterioles in Microvascular Brain Injury and Alzheimer's disease

Microvascular brain injury (mVBI) is a common pathologic correlate of vascular contributions to cognitive impairment and dementia (VCID) that leads to white matter (WM) injury. VCID appears to arise from chronic recurrent WM ischemia. We hypothesized that in mVBI WM injury is specifically attributed to vasodilator dysfunction of WM penetrating arterioles. We analyzed 38 cases of mVBI with low and high Alzheimer's disease (AD) neuropathologic changes in prefrontal cortex WM from rapid autopsies in a population‐based cohort where VCID and AD frequently occur. Arteriolar vasodilator function was quantified by videomicroscopy. Acetylcholine‐mediated arteriolar dilation in mVBI with low AD pathology was significantly reduced in WM penetrators relative to pial arterioles. Astrogliosis‐defined WM injury was associated with impaired vasodilator function of WM penetrating arterioles. In mVBI with high AD pathology vasodilator function of WM penetrating arterioles was further diminished. Presence of moderate/frequent neuritic plaques and cerebral amyloid angiopathy were associated with impaired dilation in WM penetrating, but not in pial arterioles. In conclusion, we successfully assessed vasodilator function of human WM penetrating arterioles in postmortem rapid autopsy samples. We found that selectively impaired vasodilator function of WM penetrating arterioles in mVBI occurs in association with WM injury and AD neuropathologic change.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Review: Relationship of type 2 diabetes to human brain pathology.

Type 2 diabetes (T2D) and Alzheimer's disease (AD) are both highly prevalent diseases worldwide, and each is associated with high-morbidity and high-mortality. Numerous clinical studies have consistently shown that T2D confers a two-fold increased risk for a dementia, including dementia attributable to AD. Yet, the mechanisms underlying this relationship, especially nonvascular mechanisms, remain debated. Cerebral vascular disease (CVD) is likely to be playing a role. But increased AD neuropathologic changes (ADNC), specifically neuritic amyloid plaques (AP) and neurofibrillary tangles (NFT), are also posited mechanisms. The clinicopathological studies to date demonstrate T2D to be consistently associated with infarcts, particularly subcortical lacunar infarcts, but not ADNC, suggesting the association of T2D with dementia may largely be mediated through CVD. Furthermore, growing interest exists in insulin resistance (IR), particularly IR within the brain itself, which may be an associated but distinct phenomenon from T2D, and possibly itself associated with ADNC. Other mechanisms largely related to protein processing and efflux in the central nervous system with altered function in T2D may also be involved. Such mechanisms include islet amyloid polypeptide (or amylin) deposition, co-localized with beta-amyloid and found in more abundance in the AD temporal cortex, blood-brain barrier breakdown and dysfunction, potentially related to pericyte degeneration, and disturbance of brain lymphatics, both in the glial lymphatic system and the newly discovered discrete central nervous system lymph vessels. Medical research is ongoing to further disentangle the relationship of T2D to dementia in the ageing human brain.

In vivo [18F]-AV-1451 tau-PET imaging in sporadic Creutzfeldt-Jakob disease.

To determine whether specific patterns of [18F]-AV-1451 tau-PET retention are observed in patients with autopsy-proven sporadic Creutzfeldt-Jakob disease (CJD). In vivo [18F]-AV-1451 PET neuroimaging was performed in 5 patients with sporadic CJD (median age, 66 years [63-74]), and results were compared to cognitively normal (CN) persons (n = 44; median age, 68 years [63-74]) and to participants with very mild Alzheimer disease (AD) dementia (n = 8; median age, 77 years [63-90]). Autopsy was completed in all patients with CJD, confirming the clinical diagnosis and permitting characterization of AD neuropathologic change (ADNC). All patients with CJD presented with rapidly progressive dementia, typical magnetic resonance brain imaging changes, and elevated CSF total tau (median = 6,519; range = 1,528-13,240 pg/mL). Death occurred within 9 months of symptom onset, with a median 1 month (0.2-3.3) interval from [18F]-AV-1451 PET to autopsy. No unique pattern of [18F]-AV-1451 retention was observed on visual inspection. Summary standardized uptake value ratios in patients with CJD (1.17, 1.08-1.36) were indistinguishable from CN persons (1.14, 0.84-1.54; p = 0.6), and well below those of participants with AD (2.23, 1.60-3.04; p ≤ 0.01). [18F]-AV-1451 retention in patients with CJD and CN persons was similar in brain areas frequently affected in AD and CJD. Neuropathologic analysis confirmed the clinical diagnosis in all patients with CJD. Four patients with CJD also had low-level ADNC (A1B1C0); one patient had intermediate-level ADNC (A2B2C1/2). Increased [18F]-AV-1451 retention was not observed in patients with rapidly progressive dementia due to sporadic CJD. The [18F]-AV-1451 PET tracer maintains good specificity for paired helical tau filaments associated with AD dementia.

Vasodilator dysfunction and oligodendrocyte dysmaturation in aging white matter.

Microvascular brain injury (mVBI) is a common pathological correlate of vascular contributions to cognitive impairment and dementia (VCID) that leads to white matter (WM) injury (WMI). VCID appears to arise from chronic recurrent white matter ischemia that triggers oxidative stress and an increase in total oligodendrocyte lineage cells. We hypothesized that mVBI involves vasodilator dysfunction of white matter penetrating arterioles and aberrant oligodendrocyte progenitor cell (OPC) responses to WMI. We analyzed cases of mVBI with low Alzheimer's disease neuropathological change in prefrontal cortex WM from rapid autopsies in a population-based cohort where VCID frequently occurs. Arteriolar vasodilator function was quantified by videomicroscopy. OPC maturation was quantified using lineage specific markers. Acetylcholine-mediated arteriolar dilation in mVBI was significantly reduced in WM penetrators relative to pial arterioles. Astrogliosis-defined WMI was positively associated with increased OPCs and was negatively associated with decreased mature oligodendrocytes. Selectively impaired vasodilator function of WM penetrating arterioles in mVBI occurs in association with aberrant differentiation of OPCs in WMI, which supports that myelination disturbances in VCID are related to disrupted maturation of myelinating oligodendrocytes. Ann Neurol 2018;83:142-152.

Application of the condensed protocol for the NIA-AA guidelines for the neuropathological assessment of Alzheimer's disease in an academic clinical practice.

In response to concerns regarding resource expenditures required to implement fully the 2012 National Institute on Aging and the Alzheimer's Association (NIA-AA) Sponsored Guidelines for the neuropathological assessment of Alzheimer's disease (AD), we previously developed a sensitive and cost-reducing condensed protocol (CP) at the University of Washington (UW) Alzheimer's Disease Research Center (ADRC) that consolidated the recommended NIA-AA protocol into fewer cassettes requiring fewer immunohistochemical stains. The CP was not designed to replace NIA-AA protocols, but instead to make the NIA-AA criteria accessible to clinical and forensic neuropathology practices where resources limit full implementation of NIA-AA guidelines. In this regard, we developed practical criteria to instigate CP sampling and immunostaining, and applied these criteria in an academic clinical neuropathological practice. During the course of 1 year, 73 cases were sampled using the CP; of those, 53 (72.6%) contained histological features that prompted CP work-up. We found that the CP resulted in increased identification of AD and Lewy body disease neuropathological changes from what was expected using a clinical history-driven work-up alone, while saving approximately $900 per case. This study demonstrates the feasibility and cost-savings of the CP applied to a clinical autopsy practice, and highlights potentially unrecognised neurodegenerative disease processes in the general ageing community.

Retinal thickness correlates with parietal cortical atrophy in early-onset Alzheimer's disease and controls

IntroductionThe retina may reflect Alzheimer's disease (AD) neuropathological changes and is easily visualized with optical coherence tomography (OCT). Retinal thickness decrease has been correlated to AD, however, without information on amyloid status. We correlated retinal (layer) thickness to AD biomarkers in amyloid-positive early-onset AD (EOAD) patients and amyloid-negative controls. MethodsWe measured macular thickness and peripapillary retinal nerve fiber layer thickness with OCT in 15 EOAD patients and 15 controls and correlated retinal thickness to visual rating scores for atrophy on magnetic resonance imaging. ResultsTotal macular thickness correlated to parietal cortical atrophy in both groups (Spearman ρ −0.603, P = .001). Macular and peripapillary retinal nerve fiber layer thicknesses were not significantly decreased in EOAD compared to controls. DiscussionRetinal thickness does not discriminate EOAD from controls but is correlated to parietal cortical atrophy in both groups. These findings may suggest reflection of cerebral cortical changes in the retina, independent of amyloid.

Mixed neuropathologies and associations with domain-specific cognitive decline.

To test whether decline in specific cognitive domains associated with Alzheimer disease neuropathologic change (ADNC) is modified by co-occurrence of other neuropathologies such as Lewy body disease (LBD) or vascular brain injury (VBI). Data came from 1,603 autopsied participants evaluated at US Alzheimer's Disease Centers. Standardized z scores in memory, attention, language, and executive function were derived from neuropsychological test scores assessed at each annual visit. Multivariable linear mixed-effects models assessed associations between neuropathologies and longitudinal trajectories of domain scores. Compared to other participants, those with ADNC + LBD generally had worse cognitive trajectories, particularly lower initial executive function and faster attention decline. Participants with ADNC + VBI typically had less impairment and slower decline. Interactions were significant between LBD and ADNC for memory (p = 0.046) and between VBI and ADNC for language (p = 0.03); decline was slower than expected if these neuropathologies acted additively on the rate of decline. In secondary models, these interactions were limited to those with high ADNC (but not intermediate ADNC). In a subset of 260 participants with data on microinfarct location, cortical and subcortical microinfarcts were associated with decline in memory, language, and executive function in those without ADNC, but this effect was reduced among those with ADNC. ADNC + LBD (but not ADNC + VBI) was associated with poorer executive function and attention compared to other pathology groupings. However, the effect of co-occurring pathologies on cognitive trajectories may depend on the severity of ADNC. Future studies using antemortem biomarkers should seek to replicate these neuropathologic observations.