Alzheimer's Disease-related Changes Research Articles

Retinal thickness and vascular parameters using optical coherence tomography in Alzheimer's disease: a meta-analysis.

Examining the retinal tissue has the potential to provide a unique method and technique to quantify Alzheimer's disease-related changes in participants at various stages of the disease. In this meta-analysis, we aimed to investigate the association of various optical coherence tomography parameters with Alzheimer's disease and whether retinal measurements can be used to differentiate between Alzheimer's disease and control subjects. Scientific databases including Google Scholar, Web of Science, and PubMed were systematically searched for published articles that evaluated retinal nerve fiber layer thickness and retinal microvascular network in Alzheimer's disease and control subjects. Seventy-three studies (5850 participants, including 2249 Alzheimer's disease patients and 3601 controls) were included in this meta-analysis. Relative to controls, Alzheimer's disease patients had a significantly lower global retinal nerve fiber layer thickness (standardized mean difference [SMD] = -0.79, 95% confidence intervals [CI]: -1.03 to -0.54, P < 0.00001) as well as each quadrant being thinner in Alzheimer's disease versus controls. Regarding macular parameters, values measured by optical coherence tomography were significantly lower in Alzheimer's disease than controls for macular thickness (pooled SMD: -0.44, 95% CI: -0.67 to -0.20, P = 0.0003), foveal thickness (pooled SMD = -0.39, 95% CI: -0.58 to -0.19, P < 0.0001), ganglion cell inner plexiform layer (SMD = -1.26, 95% CI: -2.24 to -0.27, P = 0.01) and macular volume (pooled SMD = -0.41, 95% CI -0.76 to -0.07, P = 0.02). Analysis using optical coherence tomography angiography parameters revealed mixed results between Alzheimer's disease and controls. Superficial vessel density (pooled SMD = -0.42, 95% CI: -0.68 to -0.17, P = 0.0001) and deep vessel density (pooled SMD = -0.46, 95% CI: -0.75 to -0.18, P = 0.001) were found to be thinner in Alzheimer's disease patients whereas the foveal avascular zone (SMD = 0.84, 95% CI: 0.17-1.51, P = 0.01) was larger in controls. Vascular density and thickness of various retinal layers were decreased in Alzheimer's disease patients compared to controls. Our results provide evidence for optical coherence tomography technology having the potential to detect retinal and microvascular changes in patients diagnosed with Alzheimer's disease and aid in monitoring and early diagnosis methods.

Tau seeds are widespread in the brain at the earliest stages of Alzheimer's disease-related changes.

Alzheimer's disease (AD) is pathologically characterized by the systematic spread of 3R/4R tau species with progressing disease. Current imaging and CSF in-vivo assessments of tau are thought to reflect more mature tangle neuropathology. However, earlier oligomeric tau species are indicated to have greater neurotoxicity than mature forms and it is largely unknown how tau seeds correlate with histological indicators of AD. Furthermore, tau co-pathology is thought to influence features and progression of other neurodegenerative diseases including Lewy body disease (LBD); yet reliable measurements of tau seeds in such diseases remains an unmet need. Here, we use tau real-time quaking-induced conversion (RT-QuIC) assays to directly measure bioactive tau seeds in brain samples across a spectrum of neurodegenerative diseases to determine tau seeding activities at different stages of AD related changes. Tau RT-QuIC exploits the seeded polymerization growth mechanism of tau filaments, with sensitivities in the low fM range, allowing quantitation of disease-associated aggregates with unprecedented sensitivity and selectivity. Tau RT-QuIC assays were used to quantitate tau seeds in mid-frontal lobe brain tissue from 64 cases including subjects with neuropathologically confirmed AD (n=15), Parkinson's disease (n=7), multiple system atrophy (n=6), LBD (n=14), frontotemporal lobar degeneration (n=4), progressive supranuclear palsy (n=6), corticobasal degeneration (n=2), early Alzheimer's changes (Braak I-III) (n=7), and controls (n=3). All cases had Braak tau staging and frontal lobes were immunohistochemically stained for tau with NFT1. 3R/4R tau seeding activity is typically 100-1000-fold higher in cases with a primary AD diagnosis compared to controls, 4R tauopathies, and synucleinopathies, consistent with our prior observations. Seeding activity positively correlated with Braak tau stage, a histological measure of tau accumulation, with increased tau seeding activities at higher Braak stages. Tau seeds are detectable in the frontal lobe even at Braak I, a stage at which frontal lobe lacks histologically visible tau deposits. Ultrasensitive RT-QuIC assays detect tau seeds at the earliest stages of disease processes, prior to histopathological evidence of more mature tau accumulations and can indicate co-occurrence of tau pathology in non-AD cases. Tau seeding activity correlates with overall Braak tau stage, raising the possibility of quantitative value of tau RT-QuIC assays.

Fatty acids and beyond: Age and Alzheimer's disease related changes in lipids reveal the neuro-nutraceutical potential of lipids in cognition

Lipids are essential in maintaining brain function, and lipid profiles have been reported to be altered in aged and Alzheimer's disease (AD) brains as compared to healthy mature brains. Both age and AD share common metabolic hallmarks such as increased oxidative stress and perturbed metabolic function, and age remains the most strongly correlated risk factor for AD, a neurodegenerative disease.A major accompanying pathological symptom of these conditions is cognitive impairment, which is linked with changes in lipid metabolism. Thus, nutraceuticals that affect brain lipid metabolism or lipid levels as a whole have the potential to ameliorate cognitive decline. Lipid analyses and lipidomic studies reveal changes in specific lipid types with aging and AD, which can identify potential lipid-based nutraceuticals to restore the brain to a healthy lipid phenotype. The brain lipid profile can be influenced directly with dietary administration of lipids themselves, although because of synergistic effects of nutrients it may be more useful to consider a multi-component diet rather than single nutrient supplementation. Gut microbiota also serve as a source of beneficial lipids, and the value of treatments that manipulate the composition of gut microbiome should not be ignored. Lastly, instead of direct supplementation, compounds that affect pathways involved with lipid metabolism should also be considered as a way of manipulating lipid levels to improve cognition.In this review, we briefly discuss the role of lipids in the brain, the changing lipid profile in AD, current research on lipid-based nutraceuticals and their therapeutic potential to combat cognitive impairment.

LRP1 is a master regulator of tau uptake and spread

The spread of protein aggregates during disease progression is a common theme underlying many neurodegenerative diseases. The microtubule-associated protein tau (MAPT) plays a central role in the pathogenesis of several forms of dementia known as tauopathies, including Alzheimer's disease (AD), frontotemporal dementia (FTD) and chronic traumatic encephalopathy (CTE)1. Progression of these diseases is characterized by the sequential spread and deposition of protein aggregates in a predictable pattern that correlates with clinical severity2. This observation and complementary experimental studies3,4 have suggested that tau can spread in a prion-like manner by passing to naïve cells where it templates misfolding and aggregation. However, while tau propagation has been extensively studied, the underlying cellular mechanisms remain poorly understood. Here we show that the low-density lipoprotein (LDL) receptor-related protein 1 (LRP1) controls tau endocytosis and subsequent spread. Knockdown of LRP1 significantly reduced tau uptake in H4 neuroglioma cells and iPS-derived neurons. The interaction between tau and LRP1 is mediated by lysine residues in the microtubule binding repeat region of tau. Furthermore, we find that downregulation of LRP1 in an in vivo mouse model of tau spread effectively reduced tau propagation between neurons. Our results identify LRP1 as a key regulator of tau spread in the brain and, thus, as a novel target for diseases of tau spread and aggregation. 1 Goedert, M., Eisenberg, D. S. & Crowther, R. A. Propagation of Tau Aggregates and Neurodegeneration. Annu Rev Neurosci 40, 189-210, doi:10.1146/annurev-neuro-072116-031153 (2017). 2 Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82, 239-259, doi:10.1007/bf00308809 (1991). 3 de Calignon, A. et al. Propagation of tau pathology in a model of early Alzheimer's disease. Neuron 73, 685-697, doi:10.1016/j.neuron.2011.11.033 (2012). 4 Guo, J. L. et al. Unique pathological tau conformers from Alzheimer's brains transmit tau pathology in nontransgenic mice. J Exp Med 213, 2635-2654, doi:10.1084/jem.20160833 (2016).

Dream Enactment Behavior Disorder Associated with Pallido-Nigro-Luysian Degeneration and Tau Proteinopathy.

Pallido-nigro-luysian atrophy (PNLA) is a rare neurodegenerative disorder with only a few cases reported to date. Although the clinical picture usually resembles progressive supranuclear palsy, pathological examination reveals more selective atrophy and loss of neurons in the globus pallidus, substantia nigra and subthalamic nucleus. To describe the clinical features and pathological findings of a patient with PNLA. Case report with clinico-pathological discussion. An 83-year-old man presented to our clinic with a vertical supranuclear gaze palsy, parkinsonism, gait impairment and sleep abnormalities suggestive of REM-sleep behavior disorder. Neuropathological examination 5 years after symptom onset revealed subcortical tau proteinopathy compatible with a PNLA pattern. There was also an associated mild degree of limbic/subcortical inflammatory response, Alzheimer's disease-related changes, as well as argyrophilic grain disease. We present a comprehensive clinico-pathological discussion of a patient with PNLA. Besides parkinsonism and vertical supranuclear gaze palsy, the patient also had a sleep disorder, clinically suggestive of REM behavioral disorder, which has not been previously reported in PNLA. We expand the clinical phenotype of this rare condition and provide neuropathological evidence for the associated abnormalities.

Copathology in Progressive Supranuclear Palsy: Does It Matter?

The influence of concomitant brain pathologies on the progression rate in PSP is unclear. To analyze the frequency and severity of copathologies and their impact on the progression in PSP. We analyzed clinic-pathological features of 101 PSP patients. Diagnoses and stages of copathologies were established according to standardized criteria, including Alzheimer's disease-related pathology, argyrophilic grains, Lewy-related pathology, transactive response DNA-binding protein 43 pathology, fused in sarcoma pathology, cerebral amyloid angiopathy, and small vessel disease. Demographic data and major clinical milestones (frequency and latency to onset) were extracted from patients' files. Only 8% of 101 patients presented with pure PSP pathology without any copathology. Alzheimer's disease-related pathology was the most frequent (84%), followed by argyrophilic grains (58%), both occurring as single copathology or in combination with other proteinopathies or cerebrovascular disease. Lewy-related and transactive response DNA-binding protein 43 copathology occurred rarely (8% and 6%, respectively). Fused in sarcoma-positive cases were not found. While being common, copathology was mostly mild in severity, with the exception of frequently widespread argyrophilic grains. Small vessel disease was also frequent (65%). Cerebral amyloid angiopathy occurred only in the presence of Alzheimer's disease-related changes (25%). The copathologies did not have major impact on prevalence and time frame of major disease milestones. In PSP, concomitant neurodegenerative proteinopathies or cerebrovascular diseases are frequent, but generally mild in severity. Our data confirmed that four repeat tau is still the most relevant target for PSP, whereas the impact of copathologies on progression rate appears to be of less importance. This is relevant information for the development of disease-modifying therapies. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Age-related retinal thickness in Down's syndrome: A high-risk population for dementia

IntroductionPeople with Down's syndrome (DS) have a high prevalence of early-onset Alzheimer's disease. Early markers of Alzheimer's disease pathology identifiable before clinical change are needed for the evaluation of preventative treatments. The retina, an extension of the brain, may provide a noninvasive imaging site. MethodsForty-nine adults with DS and 36 age-matched controls completed retinal nerve fibre layer (RNFL) assessments using optical coherence tomography. RNFL thickness was analyzed in relation to cognitive status and age and previously acquired cortical thickness and cerebral amyloid β binding data in a subgroup. ResultsRNFL thickness was greater in the DS group and did not show age-related thinning. RNFL correlated positively with cognitive scores and cortical thickness and was reduced in participants with positive cerebral amyloid β binding. DiscussionIncreased RNFL in adults with DS may represent early Alzheimer's disease–related changes. Thinning was present in those with cerebral amyloid β binding, independent of age.

Fasudil in combination BMSCS attenuates Alzheimer's disease-related changes through the regulation of the peripheral immune system

Fasudil in combination BMSCS attenuates Alzheimer's disease-related changes through the regulation of the peripheral immune system

Plasma Amyloid-β and Alzheimer's Disease-Related Changes in Late-Life Depression.

To elucidate an involvement of amyloid dysmetabolism in the pathophysiology of depression, we investigated associations of plasma amyloid-β (Aβ) levels with Alzheimer's disease-related changes in neuroimaging and cognitive dysfunction in patients with late-life depression. Higher plasma Aβ40, but not Aβ42 nor Aβ40/Aβ42 ratio, was associated with higher degree of parahippocampal atrophy and lower verbal fluency performance. Indeed, high plasma Aβ40 predicted poor cognitive prognosis of depressed patients with mild cognitive impairment. As an anti-depressive treatment, electroconvulsive therapy (ECT) resulted in a marginally significant reduction of plasma Aβ40 compared to pharmacotherapy alone, suggesting protective effects of ECT against amyloid dysmetabolism.

Heroin abuse exaggerates age-related deposition of hyperphosphorylated tau and p62-positive inclusions

The observation of increased hyperphosphorylated tau levels correlating with microglial activation in opiate abusers has been interpreted as predisposition to accelerated Alzheimer disease–related changes. The present study focused on evaluating additional neurodegeneration-related proteins, including α-synuclein and TDP-43, and p62-positive deposits. We performed a systematic mapping of protein deposits in the brains of 27 individuals with documented heroin addiction (age: 19–40 years) and compared with 11 controls (age: 15–40 years). We confirm previous findings that heroin addiction associates with tau hyperphosphorylation in predilection brain areas for aging and Alzheimer disease. Furthermore, we show that this occurs also in areas implicated in the molecular disturbances and in vivo neuronal networks related to heroin abuse. There was, however, no presence of amyloid-beta deposits. We extend previous findings by showing the lack of TDP-43 or α-synuclein pathology and emphasize the independent effect of the duration of drug use on the appearance of age-related p62-positive neuritic profiles. These observations provide unique insights about neuropathological alterations in the brains of young heroin addicts and have implications about brain aging and the influences of environmental and toxic factors.

Alzheimer's-related changes in non-demented essential tremor patients vs. controls: Links between tau and tremor?

In addition to tremor, patients with essential tremor (ET) may exhibit non-motor features, including a range of cognitive deficits. Several prospective, population-based epidemiological studies have reported an association between ET and incident dementia, especially Alzheimer's disease (AD). Moreover, in a brain repository-based study, a larger than expected proportion of ET patients also developed pathological changes characteristic of progressive supranuclear palsy, further suggesting a link between ET and tau pathology. We selected a group of ET patients that were free of dementia clinically and without AD on postmortem examination. Our hypothesis was that neuronal tauopathic burden would be higher in the brains of these ET patients compared to controls. We compared Braak stage for neuronal tangles and Consortium to Establish a Registry for Alzheimer's Disease (CERAD) scores for neuritic plaques in the two groups. The two groups were similar in age (82.6±6.0 vs. 80.4±8.1, p=0.22). The 40 ET patients had a higher Braak neurofibrillary stage than 32 controls (means: 2.2±1.2 vs. 1.2±1.1; medians: 2.0 vs. 1.0, p<0.001). Meanwhile, CERAD scores for neuritic plaques were similar in patients and controls (means: 0.6±0.9 vs. 0.5±0.6; medians: 0.0 vs. 0.0, p=0.83). While ET itself is not a tauopathy (i.e., a neurodegenerative disorder among whose main features are accumulation of hyperphosphorylated tau protein), ET may predispose individuals to accumulate more widespread cellular tau aggregates, and thus tau could play a central role in the cognitive impairment that can accompany ET.

Alzheimer's disease-related changes in regional spontaneous brain activity levels and inter-region interactions in the default mode network

The degree of Granger causal modeling estimated influence for a brain region was reported to predict its blood oxygenation level-dependent (BOLD) activity level in the resting-state default mode network (DMN). Many brain disorders, such as Alzheimer's disease (AD), may alter the influence strength, activity levels, or both. Whether the relationship or prediction between these two will be affected under disease condition is unknown. In this study, the spontaneous brain activity, and inter-regional Granger causality connection were investigated over eight core DMN regions in AD patients in contrast to that in normal controls. Compared to normal control (NC), AD patients had both decreased BOLD activity level and Granger causal influence in medial prefrontal cortex and decreased activity level in inferior parietal cortex showed. However, the positive correlation between the BOLD activity level and the degree of the Granger causal modeling defined influence was found not altered by AD.

Identification of gene pathways implicated in Alzheimer's disease using longitudinal imaging phenotypes with sparse regression

We present a new method for the detection of gene pathways associated with a multivariate quantitative trait, and use it to identify causal pathways associated with an imaging endophenotype characteristic of longitudinal structural change in the brains of patients with Alzheimer's disease (AD). Our method, known as pathways sparse reduced-rank regression (PsRRR), uses group lasso penalised regression to jointly model the effects of genome-wide single nucleotide polymorphisms (SNPs), grouped into functional pathways using prior knowledge of gene–gene interactions. Pathways are ranked in order of importance using a resampling strategy that exploits finite sample variability. Our application study uses whole genome scans and MR images from 99 probable AD patients and 164 healthy elderly controls in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. 66,182 SNPs are mapped to 185 gene pathways from the KEGG pathway database. Voxel-wise imaging signatures characteristic of AD are obtained by analysing 3D patterns of structural change at 6, 12 and 24 months relative to baseline. High-ranking, AD endophenotype-associated pathways in our study include those describing insulin signalling, vascular smooth muscle contraction and focal adhesion. All of these have been previously implicated in AD biology. In a secondary analysis, we investigate SNPs and genes that may be driving pathway selection. High ranking genes include a number previously linked in gene expression studies to β-amyloid plaque formation in the AD brain (PIK3R3, PIK3CG, PRKCA and PRKCB), and to AD related changes in hippocampal gene expression (ADCY2, ACTN1, ACACA, and GNAI1). Other high ranking previously validated AD endophenotype-related genes include CR1, TOMM40 and APOE.

Episodic memory of APOE ε4 carriers is correlated with fractional anisotropy, but not cortical thickness, in the medial temporal lobe

The ε4 allele of apolipoprotein E (apoE, protein; APOE, gene) is the most important genetic risk factor for the development of Alzheimer's disease (AD). Cortical structures in the medial temporal lobe (MTL) are important for memory function and are affected early in AD. Both gray matter (GM) and white matter (WM) structures in the MTL have been reported to display AD related changes in healthy APOE ε4 carriers, but the effects are relatively small and somewhat deviating. Still, there is a lack of studies directly linking structural measures with performance on psychometric tests in ε4+ individuals. We hypothesized that intact WM integrity in the MTL facilitates episodic memory, and predicted a higher correlation between WM integrity and memory performance in APOE ε4 carriers due to a possible limiting effect of WM microstructure. In the present study of 92 healthy (MMSE>27) participants we acquired T1 3D and DTI images from a 1.5T MRI scanner, and tested the participants with California Verbal Learning Test II (CVLT-II). The study had two main aims: 1) to relate verbal memory performance to entorhinal WM (EWM) integrity in APOE ε4 carriers and non-carriers, and 2) to investigate APOE ε4 effects on EWM and EC thickness. We observed a strong, positive correlation between FA in the EWM and memory performance, which was driven solely by APOE ε4 carriers. These effects were significant while controlling for age, sex, EWM volume and EC thickness. Although EC thickness was significantly reduced in ε4 carriers, we did not find a relationship between EC thickness and memory performance. Thus, increased susceptibility of the WM structures underpinning the entorhinal-hippocampal network, offers a plausible explanation for the earlier onset of cognitive decline previously reported in APOE ε4 carriers.

IC‐P‐049: Exploring the biomarker cascade model: Relating cortical volume loss to [11C]PiB, [18F]FDG and MMSE over time in Alzheimer's disease patients and normal controls

two years before conversion, atrophy has spread to large parts of the temporal and frontal lobes, much of the cingulate gyrus and parts of the orbitofrontal region. Twelve months before conversion, atrophy is present over all the cortex except the occipital lobe and the sensory-motor areas. Six months later and at conversion this pattern persists, but with more severe atrophy.Conclusions: Focal atrophy can be observed in patients with MCI three years before they are diagnosedwith clinically definite AD. The atrophy accelerates during the MCI stage and affects the entire cortex except the occipital and sensory-motor cortex at the time of diagnosis —not unlike the progressive patterns of amyloid deposition described by Braak [7].

IC‐P‐116: Alzheimer's disease–related changes in subfields of the hippocampal formation using 7T MRI

Post-mortem studies indicate that subfields of the hippocampal formation are differentially affected by normal aging and Alzheimer's Disease (AD). Recent studies on 3-4Tesla MRI confirm these observations, but mostly assessed the subfields only in the body of the hippocampus or assessed only three subfields. We developed and validated a protocol using isotropic voxels (0.70 mm 3) at 7T MRI to delineate subfields of the hippocampal formation along its full length. In this pilot study using this protocol, we examined whether subfield volumes differ between patients with Mild Cognitive Impairment (MCI)/AD and older persons with normal cognition. 17 patients (59% women) with MCI (n = 10) or AD (n = 7) were recruited at the UMC Utrecht and 17 elders (65% women) with normal cognition were recruited through GPs in the region. Subjects were scanned with a T2 sequence on a 7T MRI whole body scanner (Philips Healthcare). One rater (LEMW) manually outlined the Entorhinal Cortex (ERC), subiculum (SUB), Cornu Ammonis 1 (CA1), CA2, CA3, Dentate Gyrus (DG) & CA4 and the tail of the left hippocampal formation from coronal images, blinded to group allocation. Intracranial Volume (ICV) was assessed using unified segmentation as implemented in SPM8 (Ashburner&Friston, 2005). Subfield volumes were transformed to z-scores. Mean ± SD age was 74 ± 8 years in MCI/AD patients, and 68 ± 3 in controls. Mean MMSE scores were 25 ± 3 and 29 ± 1, respectively. Regression analyses, adjusted for age, sex and ICV, with z-scores of subfield volumes as dependent variable showed (borderline) significant differences between patients and controls for CA1 (B = -0.88, 95%CI -1.50 to -0.26; P = 0.007), DG&CA4 (B = -0.87, 95%CI -1.56 to -0.19; P = 0.014), CA3 (B = -0.80, 95%CI -1.60 to 0.001; P = 0.050), and SUB (B = -0.77, 95% CI -1.49 to -0.049; P = 0.037). No significant differences in subfield volumes were found for ERC (B = -0.34, 95%CI -1.11 to 0.43; P = 0.38), CA2 (B = -0.50, 95%CI -1.28 to 0.29; P = 0.21), and tail (B = 0.01, 95%CI -0.81 to 0.83; P = 0.98).

P2‐409: Alzheimer's disease–related changes in plasma cortisol levels and gene involvement in the AIBL study

paradigm is being used for ERP testing. Wavelet decomposition of ERP waves will be used to train artificial neural networks (ANNs) to automatically classify AD from control subjects.Results:Recruitment of 47 subjects (39 controls, 8 ADs) has been completed. As shown in attached table, preliminary analysis of 8 AD and 8 ageand education-matched control subjects reveals a statistically significant difference in the latency of P300 peak at electrode Fz in response to the distracter tone (p < 0.05). It is expected that sufficient number of AD subjects will be recruited by June 2012 to enable training of ANNs based on ERP data. Conclusions: Preliminary analysis of ERP data demonstrate a promising trend in P300 latency for discriminating between early AD and healthy controls. Depending on recruitment, classification data will be presented along with updated statistical analyses.

P.5.e.005 Levodopa in vascular extrapyramidal syndrome – is it beneficial or not?

The cAMP-dependent protein kinase (PKA) has been implicated in the Alzheimer's disease pathology of abnormal tau phosphorylation leading to neurofibrillary tangle (NFT) formation, as well as in amyloid precursor protein α-secretase processing. In the present study, we determined whether [3H]cAMP binding to cytosolic and particulate PKA showed any relationship to the extent of Alzheimer's disease pathology at post-mortem. Autoradiographic [3H]cAMP binding to cytosolic and particulate PKA was measured in sections of entorhinal cortex/hippocampal formation from 23 cases that had been staged for Alzheimer's disease-related neurofibrillary changes and amyloid deposits according to Braak and Braak [H. Braak, E. Braak, Neuropathological staging of Alzheimer's-related changes, Acta Neuropathol. 82 (1991) 239–259]. [3H]cAMP binding to cytosolic PKA showed statistically significant reductions in the entorhinal cortex (P<0.01, ANOVA) with respect to neurofibrillary changes. Post-hoc analysis with Fisher's PLSD test showed significant reductions of [3H]cAMP binding to cytosolic PKA at the isocortical stages (V and VI), compared to the non-pathological (O) (by 55%, P<0.01), transentorhinal (I and II) (by 58%, P<0.001) and limbic (III and IV) (by 45%, P<0.05) stages. A significant reduction (by 25%, P<0.05) was also seen in the transentorhinal compared to the limbic stages. [3H]cAMP binding to cytosolic PKA showed no significant alterations with respect to neurofibrillary changes in either the subiculum, CA1–CA4 subfields of the hippocampus or the dentate gyrus. [3H]cAMP binding to cytosolic PKA also showed significant declines in the entorhinal cortex (P<0.01) and subiculum (P<0.05) with respect to staging for amyloid deposits. Post-hoc analysis with Fisher's PLSD test showed significant reductions of [3H]cAMP binding to cytosolic PKA in the entorhinal cortex at amyloid stage C compared to stages O (by 41%, P<0.01) and A (by 38%, P<0.01). In the subiculum, there were significant reductions of [3H]cAMP binding at stages C (by 41%, P<0.01) and B (by 40%, P<0.05), respectively, compared to stage O. [3H]cAMP binding to particulate PKA did not show significant relationships to staging for either neurofibrillary changes or amyloid deposits in either the entorhinal cortex or any of the hippocampal subregions. These findings suggest that whereas [3H]cAMP binding to cytosolic PKA in the entorhinal cortex is reduced with progression of neurofibrillary and amyloid pathology, other hippocampal regions show a preservation of cytosolic and particulate PKA even in late stage pathologies.

Predisposition to accelerated Alzheimer-related changes in the brains of human immunodeficiency virus negative opiate abusers

Cognitive impairment is a recognized effect of drug misuse, including the use of opiates. The pathological basis for this is unknown but the temporal and frontal cortices have been implicated. We have shown previously that deposits of hyperphosphorylated tau in drug user brains exceed those seen in age-matched controls. The present quantitative study of hyperphosphorylated tau and beta amyloid in drug user brains allows comparison with the related pathology in Alzheimer's disease. Brains were obtained from the Edinburgh Medical Research Council Brain Banks, comprising 39 human immunodeficiency virus negative drug users, five subjects with Alzheimer's disease and 37 age-matched, cognitively normal controls, all legally and ethically approved for research. Hyperphosphorylated tau positive (AT8, AT100) neuropil threads were significantly increased in the frontal and temporal cortex, and in the locus coeruleus, of drug users aged > 30 years (all P = 0.04). Under the age of 30 years, drug users showed a similar increase in neuropil threads compared with controls, but this reached significance only in the frontal cortex (P = 0.03). Immunopositivity for both three- and four-repeat tau was present in drug user brains. There was a direct relationship between the numbers of neuropil threads and of neurofibrillary tangles: neurofibrillary tangles were sparse in brains that had neuropil thread counts below 200 cm(2). Hyperphosphorylated tau positive neuropil threads increased at a faster rate in drug users than in controls and the levels of the phosphorylating enzyme, GSK-3, was raised in drug user brains. Beta amyloid (AB4, AB42 and 4G8) was raised in drug user brains (mainly as shadow plaques) but not significantly different from controls and there was no correlation between high beta amyloid and hyperphosphorylated tau in individual cases. Hyperphosphorylated tau levels correlated significantly (P = 0.038) with microglial activation in drug users but not in controls. The levels of hyperphosphorylated tau in drug users fell far short of those seen in Alzheimer's disease but overlapped with those in elderly controls. We conclude that drug users show early Alzheimer's disease-related brain pathology that may be the basis for cognitive impairment and that neuroinflammation is an early accompanying feature. This provides an opportunity to study the pathogenesis of tau pathology in the human brain.

The Effect of Mifepristone (RU 486) on Plasma Cortisol in Alzheimer’s Disease

The glucocorticoid receptor (GR) antagonist mifepristone (RU-486) has been reported to increase early morning plasma ACTH/cortisol in diverse non-demented populations. This pilot study examined the cortisol response to RU 486 in patients with Alzheimer's disease (AD), a condition associated with abnormalities in various aspects of the hypothalamic-pituitary-adrenal (HPA) axis. Nine AD subjects were randomized in a placebo-controlled parallel study: 4 in the placebo group and 5 in the RU 486 group. Subjects received oral doses of RU 486 (200 mg) or placebo daily for 6-weeks. Morning plasma cortisol was determined at baseline, at 12 h following the first study drug dose, and weekly thereafter. RU 486 resulted in a significant increase in cortisol levels [F(1,6)=65.32; P<0.001]. The magnitude of this increase grew over the course of the study [F(1,6)=63.17; P<0.001], was not related to cortisol suppression after dexamethasone and appeared greater than that reported in the literature in younger populations in response to the same drug regimen. However, further studies with age-matched controls should be done to determine possible AD related changes in this response.