Mixed Alzheimer's Disease Research Articles

Tau PET positivity predicts clinically relevant cognitive decline driven by Alzheimer's disease compared to comorbid cases; proof of concept in the ADNI study.

β-amyloid (Aβ) pathology is not always coupled with Alzheimer's disease (AD) relevant cognitive decline. We assessed the accuracy of tau PET to identify Aβ(+) individuals who show prospective disease progression. 396 cognitively unimpaired and impaired individuals with baseline Aβ and tau PET and a follow-up of ≥ 2 years were selected from the Alzheimer's Disease Neuroimaging Initiative dataset. The participants were dichotomously grouped based on either clinical conversion (i.e., change of diagnosis) or cognitive deterioration (fast (FDs) vs. slow decliners (SDs)) using data-driven clustering of the individual annual rates of cognitive decline. To assess cognitive decline in individuals with isolated Aβ(+) or absence of both Aβ and tau (T) pathologies, we investigated the prevalence of non-AD comorbidities and FDG PET hypometabolism patterns suggestive of AD. Baseline tau PET uptake was higher in Aβ(+)FDs than in Aβ(-)FD/SDs and Aβ(+)SDs, independently of baseline cognitive status. Baseline tau PET uptake identified MCI Aβ(+) Converters and Aβ(+)FDs with an area under the curve of 0.85 and 0.87 (composite temporal region of interest) respectively, and was linearly related to the annual rate of cognitive decline in Aβ(+) individuals. The T(+) individuals constituted largely a subgroup of those being Aβ(+) and those clustered as FDs. The most common biomarker profiles in FDs (n = 70) were Aβ(+)T(+) (n = 34, 49%) and Aβ(+)T(-) (n = 19, 27%). Baseline Aβ load was higher in Aβ(+)T(+)FDs (M = 83.03 ± 31.42CL) than in Aβ(+)T(-)FDs (M = 63.67 ± 26.75CL) (p-value = 0.038). Depression diagnosis was more prevalent in Aβ(+)T(-)FDs compared to Aβ(+)T(+)FDs (47% vs. 15%, p-value = 0.021), as were FDG PET hypometabolism pattern not suggestive of AD (86% vs. 50%, p-value = 0.039). Our findings suggest that high tau PET uptake is coupled with both Aβ pathology and accelerated cognitive decline. In cases of isolated Aβ(+), cognitive decline may be associated with changes within the AD spectrum in a multi-morbidity context, i.e., mixed AD.

Contribution of alpha-synuclein pathology to cerebral glucose metabolism in patients with amnestic MCI.

The in vivo detection of mixed Alzheimer's disease (AD) and α-synuclein (αSyn) pathology is important for clinical management and prognostic stratification. We investigated the contribution of αSyn pathology, detected by cerebrospinal fluid (CSF) seed amplification assay (αSyn SAA), on [18F]-fluorodeoxyglucose positron emission tomography (FDG PET) pattern in subjects with amnestic mild cognitive impairment (aMCI). We included 562 aMCI participants and 204 cognitively normalcontrols (CN) with available αSyn SAA and cerebral metabolic rate for glucose utilization (rCMRgl) data. 24% of aMCI cases were positive (+) for CSF αSyn SAA. Compared to CN, both αSyn+ and negative (-) aMCI participants showed reductions in rCMRgl within AD typical regions. αSyn+ aMCI had lower rCMRgl within AD and dementia with Lewy bodies (DLB) typical regions compared to αSyn- aMCI, even after stratification according to the CSF AT(N) system. αSyn pathology contributes to a distinct FDG PET pattern in aMCI. αSyn pathology can be detected in vivo by CSF αSyn SAA. We investigated the FDG PET pattern in aMCI patients with CSF αSyn SAA positivity. αSyn+ aMCI showed a marked brain hypometabolism in AD and DLB typical regions.

Citicoline: A Cholinergic Precursor with a Pivotal Role in Dementia and Alzheimer's Disease.

Citicoline is a naturally occurring compound with pleiotropic effects on neuronal function and cognitive processes. Based on previous studies, which shed light on the positive effects of citicoline 1 g when combined with acetylcholinesterase inhibitors (AChEIs) and/or memantine, we further investigated the benefits of citicoline in combination therapy in Alzheimer's disease and mixed dementia. We integrated the datasets of CITIMEM and CITIDEMAGE, increasing the overall sample size to enhance statistical power. We analyzed data from these two investigator-initiated studies involving 295 patients. The primary outcome was the assessment over time of the effects of combined treatment versus memantine given alone or AChEI plus memantine on cognitive functions assessed by Mini-Mental State Examination (MMSE). The secondary outcomes were the influence of combined treatment on daily life functions, mood, and behavioral symptoms assessed by activities of daily life (ADL) and instrumental ADL, Geriatric Depression Scale, and Neuropsychiatric Inventory Scale. One-hundred-forty-three patients were treated with memantine and/or AChEI (control group), and 152 patients were treated with memantine and/or AChEI plus citicoline 1 g/day orally (Citicoline group). A significant difference in MMSE score was found in the average between the two groups of treatment at 6 and 12 months. This study confirmed the effectiveness of combined citicoline treatment in patients with mixed dementia and Alzheimer's disease, with a significant effect on the increase of MMSE score over time. The treated group also showed a significant reduction in the Geriatric Depression Scale and a significant increase in the instrumental ADL scale.

Using principal component analysis to determine which vestibular stimuli provide best biomarkers for separating Alzheimer's from mixed Alzheimer's disease.

Alzheimer's disease (AD) is often mixed with cerebrovascular disease (AD-CVD). Heterogeneity of dementia etiology and the overlapping of neuropathological features of AD and AD-CVD make feature identification of the two challenging. Separation of AD from AD-CVD is important as the optimized treatment for each group may differ. Recent studies using vestibular responses recorded from electrovestibulography (EVestG™) have offered promising results for separating these two pathologies. An EVestG measurement records responses to several different physical stimuli (called tilts). In previous research, the number of EVestG features from different tilts was selected based on physiological intuition to classify AD from AD-CVD. As the number of potential characteristic features from all tilts can be very large, in this study, we used an algorithm based on principal component analysis (PCA) to rank the most effective vestibular stimuli for differentiating AD from AD-CVD. Analyses were performed on the EVestG signals of 28 individuals with AD and 24 with AD-CVD. The results of this study showed that tilts simulating the otolithic organs (utricle and saccule) generated the most characteristic features for separating AD from AD-CVD.

Lewy body pathology modifies risk factors for cerebral amyloid angiopathy when comorbid with Alzheimer's disease pathology.

Cerebral amyloid angiopathy (CAA) often accompanies dementia-associated pathologies and is important in the context of anti-amyloid monoclonal therapies and risk of hemorrhage. We conducted a retrospective neuropathology-confirmed study of 2384 participants in the National Alzheimer Coordinating Center cohort (Alzheimer's disease [AD], n=1175; Lewy body pathology [LBP], n=316; and mixed AD and LBP [AD-LBP], n=893). We used logistic regression to evaluate age, sex, education,APOE ε4, neuritic plaques, and neurofibrillary tangles (NFTs) in CAA risk. APOE ε4 increased CAA risk in all three groups, while younger age and higher NFT stages increased risk in AD and AD-LBP. In AD-LBP, male sex and lower education were additional risk factors. The odds of APOE ε4 carrier homozygosity related to CAA was higher in LBP (25.69) and AD-LBP (9.50) than AD (3.17). AD and LBPs modify risk factors for CAA and should be considered in reviewing the risk of CAA. Lewy body pathology modifies risk factors for cerebral amyloid angiopathy (CAA) when present along with Alzheimer's disease (AD) neuropathology. In the context of anti-amyloid monoclonal therapies and their associated risks for hemorrhage, the risk of underlying CAA in mixed dementia with Lewy body pathology needs to be considered.

Impact of incidental synucleinopathy in mild cognitive impairment due to Alzheimer disease.

Recent evidence suggests that the presence of α-synuclein Lewy bodies (LBs) correlates with accelerated disease progression in patients with Alzheimer disease (AD) but it is unclear whether this effect is also exerted in the mild cognitive impairment (MCI) phase of AD. We sought to determine whether incidental LB pathology in patients with MCI due to AD is associated with a faster rate of cognitive decline compared to MCI controls without LB pathology. We identified patients within the National Alzheimer's Coordinating Center (NACC) database with MCI due to AD and stratified the cohort by the presence or absence of synucleinopathy. We utilized a repeated measures longitudinal analysis of Mini-Mental State Examination (MMSE) scores to determine whether the decline in performance occurred at a greater rate in the synucleinopathy patients. A total of 206 participants were studied; 80 had coincident synucleinopathy. The rate of decline in MMSE scores between the groups did not differ. This may suggest that a synergistic effect of LB and AD neuropathology is only appreciable in the later stages of disease progression. Further investigation into the effect of mixed LB and AD pathology in the early stages of cognitive impairment is warranted to highlight opportunities for targeted early intervention in patients.

Mixed Dementia Alzheimer and Lewy body with congenital diseases: Case Study

Objectives: Dementia due to Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are the diseases that appear together, especially in elderly people. Still, clinical identification of dementia is difficult in such circumstances. Therefore, we conducted a case study with a comprehensive prospective clinical assessment and complete mental, physical, and psychiatric examination to diagnose such mixed cases clinically and for curative management of mixed dementia of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). Case: a 76 years old woman have anxiety that fluctuated. The history of medical disorders, physical examination and supporting examinations, was found that the patient had hypertension, dyslipidemia, hypothyroidism in treatment, Barrett's esophagus in therapy, osteoarthritis genu dextra, history of malnutrition, breast cancer and hysterectomy. The patient was advised to administer antipsychotics because the patient's agitation was severe and the caregiver's distress was high. The patient improved with pharmacological therapy and family monitoring support. Conclusion: The diagnosis of mixed dementia patients (Alzheimer's disease (AD) and dementia with Lewy bodies (DLB)) with a medical history of congenital disease has overlapping symptoms so that very selective drug treatment is needed so as not to worsen the condition of other diseases. The supportive role of the family can help cure mixed Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) by creating a logbook of daily behavior and symptoms that appear in the patient.

Characterization of cerebellar amyloid-β deposits in Alzheimer disease.

Cerebellar amyloid-β (Aβ) plaques are a component of the diagnostic criteria used in Thal staging and ABC scoring for Alzheimer disease (AD) neuropathologic change. However, Aβ deposits in this anatomic compartment are unique and under-characterized; and their relationship with other pathological findings are largely undefined. In 73 cases of pure or mixed AD with an A3 score in the ABC criteria, parenchymal (plaques) and vascular (cerebral amyloid angiopathy [CAA]) cerebellar Aβ-42 deposits were characterized with respect to localization, morphology, density, and intensity. Over 85% of cases demonstrated cerebellar Aβ-42 parenchymal staining that correlated with a Braak stage V-VI/B3 score (p < 0.01). Among the 63 with cerebellar Aβ-42 deposits, a diffuse morphology was observed in 75% of cases, compact without a central dense core in 32%, and compact with a central dense core in 16% (all corresponding to plaques evident on hematoxylin and eosinstaining). Cases with Purkinje cell (PC) loss showed higher proportions of PC layer Aβ-42 staining than cases without PC loss (88% vs 44%, p = 0.02), suggesting a link between Aβ-42 deposition and PC damage. Among all 73 cases, CAA was observed in the parenchymal vessels of 19% of cases and in leptomeningeal vessels in 44% of cases.

APOE2 Exacerbates TDP-43 Related Toxicity in the Absence of Alzheimer Pathology.

Recent evidence supports a link between increased TDP-43 burden and the presence of an APOE4 gene allele in Alzheimer's disease (AD); however, it is difficult to conclude the direct effect of APOE on TDP-43 pathology due to the presence of mixed AD pathologies. The goal of this study is to address how APOE isoforms impact TDP-43 pathology and related neurodegeneration in the absence of typical AD pathologies. We overexpressed human TDP-43 via viral transduction in humanized APOE2, APOE3, APOE4 mice, and murine Apoe-knockout (Apoe-KO) mice. Behavior tests were performed across ages. Animals were harvested at 11months of age and TDP-43 overexpression-related neurodegeneration and gliosis were assessed. To further address the human relevance, we analyzed the association of APOE with TDP-43 pathology in 160 postmortem brains from autopsy-confirmed amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) in the Mayo Clinic Brain Bank. We found that TDP-43 overexpression induced motor function deficits, neuronal loss, and gliosis in the motor cortex, especially in APOE2 mice, with much milder or absent effects in APOE3, APOE4, or Apoe-KO mice. In the motor cortex of the ALS and FTLD-MND postmortem human brains, we found that the APOE2 allele was associated with more severe TDP-43-positive dystrophic neurites. Our data suggest a genotype-specific effect of APOE on TDP-43 proteinopathy and neurodegeneration in the absence of AD pathology, with the strongest association seen with APOE2. ANN NEUROL 2023;93:830-843.

Association of cerebral microvascular dysfunction and white matter injury in Alzheimer's disease.

Patients with Alzheimer's disease (AD) often have cerebral white matter (WM) hyperintensities on MRI and microinfarcts of presumed microvascular origin pathologically. Here, we determined if vasodilator dysfunction of WM-penetrating arterioles is associated with pathologically defined WM injury and disturbances in quantitative MRI-defined WM integrity in patients with mixed microvascular and AD pathology. We analyzed tissues from 28 serially collected human brains from research donors diagnosed with varying degrees of AD neuropathologic change (ADNC) with or without cerebral microinfarcts (mVBI). WM-penetrating and pial surface arteriolar responses to the endothelium-dependent agonist bradykinin were quantified ex vivo with videomicroscopy. Vascular endothelial nitric oxide synthase (eNOS) and NAD(P)H-oxidase (Nox1,2 and 4 isoforms) expression were measured with quantitative PCR. Glial fibrillary acidic protein (GFAP)-labeled astrocytes were quantified by unbiased stereological approaches in regions adjacent to the sites of WM-penetrating vessel collection. Post-mortem diffusion tensor imaging (DTI) was used to measure mean apparent diffusion coefficient (ADC) and fractional anisotropy (FA), quantitative indices of WM integrity. In contrast to pial surface arterioles, white matter-penetrating arterioles from donors diagnosed with high ADNC and mVBI exhibited a significantly reduced dilation in response to bradykinin when compared to the other groups. Expression of eNOS was reduced, whereas Nox1 expression was increased in WM arterioles in AD and mVBI cases. WM astrocyte density was increased in AD and mVBI, which correlated with a reduced vasodilation in WM arterioles. Moreover, in cases with low ADNC, bradykinin-induced WM arteriole dilation correlated with lower ADC and higher FA values. Comorbid ADNC and mVBI appear to synergistically interact to selectively impair bradykinin-induced vasodilation in WM-penetrating arterioles, which may be related to reduced nitric oxide- and excess reactive oxygen species-mediated vascular endothelial dysfunction. WM arteriole vasodilator dysfunction is associated with WM injury, as supported by reactive astrogliosis and MRI-defined disrupted WM microstructural integrity.

Clinical Trajectories at the End of Life in Autopsy-Confirmed Dementia Patients With Alzheimer Disease and Lewy Bodies Pathologies.

Evaluating and understanding the heterogeneity in dementia course has important implications for clinical practice, health care decision-making, and research. However, inconsistent findings have been reported with regard to the disease courses of the 2 most common dementias: Alzheimer disease (AD) and dementia with Lewy bodies (DLB). Using autopsy-confirmed diagnoses, we aimed to examine the disease trajectories in the years before death among patients with dementia with pure AD, pure DLB, or mixed (AD and DLB) pathologies. The current retrospective longitudinal study included 62 participants with autopsy-confirmed diagnoses of pure AD (n = 34), mixed AD and DLB (AD + DLB; n = 17), or pure DLB (n = 11) from the Predictors 2 Cohort Study, a prospective, clinic-based, cohort of patients with dementia. Generalized estimating equation models, with time zero at death, were used to examine the trajectory of cognition (Folstein Mini-Mental State Examination [MMSE]), function (activities of daily living [ADL]), and Dependence Scale among patients with different autopsy-confirmed diagnosis (pure AD, AD + DLB, and pure DLB). The models were adjusted for age, sex, education, and baseline features including extrapyramidal signs, MMSE, ADL, and Dependence Scale. The participants on average received 9.4 ± 4.6 assessments at 6-month intervals during a mean 5.4 ± 2.9 years of follow-up. The 3 groups were similar in both cognition and function status at baseline. Cognition and function were highly correlated among patients with AD + DLB but not in pure AD or pure DLB at baseline. Patients of the 3 groups all declined in both cognition and function but had different trajectories of decline. More specifically, the patients with pure DLB experienced approximately double the rate of both cognitive decline and functional decline than the patients with pure AD, and the mixed pathology group showed double the rate of functional decline as compared to pure AD. In this longitudinal study, we found that among patients with dementia, those with Lewy body pathology experienced faster cognitive and functional decline than those with pure AD pathology.

TDP-43 promotes tau accumulation and selective neurotoxicity in bigenic Caenorhabditis elegans.

ABSTRACTAlthough amyloid β (Aβ) and tau aggregates define the neuropathology of Alzheimer's disease (AD), TDP-43 has recently emerged as a co-morbid pathology in more than half of patients with AD. Individuals with concomitant Aβ, tau and TDP-43 pathology experience accelerated cognitive decline and worsened brain atrophy, but the molecular mechanisms of TDP-43 neurotoxicity in AD are unknown. Synergistic interactions among Aβ, tau and TDP-43 may be responsible for worsened disease outcomes. To study the biology underlying this process, we have developed new models of protein co-morbidity using the simple animal Caenorhabditis elegans. We demonstrate that TDP-43 specifically enhances tau but not Aβ neurotoxicity, resulting in neuronal dysfunction, pathological tau accumulation and selective neurodegeneration. Furthermore, we find that synergism between tau and TDP-43 is rescued by loss-of-function of the robust tau modifier sut-2. Our results implicate enhanced tau neurotoxicity as the primary driver underlying worsened clinical and neuropathological phenotypes in AD with TDP-43 pathology, and identify cell-type specific sensitivities to co-morbid tau and TDP-43. Determining the relationship between co-morbid TDP-43 and tau is crucial to understand, and ultimately treat, mixed pathology AD.

Elevated C-Reactive Protein in Alzheimer's Disease Without Depression in Older Adults: Findings From the Health and Retirement Study.

We examined the association between differential diagnoses of major stroke and probable Alzheimer's disease (AD) and mixed AD on C-reactive protein (CRP) in older adults with and without depression. Secondary data analyses examined associations between blood-based measures of probable peripheral inflammation using CRP collected from dried blood spots in the Health and Retirement Study, a nationally representative sample of individuals aged 50 and older. A validated pattern-recognition algorithm was utilized to identify cognitive decline indicative of probable AD, mixed AD, and major stroke. Negative binomial regressions were utilized to model concentrations of serologic CRP. On average, participants (N = 4 601) were 70 years old, female, and non-Hispanic White. Mixed AD participants had a 0.26 mg/dL increase in CRP compared to unimpaired participants, controlling for demographics, health behaviors, and comorbidities. Those with mixed AD had 2.14 times increased odds of having high CRP (odds ratio = 2.14 [1.19-3.85]). In analyses stratified by depression, adults with mixed AD and without depression had an additional 0.37 mg/dL increase in CRP (SE = 0.06; p < .001) compared to unimpaired adults. Those with AD without depression had a 0.20 mg/dL increase in CRP (SE = 0.07; p < .01). Age was not associated with increased CRP in nondepressed older adults. Depressed adults with major stroke had a -0.26 mg/dL decrease in CRP (SE = 0.11; p = .02), controlling for hypertension, alcoholic drinks/beverages per week, and smoking status. Concentration modeling revealed that participants with major stroke, probable AD, and probable mixed AD without depression had significantly higher CRP concentrations when compared to unimpaired older adults.

Blood Pressure in Different Dementia Disorders, Mild Cognitive Impairment, and Subjective Cognitive Decline.

The aim of the study was to investigate whether blood pressure (BP) differed among people with different dementia diagnoses, mild cognitive impairment, and subjective cognitive decline and whether BP differences were observed across age and sex. Our study population comprised clinical data from 6,236 patients (53.5% women) aged 45–97 years (Mean = 73.9, SD = 9.6) referred to dementia assessment in 42 outpatient clinics across Norway during 2009–2019. Patients with the following diagnoses were included: Subjective cognitive decline (SCD), Mild cognitive impairment (MCI), dementia due to Alzheimer’s disease (AD), Vascular dementia (VaD), mixed AD and VaD, and dementia in Parkinson’s disease/Lewy body disease (PDD/LBD). For all diagnostic groups, SBP increased with age until about 80 years, after which it trended downward, whereas DBP declined after 60 years of age for all diagnostic groups. Patients aged 65 years and younger with SCD had lower SBP compared to AD patients at the same age, but SBP increased rapidly with increasing age, resulting in a substantially higher SBP at 80 + years compared with all other diagnostic groups. No other differences in SBP or diastolic blood pressure (DBP) were found among patients with the different dementia diagnosis. Neither SBP nor DBP differed between MCI and AD groups. An interaction between age and gender was found for SBP at younger ages, as women started out with a lower pressure than men did but ended up with higher SBP.ConclusionAmong 80+ patients, blood pressure did not differ as a function of the various dementia disorders. The SBP for the SCD patients of various age groups differed from all other diagnostic groups, indicating either that internal regulation of BP in older people is a risk factor for dementia or that brain damage causing dementia or MCI may led to changes in blood pressure. Brain aging seems to influence SBP differently in men and women.

COVID-19 Epidemic in Argentina: Worsening of Behavioral Symptoms in Elderly Subjects With Dementia Living in the Community.

In Argentina, the quality of care that elderly subjects with dementia living in the community received has been deeply affected by COVID-19 epidemic. Our objective was to study to what extend mandatory quarantine imposed due to COVID-19 had affected behavioral symptoms in subjects with dementia after the first 8 weeks of quarantine. We invited family members to participate in a questionnaire survey. The sample consisted of family caregivers (n = 119) of persons with AD or related dementia living at home. We designed a visual analog scale to test the level of the burden of care of family members. Items inquired in the survey included type and setting (home or day care center) of rehabilitation services (physical/occupational/cognitive rehabilitation) and change in psychotropic medication and in behavioral symptoms that subjects with dementia experienced before and during the epidemic. Characteristics of people with dementia and their caregivers were analyzed with descriptive statistics using the chi-square tests, p < 0.01 was considered significant. Results: The sample included older adults with dementia. Mean age: 81.16 (±7.03), 35% of the subjects had more than 85 years of age. Diagnosess were 67% Alzheimer´s dementia and 26% mixed Alzheimer´s disease (AD). Stages were 34.5% mild cases, 32% intermediate stage, and 33% severe cases as per Clinical dementia Rating score. In 67% of the sample, a family member was the main caregiver. Important findings were increased anxiety (43% of the sample), insomnia (28% of the subjects), depression (29%), worsening gait disturbance (41%), and increase use of psychotropics to control behavioral symptoms. When we compared the frequency of behavioral symptoms within each dementia group category, we found that anxiety, depression, and insomnia were more prevalent in subjects with mild dementia compared to subjects with severe dementia. We analyzed the type and pattern of use of rehabilitation services before and during the isolation period, and we observed that, as a rule, rehabilitation services had been discontinued in most subjects due to the quarantine. We concluded from our analysis that during COVID-19 epidemic there was a deterioration of behavioral symptoms in our population of elderly dementia subjects living in the community. Perhaps, our findings are related to a combination of social isolation, lack of outpatient rehabilitation services, and increased stress of family caregivers. It is necessary to develop a plan of action to help dementia subjects deal with the increased stress that this epidemic imposed on them.

Confirmation of 123I-FP-CIT SPECT Quantification Methods in Dementia with Lewy Bodies and Other Neurodegenerative Disorders.

Our rationale was to conduct a retrospective study comparing 3 123I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane (123I-FP-CIT) SPECT quantitative methods in patients with neurodegenerative syndromes as referenced to neuropathologic findings. Methods:123I-FP-CIT-SPECT and neuropathologic findings among patients with neurodegenerative syndromes from the Mayo Alzheimer Disease Research Center and Mayo Clinic Study of Aging were examined. Three 123I-FP-CIT SPECT quantitative assessment methods-MIMneuro, DaTQUANT, and manual region-of-interest creation on a workstation-were compared with neuropathologic findings describing the presence or absence of Lewy body disease (LBD). Striatum-to-background ratios (SBRs) generated by DaTQUANT were compared with the calculated SBRs of the manual method and MIMneuro. The left and right SBRs for caudate, putamen, and striatum were evaluated with the manual method. For DaTQUANT and MIMneuro, the left, right, total, and average SBRs and z scores for whole striatum, caudate, putamen, anterior putamen, and posterior putamen were calculated. Results: The cohort included 24 patients (20 [83%] male, mean age for all patients at death, 75.4 ± 10.0 y). The antemortem clinical diagnoses were Alzheimer disease dementia (n = 6), probable dementia with Lewy bodies (n = 12), mixed Alzheimer disease dementia and probable dementia with Lewy bodies (n = 1), Parkinson disease with mild cognitive impairment (n = 2), corticobasal syndrome (n = 1), idiopathic rapid-eye-movement sleep behavior disorder (n = 1), and behavioral-variant frontotemporal dementia (n = 1). Seventeen (71%) had LBD. All 3 123I-FP-CIT SPECT quantitative methods had an area under the receiver-operating-characteristics curve ranging from more than 0.93 to up to 1.000 (P < 0.001) and showed excellent discrimination between LBD and non-LBD patients in each region assessed (P < 0.001). There was no significant difference between the accuracy of the regions in discriminating the 2 groups, with good discrimination for both caudate and putamen. Conclusion: All 3 123I-FP-CIT SPECT quantitative methods showed excellent discrimination between LBD and non-LBD patients in each region assessed, using both SBRs and z scores.

Modeling Mixed Vascular and Alzheimer's Dementia Using Focal Subcortical Ischemic Stroke in Human ApoE4-TR:5XFAD Transgenic Mice.

Subcortical white matter ischemic lesions are increasingly recognized to have pathologic overlap in individuals with Alzheimer's disease (AD). The interaction of white matter ischemic lesions with amyloid pathology seen in AD is poorly characterized. We designed a novel mouse model of subcortical white matter ischemic stroke and AD that can inform our understanding of the cellular and molecular mechanisms of mixed vascular and AD dementia. Subcortical white matter ischemic stroke underlying forelimb motor cortex was induced by local stereotactic injection of an irreversible eNOS inhibitor. Subcortical white matter ischemic stroke or sham procedures were performed on human ApoE4-targeted-replacement (TR):5XFAD mice at 8weeks of age. Behavioral tests were done at 7, 10, 15, and 20weeks. A subset of animals underwent 18FDG-PET/CT. At 20weeks of age, brain tissue was examined for amyloid plaque accumulation and cellular changes. Compared with sham E4-TR:5XFAD mice, those with an early subcortical ischemic stroke showed a significant reduction in amyloid plaque burden in the region of cortex overlying the subcortical stroke. Cognitive performance was improved in E4-TR:5XFAD mice with stroke compared with sham E4-TR:5XFAD animals. Iba-1+ microglial cells in the region of cortex overlying the subcortical stroke were increased in number and morphologic complexity compared with sham E4-TR:5XFAD mice, suggesting that amyloid clearance may be promoted by an interaction between activated microglia and cortical neurons in response to subcortical stroke. This novel approach to modeling mixed vascular and AD dementia provides a valuable tool for dissecting the molecular interactions between these two common pathologies.

Risk factors for earlier dementia onset in autopsy-confirmed Alzheimer's disease, mixed Alzheimer's with Lewy bodies, and pure Lewy body disease.

Clinical Alzheimer's disease (AD) and dementia with Lewy bodies often have mixed AD and Lewy pathology, making it difficult to delineate risk factors. Six risk factors for earlier dementia onset due to autopsy-confirmed AD (n = 647), mixed AD and Lewy body disease (AD + LBD; n = 221), and LBD (n = 63) were entered into multiple linear regressions using data from the National Alzheimer's Coordinating Center. In AD and AD + LBD, male sex and apolipoprotein E (APOE) ɛ4 alleles each predicted a 2- to 3-year-earlier onset and depression predicted a 3-year-earlier onset. In LBD, higher education predicted earlier onset and depression predicted a 5.5-year-earlier onset. Male sex and APOE ɛ4 alleles increase risk for earlier dementia onset in AD but not LBD. Depression increases risk for earlier dementia onset in AD, LBD, and AD + LBD, but evaluating the course, treatment, and severity is needed in future studies.

Differences in Regional Cerebral Blood Flow between Mixed Dementia and Alzheimer's Disease

Differences in Regional Cerebral Blood Flow between Mixed Dementia and Alzheimer's Disease

Atherosclerosis, Hypertension, and Diabetes in Alzheimer's Disease, Vascular dementia, and Mixed Dementia: Prevalence and Presentation.

Background: Alzheimer's disease (AD) is the most prevalent cause of dementia with vascular dementia (VaD) being second alongside with mixed AD and VaD, according to some. For some time, it has been proposed that cardiovascular disease (CaVD), hypertension, and diabetes mellitus (DM), which are known risk factors for VaD, also are associated with and contribute to the development of AD. Objective: The aim of this study was to investigate the prevalence of these proposed general risk factors, and to document presence of CaVD as evidenced from clinical records or from autopsy findings, further to correlate these with the diagnoses AD, VaD and mixed AD-VaD (MD), respectively. Methods: Autopsy reports at the Clinical Department of Pathology in Lund from 1992-2017 were analyzed. All cases with a complete autopsy report and a neuropathologically diagnosed dementia disorder (AD, VaD, or MD) were selected on the condition of a clinical diagnosis of dementia. Clinical data were retrieved through medical records and the Swedish National Diabetes Register (NDR). A total of 268 subjects were included. Results: In AD, there was less CaVD as significantly less organ/tissue findings (p < 0.05), significantly less hypertension (p < 0.001), and likewise significantly less DM (p = 0.0014) than in VaD, with the MD group results being set between these two in all aspects studied. Conclusion: AD and VaD exhibit such different profiles of organ and vascular damage as well as of hypertension and DM that they clearly point toward different pathogenic origin with low likelihood of shared risk factors. (Less)