Pure Alzheimer's Disease Research Articles

In vivo detection of Alzheimer's and Lewy body disease concurrence: Clinical implications and future perspectives.

The recent introduction of seed amplification assays (SAAs) detecting misfolded α-synuclein, a pathology-specific marker for Lewy body disease (LBD), has allowed the in vivo identification and phenotypic characterization of patients with co-occurring Alzheimer's disease (AD) and LBD since the early clinical or even preclinical stage. We reviewed studies with an in vivo biomarker-based diagnosis of AD-LBD copathology. Studies in large cohorts of cognitively impaired individuals have shown that cerebrospinal fluid (CSF) biomarkers detect the coexistence of AD and LB pathology in approximately 20%-25% of them, independently of the primary clinical diagnosis. Compared to those with pure AD, AD-LBD patients showed worse global cognition, especially in attentive/executive and visuospatial functions, and worse motor functions. In cognitively unimpaired individuals, concurrent AD-LBD pathologies predicted longitudinal cognitive progression with faster worsening of global cognition, memory, and attentive/executive functions. Future research studies aiming for a better precision medicine approach should develop SAAs further to reach a quantitative evaluation or staging of each underlying pathology using a single biofluid sample. α-Synuclein seed amplification assays (SAAs) provide a specific marker for Lewy body disease (LBD). SAAs allow for the in vivo identification of co-occurring LBD in patients with Alzheimer's disease (AD). AD-LBD coexist in 20-25% of cognitively impaired elderly individuals, and ∼8% of those asymptomatic. Compared to pure AD, AD-LBD causes a faster worsening of cognitive functions. AD-LBD is associated with worse attentive/executive, memory, visuospatial and motor functions.

Clinical and diagnostic implications of Alzheimer's disease copathology in Lewy body disease.

Concomitant Alzheimer's disease (AD) pathology is a frequent event in the context of Lewy body disease (LBD), occurring in approximately half of all cases. Evidence shows that LBD patients with AD copathology show an accelerated disease course, a greater risk of cognitive decline and an overall poorer prognosis. However, LBD-AD cases may show heterogeneous motor and non-motor phenotypes with a higher risk of dementia and, consequently, be not rarely misdiagnosed. In this review, we summarize the current understanding of LBD-AD by discussing the synergistic effects of AD neuropathological changes and Lewy pathology and their clinical relevance. Furthermore, we provide an extensive overview of neuroimaging and fluid biomarkers under assessment for use in LBD-AD and their possible diagnostic and prognostic values. AD pathology can be predicted in vivo by means of CSF, MRI and PET markers, whereas the most promising technique to date for identifying Lewy pathology in different biological tissues is the α-synuclein seed amplification assay. Pathological imaging and CSF AD biomarkers are associated with a higher likelihood of cognitive decline in LBD but do not always mirror the neuropathological severity as in pure AD. Implementing the use of blood-based AD biomarkers might allow faster screening of LBD patients for AD copathology, thus improving the overall diagnostic sensitivity for LBD-AD. Finally, we discuss the literature on novel candidate biomarkers being exploited in LBD-AD to investigate other aspects of neurodegeneration, such as neuroaxonal injury, glial activation and synaptic dysfunction. The thorough characterization of AD copathology in LBD should be taken into account when considering differential diagnoses of dementia syndromes, to allow prognostic evaluation on an individual level, and to guide symptomatic and disease-modifying therapies.

Neuroinflammation is associated with Alzheimer’s disease co-pathology in dementia with Lewy bodies

BackgroundNeuroinflammation and Alzheimer’s disease (AD) co-pathology may contribute to disease progression and severity in dementia with Lewy bodies (DLB). This study aims to clarify whether a different pattern of neuroinflammation, such as alteration in microglial and astroglial morphology and distribution, is present in DLB cases with and without AD co-pathology.MethodsThe morphology and load (% area of immunopositivity) of total (Iba1) and reactive microglia (CD68 and HLA-DR), reactive astrocytes (GFAP) and proteinopathies of alpha-synuclein (KM51/pser129), amyloid-beta (6 F/3D) and p-tau (AT8) were assessed in a cohort of mixed DLB + AD (n = 35), pure DLB (n = 15), pure AD (n = 16) and control (n = 11) donors in limbic and neocortical brain regions using immunostaining, quantitative image analysis and confocal microscopy. Regional and group differences were estimated using a linear mixed model analysis.ResultsMorphologically, reactive and amoeboid microglia were common in mixed DLB + AD, while homeostatic microglia with a small soma and thin processes were observed in pure DLB cases. A higher density of swollen astrocytes was observed in pure AD cases, but not in mixed DLB + AD or pure DLB cases. Mixed DLB + AD had higher CD68-loads in the amygdala and parahippocampal gyrus than pure DLB cases, but did not differ in astrocytic loads. Pure AD showed higher Iba1-loads in the CA1 and CA2, higher CD68-loads in the CA2 and subiculum, and a higher astrocytic load in the CA1-4 and subiculum than mixed DLB + AD cases. In mixed DLB + AD cases, microglial load associated strongly with amyloid-beta (Iba1, CD68 and HLA-DR), and p-tau (CD68 and HLA-DR), and minimally with alpha-synuclein load (CD68). In addition, the highest microglial activity was found in the amygdala and CA2, and astroglial load in the CA4. Confocal microscopy demonstrated co-localization of large amoeboid microglia with neuritic and classic-cored plaques of amyloid-beta and p-tau in mixed DLB + AD cases.ConclusionsIn conclusion, microglial activation in DLB was largely associated with AD co-pathology, while astrocytic response in DLB was not. In addition, microglial activity was high in limbic regions, with prevalent AD pathology. Our study provides novel insights into the molecular neuropathology of DLB, highlighting the importance of microglial activation in mixed DLB + AD.

Multiomics Blood-Based Biomarkers Predict Alzheimer’s Predementia with High Specificity in a Multicentric Cohort Study

BackgroundThe primary criteria for diagnosing mild cognitive impairment (MCI) due to Alzheimer’s Disease (AD) or probable mild AD dementia rely partly on cognitive assessments and the presence of amyloid plaques. Although these criteria exhibit high sensitivity in predicting AD among cognitively impaired patients, their specificity remains limited. Notably, up to 25% of non-demented patients with amyloid plaques may be misdiagnosed with MCI due to AD, when in fact they suffer from a different brain disorder. The introduction of anti-amyloid antibodies complicates this scenario. Physicians must prioritize which amyloid-positive MCI patients receive these treatments, as not all are suitable candidates. Specifically those with non-AD amyloid pathologies are not primary targets for amyloid-modifying therapies. Consequently there is an escalating medical necessity for highly specific blood biomarkers that can accurately detect pre-dementia AD, thus optimizing amyloid antibody prescription.ObjectivesThe objective of this study was to evaluate a predictive model based on peripheral biomarkers to identify MCI and mild dementia patients who will develop AD dementia symptoms in cognitively impaired population with high specificity.DesignPeripheral biomarkers were identified in a gene transfer-based animal model of AD and then validated during a retrospective multi-center clinical study.SettingParticipants from 7 retrospective cohorts (US, EU and Australia).ParticipantsThis study followed 345 cognitively impaired individuals over up to 13 years, including 193 with MCI and 152 with mild dementia, starting from their initial visits. The final diagnoses, established during their last assessments, classified 249 participants as AD patients and 96 as having non-AD brain disorders, based on the specific diagnostic criteria for each disorder subtype. Amyloid status, assessed at baseline, was available for 82.9% of the participants, with 61.9% testing positive for amyloid. Both amyloid-positive and negative individuals were represented in each clinical group. Some of the AD patients had co-morbidities such as metabolic disorders, chronic diseases, or cardiovascular pathologies.MeasurementsWe developed targeted mass spectrometry assays for 81 blood-based biomarkers, encompassing 45 proteins and 36 metabolites previously identified in AAV-AD rats.MethodsWe analyzed blood samples from study participants for the 81 biomarkers. The B-HEALED test, a machine learning-based diagnostic tool, was developed to differentiate AD patients, including 123 with Prodromal AD and 126 with mild AD dementia, from 96 individuals with non-AD brain disorders. The model was trained using 70% of the data, selecting relevant biomarkers, calibrating the algorithm, and establishing cutoff values. The remaining 30% served as an external test dataset for blind validation of the predictive accuracy.ResultsIntegrating a combination of 19 blood biomarkers and participant age, the B-HEALED model successfully distinguished participants that will develop AD dementia symptoms (82 with Prodromal AD and 83 with AD dementia) from non-AD subjects (71 individuals) with a specificity of 93.0% and sensitivity of 65.4% (AUROC=81.9%, p<0.001) during internal validation. When the amyloid status (derived from CSF or PET scans) and the B-HEALED model were applied in association, with individuals being categorized as AD if they tested positive in both tests, we achieved 100% specificity and 52.8% sensitivity. This performance was consistent in blind external validation, underscoring the model’s reliability on independent datasets.ConclusionsThe B-HEALED test, utilizing multiomics blood-based biomarkers, demonstrates high predictive specificity in identifying AD patients within the cognitively impaired population, minimizing false positives. When used alongside amyloid screening, it effectively identifies a nearly pure prodromal AD cohort. These results bear significant implications for refining clinical trial inclusion criteria, facilitating drug development and validation, and accurately identifying patients who will benefit the most from disease-modifying AD treatments.

Tau maturation in the clinicopathological spectrum of Lewy body and Alzheimer's disease.

Alzheimer's disease neuropathologic change and alpha-synucleinopathy commonly co-exist and contribute to the clinical heterogeneity of dementia. Here, we examined tau epitopes marking various stages of tangle maturation to test the hypotheses that tau maturation is more strongly associated with beta-amyloid compared to alpha-synuclein, and within the context of mixed pathology, mature tau is linked to Alzheimer's disease clinical phenotype and negatively associated with Lewy body dementia. We used digital histology to measure percent area-occupied by pathology in cortical regions among individuals with pure Alzheimer's disease neuropathologic change, pure alpha-synucleinopathy, and a co-pathology group with both Alzheimer's and alpha-synuclein pathologic diagnoses. Multiple tau monoclonal antibodies were used to detect early (AT8, MC1) and mature (TauC3) epitopes of tangle progression. We used linear/logistic regression to compare groups and test the association between pathologies and clinical features. There were lower levels of tau pathology (β = 1.86-2.96, p < 0.001) across all tau antibodies in the co-pathology group compared to the pure Alzheimer's pathology group. Among individuals with alpha-synucleinopathy, higher alpha-synuclein was associated with greater early tau (AT8 β = 1.37, p < 0.001; MC1 β = 1.2, p < 0.001) but not mature tau (TauC3 p = 0.18), whereas mature tau was associated with beta-amyloid (β = 0.21, p = 0.01). Finally, lower tau, particularly TauC3 pathology, was associated with lower frequency of both core clinical features and categorical clinical diagnosis of dementia with Lewy bodies. Mature tau may be more closely related to beta-amyloidosis than alpha-synucleinopathy, and pathophysiological processes of tangle maturation may influence the clinical features of dementia in mixed Lewy-Alzheimer's pathology.

Distinct tau and alpha-synuclein molecular signatures in Alzheimer’s disease with and without Lewy bodies and Parkinson’s disease with dementia

Alpha-synuclein (aSyn) pathology is present in approximately 50% of Alzheimer’s disease (AD) cases at autopsy and might impact the age-of-onset and disease progression in AD. Here, we aimed to determine whether tau and aSyn profiles differ between AD cases with Lewy bodies (AD-LB), pure AD and Parkinson’s disease with dementia (PDD) cases using epitope-, post-translational modification- (PTM) and isoform-specific tau and aSyn antibody panels spanning from the N- to C-terminus. We included the middle temporal gyrus (MTG) and amygdala (AMY) of clinically diagnosed and pathologically confirmed cases and performed dot blotting, western blotting and immunohistochemistry combined with quantitative and morphological analyses. All investigated phospho-tau (pTau) species, except pT181, were upregulated in AD-LB and AD cases compared to PDD and control cases, but no significant differences were observed between AD-LB and AD subjects. In addition, tau antibodies targeting the proline-rich regions and C-terminus showed preferential binding to AD-LB and AD brain homogenates. Antibodies targeting C-terminal aSyn epitopes and pS129 aSyn showed stronger binding to AD-LB and PDD cases compared to AD and control cases. Two pTau species (pS198 and pS396) were specifically detected in the soluble protein fractions of AD-LB and AD subjects, indicative of early involvement of these PTMs in the multimerization process of tau. Other phospho-variants for both tau (pT212/S214, pT231 and pS422) and aSyn (pS129) were only detected in the insoluble protein fraction of AD-LB/AD and AD-LB/PDD cases, respectively. aSyn load was higher in the AMY of AD-LB cases compared to PDD cases, suggesting aggravated aSyn pathology under the presence of AD pathology, while tau load was similar between AD-LB and AD cases. Co-localization of pTau and aSyn could be observed within astrocytes of AD-LB cases within the MTG. These findings highlight a unique pathological signature for AD-LB cases compared to pure AD and PDD cases.

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.

QEEG‐based TabNet classifier for dementia pathologies: Alzheiemer’s disease and Lewy body disease

AbstractBackgroundEarly screening and prevention of dementia are widely discussed and studied in the current healthcare paradigm. However, about 70 percent of dementia diagnoses are categorized into Alzheimer’s disease (AD), neglecting the presence and influence of Lewy body. The present study aims to distinguish Alzheimer’s disease dementia (pure AD) and Lewy body dementia (pure LBD) through quantitative electroencephalogram (QEEG)‐based classification algorithm. The mixed dementia that exhibits both AD and LBD related propensities were further tested for the verification of the established classification model.Method19 channel EEG data were recorded in accordance with the 10‐20 system in eyes‐closed resting state. The acquired data were bandpass filtered into the range of interest (1‐45Hz) and re‐referenced into common average reference. Artifacts were removed by bad epoch rejection and independent component analysis (ICA) through an automated, cloud‐based QEEG analysis platform iSyncBrain®. Henceforth, sensor‐level features were extracted and computed for the training of TabNet structure. Due to the data imbalance (N = 146, Pure AD = 48, Pure LBD = 102), time window‐based augmentation has been applied to establish the final dataset (N = 7292, Pure AD = 3376, Pure LBD = 3916), which were then split into 8 to 2 ratio for the training and testing of the classification model. In addition, mixed dementia (N = 136) data were used to further validate the model’s performance.ResultThe best classification model yielded test accuracy of 80% with pure AD sensitivity at 80% and pure LBD sensitivity 80%. Moreover, the predicted probability distribution for the mixed dementia data were prominently concentrated around 0.5, which reflect that both pure AD and LBD properties exist.ConclusionAlong with the promising classification performance of the established classification model, the centered probability distribution of the mixed dementia data reflect that the model can well distinguish the characteristics that are specific to pure AD and LBD.

Screening of Mild Cognitive Impairment Subtypes Through the Training of 1D Convolutional Neural Network with QEEG Features

AbstractBackgroundThe pre‐clinical stage of dementia, mild cognitive impairment (MCI) carries various pathological pathways and respective prognoses. The two foremost causes of MCI and dementia that have been identified through autopsy diagnoses are Amyloid plaques and Lewy body, commonly referred to as Alzheimer’s disease (AD) and Lewy body disease (LBD) respectively. Although correct identification of pathological pathways plays a crucial role in effective designing of treatment methods, MCI subtypes are underexploited in the current diagnostic paradigm due to multiple reasons, mainly cost‐effectiveness. Hence, we utilized quantitative electroencephalography (QEEG) that are cheap and convenient to record in the distinguishment of MCI subtypes.MethodA total of 151 MCI patients’ EEG data were aggregated into 3 groups, pure AD (n = 29), pure LBD (n = 88), and mixed (n = 34). The mixed type was further subdivided into main AD (n = 31) and main LBD (n = 3) groups, in accordance with AD/LBD tendency exhibited by the patients. The clinical labelling was brought by the experienced experts of Yonsei Severance hospital, South Korea.1D SE‐ResNet‐based classification model was established for quantitative investigation of AD and LBD propensity. The power spectrum density (PSD) in dB/Hz scale were computed from the EEG data and were used to train the model. Due to the small number of data, augmentation was applied to the training data. The final dataset was split into 8 to 1 to 1 ratio (Train n = 7092: 2274 pure AD + main AD; 3694 pure LBD + main LBD, Validation n = 14: 6 pure AD + main AD; 8 Pure LBD + main LBD, Test n = 15: 6 pure AD + main AD; 9 pure LBD + main LBD).ResultThe classification model showed validation results of 85.7% accuracy, 83.3% AD sensitivity and 87.5% LBD sensitivity. Test results were at 92.8% accuracy, 83.3% AD sensitivity and 88.9% LBD sensitivity.ConclusionQEEG‐based deep learning classifier developed in this study successfully distinguished the two main causes of cognitive degeneration in MCI patients. Our model can help identify subtype‐specific spectral trends, which could also make contributions in the establishment of effective treatment methods for MCI.

Single‐nuclei transcriptomic identifies type‐specific neuronal cell vulnerability and non‐neuronal molecular changes in Amnestic and Logopenic Variant Primary Progressive Aphasia Alzheimer’s disease

AbstractBackgroundIndividuals with neuropathological criteria for Alzheimer’s disease (AD) may manifest with atypical clinical syndromes. Past work showed that the neurobiological basis for these differences is related to specific neuronal vulnerabilities for tau pathology. For instance, amnestic cases have a higher burden of neurofibrillary changes in CA1. In contrast, logopenic variant primary progressive aphasia (lvPPA) cases have a higher tau burden in the superior temporal gyrus (STG). Single‐cell technology enables investigations on the molecular basis of differential neuronal vulnerability in AD. Therefore, we investigated factors underlying selective vulnerability using brain samples from individuals with pure AD with different clinical manifestations.MethodsnRNA Sequencing using the Chromium Single Cell 3′ (10X Genomics, USA) on nuclei cells extracted from the CA1 sector and posterior STG of postmortem brain tissue of 24 individuals either meeting pathological criteria for AD (A3B3C3; 12 amnestic and eight lvPPA) and healthy controls (A≤1B≤1C≤1; n = 4) (Table 1, Fig. 1A/B). Bioinformatics analyses were conducted using Cell Ranger and R software. Comparisons between cell subpopulations were conducted with Wald statistical test, and p‐values &lt; .05 were considered significant.ResultAfter quality control, we recovered 98,180 nuclei with a mean of 2,130 genes per nuclei. Upon cross‐sample alignment and t‐stochastic neighborhood embedding clustering (Fig. 1C), we found 21 excitatory neuronal subpopulations (Exc‐sub) in CA1 and 26 in STG, and 22 and 27 inhibitory neuronal subpopulations (Inh‐sub) in CA1 and STG, respectively; 16 astrocytes subpopulations in both areas and 20 microglia subpopulations in CA1 and 17 in STG (Fig. 2). One STG Exc‐sub, expressing CUX2 and LAMP5 genes showed vulnerability in lvPPA patients. Also, one STG Inh‐sub, expressing the ADARB2 gene, showed vulnerability for all AD patients. Furthermore, two astrocytes subpopulations (one in both areas and one in STG) and three STG microglia subpopulations showed proportional composition changes comparing AD patients and HC.ConclusionOur preliminary study identified a vulnerable population of excitatory neurons related to lvPPA. We are conducting validation studies using quantitative pathology to confirm these results. Furthermore, analysis of a higher number of cases is ongoing and will continue to inform on factors associated with neuronal vulnerability.

Dopamine transporter positron emission tomography in patients with Alzheimer’s disease with Lewy body disease features

In 36 normal controls (NC), 37 patients with Alzheimer’s disease (AD) without parkinsonism (ADP-), 31 AD with parkinsonism (ADP+), and 40 AD with dementia with Lewy bodies (ADDLB), dual-phase dopamine transporter (DAT) positron emission tomography (PET) were performed to evaluate the diagnostic performance of DAT and early-to-delayed uptake ratios (E/Ds) in the anterior caudate (AC), posterior caudate (PC), anterior putamen (AP), posterior putamen (PP), and substantia nigra (SN) to differentiate ADP+/ADDLB from NC, and their effects on parkinsonism and cognition. DAT-SN and E/D-PP showed higher accuracies to differentiate ADP+/ADDLB from NC than DAT-PP. Among AD patients, lower DAT in the putamen and PC and higher E/Ds in the striatum were associated with severe parkinsonism, while higher E/Ds in the putamen, PC, and SN were associated with executive dysfunction. Our results suggest that decreased DAT-SN and increased E/D-PP could be biomarkers differentiating ADP+/ADDLB from pure AD and controls. Meanwhile, increased E/Ds in the putamen could reflect the severity of DLB presenting with parkinsonism and executive dysfunction among AD patients.

Distinct Patterns of Hippocampal Pathology in Alzheimer's Disease with Transactive Response DNA-binding Protein 43.

Age-related dementia syndromes are often not related to a single pathophysiological process, leading to multiple neuropathologies found at autopsy. An amnestic dementia syndrome can be associated with Alzheimer's disease (AD) with comorbid transactive response DNA-binding protein 43 (TDP-43) pathology (AD/TDP). Here, we investigated neuronal integrity and pathological burden of TDP-43 and tau, along the well-charted trisynaptic hippocampal circuit (dentate gyrus [DG], CA3, and CA1) in participants with amnestic dementia due to AD/TDP, amnestic dementia due to AD alone, or non-amnestic dementia due to TDP-43 proteinopathy associated with frontotemporal lobar degeneration (FTLD-TDP). A total of 48 extensively characterized cases (14 AD, 16 AD/TDP, 18 FTLD-TDP) were analyzed using digital HALO software (Indica Labs, Albuquerque, NM, USA) to quantify pathological burden and neuronal loss. In AD/TDP and FTLD-TDP, TDP-43 immunoreactivity was greatest in the DG. Tau immunoreactivity was significantly greater in DG and CA3 in AD/TDP compared with pure AD. All clinical groups showed the highest amounts of neurons in DG, followed by CA3, then CA1. The AD and AD/TDP groups showed lower neuronal counts compared with the FTLD-TDP group across all hippocampal subregions consistent with the salience of the amnestic phenotype. We conclude that AD/TDP can be distinguished from AD and FTLD-TDP based on differential regional distributions of hippocampal tau and TDP-43. Findings suggest that tau aggregation in AD/TDP might be enhanced by TDP-43. ANN NEUROL 2023;94:1036-1047.

Phonemic Fluency in pathologically confirmed Alzheimer’s disease (AD) versus AD with Lewy Bodies

AbstractBackgroundAlthough Alzheimer’s Disease (AD) and Lewy Body Disease (LBD) have distinct underlying pathologies, the clinical differentiation of these disorders remains challenging, particularly AD versus mixed AD/LBD. Previous studies have shown that patients with mixed AD/DLB can have lower total output phonemic fluency than patients with AD. Examining the qualitative features of fluency performance may offer an even more sensitive approach to detecting group differences. One potentially useful measure is the ability to sustain generation of words over time; that is, whether a participant continues producing words across the full 60 seconds, or whether their responses “drop off”. A “drop off” in verbal generation on fluency tasks has previously been reported in Mild Cognitive Impairment due to AD. We assessed whether this qualitative phonemic fluency score would differ between autopsy confirmed AD versus mixed AD/DLB or DLB.MethodParticipants with postmortem pathological diagnoses of AD (n = 15) and DLB (mixed or pure DLB; n = 8) were included in the present study. Participants completed phonemic fluency task at their baseline visit as part of a neuropsychological battery of tests. Participants were asked to generate as many words as possible that start with a given letter in one minute across three trials (i.e., C, F, L). The drop off in phonemic fluency over time was calculated by dividing the number of words produced in the second half of the test (i.e. second 30‐second interval) by the total number of words generated across 60 seconds. Group differences were analyzed using a one‐way analysis of variance (ANOVA).ResultWhereas total CFL score did not differ in this sample (p = .21), patients with DLB produced a significantly higher proportion of words in the second half of the CFL test (M = 0.40; SD = 0.14), compared to patients with pure AD (M = 0.27, SD = 0.10), p = 0.016.ConclusionNovel scoring of the CFL test may help to differentiate cases with pure AD and cases with DLB pathology. In the current study, pure AD patients had more difficulty in sustaining word generation over 60 seconds. Future research should continue to look at different ways to score and analyze neuropsychological assessments to improve early differential diagnosis.

Association of Younger Age and APOE ɛ4 Carrier Status with Cerebral Amyloid Angiopathy in Pure and Mixed Alzheimers Disease Neuropathology (P3-6.004)

<h3>Objective:</h3> To determine how key clinical and neuropathology factors relate to the odds of cerebral amyloid angiopathy (CAA) at autopsy in both ‘pure Alzheimers Disease (AD)’ and mixed neuropathology of AD with Lewy body pathology (AD+LBP). <h3>Background:</h3> Presence of CAA has important therapeutic implications in the clinical decision to use new generation anti-amyloid therapies in AD. <h3>Design/Methods:</h3> A retrospective longitudinal cohort study was conducted among 2068 participants in the National Alzheimer Coordinating Center database with a mean interval of 5.7 (SD 2.8) years from initial visit to autopsy. These included autopsy-confirmed AD, n=1175 or AD +LBP, n=893 with CAA data. Correlations between CAA severity, Braak and neurotic scores and logistic regression models evaluating age (younger &lt;65yrs vs older≥65yrs), sex, APOE <i>ɛ4</i> carrier status, Braak stage and neuritic plaque score were completed in AD and mixed AD+LBP. <h3>Results:</h3> Younger age (O.R. 2.13, [95% CI, 1.33–3.33], p=0.002) and <i>APOE ɛ4</i> (O.R. 2.62, [95% CI, 1.94–3.56], p&lt;0.001) were significant predictors of CAA in AD, while <i>APOE ɛ4</i> (O.R. 3.18, [95% CI, 2.2–4.6], p&lt;0.001) was significant in AD+LBP. Only among older individuals in both groups, CAA severity correlated to Braak stage [AD ρ=0.12 (0.06, 0.18, p&lt;0.001), AD+LBP ρ=0.16 (0.09, 0.24, p&lt;0.001)] and neuritic score [AD ρ=0.10 (0.04, 0.16, p=0.002), AD+LBP ρ=0.12 (0.04, 0.19, p=0.002)]. When controlling for Braak stage, the odds of CAA were lower in AD among older age individuals [O.R. 0.50 (0.30–0.80), p=0.004] but not in AD+LBP [O.R. 0.92(0.56–1.53), p=0.75]. <h3>Conclusions:</h3> Younger age and <i>APOE ɛ4</i> carrier status had a higher odds of CAA despite controlling for Braak stage and neuritic plaque score in ‘pure AD’. Among older individuals higher Braak stage and neuritic plaque score were correlated to CAA severity in AD and AD+LBP. These results are of importance in the recognition of patients at the highest risk of CAA in both AD and mixed AD+LBP. <b>Disclosure:</b> Dr. Pillai has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Springer Nature. Dr. Pillai has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Current Treatment Options in Neurology. The institution of Dr. Pillai has received research support from Alzheimer’s Association. The institution of Dr. Pillai has received research support from Keep Memory Alive Foundation . The institution of Dr. Pillai has received research support from NIA. Dr. Pillai has received personal compensation in the range of $500-$4,999 for serving as a Reviewer with DOD. Dr. Pillai has received personal compensation in the range of $500-$4,999 for serving as a Reviewer with RGC Hong kong. James Bena has nothing to disclose. Dr. Leverenz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Acadia. Dr. Leverenz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Leverenz has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eisai.

Costs During the Last Five Years of Life for Patients with Clinical and Pathological Confirmed Diagnosis of Lewy Body Dementia and Alzheimer's Disease.

Little is known regarding healthcare expenditures for patients with dementia with Lewy bodies (DLB) during the end of life. This study estimated Medicare expenditures during the last 5 years of life in a decedent sample of patients who were clinically diagnosed with Alzheimer's disease (AD) or DLB and had autopsy confirmed diagnosis. The study included 58 participants clinically diagnosed with mild dementia at study entry (AD: n = 44, DLB: n = 14) and also had autopsy-confirmed diagnoses of pure AD (n = 32), mixed AD+Lewy body (LB) (n = 5), or pure LB (n = 11). Total Medicare expenditures were compared by clinical and pathology confirmed diagnosis, adjusting for sex, age at death, and patient's cognition, function, comorbidities, and psychiatric and extrapyramidal symptoms. When pathology diagnoses were not considered, predicted annualized total Medicare expenditures during the last 5 years of life were similar between clinically diagnosed AD ($7,465±1,098) and DLB ($7,783±1,803). When clinical diagnoses were not considered, predicted expenditures were substantially higher in patients with pathology confirmed mixed AD+LB ($12,005±2,455) than either pure AD ($6,173±941) or pure LB ($4,629±1,968) cases. Considering clinical and pathology diagnosis together, expenditures for patients with clinical DLB and pathology mixed AD+LB ($23,592±3,679) dwarfed other groups. Medicare expenditures during the last 5 years of life were substantially higher in patients with mixed AD+LB pathology compared to those with pure-AD and pure-LB pathologies, particularly in those clinically diagnosed with DLB. Results highlight the importance of having both clinical and pathology diagnoses in examining healthcare costs.

MRI-based basal forebrain atrophy and volumetric signatures associated with limbic TDP-43 compared to Alzheimer's disease pathology

BackgroundIt is not clear to which degree limbic TDP-43 pathology associates with a cholinergic deficit in the absence of Alzheimer's disease (AD) pathology. ObjectiveReplicate and extend recent evidence on cholinergic basal forebrain atrophy in limbic TDP-43 and evaluate MRI based patterns of atrophy as a surrogate marker for TDP-43. MethodsWe studied ante-mortem MRI data of 11 autopsy cases with limbic TDP-43 pathology, 47 cases with AD pathology, and 26 mixed AD/TDP-43 cases from the ADNI autopsy sample, and 17 TDP-43, 170 AD, and 58 mixed AD/TDP-43 cases from the NACC autopsy sample. Group differences in basal forebrain and other brain volumes of interest were assessed using Bayesian ANCOVA. We assessed the diagnostic utility of MRI based patterns of brain atrophy using voxel-based receiver operating characteristics and random forest analyses. ResultsIn the NACC sample, we found moderate evidence for the absence of a difference in basal forebrain volumes between AD, TDP-43, and mixed pathologies (Bayes factor(BF)10 = 0.324), and very strong evidence for lower hippocampus volume in TDP-43 and mixed cases compared with AD cases (BF10 = 156.1). The ratio of temporal to hippocampus volume reached an AUC of 75% for separating pure TDP-43 from pure AD cases. Random-forest analysis between TDP-43, AD, and mixed pathology reached only a multiclass AUC of 0.63 based on hippocampus, middle-inferior temporal gyrus, and amygdala volumes. Findings in the ADNI sample were consistent with these results. ConclusionA comparable degree of basal forebrain atrophy in pure TDP-43 cases compared to AD cases encourages studies on the effect of cholinergic treatment in amnestic dementia due to TDP-43. A distinct pattern of temporo-limbic brain atrophy may serve as a surrogate marker to enrich samples in clinical trials for the presence of TDP-43 pathology.

Different metabolic and clinical profiles between patients with pure Alzheimer dementia and epileptic Alzheimer dementia: a metabolic study

Aim: To investigate the clinical characteristics and cerebral FDG PET metabolisms of dementia patients who were also diagnosed with epilepsy and compare the differences with pure Alzheimer dementia patients.Methods: In this case-control study, a total of 14 patients, 7 patients with pure Alzheimer disease as a control group and 7 age and gender-matched patients with Alzheimer disease and concomitant epilepsy as a study group, were included. Detailed neurocognitive battery and brain fludeoxyglucose positron emission tomography (FDG PET-CT) were performed for all subjects.Results: In comparison of neurocognitive test scores, there was no significant difference between the study and control groups. However, geriatric depression scale scores were significantly lower in study group than the controls (p= 0.026). In cerebral FDG-PET CT profiles of subjects we detected significantly lower metabolism in left and right cerebellum, left lentiform nucleus, right thalamus and vermis in the study group (p=0.008, p=0.023, p=0.003, p=0.002, p=0.002, respectively). In the right parietotemporal cortex and right and left associative visual cortex, we found higher metabolism in the study group than controls (p=0.023, p=0.012, p=0.003, respectively).Conclusion: Epileptic patients with Alzheimer’s dementia may have distinct clinical and metabolic profiles, than pure Alzheimer’s disease patients. Even if there is no difference in the neurocognitive clinical scores of the patients, depression and related functional abnormalities may be a biomarker of epileptic AD.

Visuoconstruction Errors in pathologically confirmed Alzheimer’s disease versus Alzheimer’s disease with Lewy Body disease patients

AbstractBackgroundClinical differentiation of Alzheimer’s disease (AD) versus Lewy Body Disease (LBD; including mixed AD‐LBD) is challenging, as both diseases overlap in cognitive symptoms. This can lead to misdiagnosis with detrimental consequences to the patient’s health. While autopsy‐based studies reveal that visuoconstruction tends to be more preserved in AD versus LBD and mixed AD‐LBD, it is well established that patients with AD also have visuoconstructional difficulties. To this end, this study examined performance on three visuoconstruction tasks and qualitatively coded errors on overlapping pentagons to characterize the types of constructional difficulties in pathologically confirmed AD versus LBD and mixed AD‐LBD.MethodClinical and autopsy data were available for 30 individuals (19 AD; 11 LBD /mixed AD‐LBD). Overlapping pentagons were given a final score of either 0 or 1. Pentagons were then scored across six parameters: presence of two figures, overlapping figures, 5 sides on each figure, the correct overlap of figures (diamond in the middle), presence of overwriting, and closing‐in to stimulus. Copy of a cube and a circle/diamond figure was also scored as 0 or 1. Chi‐square analyses were used to examine the frequency of impairment on each visuoconstruction score among the pure AD versus LBD/mixed AD‐LBD groups.ResultThe combined LBD and mixed AD‐LBD group was more frequently impaired on circle‐diamond (p = .002), pentagons total score (p = .001), and two pentagons sub‐scores, including the presence of 5‐sides on each figure (p = .006) and the correct pentagon overlap (p = .006). The groups were impaired with equal frequency on the remaining pentagons sub‐scores, and on the cube copy (53% of AD and 37% of LBD/mixed AD‐LBD; p = .39).ConclusionAs expected, the combined LBD and mixed AD‐LBD group was more frequently impaired on several visuoconstruction tasks in comparison to the pure AD group. Specific pentagons errors were most sensitive to group differences. Of note, both groups were impaired with equal frequency on cube copy, suggesting that the three‐dimensional component of the task best captures the visuospatial difficulties characteristic of AD. Qualitative assessment of visuoconstruction may aid in differential diagnosis.

Unified Parkinson’s Disease Rating Scale (UPDRS) motor score subscale trajectories in Dementia with Lewy Bodies and Parkinson Disease Dementia in a community autopsy cohort

AbstractBackgroundWe previously reported that in our autopsy‐confirmed cohort of Dementia with Lewy Bodies (DLB), Parkinson’s Disease Dementia (PDD) and Alzheimer’s Disease (AD), DLB with parkinsonism (DLB+Park) predicted faster progression of UPDRS‐III scores compared to PDD, DLB without parkinsonism (DLB‐Park), and AD. This study examined annualized rate of change of UPDRS‐III subscales in our cohort.MethodsData included were from participants in Arizona Study of Aging and Neurodegenerative Diseases (AZSAND) with clinicopathologic diagnosis of DLB (n = 48), PDD (n = 98) or pure AD (n = 48), and longitudinal movement exams. Mixed effects model (accounting for age, education, and sex) was used to determine predicted mean UPDRS‐III and subscale scores (0‐4) for all groups. Individual UPDRS‐III subscale scores were derived for: Body Bradykinesia, Limb Bradykinesia, Gait, Postural Instability, Limb Rest Tremor, Neck Rigidity and Limb Rigidity. Where applicable, scores for multiple limbs involved were averaged.ResultsLongitudinal data was analyzed for over 1430‐participant years. Parkinsonism was present in 65.6% of DLB participants. PDD participants were more likely to be treated with dopaminergic agents (87.8%) compared to (p&lt;0.001) DLB+Park (57.6%), DLB‐park (0%) and AD (2.1%). Frequency (29.4% vs. 29.0%) and severity (mean±SE = 0.4±0.07 and 0.4±0.12) of Limb Rest Tremor was similar for PDD and DLB+park. Limb Bradykinesia frequency and severity were PDD: 100%, 2.4±0.11, DLB+Park: 96.8%, 2.1±0.18, DLB‐Park: 20%, 0.4±0.23, and AD: 62%, 1.1±0.16. Frequency of gait abnormality was 98.5% in PDD, 90.3% in DLB+park, 60% in DLB‐Park and 57.8% in AD. Rigidity was most frequent in the PDD group (88.2%), followed by DLB+Park (71%), AD (19.6%), and none DLB‐park (0%). Over 8 years trajectories for limb bradykinesia and gait were greater for DLB+park than PDD (Figure 1, Cohen’s d range 0.89‐2.18 and 0.63‐1.99 over 8 years, p&lt;0.001).ConclusionOur results suggest that DLB+Park group have faster motor progression predominantly related to gait abnormalities and limb bradykinesia. Future analyses will explore more convergent data, integrated effects of various measures and their differential contributions in this cohort.

Heart rate variability: a novel biomarker for agitation propensity in Alzheimer’s disease?

AbstractBackgroundAgitation, a common symptom in Alzheimer’s disease (AD), may be related to impaired emotion regulation capacity with involvement of autonomic networks. Heart rate variability (HRV), an index of integrity of neural networks involved in autonomic function and emotion regulation, could be a potential marker of agitation propensity. We investigated the cross‐sectional and longitudinal association between HRV and agitation prevalence in AD using the Atherosclerosis Risk in Communities (ARIC) Study cohort that followed up participants from 1987–2013.MethodParticipants at ARIC visit 5 who were clinically diagnosed with dementia (or MCI that subsequently progressed to dementia) primarily or wholly attributed to AD were included. Agitation at visit 5 was defined based on the Neuropsychiatric Inventory agitation/aggression subscale alone, or a composite score comprising agitation/aggression, irritability, disinhibition, and aberrant motor behavior subscales. HRV measures at visits 1–5 were the root mean square of successive differences in R‐R intervals (RMSSD) and standard deviation of normal‐to‐normal R‐R intervals (SDNN) obtained from resting, supine, standard twelve‐lead electrocardiograms. The associations between agitation and visit 5 HRV or visit 1–5 change in HRV (defined as individual slope coefficients from mixed effects models) were assessed using simple regression models.ResultsAmong 456 participants who had dementia during the study, N = 302 received a primary diagnosis of AD, of whom N = 120 were classified with pure AD (see Flowchart). In the pure AD subgroup, a 0.1 log‐unit higher RMSSD (odds ratio = 1.14 [1.03‐1.29]) and positive RMSSD change over the preceding two decades (odds ratio = 2.23 [1.24‐4.38]) were associated with agitation point prevalence after accounting for heart rate (change), age, sex, cognitive status, study site and race. A 0.1 log‐unit change in HRV approximated the observed difference in HRV with each decade of age. The associations persisted after accounting for use of medications with autonomic effects.ConclusionThe finding that higher HRV was associated with agitation point prevalence in N = 120 participants clinically diagnosed with dementia solely due to AD supports the potential use of HRV as a biomarker of agitation propensity, and autonomic dysfunction as a target of treatment. Future studies are needed to explore this relationship alongside measures of emotion regulation and locus coeruleus‐noradrenergic system integrity.