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TAR-DNA binding protein-43 (TDP-43) proteinopathy is seen in multiple brain diseases. A standardized terminology was recommended recently for common age-related TDP-43 proteinopathy: limbic-predominant, age-related TDP-43 encephalopathy (LATE) and the underlying neuropathological changes, LATE-NC. LATE-NC may be co-morbid with Alzheimer’s disease neuropathological changes (ADNC). However, there currently are ill-defined diagnostic classification issues among LATE-NC, ADNC, and frontotemporal lobar degeneration with TDP-43 (FTLD-TDP). A practical challenge is that different autopsy cohorts are composed of disparate groups of research volunteers: hospital- and clinic-based cohorts are enriched for FTLD-TDP cases, whereas community-based cohorts have more LATE-NC cases. Neuropathological methods also differ across laboratories. Here, we combined both cases and neuropathologists’ diagnoses from two research centres—University of Pennsylvania and University of Kentucky. The study was designed to compare neuropathological findings between FTLD-TDP and pathologically severe LATE-NC. First, cases were selected from the University of Pennsylvania with pathological diagnoses of either FTLD-TDP (n = 33) or severe LATE-NC (mostly stage 3) with co-morbid ADNC (n = 30). Sections from these University of Pennsylvania cases were cut from amygdala, anterior cingulate, superior/mid-temporal, and middle frontal gyrus. These sections were stained for phospho-TDP-43 immunohistochemically and evaluated independently by two University of Kentucky neuropathologists blinded to case data. A simple set of criteria hypothesized to differentiate FTLD-TDP from LATE-NC was generated based on density of TDP-43 immunoreactive neuronal cytoplasmic inclusions in the neocortical regions. Criteria-based sensitivity and specificity of differentiating severe LATE-NC from FTLD-TDP cases with blind evaluation was ∼90%. Another proposed neuropathological feature related to TDP-43 proteinopathy in aged individuals is ‘Alpha’ versus ‘Beta’ in amygdala. Alpha and Beta status was diagnosed by neuropathologists from both universities (n = 5 raters). There was poor inter-rater reliability of Alpha/Beta classification (mean κ = 0.31). We next tested a separate cohort of cases from University of Kentucky with either FTLD-TDP (n = 8) or with relatively ‘pure’ severe LATE-NC (lacking intermediate or severe ADNC; n = 14). The simple criteria were applied by neuropathologists blinded to the prior diagnoses at University of Pennsylvania. Again, the criteria for differentiating LATE-NC from FTLD-TDP was effective, with sensitivity and specificity ∼90%. If more representative cases from each cohort (including less severe TDP-43 proteinopathy) had been included, the overall accuracy for identifying LATE-NC was estimated at >98% for both cohorts. Also across both cohorts, cases with FTLD-TDP died younger than those with LATE-NC (P

Background: Actuarial and statistical methods have been proposed as alternatives to conventional methods of diagnosing mild cognitive impairment (MCI), with the aim of enhancing diagnostic and prognostic validity, but have not been compared in racially diverse samples. Objective: We compared the agreement of consensus, actuarial, and statistical MCI diagnostic methods, and their relationship to race and prognostic indicators, among diverse older adults. Methods: Participants (N = 354; M age = 71; 68% White, 29% Black) were diagnosed with MCI or normal cognition (NC) according to clinical consensus, actuarial neuropsychological criteria (Jak/Bondi), and latent class analysis (LCA). We examined associations with race/ethnicity, longitudinal cognitive and functional change, and incident dementia. Results: MCI rates by consensus, actuarial criteria, and LCA were 44%, 53%, and 41%, respectively. LCA identified three MCI subtypes (memory; memory/language; memory/executive) and two NC classes (low normal; high normal). Diagnostic agreement was substantial, but agreement of the actuarial method with consensus and LCA was weaker than the agreement between consensus and LCA. Among cases classified as MCI by actuarial criteria only, Black participants were over-represented, and outcomes were generally similar to those of NC participants. Consensus diagnoses best predicted longitudinal outcomes overall, whereas actuarial diagnoses best predicted longitudinal functional change among Black participants. Conclusion: Consensus diagnoses optimize specificity in predicting dementia, but among Black older adults, actuarial diagnoses may be more sensitive to early signs of decline. Results highlight the need for cross-cultural validity in MCI diagnosis and should be explored in community- and population-based samples.

Limbic-predominant age-related TDP-43 encephalopathy (LATE) is characterized by the accumulation of TAR-DNA-binding protein 43 (TDP-43) aggregates in older adults. LATE coexists with Lewy body disease (LBD) as well as other neuropathological changes including Alzheimer’s disease (AD). We aimed to identify the pathological, clinical, and genetic characteristics of LATE in LBD (LATE-LBD) by comparing it with LATE in AD (LATE-AD), LATE with mixed pathology of LBD and AD (LATE-LBD + AD), and LATE alone (Pure LATE). We analyzed four cohorts of autopsy-confirmed LBD (n = 313), AD (n = 282), LBD + AD (n = 355), and aging (n = 111). We assessed the association of LATE with patient profiles including LBD subtype and AD neuropathologic change (ADNC). We studied the morphological and distributional differences between LATE-LBD and LATE-AD. By frequency analysis, we staged LATE-LBD and examined the association with cognitive impairment and genetic risk factors. Demographic analysis showed LATE associated with age in all four cohorts and the frequency of LATE was the highest in LBD + AD followed by AD, LBD, and Aging. LBD subtype and ADNC associated with LATE in LBD or AD but not in LBD + AD. Pathological analysis revealed that the hippocampal distribution of LATE was different between LATE-LBD and LATE-AD: neuronal cytoplasmic inclusions were more frequent in cornu ammonis 3 (CA3) in LATE-LBD compared to LATE-AD and abundant fine neurites composed of C-terminal truncated TDP-43 were found mainly in CA2 to subiculum in LATE-LBD, which were not as numerous in LATE-AD. Some of these fine neurites colocalized with phosphorylated α-synuclein. LATE-LBD staging showed LATE neuropathological changes spread in the dentate gyrus and brainstem earlier than in LATE-AD. The presence and prevalence of LATE in LBD associated with cognitive impairment independent of either LBD subtype or ADNC; LATE-LBD stage also associated with the genetic risk variants of TMEM106B rs1990622 and GRN rs5848. These data highlight clinicopathological and genetic features of LATE-LBD.

Frontotemporal lobar degeneration proteinopathies with tau inclusions (FTLD-Tau) or TDP-43 inclusions (FTLD-TDP) are associated with clinically similar phenotypes. However, these disparate proteinopathies likely differ in cellular severity and regional distribution of inclusions in white matter (WM) and adjacent grey matter (GM), which have been understudied. We performed a neuropathological study of subcortical WM and adjacent GM in a large autopsy cohort (n = 92; FTLD-Tau = 37, FTLD-TDP = 55) using a validated digital image approach. The antemortem clinical phenotype was behavioral-variant frontotemporal dementia (bvFTD) in 23 patients with FTLD-Tau and 42 with FTLD-TDP, and primary progressive aphasia (PPA) in 14 patients with FTLD-Tau and 13 with FTLD-TDP. We used linear mixed-effects models to: (1) compare WM pathology burden between proteinopathies; (2) investigate the relationship between WM pathology burden and WM degeneration using luxol fast blue (LFB) myelin staining; (3) study regional patterns of pathology burden in clinico-pathological groups. WM pathology burden was greater in FTLD-Tau compared to FTLD-TDP across regions (beta = 4.21, SE = 0.34, p p = 0.002) and FTLD-TDP (beta = 0.40, SE = 0.08, p p

Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present international study, we addressed the question of whether or not sequential distribution patterns can be recognized for PSP pathology. We evaluated heat maps and distribution patterns of neuronal, astroglial, and oligodendroglial tau pathologies and their combinations in different clinical subtypes of PSP in postmortem brains. We used conditional probability and logistic regression to model the sequential distribution of tau pathologies across different brain regions. Tau pathology uniformly predominates in the neurons of the pallido-nigro-luysian axis in different clinical subtypes. However, clinical subtypes are distinguished not only by total tau load but rather cell-type (neuronal versus glial) specific vulnerability patterns of brain regions suggesting distinct dynamics or circuit-specific segregation of propagation of tau pathologies. For Richardson syndrome (n = 81) we recognize six sequential steps of involvement of brain regions by the combination of cellular tau pathologies. This is translated to six stages for the practical neuropathological diagnosis by the evaluation of the subthalamic nucleus, globus pallidus, striatum, cerebellum with dentate nucleus, and frontal and occipital cortices. This system can be applied to further clinical subtypes by emphasizing whether they show caudal (cerebellum/dentate nucleus) or rostral (cortical) predominant, or both types of pattern. Defining cell-specific stages of tau pathology helps to identify preclinical or early-stage cases for the better understanding of early pathogenic events, has implications for understanding the clinical subtype-specific dynamics of disease-propagation, and informs tau-neuroimaging on distribution patterns. Electronic supplementary material The online version of this article (10.1007/s00401-020-02158-2) contains supplementary material, which is available to authorized users.

Recent models of Alzheimer's disease progression propose that disease may be transmitted between brain areas either via local diffusion or long-distance transport via white matter fibre pathways. However, it is unclear whether such models are applicable in non-amnestic Alzheimer's disease, which is associated with domain-specific cognitive deficits and relatively spared episodic memory. To date, the anatomical progression of disease in non-amnestic patients remains understudied. We used longitudinal imaging to differentiate earlier atrophy and later disease spread in three non-amnestic variants, including logopenic-variant primary progressive aphasia (n = 25), posterior cortical atrophy (n = 20), and frontal-variant Alzheimer's disease (n = 12), as well as 17 amnestic Alzheimer's disease patients. Patients were compared to 37 matched controls. All patients had autopsy (n = 7) or CSF (n = 67) evidence of Alzheimer's disease pathology. We first assessed atrophy in suspected sites of disease origin, adjusting for age, sex, and severity of cognitive impairment; we then performed exploratory whole-brain analysis to investigate longitudinal disease spread both within and outside these regions. Additionally, we asked whether each phenotype exhibited more rapid change in its associated disease foci than other phenotypes. Finally, we investigated whether atrophy was related to structural brain connectivity. Each non-amnestic phenotype displayed unique patterns of initial atrophy and subsequent neocortical change that correlated with cognitive decline. Longitudinal atrophy included areas both proximal to and distant from sites of initial atrophy, suggesting heterogeneous mechanisms of disease spread. Moreover, regional rates of neocortical change differed by phenotype. Logopenic-variant patients exhibited greater initial atrophy and more rapid longitudinal change in left lateral temporal areas than other groups. Frontal-variant patients had pronounced atrophy in left insula and middle frontal gyrus, combined with more rapid atrophy of left insula than other non-amnestic patients. In the medial temporal lobes, non-amnestic patients had less atrophy at their initial scan than amnestic patients, but longitudinal rate of change did not differ between patient groups. Medial temporal sparing in non-amnestic Alzheimer's disease may thus be due in part to later onset of medial temporal degeneration than in amnestic patients rather than different rates of atrophy over time. Finally, the magnitude of longitudinal atrophy was predicted by structural connectivity, measured in terms of node degree; this result provides indirect support for the role of long-distance fibre pathways in the spread of neurodegenerative disease. 10.1093/brain/awz091_video1 awz091media1 6041544065001.

Objective To measure postmortem burden of frontotemporal lobar degeneration (FTLD) with TDP-43 (FTLD-TDP) or tau (FTLD-Tau) proteinopathy across hemispheres in primary progressive aphasia (PPA) using digital histopathology and to identify clinicopathological correlates of these distinct proteinopathies. Methods In an autopsy cohort of PPA (FTLD-TDP = 13, FTLD-Tau = 14), we analyzed laterality and regional distribution of postmortem pathology, quantified using a validated digital histopathological approach, in available brain tissue from up to 8 cortical regions bilaterally. We related digital pathology to antemortem structural neuroimaging and specific clinical language features. Results Postmortem cortical pathology was left-lateralized in both FTLD-TDP (beta = -0.15, standard error [SE] = 0.05, p = 0.007) and FTLD-Tau (beta = -0.09, SE = 0.04, p = 0.015), but the degree of lateralization decreased with greater overall dementia severity before death (beta = -8.18, SE = 3.22, p = 0.015). Among 5 core pathology regions sampled, we found greatest pathology in left orbitofrontal cortex (OFC) in FTLD-TDP, which was greater than in FTLD-Tau (F = 47.07, df = 1,17, p

ObjectiveTo examine the association of biologic therapy use for psoriasis with incident psoriatic arthritis (PsA) diagnosis.MethodsA retrospective cohort study was conducted in the OptumInsights Electronic Health Record Database between 2006 and 2017 among patients with psoriasis between the ages of 16 and 90 initiating a therapy for psoriasis (oral, biologic or phototherapy). The incidence of PsA was calculated within each therapy group. Multivariable Cox models were used to calculate the HR for biologic versus oral or phototherapy using biologics as a time-varying exposure and next in a propensity score-matched cohort.ResultsAmong 1 93 709 patients with psoriasis without PsA, 14 569 biologic and 20 321 cumulative oral therapy and phototherapy initiations were identified. Mean age was lower among biologic initiators compared with oral/phototherapy initiators (45.9 vs 49.8). The incidence of PsA regardless of therapy exposure was 9.75 per 1000 person-years compared with 77.26 among biologic users, 61.99 among oral therapy users, 26.11 among phototherapy users and 5.85 among those without a prescription for one of the target therapies. Using a multivariable adjustment approach with time-varying exposure, adjusted HR (95% CI) for biologic users was 4.48 (4.23 to 4.75) compared with oral or phototherapy users. After propensity score matching, the HR (95% CI) was 2.14 (2.00 to 2.28).ConclusionsIn this retrospective cohort study, biologic use was associated with the development of PsA among patients with psoriasis. This may be related to confounding by indication and protopathic bias. Prospective studies are needed to address this important question.

The T allele in rs1768208 located in or near the myelin oligodendrocyte basic protein gene (MOBP) is a risk factor for frontotemporal degeneration pathology. We evaluated the hypothesis that the presence of a T allele in rs1768208 will be associated with rate of cognitive decline in behavioral variant frontotemporal degeneration (bvFTD) related to compromised frontal networks. We studied 81 individuals clinically diagnosed with bvFTD who were genotyped for rs1768208 and coded using a dominant model reflecting the presence (i.e., MOBP +) or absence (MOBP −) of the T risk allele. Linear mixed-effects models assessed the association of genotype on neuropsychological performance over time. Regression analyses examined differences in network structure by MOBP genotype. We found a genotype by time interaction for declining cognitive performance, whereby MOBP + individuals demonstrated faster rates of decline in executive function. The presence of a MOBP risk allele was associated with degradation of white matter network features in the frontal lobe. These findings suggest that individual genetic variation may contribute to heterogeneity in clinical progression.

Objectives: This exploratory analysis examined the putative antidepressant effect of Matricaria chamomilla L. (chamomile) extract in subjects with generalized anxiety disorder (GAD) with or without comorbid depression. It was hypothesized that chamomile extract would demonstrate similar anxiolytic activity in both subgroups, but superior antidepressant activity in GAD subjects with comorbid depression. Design: As part of a randomized double-blind placebo-controlled trial of chamomile extract for relapse prevention of GAD, 179 subjects received initial therapy with open-label chamomile extract 1500 mg daily for 8 weeks. Linear mixed-effect models were used to identify clinically meaningful changes in anxiety and depression symptoms between diagnostic subgroups. Settings/Location: The study took place at the University of Pennsylvania in Philadelphia, PA. Subjects: Subjects were ≥18 years old with a primary DSM IV-TR diagnosis of GAD. They were subcategorized into two diagnostic groups: GAD without comorbid depression (n = 100) and GAD with comorbid depression (n = 79). Interventions: Open-label chamomile extract 1500 mg was given daily for 8 weeks. Outcome measures: Generalized anxiety disorder (GAD-7), Hamilton rating scale for anxiety, Beck anxiety inventory, Hamilton rating scale for depression (HRSD), the six-item core HRSD (items 1, 2, 3, 7, 8, and 13), and the Beck depression inventory (BDI). Results: The authors observed similar anxiolytic effects over time in both diagnostic subgroups. However, there was a greater reduction in HRSD core symptom scores (p

Treatment considerations for epilepsy patients requiring anticoagulation are changing, and actual prescribing practices have not been characterized. We used the 2010-2018 Optum Clinformatics® Data Mart Database to estimate the annual prevalence and distinguish the patterns of oral anticoagulants (OACs) co-dispensed with antiepileptic drugs (AEDs) among adults with epilepsy. Monotonic trends were assessed using the Spearman rank correlation coefficient (ρ). Multivariable logistic regression models were built to evaluate the associations of sociodemographic characteristics. Among 345,892 adults with epilepsy (56.5% female; median age 61, IQR 46-74) on studied AEDs, the prevalence per thousand of concurrent OACs increased from 58.4 in 2010 to 92.0 in 2018 (OR 1.63, CI 1.58-1.69). Direct-acting oral anticoagulant (DOAC) use rapidly increased from 2010 to 2018 (ρ = 1.00; P 0.001), with a corresponding decrease in warfarin use (ρ = -0.97; P 0.001). Among OAC/AED dispensings in 2018, warfarin was more likely to be co-dispensed with potentially interacting, enzyme-inducing antiepileptic drugs (EI-AEDs) versus presumably non-interacting, non-enzyme inducing antiepileptic drugs (OR 1.48, CI 1.38-1.59). Characteristics independently associated with concurrent OAC/EI-AED use included younger age, female sex, white race, net worth$250 K, and lower education levels. Our findings demonstrate the expanding use and evolving patterns of OAC/AED co-dispensing, and ensuing critical need to further understanding regarding postulated interactions.

Cerebral amyloid angiopathy (CAA), limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) and Lewy bodies occur in the absence of clinical and neuropathological Alzheimer’s disease, but their prevalence and severity dramatically increase in Alzheimer’s disease. To investigate how plaques, tangles, age and apolipoprotein E ε4 (APOE ε4) interact with co-pathologies in Alzheimer’s disease, we analysed 522 participants ≥50 years of age with and without dementia from the Center for Neurodegenerative Disease Research (CNDR) autopsy program and 1340 participants in the National Alzheimer's Coordinating Center (NACC) database. Consensus criteria were applied for Alzheimer’s disease using amyloid phase and Braak stage. Co-pathology was staged for CAA (neocortical, allocortical, and subcortical), LATE-NC (amygdala, hippocampal, and cortical), and Lewy bodies (brainstem, limbic, neocortical, and amygdala predominant). APOE genotype was determined for all CNDR participants. Ordinal logistic regression was performed to quantify the effect of independent variables on the odds of having a higher stage after checking the proportional odds assumption. We found that without dementia, increasing age associated with all pathologies including CAA (odds ratio 1.63, 95% confidence interval 1.38–1.94, P

Purpose Early cognitive symptoms such as word-finding difficulty (WFD) in daily conversation are common in Parkinson's disease (PD), but studies have been limited by a lack of feasible, quantitative measures. Linguistic analysis, focused on pauses in speech, may yield markers of impairment of cognition and communication in PD. The objective of this study was to evaluate the relationship of linguistic markers in semistructured speech to WFD symptoms and cognitive function in PD. Method Speech recordings of description of the Cookie Theft picture in 53 patients with PD without dementia and 23 elderly controls were analyzed with Praat software. Montreal Cognitive Assessment (MoCA; Nasreddine et al., 2005), category naming fluency, and confrontation naming tests were administered. Questionnaires rating WFD symptoms and cognitive instrumental activities of daily living were completed. We determined the relationships between (a) pause length and location, (b) MoCA score, and (c) WFD symptoms, using Pearson's correlations and multivariate regression models. Results Compared with controls, patients with PD had more pauses within utterances as well as fewer words per minute and a lower percentage of well-formed sentences. Pauses within utterances differed significantly between PD–mild cognitive impairment and normal cognition ( p < .001). Words per minute and percentage of well-formed sentences were predictive of MoCA in multivariate regression models. Pauses before verbs were associated with patient-reported severity of WFD symptoms ( p = .006). Conclusions Linguistic markers including pauses within utterances distinguish patients with PD with mild cognitive symptoms from elderly controls. These markers are associated with global cognitive function before the onset of dementia. Pauses before verbs and grammatical markers may index early cognitive symptoms such as WFD that may interfere with functional communication. Supplemental Material https://doi.org/10.23641/asha.6615401

OBJECTIVE: The current study establishes normative Sniffin’ Sticks Odor Identification Test (SS-OIT) scores for cognitively intact older adults. METHOD: Two hundred and twenty-six cognitively normal older adults were identified as eligible for the current study (Mean Age = 70.49 years; 71.7% female). Important demographic covariates were identified using step-wise regression, and a normative regression equation was developed. RESULTS: Analyses of the effects of demographic variables (including age, education, and sex) on SS-OIT performance revealed that age was the only significant predictor, b = −0.07, SE(b) = .01, p < .01. A final regression equation was determined and normative data are reported in 5-year increments for a number of percentile ranks. CONCLUSIONS: Normative performance on the SS-OIT for adults over the age of 50 was established in a large and demographically diverse sample. These data are needed in order for clinicians to be able to include olfactory testing, a sensitive marker of neurodegeneration, in their assessment armamentarium.

To evaluate whether occupational attainment influences the trajectory of longitudinal cognitive decline in behavioral variant frontotemporal degeneration (bvFTD). Single-center, retrospective, longitudinal study. Sixty-three patients meeting consensus criteria for bvFTD underwent evaluation at the University of Pennsylvania Frontotemporal Degeneration Center. All patients were studied longitudinally on letter-guided fluency, category-naming fluency and Boston Naming Test (BNT). Occupational attainment was defined categorically by assigning each individual’s occupation to a professional or non-professional category. Linear mixed-effects models evaluated the interaction of neuropsychological performance change with occupational status. Regression analyses were used to relate longitudinal decline in executive function to baseline MRI grey matter atrophy. Higher occupational status was associated with a more severe slope of cognitive decline on letter-guided fluency and category-naming fluency, but not BNT. Faster rates of longitudinal decline on letter-guided and category-naming fluency were associated with more severe baseline grey matter atrophy in right dorsolateral and inferior frontal regions. Our longitudinal findings suggest that bvFTD individuals with higher lifetime cognitive experience demonstrate more rapid decline on measures of executive function. This finding converges with cross-sectional evidence suggesting that lifetime cognitive experiences contribute to heterogeneity in clinical progression in bvFTD.

ObjectiveTo test the association of antemortem CSF biomarkers with postmortem pathology in Lewy body disorders (LBD).MethodsPatients with autopsy-confirmed LBD (n = 24) and autopsy-confirmed Alzheimer disease (AD) (n = 23) and cognitively normal (n = 36) controls were studied. In LBD, neuropathologic criteria defined Lewy body α-synuclein (SYN) stages with medium/high AD copathology (SYN + AD = 10) and low/no AD copathology (SYN − AD = 14). Ordinal pathology scores for tau, β-amyloid (Aβ), and SYN pathology were averaged across 7 cortical regions to obtain a global cerebral score for each pathology. CSF total tau (t-tau), phosphorylated tau at threonine181, and Aβ1-42 levels were compared between LBD and control groups and correlated with global cerebral pathology scores in LBD with linear regression. Diagnostic accuracy for postmortem categorization of LBD into SYN + AD vs SYN − AD or neocortical vs brainstem/limbic SYN stage was tested with receiver operating curves.ResultsSYN + AD had higher CSF t-tau (mean difference 27.0 ± 8.6 pg/mL) and lower Aβ1-42 (mean difference −84.0 ± 22.9 g/mL) compared to SYN − AD (p < 0.01, both). Increasing global cerebral tau and plaque scores were associated with higher CSF t-tau (R2 = 0.15–0.16, p < 0.05, both) and lower Aβ1-42 (R2 = 0.43–0.49, p < 0.001, both), while increasing cerebral SYN scores were associated with lower CSF Aβ1-42 (R2 = 0.31, p < 0.001) and higher CSF t-tau/Aβ1-42 ratio (R2 = 0.27, p = 0.01). CSF t-tau/Aβ1-42 ratio had 100% specificity and 90% sensitivity for SYN + AD, and CSF Aβ1-42 had 77% specificity and 82% sensitivity for neocortical SYN stage.ConclusionsHigher antemortem CSF t-tau/Aβ1-42 and lower Aβ1-42 levels are predictive of increasing cerebral AD and SYN pathology. These biomarkers may identify patients with LBD vulnerable to cortical SYN pathology who may benefit from both SYN and AD-targeted disease-modifying therapies.

BACKGROUND People with PD are at high risk of developing cognitive impairment and dementia. Cross-sectional studies have identified candidate biomarkers associated with cognitive decline. However, longitudinal studies on this topic are rarer, and few have investigated the use of biomarker panels encompassing multiple modalities. The objective of this study was to find baseline predictors of cognitive decline in longitudinally followed, nondemented Parkinson's disease patients. METHODS We performed a prospective cohort study of 100 PD patients with a median disease duration of 6.4 years. All participants were nondemented at baseline. We examined 16 baseline biomarkers from clinical, genetic, biochemical, and MRI-based imaging modalities for their association with longitudinal cognitive decline for up to 8 years. We investigated biomarkers individually, as well as in a multivariate linear mixed-effects model encompassing multimodal biomarkers, with change in the Mattis Dementia Rating Scale-2 over time as the primary outcome. Annual consensus process-derived cognitive diagnosis was used for Cox proportional hazards modeling of risk for cognitive decline. RESULTS In multivariate analysis, the presence of the APOE E4 allele, thought disorder, and an Alzheimer's disease pattern of brain atrophy (spatial pattern of abnormality for recognition of early Alzheimer's disease index) best predicted cognitive decline, with APOE E4 genotype exerting the greatest effect. The presence of the APOE E4 allele was associated with a 3.5 times higher risk of worsening cognitive diagnosis over time (HR, 3.53; 95% CI, 1.52-8.24; P

Background The relationship between statins and cognition in Parkinson's disease (PD) is poorly understood. Objectives Analyses were performed to determine associations between statin use and cross-sectional and longitudinal cognitive performance in PD. Methods Neuropsychological tests, medication logs, and ratings of functional abilities were collected from 313 PD participants longitudinally. Results At baseline, statin users (SU; N = 129) were older, more likely male, and had shorter PD duration than non-statin users (NSU; N = 184). In Cross-sectional analysis, SU performed better on global cognition, Trails B, semantic fluency, and phonemic fluency tasks. Rate of long-term global cognitive (Dementia Rating Scale-2 and MoCA) decline was significantly less in SU.

Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is associated with the accumulation of pathological neuronal and glial intracytoplasmic inclusions as well as accompanying neuron loss. We explored if cortical neurons detected by NeuN decreased with increasing TDP-43 inclusion pathology in the postmortem brains of 63 patients with sporadic and familial FTLD-TDP. Semi-automated quantitative algorithms to quantify histology in tissue sections stained with antibodies specific for pathological or phosphorylated TDP-43 (pTDP-43) and NeuN were developed and validated in affected (cerebral cortex) and minimally affected (cerebellar cortex) brain regions of FTLD-TDP cases. Immunohistochemistry (IHC) for NeuN and other neuronal markers found numerous neurons lacking reactivity, suggesting NeuN may reflect neuron health rather than neuron loss in FTLD. We found three patterns of NeuN and pTDP-43 reactivity in our sample of cortical tissue representing three intracortical region-specific stages of FTLD-TDP progression: Group 1 showed low levels of pathological pTDP-43 and high levels NeuN, while Group 2 showed increased levels of pTDP-43, and Group 3 tissues were characterized by reduced staining for both pTDP-43 and NeuN. Comparison of non-C9orf72/GRN FTLD-TDP with cases linked to both GRN mutations and C9orf72 expansions showed a significantly increased frequency of Group 3 histopathology in the latter cases, suggesting more advanced cortical disease. Hence, we propose that IHC profiles of pTDP-43 and NeuN reflect the burden of pTDP-43 and its deleterious effects on neuron health. Electronic supplementary material The online version of this article (10.1186/s40478-017-0471-3) contains supplementary material, which is available to authorized users.

The term "aging-related tau astrogliopathy" (ARTAG) describes pathological accumulation of abnormally phosphorylated tau protein in astrocytes. We evaluated the correlates of ARTAG types (i.e., subpial, subependymal, white and gray matter, and perivascular) in different neuroanatomical regions. Clinical, neuropathological, and genetic (eg, APOE ε4 allele, MAPT H1/H2 haplotype) data from 628 postmortem brains from subjects were investigated; most of the patients had been longitudinally followed at the University of Pennsylvania. We found that (i) the amygdala is a hotspot for all ARTAG types; (ii) age at death, male sex, and presence of primary frontotemporal lobar degeneration (FTLD) tauopathy are significantly associated with ARTAG; (iii) age at death, greater degree of brain atrophy, ventricular enlargement, and Alzheimer disease (AD)-related variables are associated with subpial, white matter, and perivascular ARTAG types; (iv) AD-related variables are associated particularly with lobar white matter ARTAG; and (v) gray matter ARTAG in primary FTLD-tauopathies appears in areas without neuronal tau pathology. We provide a reference map of ARTAG types and propose at least 5 constellations of ARTAG. Furthermore, we propose a conceptual link between primary FTLD-tauopathy and ARTAG-related astrocytic tau pathologies. Our observations serve as a basis for etiological stratification and definition of progression patterns of ARTAG.

Distinct neuronal and glial tau pathologies define corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). Additional Alzheimer disease, TDP-43, and Lewy body copathologies are also common. The interplay of these pathologies with clinical symptoms remains unclear as individuals can present with corticobasal syndrome, frontotemporal dementia, PSP, or atypical Parkinsonism and may have additional secondary impairments. We report clinical, pathological, and genetic interactions in a cohort of CBD and PSP cases. Neurofibrillary tangles and plaques were common. Apolipoprotein E (APOE)ε4 carriers had more plaques while PSP APOEε2 carriers had fewer plaques. TDP-43 copathology was present and age-associated in 14% of PSP, and age-independent in 33% of CBD. Lewy body copathology varied from 9% to 15% and was not age-associated. The primary FTD-Tau burden—a sum of the neuronal, astrocytic and oligodendrocytic tau—was not age-, APOE-, or MAPT-related. In PSP, FTD-Tau, independent of copathology, associated with executive, language, motor, and visuospatial impairments, while PSP with Parkinsonism had a lower FTD-Tau burden, but this was not the case in CBD. Taken together, our results indicate that the primary tauopathy burden is the strongest correlate of clinical PSP, while copathologies are principally determined by age and genetic risk factors.

Objective Common variants near TMEM106B associate with risk of developing frontotemporal dementia (FTD). Emerging evidence suggests a role for TMEM106B in neurodegenerative processes beyond FTD. We evaluate the effect of TMEM106B genotype on cognitive decline across multiple neurogenerative diseases. Methods We longitudinally followed 870 subjects with diagnoses of Parkinson disease (PD; n = 179), FTD (n = 179), Alzheimer disease (AD; n = 300), memory-predominant mild cognitive impairment (MCI; n = 75), or neurologically normal control subjects (NC; n = 137) at the University of Pennsylvania (UPenn). All participants had annual Mini-Mental State Examination (MMSE; median follow-up duration = 3.0 years) and were genotyped at TMEM106B index single nucleotide polymorphism rs1990622. Genotype effects on cognition were confirmed by extending analyses to additional cognitive instruments (Mattis Dementia Rating Scale-2 [DRS-2] and Montreal Cognitive Assessment [MoCA]) and to an international validation cohort (Parkinson's Progression Markers Initiative [PPMI], N = 371). Results The TMEM106B rs1990622T allele, linked to increased risk of FTD, associated with greater MMSE decline over time in PD subjects but not in AD or MCI subjects. For FTD subjects, rs1990622T associated with more rapid decrease in MMSE only under the minor-allele, rs1990622C , dominant model. Among PD patients, rs1990622T carriers from the UPenn cohort demonstrated more rapid longitudinal decline in DRS-2 scores. Finally, in the PPMI cohort, TMEM106B risk allele carriers demonstrated more rapid longitudinal decline in MoCA scores. Interpretation Irrespective of cognitive instrument or cohort assessed, TMEM106B acts as a genetic modifier for cognitive trajectory in PD. Our results implicate lysosomal dysfunction in the pathogenesis of cognitive decline in 2 different proteinopathies. ANN NEUROL 2019;85:801-811.

OBJECTIVE: We tested 2 hypotheses regarding age at onset within familial epilepsies: (1) family members with epilepsy tend to have similar ages at onset, independent of epilepsy syndrome; and (2) age at onset is younger in successive generations after controlling for sampling bias. METHODS: We analyzed clinical data collected by the Epi4K Consortium (303 multiplex families, 1,120 individuals). To test hypothesis 1, we used both linear mixed models commonly used for heritability analysis and Cox regression models with frailty terms to assess clustering of onset within families after controlling for other predictors. To test hypothesis 2, we used mixed effects models, pairwise analyses, and survival analysis to address sampling-related bias that may mimic anticipation. RESULTS: Regarding hypothesis 1, age at seizure onset was significantly heritable (intraclass correlation coefficient = 0.17, p < 0.001) after adjusting for epilepsy type, sex, site, history of febrile seizure, and age at last observation. This finding remained significant after adjusting for epilepsy syndromes, and was robust across statistical methods in all families and in generalized families. Regarding hypothesis 2, the mean age at onset decreased in successive generations (p < 0.001). After adjusting for age at last observation, this effect was not significant in mixed effects models (p = 0.14), but remained significant in pairwise (p = 0.0003) and survival analyses (p = 0.02). INTERPRETATION: Age at seizure onset is an independent familial trait, and may have genetic determinants distinct from the determinants of particular epilepsy syndromes. Younger onsets in successive generations can be explained in part by sampling bias, but the presence of genetic anticipation cannot be excluded. ANN NEUROL 2019.

INTRODUCTION: Psychosis is common among patients with Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Limited data exist on the most effective therapies. METHODS: Retrospective cohort study comparing patients with PD or DLB initiated on quetiapine or pimavanserin for psychosis. Primary outcome was time to discontinuation of pimavanserin or quetiapine using Kaplan-Meier survival analysis. We hypothesized the rate of antipsychotic discontinuation would be lower in the pimavanserin group. Subjects were included if the indication for treatment was psychosis and excluded if there was a history of major mental illness or no follow up data were available. RESULTS: Forty-seven patients were included in the quetiapine cohort and 45 in the pimavanserin cohort. Patients in the pimavanserin cohort were more likely to have a diagnosis of DLB (33% vs. 11%, P = 0.01) and to have been prescribed an antipsychotic previously (62% vs. 6%, P < 0.01); otherwise, the groups were similar. Time to discontinuation analysis, which accounts for efficacy, safety and tolerability, revealed a lower early pimavanserin discontinuation rate and a higher late pimavanserin discontinuation rate (HR < 1 before day 43, HR > 1 after day 43; P = 0.04). There was no difference in mortality in the pimavanserin group compared to the quetiapine group (HR 0.37, 95% CI 0.06 to 2.45; P = 0.88). More individuals had a documented secondary indication for taking quetiapine than pimavanserin (38% vs. 4%; P = 0.001). CONCLUSION: Accounting for efficacy, safety and tolerability, pimavanserin may be more clinically useful for promptly managing psychosis, while quetiapine may confer additional secondary benefits long-term.

Great heterogeneity exists in survival and the interval between onset of motor symptoms and dementia symptoms across synucleinopathies. We aimed to identify genetic and pathological markers that have the strongest association with these features of clinical heterogeneity in synucleinopathies.In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of patients with Lewy body disorders with autopsy-confirmed α synucleinopathy (as of Oct 1, 2015) who were previously included in other studies from five academic institutions in five cities in the USA. We used histopathology techniques and markers to assess the burden of tau neurofibrillary tangles, neuritic plaques, α-synuclein inclusions, and other pathological changes in cortical regions. These samples were graded on an ordinal scale and genotyped for variants associated with synucleinopathies. We assessed the interval from onset of motor symptoms to onset of dementia, and overall survival in groups with varying levels of comorbid Alzheimer's disease pathology according to US National Institute on Aging-Alzheimer's Association neuropathological criteria, and used multivariate regression to control for age at death and sex.On the basis of data from 213 patients who had been followed up to autopsy and met inclusion criteria of Lewy body disorder with autopsy-confirmed α synucleinopathy, we identified 49 (23%) patients with no Alzheimer's disease neuropathology, 56 (26%) with low-level Alzheimer's disease neuropathology, 45 (21%) with intermediate-level Alzheimer's disease neuropathology, and 63 (30%) with high-level Alzheimer's disease neuropathology. As levels of Alzheimer's disease neuropathology increased, cerebral α-synuclein scores were higher, and the interval between onset of motor and dementia symptoms and disease duration was shorter (p0·0001 for all comparisons). Multivariate regression showed independent negative associations of cerebral tau neurofibrillary tangles score with the interval between onset of motor and dementia symptoms (β -4·0, 95% CI -5·5 to -2·6; p0·0001; RAlzheimer's disease neuropathology is common in synucleinopathies and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tangles burden, in addition to α-synuclein pathology and amyloid plaque pathology, are the strongest pathological predictors of a shorter interval between onset of motor and dementia symptoms and survival. Diagnostic criteria based on reliable biomarkers for Alzheimer's disease neuropathology in synucleinopathies should help to identify the most appropriate patients for clinical trials of emerging therapies targeting tau, amyloid-β or α synuclein, and to stratify them by level of Alzheimer's disease neuropathology.US National Institutes of Health (National Institute on Aging and National Institute of Neurological Disorders and Stroke).

Background Generalized Anxiety Disorder (GAD) is one of the most common anxiety disorders treated in primary care, yet current therapies have limited efficacy and substantial side effects. Purpose To evaluate long-term chamomile (Matricaria chamomilla L.) use for prevention of GAD symptom relapse. Methods Outpatients from primary care practices and local communities with a primary diagnosis of moderate-to-severe GAD were enrolled for this two-phase study at a large US academic medical center. During Phase 1, eligible participants received 12 weeks of open-label therapy with chamomile pharmaceutical grade extract 1500 mg (500 mg capsule 3 times daily). During Phase 2, treatment responders were randomized to either 26 weeks of continuation chamomile therapy or placebo in a double-blinded, placebo-substitution design. The primary outcome was time to relapse during continuation therapy, analyzed using Cox proportional hazards. Secondary outcomes included the proportion who relapsed, treatment-emergent adverse events, and vital sign changes. This study is registered at ClinicalTrials.gov, identifier NCT01072344. Results Between March 1, 2010, and June 30, 2015, we enrolled 179 participants. Of those, 93 (51.9%) were responders and agreed to continue in the double-blind randomized controlled trial. A numerically greater number of placebo-switched (n = 12/47; 25.5%) versus chamomile-continuation (n = 7/46; 15.2%) participants relapsed during follow-up. Mean time to relapse was 11.4 ± 8.4 weeks for chamomile and 6.3 ± 3.9 weeks for placebo. Hazard of relapse was non-significantly lower for chamomile (hazard ratio, 0.52; 95% CI, 0.20–1.33; P = 0.16). During follow-up, chamomile participants maintained significantly lower GAD symptoms than placebo (P = 0.0032), with significant reductions in body weight (P = 0.046) and mean arterial blood pressure (P = 0.0063). Both treatments had similar low adverse event rates. Conclusions Long-term chamomile was safe and significantly reduced moderate-to-severe GAD symptoms, but did not significantly reduce rate of relapse. Our limited sample size and lower than expected rate of placebo group relapse likely contributed to the non-significant primary outcome finding. Possible chamomile superiority over placebo requires further examination in large-scale studies.

Insomnia is a prevalent and persistent side effect of cancer, which if left unaddressed, can be unremitting and negatively influence physical and mental well-being. Acupuncture and Cognitive Behavioral Therapy (CBT) are commonly used non-pharmacological treatments that are efficacious for treating insomnia in cancer patients; however, little is known about the comparative effectiveness of these options. The goal of personalized medicine is to determine which treatments are most effective for which individuals, and patient preference for treatment is a particularly important contributor to adherence and outcomes. Here we describe the design of a clinical trial that begins to determine how best to personalize the treatment of insomnia for cancer survivors. This project is a randomized controlled comparative effectiveness trial with a nested qualitative study comparing acupuncture and CBT for insomnia and co-morbid symptoms in a heterogeneous sample of 160 cancer survivors. The primary aim is to determine which treatment is associated with the largest reduction in insomnia severity. The secondary aim is to examine the demographic, clinical, and psychological characteristics that predict and/or moderate treatment effect. Patients will receive ten treatments of acupuncture or 7 sessions of CBT over eight weeks and complete validated patient-reported outcome measures of sleep and co-morbid symptoms at baseline, mid-treatment, post-treatment, and at three-months to assess durability of effect. The results of the proposed study have the potential to improve healthcare outcomes by helping cancer survivors and their caregivers make informed and evidence-based decisions, leading to patient-centered and personalized care for cancer survivors with insomnia.

ObjectiveTo determine autosomal dominant genetic predictors of survival in individuals with behavioral variant frontotemporal degeneration (bvFTD).MethodsA retrospective chart review of 174 cases with a clinical phenotype of bvFTD but no associated elementary neurologic features was performed, with diagnosis either autopsy-confirmed (n = 57) or supported by CSF evidence of non-Alzheimer pathology (n = 117). Genetic analysis of the 3 most common genes with pathogenic autosomal dominant mutations associated with frontotemporal degeneration was performed in all patients, which identified cases with C9orf72 expansion (n = 28), progranulin (GRN) mutation (n = 12), and microtubule-associated protein tau (MAPT) mutation (n = 10). Cox proportional hazards regressions were used to test for associations between survival and mutation status, sex, age at symptom onset, and education.ResultsAcross all patients with bvFTD, the presence of a disease-associated pathogenic mutation was associated with shortened survival (hazard ratio [HR] 2.164, 95% confidence interval [CI] 1.391, 3.368). In separate models, a GRN mutation (HR 2.423, 95% CI 1.237, 4.744), MAPT mutation (HR 8.056, 95% CI 2.938, 22.092), and C9orf72 expansion (HR 1.832, 95% CI 1.034, 3.244) were each individually associated with shorter survival relative to sporadic bvFTD. A mutation on the MAPT gene results in an earlier age at onset than a C9orf72 expansion or mutation on the GRN gene (p = 0.016).ConclusionsOur findings suggest that autosomal dominantly inherited mutations, modulated by age at symptom onset, associate with shorter survival among patients with bvFTD. We suggest that clinical trials and clinical management should consider mutation status and age at onset when evaluating disease progression.

To use digital histology in a large autopsy cohort of Lewy body disorder (LBD) patients with dementia to test the hypotheses that co-occurring Alzheimer disease (AD) pathology impacts the anatomic distribution of α-synuclein (SYN) pathology and that co-occurring neocortical tau pathology in LBDs associates with worse cognitive performance and occurs in a pattern differing from AD.Fifty-five autopsy-confirmed LBD (Parkinson disease with dementia, n = 36; dementia with Lewy bodies, n = 19) patients and 25 AD patients were studied. LBD patients were categorized as having moderate/severe AD copathology (SYN + AD = 20) or little/no AD copathology (SYN-AD = 35). Digital measures of tau, β-amyloid (Aβ), and SYN histopathology in neocortical and subcortical/limbic regions were compared between groups and related to antemortem cognitive testing.SYN burden was higher in SYN + AD than SYN-AD in each neocortical region (FLBD patients with AD copathology harbor greater neocortical SYN pathology. Regional tau pathology relates to cognitive performance in LBD dementia, and its distribution may diverge from pure AD. Tau copathology contributes uniquely to the heterogeneity of cognitive impairment in LBD. Ann Neurol 2018; 1-13 ANN NEUROL 2019;85:259-271.

BackgroundInsomnia is a common and debilitating disorder experienced by cancer survivors. Although cancer survivors express a preference for using nonpharmacological treatment to manage insomnia, the comparative effectiveness between acupuncture and Cognitive Behavioral Therapy for Insomnia (CBT-I) for this disorder is unknown.MethodsThis randomized trial compared 8 weeks of acupuncture (n = 80) and CBT-I (n = 80) in cancer survivors. Acupuncture involved stimulating specific points on the body with needles. CBT-I included sleep restriction, stimulus control, cognitive restructuring, relaxation training, and education. We measured insomnia severity (primary outcome), pain, fatigue, mood, and quality of life posttreatment (8 weeks) with follow-up until 20 weeks. We used linear mixed-effects models for analyses. All statistical tests were two-sided.ResultsThe mean age was 61.5 years and 56.9% were women. CBT-I was more effective than acupuncture posttreatment (P ConclusionsAlthough both treatments produced meaningful and durable improvements, CBT-I was more effective and should be the first line of therapy. The relative differences in the comparative effectiveness between the two interventions for specific groups should be confirmed in future adequately powered trials to guide more tailored interventions for insomnia.

Lewy bodies commonly occur in Alzheimer's disease, and Alzheimer's disease pathology is frequent in Lewy body diseases, but the burden of co-pathologies across neurodegenerative diseases is unknown. We assessed the extent of tau, amyloid-β, α-synuclein and TDP-43 proteinopathies in 766 autopsied individuals representing a broad spectrum of clinical neurodegenerative disease. We interrogated pathological Alzheimer's disease (n = 247); other tauopathies (n = 95) including Pick's disease, corticobasal disease and progressive supranuclear palsy; the synucleinopathies (n = 164) including multiple system atrophy and Lewy body disease; the TDP-43 proteinopathies (n = 188) including frontotemporal lobar degeneration with TDP-43 inclusions and amyotrophic lateral sclerosis; and a minimal pathology group (n = 72). Each group was divided into subgroups without or with co-pathologies. Age and sex matched logistic regression models compared co-pathology prevalence between groups. Co-pathology prevalence was similar between the minimal pathology group and most neurodegenerative diseases for each proteinopathy: tau was nearly universal (92-100%), amyloid-β common (20-57%); α-synuclein less common (4-16%); and TDP-43 the rarest (0-16%). In several neurodegenerative diseases, co-pathology increased: in Alzheimer's disease, α-synuclein (41-55%) and TDP-43 (33-40%) increased; in progressive supranuclear palsy, α-synuclein increased (22%); in corticobasal disease, TDP-43 increased (24%); and in neocortical Lewy body disease, amyloid-β (80%) and TDP-43 (22%) increased. Total co-pathology prevalence varied across groups (27-68%), and was increased in high Alzheimer's disease, progressive supranuclear palsy, and neocortical Lewy body disease (70-81%). Increased age at death was observed in the minimal pathology group, amyotrophic lateral sclerosis, and multiple system atrophy cases with co-pathologies. In amyotrophic lateral sclerosis and neocortical Lewy body disease, co-pathologies associated with APOE ɛ4. Lewy body disease cases with Alzheimer's disease co-pathology had substantially lower Mini-Mental State Examination scores than pure Lewy body disease. Our data imply that increased age and APOE ɛ4 status are risk factors for co-pathologies independent of neurodegenerative disease; that neurodegenerative disease severity influences co-pathology as evidenced by the prevalence of co-pathology in high Alzheimer's disease and neocortical Lewy body disease, but not intermediate Alzheimer's disease or limbic Lewy body disease; and that tau and α-synuclein strains may also modify co-pathologies since tauopathies and synucleinopathies had differing co-pathologies and burdens. These findings have implications for clinical trials that focus on monotherapies targeting tau, amyloid-β, α-synuclein and TDP-43.

Aging-related tau astrogliopathy (ARTAG) describes tau pathology in astrocytes in different locations and anatomical regions. In the present study we addressed the question of whether sequential distribution patterns can be recognized for ARTAG or astroglial tau pathologies in both primary FTLD-tauopathies and non-FTLD-tauopathy cases. By evaluating 687 postmortem brains with diverse disorders we identified ARTAG in 455. We evaluated frequencies and hierarchical clustering of anatomical involvement and used conditional probability and logistic regression to model the sequential distribution of ARTAG and astroglial tau pathologies across different brain regions. For subpial and white matter ARTAG we recognize three and two patterns, respectively, each with three stages initiated or ending in the amygdala. Subependymal ARTAG does not show a clear sequential pattern. For grey matter (GM) ARTAG we recognize four stages including a striatal pathway of spreading towards the cortex and/or amygdala, and the brainstem, and an amygdala pathway, which precedes the involvement of the striatum and/or cortex and proceeds towards the brainstem. GM ARTAG and astrocytic plaque pathology in corticobasal degeneration follows a predominantly frontal-parietal cortical to temporal-occipital cortical, to subcortical, to brainstem pathway (four stages). GM ARTAG and tufted astrocyte pathology in progressive supranuclear palsy shows a striatum to frontal-parietal cortical to temporal to occipital, to amygdala, and to brainstem sequence (four stages). In Pick’s disease cases with astroglial tau pathology an overlapping pattern with PSP can be appreciated. We conclude that tau-astrogliopathy type-specific sequential patterns cannot be simplified as neuron-based staging systems. The proposed cytopathological and hierarchical stages provide a conceptual approach to identify the initial steps of the pathogenesis of tau pathologies in ARTAG and primary FTLD-tauopathies. Electronic supplementary material The online version of this article (10.1186/s40478-018-0552-y) contains supplementary material, which is available to authorized users.

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

Digital image analysis of histology sections provides reliable, high-throughput methods for neuropathological studies but data is scant in frontotemporal lobar degeneration (FTLD), which has an added challenge of study due to morphologically diverse pathologies. Here, we describe a novel method of semi-automated digital image analysis in FTLD subtypes including: Pick’s disease (PiD, n=11) with tau-positive intracellular inclusions and neuropil threads, and TDP-43 pathology type C (FTLD-TDPC, n=10), defined by TDP-43-positive aggregates predominantly in large dystrophic neurites. To do this, we examined three FTLD-associated cortical regions: mid-frontal gyrus (MFG), superior temporal gyrus (STG) and anterior cingulate gyrus (ACG) by immunohistochemistry. We used a color deconvolution process to isolate signal from the chromogen and applied both object detection and intensity thresholding algorithms to quantify pathological burden. We found object-detection algorithms had good agreement with gold-standard manual quantification of tau- and TDP-43-positive inclusions. Our sampling method was reliable across three separate investigators and we obtained similar results in a pilot analysis using open-source software. Regional comparisons using these algorithms finds differences in regional anatomic disease burden between PiD and FTLD-TDP not detected using traditional ordinal scale data, suggesting digital image analysis is a powerful tool for clinicopathological studies in morphologically diverse FTLD syndromes.

Objective To describe the incidence of, and clinical and neurobiological risk factors for, new-onset impulse control disorder (ICD) symptoms and related behaviours in early Parkinson disease (PD). Methods The Parkinson9s Progression Markers Initiative is an international, multicenter, prospective study of de novo patients with PD untreated at baseline and assessed annually, including serial dopamine transporter imaging (DAT-SPECT) and ICD assessment (Questionnaire for Impulsive-Compulsive Disorders in Parkinson9s Disease short form, QUIP). Participants were included if they screened negative on the QUIP at baseline. Kaplan-Meier curves and generalised estimating equations examined frequency and predictors of incident ICD symptoms. Results Participants were seen at baseline (n=320), year 1 (n=284), year 2 (n=217) and year 3 (n=96). Estimated cumulative incident rates of ICD symptoms and related behaviours were 8% (year 1), 18% (year 2) and 25% (year 3) and increased each year in those on dopamine replacement therapy (DRT) and decreased in those not on DRT. In participants on DRT, risk factors for incident ICD symptoms were younger age (OR=0.97, p=0.05), a greater decrease in right caudate (OR=4.03, p=0.01) and mean striatal (OR=6.90, p=0.04) DAT availability over the first year, and lower right putamen (OR=0.06, p=0.01) and mean total striatal (OR=0.25, p=0.04) DAT availability at any post-baseline visit. Conclusions The rate of incident ICD symptoms increases with time and initiation of DRT in early PD. In this preliminary study, a greater decrease or lower DAT binding over time increases risk of incident ICD symptoms, conferring additional risk to those taking DRT. Clinical trial registration NCT01141023.

Objective: To examine the influence of occupational attainment and education on survival in autopsy-confirmed cases of frontotemporal lobar degeneration (FTLD) and Alzheimer disease (AD). Methods: We performed a retrospective chart review of 83 demographically matched, autopsy-confirmed FTLD (n = 34) and AD (n = 49) cases. Each patient9s primary occupation was classified and ranked. Level of education was recorded in years. Survival was defined as time from symptom onset until death. Linear regression was used to test for associations among occupational attainment, education, and patient survival. Results: Median survival was 81 months for FTLD and 95 months for AD. Years of education and occupational attainment were similar for both groups. We found that higher occupational attainment was associated with longer survival in FTLD but not AD. Conclusions: Our findings suggest that higher occupational attainment is associated with longer survival in autopsy-confirmed FTLD. The identification of protective factors associated with FTLD survival has important implications for estimates of prognosis and longitudinal studies such as treatment trials.

Background: We performed a proof of concept trial to evaluate relative safety and efficacy of Rhodiola rosea (R. rosea) versus sertraline for mild to moderate major depressive disorder. Hypothesis: We hypothesize that R. rosea would have similar therapeutic effects as sertraline but with less adverse events. Study design: Phase II randomized placebo controlled clinical trial. Methods: 57 subjects were randomized to 12 weeks of standardized R. rosea extract, sertraline, or placebo. Changes over time in Hamilton Depression Rating (HAM-D), Beck Depression Inventory (BDI), and Clinical Global Impression Change (CGI/C) scores among groups were examined using mixed-effects models. Results: Modest, albeit statistically non-significant, reductions were observed for HAM-D, BDI, and CGI/C scores for all treatment conditions with no significant difference between groups (p = 0.79, p = 0.28, and p = 0.17, respectively). The decline in HAM-D scores was greater for sertraline (−8.2, 95% confidence interval [CI], −12.7 to −3.6) versus R. rosea (−5.1, 95% CI: −8.8 to −1.3) and placebo (−4.6, 95% CI: −8.6 to −0.6). While the odds of improving (versus placebo) were greater for sertraline (1.90 [0.44–8.20]; odds ratio [95% CI]) than R. rosea (1.39 [0.38–5.04]), more subjects on sertraline reported adverse events (63.2%) than R. rosea (30.0%) or placebo (16.7%) (p = 0.012). Conclusions: Although R. rosea produced less antidepressant effect versus sertraline, it also resulted in significantly fewer adverse events and was better tolerated. These findings suggest that R. rosea, although less effective than sertraline, may possess a more favorable risk to benefit ratio for individuals with mild to moderate depression.

Amnestic Alzheimer’s disease is characterized by early atrophy of the hippocampus and medial temporal lobes before spreading to neocortex. In contrast, non-amnestic Alzheimer’s patients have relative sparing of the hippocampus, but the pattern in which disease spreads is unclear. We examined spreading disease in non-amnestic Alzheimer’s disease using a novel magnetic resonance imaging-based analysis adapted from pathologic staging studies, applied here to cross-sectional imaging data. We selected 240 T1-weighted scans from 129 patients with pathology confirmed by autopsy or cerebrospinal fluid, and atrophy maps were computed relative to 238 scans from 115 elderly controls. For each phenotype, the frequency of atrophy in 116 brain regions was used to infer the anatomical origin of disease and its progression across 4 phases of atrophy. Results from the amnestic cohort were used to determine appropriate parameter settings for the phase assignment algorithm, based on correspondence to Braak pathology staging. Phase 1 regions, which represent the origin of disease, included hippocampus for the amnestic group (comprising 33 scans); left lateral temporal lobe for logopenic-variant primary progressive aphasia (88 scans); occipito-parietal cortex for posterior cortical atrophy (51 scans); temporo-parietal cortex for corticobasal syndrome (31 scans); and fronto-temporal cortex for behavioral/dysexecutive variant Alzheimer’s disease (37 scans). In non-amnestic patients atrophy spread to other neocortical areas in later phases, but the hippocampus exhibited only late-phase atrophy in posterior cortical atrophy and corticobasal syndrome. Region-specific phase values were also associated with regional measures of tau, amyloid-beta, neuronal loss, and gliosis for the subset of patients (n=17) with neuropathology findings; this comparison represented a first validation of the phase assignment algorithm. We subsequently assigned a phase to each patient scan based on the similarity of regional atrophy patterns with atrophy predicted for the corresponding phenotype at each phase. Scan-specific phases were correlated with disease duration as well as global and domain-specific cognition, supporting these phase values as global estimates of patients’ disease progression. Logistic regression models based on spatial overlap with model-predicted atrophy patterns reliably discriminated non-amnestic phenotypes from each other and from amnestic Alzheimer’s disease. The frequency-based phase assignment algorithm employed in the current study thus represents a promising approach for studying the neocortical origin and spread of disease in non-amnestic Alzheimer’s disease.

Introduction Suspected non-Alzheimer's pathophysiology (SNAP) is a biomarker driven designation that represents a heterogeneous group in terms of etiology and prognosis. SNAP has only been identified by cross-sectional neurodegeneration measures, whereas longitudinal measures might better reflect “active” neurodegeneration and might be more tightly linked to prognosis. We compare neurodegeneration defined by cross-sectional ‘hippocampal volume’ only (SNAP/L−) versus both cross-sectional and longitudinal ‘hippocampal atrophy rate’ (SNAP/L+) and investigate how these definitions impact prevalence and the clinical and biomarker profile of SNAP in Mild Cognitive Impairment (MCI). Methods 276 MCI patients from ADNI-GO/2 were designated amyloid “positive” (A+) or “negative” (A−) based on their florbetapir scan and neurodegeneration ‘positive’ or ‘negative’ based on cross-sectional hippocampal volume and longitudinal hippocampal atrophy rate. Results 74.1% of all SNAP participants defined by the cross-sectional definition of neurodegeneration also met the longitudinal definition of neurodegeneration, whereas 25.9% did not. SNAP/L+ displayed larger white matter hyperintensity volume, a higher conversion rate to dementia over 5 years and a steeper decline on cognitive tasks compared to SNAP/L− and the A- CN group. SNAP/L− had more abnormal values on neuroimaging markers and worse performance on cognitive tasks than the A- CN group, but did not show a difference in dementia conversion rate or longitudinal cognition. Discussion Using a longitudinal definition of neurodegeneration in addition to a cross-sectional one identifies SNAP participants with significant cognitive decline and a worse clinical prognosis for which cerebrovascular disease may be an important driver., Highlights • 74.1% of SNAP subjects also met the criteria for longitudinal neurodegeneration (L+). • SNAP/L+ had a larger WMH volume compared to the SNAP/L− group and the A- CN group. • SNAP/L+ showed a higher conversion rate and steeper cognitive decline than A- CN. • SNAP/L− showed similar conversion rate and cognitive decline as A- CN.

Epidemiological studies have identified a robust association between type II diabetes mellitus and Alzheimer disease (AD), and neurobiological studies have suggested the presence of central nervous system insulin resistance in individuals with AD. Given this association, we hypothesized that the central nervous system-penetrant insulin-sensitizing medication metformin would be beneficial as a disease-modifying and/or symptomatic therapy for AD, and conducted a placebo-controlled crossover study of its effects on cerebrospinal fluid (CSF), neuroimaging, and cognitive biomarkers. Twenty nondiabetic subjects with mild cognitive impairment or mild dementia due to AD were randomized to receive metformin then placebo for 8 weeks each or vice versa. CSF and neuroimaging (Arterial Spin Label MRI) data were collected for biomarker analyses, and cognitive testing was performed. Metformin was found to be safe, well-tolerated, and measureable in CSF at an average steady-state concentration of 95.6 ng/mL. Metformin was associated with improved executive functioning, and trends suggested improvement in learning/memory and attention. No significant changes in cerebral blood flow were observed, though post hoc completer analyses suggested an increase in orbitofrontal cerebral blood flow with metformin exposure. Further study of these findings is warranted.

Lower vitamin D levels have been associated with manifest Parkinson's disease, prompting the hypothesis that vitamin D insufficiency or deficiency may increase risk for PD.To evaluate vitamin D levels in a population at risk for developing PD.Plasma vitamin D levels were measured in the Parkinson Associated Risk Syndrome Study, a cohort of asymptomatic individuals, some of whom are at high risk for PD. Vitamin D levels were compared between subjects at high risk for PD (hyposmia and dopamine transporter scan deficit) versus all others and examined for correlations with dopaminergic system integrity.Mean vitamin D levels did not differ between groups, with a level of 27.8 ng/mL (standard deviation = 12.0) in the high-risk group versus 24.7 ng/mL (standard deviation = 9.0) in all others (P = 0.09). Vitamin D levels did not associate with putaminal dopamine transporter uptake.Our data from the asymptomatic Parkinson Associated Risk Syndrome cohort do not support the hypothesis that chronic vitamin D insufficiency threatens dopaminergic system integrity, contributing to PD pathogenesis. © 2017 International Parkinson and Movement Disorder Society.

Objective To examine how phenotype affects longitudinal decline on the Mini-Mental State Examination (MMSE) in patients with frontotemporal lobar degeneration (FTLD) and Alzheimer disease (AD). Background The MMSE is the most commonly administered assessment for dementia severity; however, the effects of phenotype on longitudinal MMSE performance in FTLD and AD have not been extensively studied. Methods Data from 185 patients diagnosed with AD (n=106) and 3 FTLD (n=79) phenotypes [behavioral variant frontotemporal dementia (bvFTD), nonfluent agrammatic variant of primary progressive aphasia (nfaPPA), and semantic variant PPA (svPPA)] were collected for up to 52 months since initial evaluation. Results Differential rates of decline were noted in that MMSE scores declined more precipitously for AD and svPPA compared with bvFTD and nfaPPA patients (P=0.001). The absolute 4-year MMSE decline given median baseline MMSE for bvFTD [14.67; 95% confidence interval (CI), 14.63-14.71] and nfaPPA (11.02; 95% CI, 10.98-11.06) were lower than svPPA (22.32; 95% CI, 22.29-22.34) or AD (22.24; 95% CI, 22.22-22.26). Conclusions These data suggest that within-group AD and FTLD phenotypes present distinct patterns of longitudinal decline on the MMSE. MMSE may not be adequately sensitive to track disease progression in some phenotypes of FTLD.

Objective: To examine how cognitive impairment affects Parkinson disease (PD) patients9 research consent capacity. Methods: A cross-sectional study of 90 patients with PD, divided using Mattis Dementia Rating Scale–2 scores into 3 groups of 30 (normal, borderline, and impaired), and 30 neurologically normal older adults completed 2 capacity interviews (an early-phase randomized and controlled drug trial and a sham-controlled surgical implantation of genetic tissue) using the MacArthur Competence Assessment Tool for Clinical Research. Expert clinicians used the interviews to classify the patients as either capable or not capable of providing their own informed consent. These judgments were compared with performance on the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE). Results: Cognitively normal PD patients typically scored well on the capacity measures. In contrast, patients with impaired cognition were not capable of providing their own informed consent: 17% (5/30) on the drug trial and 3% (1/30) on the surgery trial were judged capable. Patients with borderline impairment showed adequate performance on measures of appreciation and reasoning, but impaired performance on understanding the drug trial compared with normal controls and normal PD patients, and on understanding the surgery trial compared with normal controls. Sixty-seven percent (20/30) on the drug trial and 57% (17/30) on the surgery trial were judged capable of consent. Receiver operating characteristic analyses showed that the MMSE and MoCA could detect the likelihood of impaired capacity, with the MoCA demonstrating greater sensitivity. Conclusions: PD patients with borderline cognitive impairment have impairments in their decisional capacity. The MoCA may be useful to identify the patients at risk of impaired capacity.

The dynamics of cerebrospinal fluid (CSF) tau and Aβ biomarkers over time in Alzheimer’s disease (AD) patients from prodromal pre-symptomatic to severe stages of dementia have not been clearly defined and recent studies, most of which are cross-sectional, present conflicting findings. To clarify this issue, we analyzed the longitudinal CSF tau and Aβ biomarker data from 142 of the AD Neuroimaging Initiative (ADNI) study subjects [18 AD, 74 mild cognitive impairment (MCI), and 50 cognitively normal subjects (CN)]. Yearly follow-up CSF collections and studies were conducted for up to 48 months (median = 36 months) for CSF Aβ1–42, phosphorylated tau (p-tau181), and total tau (t-tau). An unsupervised analysis of longitudinal measurements revealed that for Aβ1–42 and p-tau181 biomarkers there was a group of subjects with stable longitudinal CSF biomarkers measures and a group of subjects who showed a decrease (Aβ1–42, mean = −9.2 pg/ml/year) or increase (p-tau181, mean = 5.1 pg/ml/year) of these biomarker values. Low baseline Aβ1–42 values were associated with longitudinal increases in p-tau181. Conversely, high baseline p-tau181 values were not associated with changes in Aβ1–42 levels. When the subjects with normal baseline biomarkers and stable concentrations during follow-up were excluded, the expected time to reach abnormal CSF levels and the mean AD values was significantly shortened. Thus, our data demonstrate for the first time that there are distinct populations of ADNI subjects with abnormal longitudinal changes in CSF p-tau181 and Aβ1–42 levels, and our longitudinal results favor the hypothesis that Aβ1–42 changes precede p-tau181 changes.

BACKGROUND Methods to detect early cognitive decline and account for heterogeneity of deficits in Parkinson's disease (PD) are needed. Quantitative methods such as latent class analysis (LCA) offer an objective approach to delineate discrete phenotypes of impairment. OBJECTIVE To identify discrete neurocognitive phenotypes in PD patients without dementia. METHODS LCA was applied to a battery of 8 neuropsychological measures to identify cognitive subtypes in a cohort of 199 non-demented PD patients. Two measures were analyzed from each of four domains: executive functioning, memory, visuospatial abilities, and language. Additional analyses compared groups on clinical characteristics and cognitive diagnosis. RESULTS LCA identified 3 distinct groups of PD patients: an intact cognition group (54.8%), an amnestic group (32.2%), and a mixed impairment group with dysexecutive, visuospatial and lexical retrieval deficits (13.1%). The two impairment groups had significantly lower instrumental activities of daily living ratings and greater motor symptoms than the intact group. Of those diagnosed as cognitively normal according to MDS criteria, LCA classified 23.2% patients as amnestic and 9.9% as mixed cognitive impairment. CONCLUSIONS Non-demented PD patients exhibit distinct neuropsychological profiles. One-third of patients with LCA-determined impairment were diagnosed as cognitively intact by expert consensus, indicating that classification using a statistical algorithm may improve detection of initial and subtle cognitive decline. This study also demonstrates that memory impairment is common in non-demented PD even when cognitive impairment is not clinically apparent. This study has implications for predicting eventual emergence of significant cognitive decline, and treatment trials for cognitive dysfunction in PD.

The frequency and clinical and pathological characteristics associated with the Gly206Ala presenilin 1 (PSEN1) mutation in Puerto Rican and non-Puerto Rican Hispanics were evaluated at the University of Pennsylvania’s Alzheimer’s Disease Center. DNAs from all cohort subjects were genotyped for the Gly206Ala PSEN1 mutation. Carriers and non-carriers with neurodegenerative disease dementias were compared for demographic, clinical, psychometric, and biomarker variables. Nineteen (12.6%) of 151 unrelated subjects with dementia were discovered to carry the PSEN1 Gly 206Ala mutation. Microsatellite marker genotyping determined a common ancestral haplotype for all carriers. Carriers were all of Puerto Rican heritage with significantly younger age of onset, but otherwise were clinically and neuropsychologically comparable to those of non-carriers with AD. Three subjects had extensive topographic and biochemical biomarker assessments that were also typical of non-carriers with AD. Neuropathological examination in one subject revealed severe, widespread plaque and tangle pathology without other meaningful disease lesions. The PSEN1 Gly206Ala mutation is notably frequent in unrelated Puerto Rican immigrants with dementia in Philadelphia. Considered together with the increased prevalence and mortality of AD reported in Puerto Rico, these high rates may reflect hereditary risk concentrated in the island which warrants further study.

To test the hypotheses that (1) antemortem cerebrospinal fluid (CSF) tau levels correlate with postmortem tau pathology in frontotemporal lobar degeneration (FTLD) and (2) tauopathy patients have higher phosphorylated-tau levels compared to transactivation response element DNA-binding protein 43 (TDP-43) proteinopathy patients while accounting for Alzheimer's disease (AD) copathology.Patients had autopsy-confirmed FTLD with tauopathy (n = 31), TDP-43 proteinopathy (n = 49), or AD (n = 26) with antemortem CSF. CSF tau levels were compared between groups and correlated with digital histology measurement of postmortem tau pathology averaged from three cerebral regions (angular gyrus, mid-frontal cortex, and anterior cingulate gyrus). Multivariate linear regression tested the association of ante mortem CSF tau levels with postmortem tau pathology adjusting for demographics.Multivariate regression found an independent association of ante mortem CSF phosphorylated tau levels with postmortem cerebral tau pathology in FTLD (Beta = 1.3; 95% confidence interval = 0.2-2.4; p0.02). After excluding patients with coincident AD-associated tau pathology accompanying sporadic FTLD, we found lower CSF phosphorylated tau levels in the TDP-43 group (median = 7.4pg/ml; interquartile range [IQR] = 6.0, 12.3; n = 26) compared to the tauopathy group (median = 12.5pg/ml; IQR = 10.7, 15.0; n = 23; Z = 2.6; p0.01).CSF phosphorylated-tau levels are positively associated with cerebral tau burden in FTLD. In vivo detection of AD copathology in sporadic FTLD patients may help stratify clinical cohorts with pure neuropathology in which low CSF phosphorylated-tau levels may have diagnostic utility to distinguish TDP-43 proteinopathy from tauopathy. Autopsy-confirmed samples are critical for FTLD biomarker development and validation. Ann Neurol 2017;82:247-258.

Background Medication non-adherence is common in Parkinson's disease (PD) and is associated with increased disability and healthcare costs. Individuals' beliefs regarding their medical conditions and treatments impact medication adherence. While instruments exist to measure patients' beliefs about medications in general, no such tool exists for PD. Objectives Create an instrument eliciting medication beliefs of persons with PD; identify demographic and clinical characteristics associated with beliefs; and examine whether beliefs are associated with dopaminergic therapy adherence. Methods We developed the Parkinson's Disease Medication Beliefs Scale (PD-Rx) in four phases: focus groups of patients and caregivers to generate items, scale development, expert and patient revision of items, and a cross-sectional validation sample (n = 75). Adherence was calculated using two approaches incorporating self-reported medication lists. Results The PD-Rx consists of 11 items covering benefits and risks of PD pharmacotherapies. The scale covers motor improvement, current adverse effects, and future concerns. Higher scores indicate more positive beliefs. Internal consistency was acceptable (Cronbach's alpha = 0.67). Test-retest reliability was 0.47. Quality of life was associated with PD-Rx scores, and lower scores were associated with non-adherence. Conclusions Negative beliefs about PD treatments are associated with lower quality of life and may be related to medication non-adherence. Further study of any causal relationship between beliefs and medication non-adherence in PD will inform the design of future patient-centered interventions to improve adherence.

Background The aim of this study was to compare the utility and diagnostic accuracy of the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) in the diagnosis of Alzheimer's disease (AD) and mild cognitive impairment (MCI) in a clinical cohort. Methods Three hundred twenty-one AD, 126 MCI, and 140 older adults with healthy cognition (HC) were evaluated using the MMSE, the MoCA, a standardized neuropsychologic battery according to the Consortium to Establish a Registry of Alzheimer's Disease (CERAD-NB), and an informant-based measure of functional impairment, the Dementia Severity Rating Scale (DSRS). Diagnostic accuracy and optimal cut-off scores were calculated for each measure, and a method for converting MoCA to MMSE scores is presented. Results The MMSE and MoCA offer reasonably good diagnostic and classification accuracy as compared with the more detailed CERAD-NB; however, as a brief cognitive screening measure, the MoCA was more sensitive and had higher classification accuracy for differentiating MCI from HC. Complementing the MMSE or the MoCA with the DSRS significantly improved diagnostic accuracy. Conclusion The findings support recent data indicating that the MoCA is superior to the MMSE as a global assessment tool, particularly in discerning earlier stages of cognitive decline. In addition, we found that overall diagnostic accuracy improves when the MMSE or MoCA is combined with an informant-based functional measure. Finally, we provide a reliable and easy conversion of MoCA to MMSE scores. However, the need for MCI-specific measures is still needed to increase the diagnostic specificity between AD and MCI.

A growing body of evidence demonstrates an association between vascular risk factors and Alzheimer’s disease. This study investigated the frequency and severity of atherosclerotic plaques in the circle of Willis in Alzheimer’s disease and multiple other neurodegenerative diseases. Semi-quantitative data from gross and microscopic neuropathological examinations in 1000 cases were analysed, including 410 with a primary diagnosis of Alzheimer’s disease, 230 with synucleinopathies, 157 with TDP-43 proteinopathies, 144 with tauopathies and 59 with normal ageing. More than 77% of subjects with Alzheimer’s disease had grossly apparent circle of Willis atherosclerosis, a percentage that was significantly higher than normal (47%), or other neurodegenerative diseases (43–67%). Age- and sex-adjusted atherosclerosis ratings were highly correlated with neuritic plaque, paired helical filaments tau neurofibrillary tangle and cerebral amyloid angiopathy ratings in the whole sample and within individual groups. We found no associations between atherosclerosis ratings and α-synuclein or TDP-43 lesion ratings. The association between age-adjusted circle of Willis atherosclerosis and Alzheimer’s disease–type pathology was more robust for female subjects than male subjects. These results provide further confirmation and specificity that vascular disease and Alzheimer’s disease are interrelated and suggest that common aetiologic or reciprocally synergistic pathophysiological mechanisms promote both vascular pathology and plaque and tangle pathology.