Clinical Syndrome Of Dementia Research Articles

The Single Toxin Origin of Alzheimer's Disease and Other Neurodegenerative Disorders Enables Targeted Approach to Treatment and Prevention.

New data suggest that the aggregation of misfolded native proteins initiates and drives the pathogenic cascade that leads to Alzheimer's disease (AD) and other age-related neurodegenerative disorders. We propose a unifying single toxin theory of brain neurodegeneration that identifies new targets and approaches to the development of disease-modifying treatments. An extensive body of genetic evidence suggests soluble aggregates of beta-amyloid (Aβ) as the primary neurotoxin in the pathogenesis of AD. New insights from fluid biomarkers, imaging, and clinical studies provide further evidence for the decisive impact of toxic Aβ species in the initiation and progression of AD. Understanding the distinct roles of soluble and insoluble amyloid aggregates on AD pathogenesis has been the key missing piece of the Alzheimer's puzzle. Data from clinical trials with anti-amyloid agents and recent advances in the diagnosis of AD demonstrate that the driving insult in biologically defined AD is the neurotoxicity of soluble Aβ aggregates, called oligomers and protofibrils, rather than the relatively inert insoluble mature fibrils and amyloid plaques. Amyloid oligomers appear to be the primary factor causing the synaptic impairment, neuronal stress, spreading of tau pathology, and eventual cell death that lead to the clinical syndrome of AD dementia. All other biochemical effects and neurodegenerative changes in the brain that are observed in AD are a response to or a downstream effect of this initial toxic insult by oligomers. Other neurodegenerative disorders follow a similar pattern of pathogenesis, in which normal brain proteins with important biological functions become trapped in the aging brain due to impaired clearance and then misfold and aggregate into neurotoxic species that exhibit prion-like behavior. These aggregates then spread through the brain and cause disease-specific neurodegeneration. Targeting the inhibition of this initial step in neurodegeneration by blocking the misfolding and aggregation of healthy proteins has the potential to slow or arrest disease progression, and if treatment is administered early in the course of AD and other neurodegenerative disorders, it may delay or prevent the onset of clinical symptoms.

Insights into the pathological basis of dementia from population-based neuropathology studies.

The epidemiological neuropathology perspective of population and community-based studies allows unbiased assessment of the prevalence of various pathologies and their relationships to late-life dementia. In addition, this approach provides complementary insights to conventional case-control studies, which tend to be more representative of a younger clinical cohort. The Cognitive Function and Ageing Study (CFAS) is a longitudinal study of cognitive impairment and frailty in the general United Kingdom population. In this review, we provide an overview of the major findings from CFAS, alongside other studies, which have demonstrated a high prevalence of pathology in the ageing brain, particularly Alzheimer's disease neuropathological change and vascular pathology. Increasing burdens of these pathologies are the major correlates of dementia, especially neurofibrillary tangles, but there is substantial overlap in pathology between those with and without dementia, particularly at intermediate burdens of pathology and also at the oldest ages. Furthermore, additional pathologies such as limbic-predominant age-related TDP-43 encephalopathy, ageing-related tau astrogliopathy and primary age-related tauopathies contribute to late-life dementia. Findings from ageing population-representative studies have implications for the understanding of dementia pathology in the community. The high prevalence of pathology and variable relationship to dementia status has implications for disease definition and indicate a role for modulating factors on cognitive outcome. The complexity of late-life dementia, with mixed pathologies, indicates a need for a better understanding of these processes across the life-course to direct the best research for reducing risk in later life of avoidable clinical dementia syndromes.

Pathologic TDP43 Associated Tri‐Glial Dysfunction in Amnestic and Non‐amnestic Clinical Dementia Syndromes: A Multiplexed Immunofluorescence Study

AbstractBackgroundAlzheimer’s disease (AD) is a substantial cause of death and disability. In addition to the plaques and tangles classically observed in AD, other co‐existing brain lesions also contribute to the development of cognitive impairment, such as pathologic trans‐active response DNA‐binding protein 43 (pTDP43). TDP43 is ubiquitously expressed in the brain and mechanistic studies suggest potential roles for TDP43 in maintaining normal physiologic conditions in glia (astrocytes, microglia, oligodendrocytes) (Bulgiani, 2022). Effective glial functioning and signaling are crucial to maintaining functional connectivity and pTDP43 is strongly associated with lower cognitive performance (Flanagan, 2018). However, pTDP43’s role in tri‐glial dysfunction remains unclear. We hypothesize that nuclear astrocytic TDP43 loss alters astrocyte‐to‐microglial signaling, and results in tri‐glial dysfunction. Here we examine glial pTDP43 subtypes in amnestic and non‐amnestic clinical dementia syndromes with matched AD pathology.MethodParaffin embedded autopsy samples (hippocampus and middle frontal cortex) were stained using multiplexed immunofluorescence (Pu.1: microglia, GLUL: astrocytes, total TDP43), and imaged. Indica Labs Halo software was used to perform quantitative analyses on whole slide images. Cases were matched for AD pathology (low and high) (Montine, 2012). Students’ t‐tests were performed to compare cell counts between groups. Kolmogorov–Smirnov test was performed to check approximate normality before applying t‐test and all measurements passed it. Clinical phenotypes (AD dementia vs. behavioral variant frontotemporal dementia (bvFTD)) and pTDP43 status were compared (n = 50). Spatial localization plots, NSInC colocalization indices, and Box plot comparisons were used to assess the impact of glial pTDP43 on the microenvironment.ResultHippocampal astrocyte counts are lowest in the AD dementia setting with the highest AD pathology burden, and presence of co‐existing pTDP43. Cases with high AD pathology had lower astrocyte counts when co‐existing pTDP43 was present when comparing both AD dementia with pTDP43 vs. AD dementia without pTDP43 (p = 0.03), and AD dementia with pTDP43 vs. bvFTD without pTDP43 (p = 0.05).ConclusionContradictory to studies showing increased GFAP in mutant TDP43 mice (Yan, 2014), the lowest astrocyte counts were found in individuals with AD dementia, highest burden of AD pathology, and presence of pTDP43. Results support the role of astroglial heterogeneity contributing to white matter dysfunction via selective vulnerability.

What every neuropathologist needs to know: condensed protocol work-up for clinical dementia syndromes.

Concerns about the costs associated with autopsy assessment of Alzheimer disease and related dementias according to 2012 NIA-AA Guidelines have been expressed since the publication of those guidelines. For this reason, we designed and validated a Condensed Protocol for the neuropathologic diagnoses of Alzheimer disease neuropathologic change, Lewy Body disease neuropathologic change, as well as chronic microvascular lesions, hippocampal sclerosis of aging, and cerebral amyloid angiopathy. In this study, the Condensed Protocol is updated to include frontotemporal lobar degeneration [FTLD] tau (corticobasal degeneration, progressive supranuclear palsy, and Pick disease), FTLD-TDP, and limbic-predominant, age-related TDP-43 encephalopathy. The same 20 brain regions are sampled and processed in 5 tissue cassettes, which reduces reagent costs by approximately 65%. Three board-certified neuropathologists were blinded to the original Northwestern University Alzheimer's Disease Research Center Original Protocol neuropathological diagnoses and all clinical history information. The results yielded near uniform agreement with the original comprehensive Alzheimer's Disease Research Center neuropathologic assessments. Diagnostic sensitivity was not impacted. In summary, our recent results show that our updated Condensed Protocol is also an accurate and less expensive alternative to the comprehensive protocols for the additional neuropathologic diagnoses of FTLD Tau and TDP43 proteinopathies.

Differential vulnerability of the dentate gyrus to tauopathies in dementias

The dentate gyrus (DG), a key hippocampal subregion in memory processing, generally resists phosphorylated tau accumulation in the amnestic dementia of the Alzheimer’s type due to Alzheimer’s disease (DAT-AD), but less is known about the susceptibility of the DG to other tauopathies. Here, we report stereologic densities of total DG neurons and tau inclusions in thirty-two brains of human participants with autopsy-confirmed tauopathies with distinct isoform profiles—3R Pick’s disease (PiD, N = 8), 4R corticobasal degeneration (CBD, N = 8), 4R progressive supranuclear palsy (PSP, N = 8), and 3/4R AD (N = 8). All participants were diagnosed during life with primary progressive aphasia (PPA), an aphasic clinical dementia syndrome characterized by progressive deterioration of language abilities with spared non-language cognitive abilities in early stages, except for five patients with DAT-AD as a comparison group. 51% of total participants were female. All specimens were stained immunohistochemically with AT8 to visualize tau pathology, and PPA cases were stained for Nissl substance to visualize neurons. Unbiased stereological analysis was performed in granule and hilar DG cells, and inclusion-to-neuron ratios were calculated. In the PPA group, PiD had highest mean total (granule + hilar) densities of DG tau pathology (p < 0.001), followed by CBD, AD, then PSP. PPA-AD cases showed more inclusions in hilar cells compared to granule cells, while the opposite was true in PiD and CBD. Inclusion-to-neuron ratios revealed, on average, 33% of all DG neurons in PiD cases contained a tau inclusion, compared to ~ 7% in CBD, 2% in AD, and 0.4% in PSP. There was no significant difference between DAT-AD and PPA-AD pathologic tau burden, suggesting that differences in DG burden are not specific to clinical phenotype. We conclude that the DG is differentially vulnerable to pathologic tau accumulation, raising intriguing questions about the structural integrity and functional significance of hippocampal circuits in neurodegenerative dementias.

Use and Perceived Effectiveness of Communication Modes Reported by Persons With Primary Progressive Aphasia.

Primary progressive aphasia (PPA) is a clinical neurodegenerative dementia syndrome characterized by early, selective, and progressive language impairment. PPA onset is gradual, providing time to potentially identify additional or alternative expressive communication modes; however, reports of communication mode use and effectiveness by persons with PPA have not been described. This study characterized the use, frequency, and perceived effectiveness of communication modes reported by individuals with PPA. Forty-one participants with mild-to-moderate PPA completed a structured interview detailing the type, frequency, and perceived effectiveness of 12 potential communication modes, categorized by technology required (no-tech, low-tech, and high-tech). The ratio of modes used was compared across technology categories with a repeated-measures generalized linear model assuming a binomial distribution with an overall Wald chi-square statistic, followed by pairwise post hoc t-test comparisons. Of the 12 communication modes assessed, participants reported using a median of eight (range: 5-10). All participants affirmed using speech, facial expressions, and talking on the phone. Frequency and perceived effectiveness ratings for these three modes were endorsed at the "some/most of the time" level for more than 80% of the participants. No-tech mode use was significantly higher than reported high-tech and low-tech modes (p = .004 and p < .0001, respectively). Even so, while some high-tech modes (apps) and some low-tech modes (nonelectronic augmentative and alternative communication) had fewer users, effectiveness ratings were moderate to high for all but one user. Persons with mild-to-moderate language impairment due to PPA report using a range of communication modes with moderate-to-high frequency and perceived effectiveness. These outcomes provide practical information when considering mode refinement or expansion during intervention to maximize communication participation. Barriers to modality use may include low awareness or access, which could be queried by future studies and supported by speech and language interventions. https://doi.org/10.23641/asha.21614262.

Caregiving Burdens in Aphasic Dementia and the Relationship to Communication Challenges

AbstractBackgroundPrimary progressive aphasia (PPA) is a clinical dementia syndrome. Impairments in language are the primary and persistent symptom, and severely limit participation in everyday activities and family conversations. PPA is also associated with high caregiving burden. Few studies have examined the relationship between conversation difficulties and caregiving burdens. We tested the hypothesis that the severity of care partner (CP) perceived conversation difficulties predicts caregiving burdens.MethodA mediation analysis focusing on the Baron‐Kenny approach was conducted using baseline data from 78 CPs (62% female) enrolled in the Communication BridgeTM‐2 randomized control trial of a speech‐language intervention for mild to moderate PPA. Measures included the Conversation Difficulties subscale of the Perception of Conversation Index‐Dementia Alzheimer’s Type (PCI‐DAT) and the subscales of Montgomery Burden Interview (MBI), namely objective burden subscale (perceived infringement on tangible aspects of life), subjective demand subscale (perception that the dependent person is overly demanding), and subjective stress subscale (perception of emotional impact). Higher ratings indicate higher burden and greater conversation difficulties.ResultCPs had a mean age of 64.5 years (SD = 10.76), education level of 16.2 years (SD = 2.77), and a relationship duration with the PPA participant of 38.6 years (SD = 15.29). Eighty‐six percent were spouses, 5% were adult children, and 9% were friends or siblings. CPs endorsed a broad range of burden severity with a mean objective burden score of 9.29/30 (Range = 6 to 26; SD = 4.01), subjective demand burden score of 5.81/15 (Range = 5 to 12; SD = 1.41), and subjective stress burden score of 8.43/20 (Range = 5 to 16; SD = 2.72) as well as a range of perceive conversation difficulties (M = 42.34/154, Range = 6 to 105, SD = 22.88). Higher conversation difficulties were associated with higher ratings of caregiving burden for objective burden (p &lt; 0.001) and subjective stress burden (p = 0.010). Significant mediating variables included activities of daily living and CP depression scores.ConclusionThe current study shows an association between both subjective and objective caregiving burden and conversation difficulties. Given this relationship, it will be important to determine whether interventions that successfully address conversation difficulties may also decrease caregiving burden.

Association of acetylcholinesterase inhibitor and memantine treatment with cognitive function in patients with clinical dementia syndrome with and without post‐mortem Alzheimer pathology

AbstractBackgroundAcetylcholinesterase inhibitors (AchE‐I) and memantine are licensed and recommended for the treatment of dementia of Alzheimer type (DAT). Between 10 and 20 % of patients with DAT, however, do not have Alzheimer’s disease (AD) pathology. It remains unclear, if these patients also benefit from treatment. This project aims to examine the association of AchE‐I and memantine use with cognitive function in patients with DAT with and without evidence of AD pathology at autopsy.MethodThis study is based on The National Alzheimer‘s Coordinating Center‐Uniform Data Set (NACC‐UDS). Inclusion of participants for this analysis was based on the following criteria: 1) Diagnosis of DAT, 2) information on the extent of AD‐neuropathological change at autopsy (ABC score high/intermediate/low/not), 3) follow‐up time ≥ 6 months, 4) ≥ 2 Mini‐Mental State Examinations (MMSE) during follow‐up.Result1483 participants with 3.8 ± 1.7 visits met inclusion criteria. Of these, 1009 participants showed an ABC score of “high”, 265 of “intermediate” and 209 of “low/not”. Use of AD‐medication was more common in participants with pronounced AD pathology (ABC score “high”: 89 %, “intermediate”: 66 %, “low/not”: 53 %). Follow‐up time was 41 ± 23 months in participants with medication compared to 36 ± 24 months in participants without medication. In the group of participants with an ABC score of “high” and “intermediate”, those with treatment showed a baseline MMSE score of 23 ± 5 and a decline of 8 ± 6 points, while those without treatment scored 26 ± 4 at baseline with a decline of 4 ± 6 points. In the cohort of participants with an ABC score of “low” and “not”, both groups with and without medication showed a baseline MMSE score of 26 ± 4 points with a decline in those with medication of 6 ± 6 points and of 3 ± 4 points in those without medication.ConclusionThe present descriptive analysis does not provide evidence for a clear association of treatment with AD medication and the presence of AD pathology in patients with DAT. Modelling analyses including covariates will be presented.

Integrated [Primary +] Memory Care Clinic.

The Integrated Memory Care Clinic (IMCC) is a model of care for people living with dementia directed by advanced practice registered nurses. The post-diagnosis model incorporates the expertise of nursing, social work and nurse practitioners certified in gerontology, palliative care and/or geriatric psychiatry. The Clinic nurse practitioners provide comprehensive and coordinated primary care for dementia and other stable chronic conditions and episodic care for minor acute illnesses. Care delivery is structured to maximize ongoing dialogue with patients and their caregivers during office visits and by phone and patient portal access. The Clinic provides a number of services to care partners, including an after-hours line, stage-based educational groups, and a monthly support group. The IMCC aims to reduce the overall burden of dementia by partnering with affected individuals and their caregivers in the co-production of care. Now at full capacity, the IMCC serves 525 active patients and their care partners with 1.3 FTE primary care nurse practitioners. The mean age is 78.6 years; most are female (63%); and 42% identify as a racial minority. The majority of patients are moderate (27% early-moderate; 36% late-moderate) stage of dementia clinical syndrome. The mean monthly rate of hospital admissions for ambulatory care sensitive conditions in 2022 is 1.42%. The published rate for this population is 13-15%. Finally, the model is financially neutral in a fee-for-service environment. Open in 2015, the IMCC has combined primary care and dementia care in one clinical practice. The IMCC developed strong rapport and trust with patients and families to achieve outstanding health outcomes. The model is an American Academy of Nursing Emerging Edge Runner, recognized by NCQA as a Patient Centered Medical Home, recognized as a Level 2 Age-Friendly Health System participant, and a Best Practice Exemplar by the Institute for Patient- and Family-Centered Care.

Diagnosis and Treatment of Cognitive and Neuropsychiatric Symptoms in Parkinson Disease and Dementia With Lewy Bodies.

This article summarizes the underlying biology and current diagnostic and treatment strategies for the cognitive and neuropsychiatric features of Parkinson disease (PD) and dementia with Lewy bodies (DLB). Cognitive impairment and neuropsychiatric symptoms have been increasingly recognized in PD and DLB, leading to improved diagnosis and treatment strategies. While PD is most associated with and diagnosed by the presence of motor symptoms, nonmotor symptoms can often be the most debilitating for patients. Neuropsychiatric symptoms are highly prevalent nonmotor features and include cognitive impairment, depression, anxiety, psychosis, impulse control disorders, and apathy. Neuropsychiatric symptoms can be difficult to recognize and diagnose in patients with PD, in part because of comorbidity and symptom overlap with core PD features. Treatment strategies are a combination of pharmacologic and nonpharmacologic interventions used in the general population and those specific to PD. DLB is a clinical dementia syndrome, often with similar cognitive, behavioral, autonomic, and motor features as PD. Moreover, DLB has shared underlying pathophysiology with PD, as both are associated with postmortem findings of α-synuclein neuropathology at autopsy and have shared genetic risk and prodromal symptoms. DLB is clinically differentiated from PD by the presenting features of cognitive impairment in DLB, compared with the variable onset of cognitive impairment occurring 1 year or more after established motor onset in PD. Thus, diagnosis and treatment of cognitive impairment and neuropsychiatric symptoms in DLB are similar to that of PD and have important implications for maintaining patient independence and providing support for caregivers because motor, cognitive, and neuropsychiatric symptoms have an additive effect on patient functional disability. A careful history and physical examination are often needed to accurately diagnose and treat the heterogeneous cognitive and behavioral symptoms of PD and DLB. Accurate diagnosis and treatment of neuropsychiatric symptoms and cognitive impairment in PD and DLB are important, as these are a considerable source of patient disability and caregiver burden.

Communication Bridge™-2 (CB2): an NIH Stage 2 randomized control trial of a speech-language intervention for communication impairments in individuals with mild to moderate primary progressive aphasia

BackgroundPrimary progressive aphasia (PPA) is a clinical dementia syndrome. Impairments in language (speaking, reading, writing, and understanding) are the primary and persistent symptoms. These impairments progress insidiously and devastate communication confidence, participation, and quality of life for persons living with PPA. Currently, there are no effective disease modifying treatments for PPA. Speech-language interventions hold promise for mitigating communication challenges and language symptoms. However, evidence regarding their efficacy in PPA is of low quality and there are currently no rigorous randomized trials.MethodCommunication Bridge™-2 (CB2) is a Stage 2, superiority, single-blind, randomized, parallel group, active-control, behavioral clinical trial delivered virtually within a telehealth service delivery model to individuals with PPA. Ninety carefully characterized participants with clinically confirmed PPA will be randomized to one of two speech-language intervention arms: (1) Communication Bridge™ a dyadic intervention based in communication participation therapy models that incorporates salient training stimuli or (2) the control intervention a non-dyadic intervention based in impairment therapy models addressing word retrieval and language production that incorporates fixed stimuli. The superiority of Communication Bridge™ over the Control arm will be evaluated using primary outcomes of communication confidence and participation. Other outcomes include accuracy for trained words and scripts. Participants complete two therapy blocks over a 12-month period. Outcomes will be measured at baseline, at each therapy block, and at 12 months post enrollment.DiscussionThe CB2 trial will supply Level 2 evidence regarding the efficacy of the Communication Bridge™ intervention delivered in a telehealth service delivery model for individuals with mild to moderate PPA. An important by-product of the CB2 trial is that these data can be used to evaluate the efficacy of speech-language interventions delivered in both trial arms for persons with PPA. The impact of these data should not be overlooked as they will yield important insights examining why interventions work and for whom, which will advance effectiveness trials for speech-language interventions in PPA.Trial RegistrationClinicalTrials.govNCT03371706. Registered prospectively on December 13, 2017.

Survival in Korean Patients with Frontotemporal Dementia Syndrome: Association with Behavioral Features and Parkinsonism

We investigated the survival time of each clinical syndrome of frontotemporal dementia (FTD) and the impacts of behavioral and motor features on survival of FTD. A total of 216 patients with FTD [82 behavioral variant FTD (bvFTD), 78 semantic variant primary progressive aphasia (svPPA), 43 non-fluent/agrammatic variant PPA (nfvPPA), 13 FTD-motor neuron disease (MND)] were enrolled from 16 centers across Korea. Behaviors and parkinsonism were assessed using the Frontal Behavioral Inventory and Unified Parkinson’s Disease Rating Scale Part III, respectively. The Kaplan–Meier method was used for the survival analysis and the Cox proportional hazards model was applied for analysis of the effect of behavioral and motor symptoms on survival, after controlling vascular risk factors and cancer. An overall median survival of FTD was 12.1 years. The survival time from onset was shortest for FTD-MND and longest for svPPA. The median survival time of patients with bvFTD was unavailable but likely comparable to that of patients with nfvPPA. In the bvFTD group, negative behavioral symptoms and akinetic rigidity were significantly associated with survival. In the nfvPPA group, the presence of dysarthria had a negative impact on survival. These findings provide useful information to clinicians planning for care.

Cognitive Test Scores and Progressive Cognitive Decline in the Aberdeen 1921 and 1936 Birth Cohorts.

The Aberdeen birth cohorts of 1921 and 1936 (ABC21 and ABC36) were subjected to IQ tests in 1932 or 1947 when they were aged about 11y. They were recruited between 1997–2001 among cognitively healthy community residents and comprehensively phenotyped in a long-term study of brain aging and health up to 2017. Here, we report associations between baseline cognitive test scores and long-term cognitive outcomes. On recruitment, significant sex differences within and between the ABC21 and ABC36 cohorts supported advantages in verbal ability and learning among the ABC36 women that were not significant in ABC21. Comorbid physical disorders were self-reported in both ABC21 and ABC36 but did not contribute to differences in terms of performance in cognitive tests. When used alone without other criteria, cognitive tests scores which fell below the −1.5 SD criterion for tests of progressive matrices, namely verbal learning, digit symbol and block design, did not support the concept that Mild Cognitive Impairment (MCI) is a stable class of acquired loss of function with significant links to the later emergence of a clinical dementia syndrome. This is consistent with many previous reports. Furthermore, because childhood IQ-type data were available, we showed that a lower cognitive performance at about 64 or 78 y than that predicted by IQ at 11 ± 0.5 y did not improve the prediction of progress to MCI or greater cognitive loss. We used binary logistic regression to explore how MCI might contribute to the prediction of later progress to a clinical dementia syndrome. In a fully adjusted model using ABC21 data, we found that non-amnestic MCI, along with factors such as female sex and depressive symptoms, contributed to the prediction of later dementia. A comparable model using ABC36 data did not do so. We propose that (1) MCI criteria restricted to cognitive test scores do not improve the temporal stability of MCI classifications; (2) pathways towards dementia may differ according to age at dementia onset and (3) the concept of MCI may require measures (not captured here) that underly self-reported subjective age-related cognitive decline.

Communication Difficulties and their Association with Caregiving Burdens in Aphasic Dementia

Primary progressive aphasia (PPA) is a clinical dementia syndrome for which there is no effective disease-modifying treatment. Impairments in language are the primary and persistent symptoms, and severely limit participation in everyday activities and family conversations. Despite this, there are no published studies examining the objective relationship between conversation difficulties and caregiving burden in PPA. We tested the hypothesis that the severity of care partner perceived conversation difficulties predicts caregiving burden using the Perception of Conversation Difficulty-Dementia Alzheimer’s Type and the Montgomery Borgatta Caregiving Burden Scale. The analysis included baseline data from 78 care partners (62% female) enrolled in the Communication BridgeTM-2 randomized control clinical trial of a speech-language intervention for PPA. Care partners had a mean age of 64.5 years (SD=10.76) and a mean relationship duration with the PPA participant of 38.6 years (SD=15.29). Eighty-six percent were spouses, 5% were adult children, and the remaining 9% were friends or siblings. Higher ratings of conversation difficulties were associated with increased caregiving burden for both objective burden (p < 0.001) and subjective stress burden (p < 0.001). The relationship between conversation difficulties and objective burden was mediated by dependence in activities of daily living and care partner depression, whereas the relationship with subjective stress burden was mediated by depression only. This is the first large scale study of care partner reported conversation difficulties and caregiving burden in PPA. The finding that conversation difficulties have a direct relationship with caregiving burden is an important consideration for interventions and outcome measurement in PPA.

Connectomics in Brain Aging and Dementia - The Background and Design of a Study of a Connectome Related to Human Disease.

The natural history of Alzheimer’s Disease (AD) includes significant alterations in the human connectome, and this disconnection results in the dementia of AD. The organizing principle of our research project is the idea that the expression of cognitive dysfunction in the elderly is the result of two independent processes — the neuropathology associated with AD, and second the neuropathological changes of cerebrovascular disease. Synaptic loss, senile plaques, and neurofibrillary tangles are the functional and diagnostic hallmarks of AD, but it is the structural changes as a consequence of vascular disease that reduce brain reserve and compensation, resulting in an earlier expression of the clinical dementia syndrome. This work is being completed under the auspices of the Human Connectome Project (HCP). We have achieved an equal representation of Black individuals (vs. White individuals) and enrolled 60% Women. Each of the participants contributes demographic, behavioral and laboratory data. We acquire data relative to vascular risk, and the participants also undergo in vivo amyloid imaging, and magnetoencephalography (MEG). All of the data are publicly available under the HCP guidelines using the Connectome Coordinating Facility and the NIMH Data Archive. Locally, we use these data to address specific questions related to structure, function, AD, aging and vascular disease in multi-modality studies leveraging the differential advantages of magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), MEG, and in vivo beta amyloid imaging.

Functional decline in the aphasic variant of Alzheimer's disease.

Primary progressive aphasia (PPA) is a clinical dementia syndrome associated with frontotemporal lobar degeneration (FTLD) or Alzheimer's disease (AD). Impairment in activities of daily living is essential for dementia diagnosis, yet less is known about the neuropathologic impact on functional decline in PPA, especially over time. Activities of Daily Living Questionnaire (ADLQ) ratings were compared by suspected underlying pathology between 17 PPAAβ+ and 11 PPAAβ- participants at 6-month intervals for 2 years using a linear mixed-effects model. A general linear model examined associations between functional decline and cortical thickness at baseline. Groups did not differ in demographics or aphasia severity at baseline, yet overall and subdomain scores of the ADLQ were significantly worse for PPAAβ+ compared to PPAAβ- (P=.015) at each interval across 18 months. Functional decline appears more pronounced and disrupts more aspects of life activities for individuals with non-semantic PPA with suspected AD versus non-AD neuropathology.

Severity Distribution of Alzheimer's Disease Dementia and Mild Cognitive Impairment in the Framingham Heart Study.

Studies providing Alzheimer's disease (AD) prevalence data have largely neglected to characterize the proportion of AD that is mild, moderate, or severe. Estimates of the severity distribution along the AD continuum, including the mild cognitive impairment (MCI) stage, are important to plan research and allocate future resources, particularly resources targeted at particular stages of disease. To characterize the distribution of severity of AD dementia and MCI among prevalent cases in the population-based Framingham Heart Study. Participants (aged 50-94) with prevalent MCI or AD dementia clinical syndrome were cross-sectionally selected from three time-windows of the population-based Framingham Heart Study in 2004-2005 (n = 381), 2006-2007 (n = 422), and 2008-2009 (n = 389). Summary estimates of the severity distribution were achieved by pooling results across time-windows. Diagnosis and severity were assessed by consensus dementia review. MCI-progressive was determined if the participant had documented progression to AD dementia clinical syndrome using longitudinal data. Among AD dementia participants, the pooled percentages were 50.4%for mild, 30.3%for moderate, and 19.3%for severe. Among all MCI and AD participants, the pooled percentages were 29.5%, 19.6%, 25.7%, and 45.2%for MCI-not-progressive, MCI-progressive, mild AD dementia, and the combined group of MCI-progressive and mild AD dementia, respectively. Distributions by age and sex were presented. The finding that half of the people living with AD have mild disease underscores the need for research and interventions to slow decline or prevent progression of this burdensome disease.

Alzheimer disease biomarker profiles in dementia with Lewy bodies

The advent of biofluid and molecular imaging biomarkers to reliably detect Alzheimer disease (AD) neuropathology in vivo has led to the increasing recognition of the complexity of clinicopathologic associations in neurodegenerative disease. For example, the clinical syndrome of dementia with Lewy bodies (DLB)1 is relatively specific to identify individuals with dementia due to underlying neocortical α-synuclein “Lewy” pathology; however, the majority of patients with DLB have sufficient additional plaque and tangle pathology at autopsy for a secondary diagnosis of AD neuropathologic change associated with poor clinical outcomes.2 Moreover, at least 50% of patients with clinical AD have additional α-synuclein pathology at autopsy.2 Thus, there is a current paradigm shift to define AD and related neurodegenerative disorders in living patients on a biological basis, rather than on a syndromic one alone. This is exemplified by the recent National Institute on Aging/Alzheimer’s Association (NIA/AA) research framework3 for biomarker classification of patients based on categorical biomarker evidence for β-amyloid plaque (A), tau neurofibrillary tangles (T), and resultant neurodegeneration (N); i.e., A/T(N) classification scheme. The purpose of this approach is to provide a common nomenclature to test hypotheses on the biological underpinnings of neurodegenerative disorders and to improve therapeutic trials by creating more biologically homogenous cohorts.3 In this issue of Neurology ®, Ferreira et al.4 apply and test clinical associations of A/T biomarker profiles in a large international cohort of 417 patients with DLB from 10 centers in the European DLB Consortium and from the Mayo Clinic.

Montreal Cognitive Assessment (MoCA) Performance and Domain-Specific Index Scores in Amnestic Versus Aphasic Dementia.

The Montreal Cognitive Assessment (MoCA) is a popular and simple-to-administer screening instrument to detect cognitive impairment. The MoCA generates a total score and six domain-specific index scores: (1) Memory, (2) Executive Functioning, (3) Attention, (4) Language, (5) Visuospatial, and (6) Orientation. It is unclear whether these MoCA scores can differentiate between distinct clinical dementia syndromes. This study compared MoCA Index scores between amnestic dementia of the Alzheimer's type (DAT) and primary progressive aphasia (PPA), a language-based dementia. Baseline MoCA data were analyzed from 33 DAT, 37 PPA, and 83 cognitively normal individuals enrolled in the Clinical Core of the Northwestern Alzheimer's Disease Center. A one-way analysis of covariance adjusted for age was used to compare MoCA scores among groups. A logistic regression model was implemented to observe individual likelihood of group affiliation based on MoCA Index scores. The mean MoCA total score was significantly higher in controls compared to both patient groups (p < .001) but did not differ between DAT and PPA groups. However, in accordance with salient clinical features commonly observed in DAT versus PPA, Memory and Orientation Index scores were lowest in the DAT group (p < .001), whereas Language and Attention Index scores were lowest in the PPA group (p < .001). Multivariate logistic regression analysis showed that the individual effects of Memory (p = .001), Language (p = .002), and Orientation (p = .025) Indices were significant. MoCA Index scores can help differentiate among distinct cognitive syndromes, suggesting it may be a useful brief screening tool to detect domain-specific cognitive impairment.

Network localization of clinical, cognitive, and neuropsychiatric symptoms in Alzheimer's disease.

There is both clinical and neuroanatomical variability at the single-subject level in Alzheimer's disease, complicating our understanding of brain-behaviour relationships and making it challenging to develop neuroimaging biomarkers to track disease severity, progression, and response to treatment. Prior work has shown that both group-level atrophy in clinical dementia syndromes and complex neurological symptoms in patients with focal brain lesions localize to brain networks. Here, we use a new technique termed 'atrophy network mapping' to test the hypothesis that single-subject atrophy maps in patients with a clinical diagnosis of Alzheimer's disease will also localize to syndrome-specific and symptom-specific brain networks. First, we defined single-subject atrophy maps by comparing cortical thickness in each Alzheimer's disease patient versus a group of age-matched, cognitively normal subjects across two independent datasets (total Alzheimer's disease patients = 330). No more than 42% of Alzheimer's disease patients had atrophy at any given location across these datasets. Next, we determined the network of brain regions functionally connected to each Alzheimer's disease patient's location of atrophy using seed-based functional connectivity in a large (n = 1000) normative connectome. Despite the heterogeneity of atrophied regions at the single-subject level, we found that 100% of patients with a clinical diagnosis of Alzheimer's disease had atrophy functionally connected to the same brain regions in the mesial temporal lobe, precuneus cortex, and angular gyrus. Results were specific versus control subjects and replicated across two independent datasets. Finally, we used atrophy network mapping to define symptom-specific networks for impaired memory and delusions, finding that our results matched symptom networks derived from patients with focal brain lesions. Our study supports atrophy network mapping as a method to localize clinical, cognitive, and neuropsychiatric symptoms to brain networks, providing insight into brain-behaviour relationships in patients with dementia.