Prevalence of and Annual Conversion Rates to Mild Cognitive Impairment and Dementia: Prospective, Longitudinal Study of an Essential Tremor Cohort.

OBJECTIVE: Despite recent attention to cognitive impairment in essential tremor, few studies examine rates of conversion to diagnoses of mild cognitive impairment and dementia. Development of dementia in essential tremor is associated with loss of functional ability and a doubling of mortality rate. This prospective, longitudinal study comprehensively reports the prevalence and incidence of, and the annual rates of conversion to, mild cognitive impairment and dementia in an essential tremor cohort. METHODS: Patients underwent detailed cognitive assessments and were assigned diagnoses of normal cognition, mild cognitive impairment, or dementia. There were 222 patients at baseline (mean age = 79.3 ± 9.7 years), and 177 patients participated in follow-up evaluations at 18, 36, 54, and 72 months (mean years of observation = 5.1 ± 1.7). Data were compared to those of historical controls and Parkinson disease patients. RESULTS: The cumulative prevalence of dementia and average annual conversion rate of mild cognitive impairment to dementia were 18.5% and 12.2%, nearly three times higher than rates in the general population, and approximately one half the magnitude of those reported for Parkinson disease patients. The cumulative prevalence of mild cognitive impairment (26.6%) was almost double that of the general population, but less than that in Parkinson disease populations. INTERPRETATION: We present the most complete exposition of the longitudinal trajectory of cognitive impairment in an essential tremor cohort yet presented. The prevalence of and conversion rates to dementia in essential tremor fall between those associated with the natural course of aging and the more pronounced rates observed in Parkinson disease. ANN NEUROL 2024;95:1193-1204.

Changes in Digital Speech Measures in Asymptomatic Carriers of Pathogenic Variants Associated With Frontotemporal Degeneration.

BACKGROUND AND OBJECTIVES: Clinical trials developing therapeutics for frontotemporal degeneration (FTD) focus on pathogenic variant carriers at preclinical stages. Objective, quantitative clinical assessment tools are needed to track stability and delayed disease onset. Natural speech can serve as an accessible, cost-effective assessment tool. We aimed to identify early changes in the natural speech of FTD pathogenic variant carriers before they become symptomatic. METHODS: In this cohort study, speech samples of picture descriptions were collected longitudinally from healthy participants in observational studies at the University of Pennsylvania and Columbia University between 2007 and 2020. Participants were asymptomatic but at risk for familial FTD. Status as "carrier" or "noncarrier" was based on screening for known pathogenic variants in the participant's family. Thirty previously validated digital speech measures derived from automatic speech processing pipelines were selected a priori based on previous studies in patients with FTD and compared between asymptomatic carriers and noncarriers cross-sectionally and longitudinally. RESULTS: A total of 105 participants, all asymptomatic, included 41 carriers: 12 men [30%], mean age 43 ± 13 years; education, 16 ± 2 years; MMSE 29 ± 1; and 64 noncarriers: 27 men [42%]; mean age, 48 ± 14 years; education, 15 ± 3 years; MMSE 29 ± 1. We identified 4 speech measures that differed between carriers and noncarriers at baseline: mean speech segment duration (mean difference -0.28 seconds, 95% CI -0.55 to -0.02, p = 0.04); word frequency (mean difference 0.07, 95% CI 0.008-0.14, p = 0.03); word ambiguity (mean difference 0.02, 95% CI 0.0008-0.05, p = 0.04); and interjection count per 100 words (mean difference 0.33, 95% CI 0.07-0.59, p = 0.01). Three speech measures deteriorated over time in carriers only: particle count per 100 words per month (ß = -0.02, 95% CI -0.03 to -0.004, p = 0.009); total narrative production time in seconds per month (ß = -0.24, 95% CI -0.37 to -0.12, p < 0.001); and total number of words per month (ß = -0.48, 95% CI -0.78 to -0.19, p = 0.002) including in 3 carriers who later converted to symptomatic disease. DISCUSSION: Using automatic processing pipelines, we identified early changes in the natural speech of FTD pathogenic variant carriers in the presymptomatic stage. These findings highlight the potential utility of natural speech as a digital clinical outcome assessment tool in FTD, where objective and quantifiable measures for abnormal behavior and language are lacking.

Conversion Rate of Essential Tremor to Essential Tremor Parkinson Disease: Data From a Prospective Longitudinal Study.

Background and Objectives: There has been a long-standing dialog as to whether essential tremor (ET) increases the risk of developing Parkinson disease (PD). While there are relevant cross-sectional data, there are almost no longitudinal prospective data. We quantified the conversion rate from ET to ETPD in a prospective longitudinal cohort study of patients with ET. We compared the observed rate with that reported in the epidemiologic literature. Methods: We enrolled patients with ET in a prospective, longitudinal study. A senior movement disorders neurologist evaluated standardized neurologic examinations every 18 months. Results: One hundred ninety-three patients with ET (mean age = 78.1 ± 9.6 years, range = 55-96) had a mean follow-up duration of 4.1 years. Seven (3.6%) converted from ET to ETPD. The incidence of PD among patients with ET was 7/792.9 person-years (py; i.e., 882.8/100,000 py). A meta-analysis of the incidence (per 100,000 py) of PD in 14 studies from 13 countries across 4 continents reported an incidence of PD = 61.21 (men, 40 years or older) and 37.55 (women, 40 years or older). The incidence/100,000 py in men peaked in the 80- to 89-year-old age group (258.47) and in women in the 80- to 89-year-old age group (103.48 py). The abovementioned published values are 3.4-23.5 times lower than the value we observed for ET. Discussion: The incidence of PD in an ET cohort is substantially higher than that reported in historical population-based control groups across numerous countries. Additional prospective longitudinal data are needed to further explore this association.

Association of Subjective Cognitive Decline With Progression to Dementia in a Cognitively Unimpaired Multiracial Community Sample.

BACKGROUND AND OBJECTIVES: This prospective study seeks to examine the utility of subjective cognitive decline (SCD) as a marker of future progression to dementia in a community-based cohort of non-Latinx White, non-Latinx Black, and Latinx individuals. Debate surrounds the utility of SCD, the subjective perception of decline in one's cognition before such impairment is evident in traditional neuropsychological assessments, as an early indicator of impending Alzheimer disease. Unfortunately, most studies examining SCD have been conducted in non-Latinx White samples and commonly exclude groups of individuals shown to be most vulnerable to dementia. METHODS: Participants were enrolled into this cohort study from the Washington Heights-Inwood Columbia Aging Project if they were cognitively unimpaired, had baseline measurement of SCD, and self-identified as non-Latinx White, non-Latinx Black, or Latinx. SCD was measured as a continuous sum of 10 items assessing cognitive complaints. Competing risk models tested the main effects of baseline SCD on progression to dementia. Models were adjusted for age, sex/gender, years of education, medical comorbidity burden, enrollment cohort, and baseline memory test performance with death jointly modelled as a function of race/ethnicity. RESULTS: A total of 4,043 (1,063 non-Latinx White, 1,267 non-Latinx Black, and 1,713 Latinx) participants were selected for this study with a mean age of 75 years, 67% women, and with a mean follow-up of 5 years. Higher baseline SCD was associated with increased rates of incident dementia over time in the full sample (hazard ratio [HR] 1.085, CI 1.047-1.125, p < 0.001) and within Latinx (HR 1.084, CI 1.039-1.130, p < 0.001) and non-Latinx Black individuals (HR 1.099, CI 1.012-1.194, p = 0.024). DISCUSSION: Overall results of this study support SCD as a prodromal marker of dementia in a multiracial community sample, and in Latinx and non-Latinx Black individuals in particular. Because models examining the risk of dementia were adjusted for baseline memory test performance, the results support the idea that SCD, a subjective reflection of one's own current cognitive functioning, contributes information above and beyond standard memory testing. Current findings highlight the importance of carefully evaluating any memory concerns raised by older adults during routine visits and underscore the potential utility of screening older adults for SCD.

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

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

Towards Defining the Neuroanatomical Basis of Late-Onset Psychiatric Symptoms.

Psychiatric symptoms, including changes in emotional processing, are a common feature of many neurodegenerative disorders, such as Alzheimer's disease, dementia with Lewy Bodies, frontotemporal dementia, and Huntington's disease. However, the neuroanatomical basis of emotional symptoms is not well defined; this stands in contrast to the relatively well-understood neuroanatomical correlates of cognitive and motor symptoms in neurodegenerative disorders. Furthermore, psychiatric diagnostic categories, as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Statistical Classification of Diseases and Related Health Problems (ICD), may have limited applicability in patients with late-onset psychiatric symptoms in the context of neurodegenerative disorders. In this clinical review, we suggest that early-onset and late-onset psychiatric symptoms have distinct etiologies, and that late-onset changes in emotional processing are likely underpinned by neurodegenerative disease. Furthermore, we suggest that an improved understanding of the neuroanatomical correlates of emotional changes in neurodegenerative disease may facilitate diagnosis and future treatment development. Finally, we propose a novel clinical approach, in a preliminary attempt to incorporate late-onset emotional symptoms alongside cognitive and motor symptoms into a clinical "algorithm," with a focus on the neuroanatomy implicated when particular combinations of emotional, cognitive, and motor features are present. We anticipate that this clinical approach will assist with the diagnosis of neurodegenerative disorders, and our proposed schema represents a move towards integrating neurologic and psychiatric classification systems.

Metacognitive monitoring in moderate and severe traumatic brain injury.

The ability to engage in self-reflective processes is a capacity that may be disrupted after neurological compromise; research to date has demonstrated that patients with traumatic brain injury (TBI) show reduced awareness of their deficits and functional ability compared to caretaker or clinician reports. Assessment of awareness of deficit, however, has been limited by the use of subjective measures (without comparison to actual performance) that are susceptible to report bias. This study used concurrent measurements from cognitive testing and confidence judgments about performance to investigate in-the-moment metacognitive experiences after moderate and severe traumatic brain injury. Deficits in metacognitive accuracy were found in adults with TBI for some but not all indices, suggesting that metacognition may not be a unitary construct. Findings also revealed that not all indices of executive functioning reliably predict metacognitive ability.

Plasma ß-amyloid and cognitive decline.

OBJECTIVES: To determine if plasma ß-amyloid (Aß) levels (1) can be linked to specific cognitive changes that constitute conversion to Alzheimer disease (AD) and (2) correspond to cognitive change independent of dementia. DESIGN: Longitudinal study including 3 visits during approximately 4¹/2 years (2000-2006). SETTING: Northern Manhattan community. PARTICIPANTS: Eight hundred eighty individuals from a population-based and ethnically diverse sample who had 2 plasma Aß measurements and were dementia free at the time of the first Aß sample; 481 remained cognitively healthy, 329 were cognitively or functionally impaired but not demented at any point, and 70 developed AD. MAIN OUTCOME MEASURES: General estimating equations tested the association between plasma Aß (baseline and change in values) and cognitive change (composite score and memory, language, and visuospatial indices). RESULTS: High baseline plasma Aß42 (P = .01) and Aß40 (P = .01) and decreasing/relatively stable Aß42 (P = .01) values were associated with faster decline in multiple cognitive domains. In those who remained cognitively healthy, high baseline plasma Aß42 (P = .01) and decreasing/relatively stable plasma Aß42 (P = .01) was associated with faster cognitive decline, primarily in memory. CONCLUSIONS: The association between plasma Aß and multiple aspects of cognition more clearly specifies the previously documented downward trajectory of plasma Aß with AD onset. The predominant association with memory seen only in healthy elderly individuals also suggests that plasma Aß is linked with even earlier neurologic changes that may or may not culminate in dementia.

The clinical diagnosis of vascular dementia: A comparison among four classification systems and a proposal for a new paradigm.

Throughout the 1990s a variety of schemes for the diagnosis of Vascular Dementia (VaD) were proposed, including the ADDTC criteria for Ischemic Vascular Dementia, the NINDS-AIREN criteria for Vascular Dementia, Bennett's criteria for Binswanger's disease, and the ICD-10 criteria for Vascular Dementia. We undertook a retrospective analysis of a series of ambulatory outpatients with dementia to determine the prevalence with which patients were diagnosed by each of these diagnostic schemes, and to survey the clinical characteristics associated with VaD. We found that the diagnostic schemes for VaD were not interchangeable; patients diagnosed with VaD using one set of criteria were not necessarily diagnosed with VaD using other criteria. The most common clinical characteristics associated with VaD, regardless of the diagnostic scheme that was used, were hypertension, extensive periventricular and deep white matter alterations on MRI (leukoaraiosis), and differential impairment on neuropsychological tests that assess the ability to establish/maintain mental set and visuoconstruction, with relatively higher scores on tests of delayed recognition memory. Interestingly, the majority of VaD patients obtained low scores on the Modified Ischemic Scale, since cortical infarcts and a history of a sudden onset and/or step-wise decline in cognitive function were rare. We conclude that the current diagnostic schemes for VaD do not necessarily consider the heterogeneous nature of VaD. A new paradigm that seeks to describe, in addition to diagnosing dementia associated with cerebrovascular disease is discussed.

Errors produced on the mini-mental state examination and neuropsychological test performance in Alzheimer's disease, ischemic vascular dementia, and Parkinson's disease.

The authors investigated whether MMSE indices designed to measure temporal and physical orientation, declarative memory, language, working memory, and motor/constructional function could differentiate patients with different dementia diagnoses: Alzheimer's disease (AD), ischemic vascular dementia (IVD), or Parkinson's disease (PD). MMSE summary scores did not differ (AD, 21.4; IVD, 21.1; PD, 22.3). The AD group scored lower than IVD or PD on temporal orientation and declarative memory, IVD lower than AD on motor/ constructional and working memory. The IVD and PD groups made more errors in writing a sentence and copying intersecting pentagons. Significant correlations were found between the orientation indices and neuropsychological tests of naming and memory, and between the working memory and motor/constructional indices and tests of executive control. Such analyses of MMSE performance could assist in formulating referral questions for cognitive assessment and in tracking the course of dementing illnesses.