Anxiety is very common in Parkinson’s disease (PD) where according to a systematic review, the average prevalence is 31%, surprisingly higher than the average 17% of depressive disorders found in PD. Only a few studies have investigated the impact of anxiety on cognitive performance and brain morphology in PD. They demonstrated anxiety to be a significant predictor of cognitive impairment, where PD patients with anxiety have shown to be twice more likely to have deficits in the memory domain compared to those without anxiety. Furthermore, poorer cognitive performance in all cognitive domains was reported to be a significant risk factor for increased anxiety the following year. Anxiety in PD has also shown reduced volume/thinning in the fronto-cingulate, anterior cingulate cortex, left parietal cortices and the precuneus, despite the scant number of studies on this topic. Hence, the objective of this study aims to determine the evolution of cognitive performance and brain morphology in PD patients with and without anxiety over a three-year span.

We analyzed the baseline and three-year follow-up Parkinson’s Progression Markers Initiative (PPMI) data of 58 PD patients. MRI 3T was processed with FreeSurfer 7.1.1 on the Compute Canada cluster “Cedar” and we extracted cortical (Desikan-atlas-based volumes, thickness, area, folding index, curvature) and volumes of subcortical structures. Additionally, anxiety subscores from the State-trait anxiety inventory as well as neuropsychological tests were analyzed. PD patients were classified in two groups: PD-no-anxiety (n=46) and PD-anxiety (n=12) (subscore of > 40 on the State anxiety scale). Two-way mixed ANOVA models were established with presence/absence of anxiety as a between-subjects factor, time (baseline and three year) as a within-subjects factor and neuropsychological and MRI data were regarded as dependent variables.

Mixed ANOVA revealed that PD-anxiety saw a significantly greater decline in performance on the Montreal Cognitive Assessment test compared to PD-no-anxiety. In addition, PD-anxiety saw their performance decline over time in the Hopkins Verbal Learning test (HVLT) immediate recall, HVLT retention and HVLT delayed recall while PD-no-anxiety saw an increase in performance. In terms of brain morphology, over the three years, PD-anxiety had a greater decrease in the frontal precentral thickness, cingulate isthmus area and thickness, and temporal regions (transverse area and inferior folding) all in the left hemisphere compared to PD-no-anxiety. In subcortical regions, PD-anxiety had a greater decrease in volume of the hippocampal cornu ammonis-1 and pallidum compared to PD-no-anxiety. By contrast, PD-anxiety showed a greater increase in curvature of the frontal middle rostral, frontal pole, parietal supramarginal, and insula cortex as well as in the folding of the parietal superior and occipital pericalcarine of the right hemisphere in comparison to PD-no-anxiety.

This study highlights the importance of taking into consideration anxiety symptoms in PD, as they contribute to poorer cognitive performance and frontal, parietal and temporal differences over time. More studies with a larger sample size are needed in order to confirm these results.

The presence of cognitive impairment corresponds with declines in adaptive functioning (Cahn-Weiner, Ready, & Malloy, 2003). Although memory loss is often highlighted as a key deficit in neurodegenerative diseases (Arvanitakis et al., 2018), research indicates that processing speed may be equally important when predicting functional outcomes in atypical cognitive decline (Roye et al., 2022). Additionally, the development of performance-based measures of adaptive functioning offers a quantifiable depiction of functional deficits within a clinical setting. This study investigated the degree to which processing speed explains the relationship between immediate/delayed memory and adaptive functioning in patients diagnosed with mild and major neurocognitive disorders using an objective measure of adaptive functioning.

Participants (N = 115) were selected from a clinical database of neuropsychological evaluations. Included participants were ages 65+ (M = 74.7, SD = 5.15), completed all relevant study measures, and were diagnosed with Mild Neurocognitive Disorder (NCD; N = 69) or Major NCD (N = 46). They were majority white (87.8%) women (53.0%). The Texas Functional Living Scale was used as a performance-based measure of adaptive functioning. The Coding subtest from the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS-CD) was used to measure information processing speed. Composite memory measures for Immediate Recall and Delayed Recall were created from subtests of the RBANS (List Learning, Story Memory, and Figure Recall) and the Wechsler Memory Scale-IV (Logical Memory and Visual Reproduction). Multiple regressions were conducted to evaluate the importance of memory and information processing speed in understanding adaptive functioning. Age and years of education were added as covariates in regression analyses.

Significant correlations (p < .001) were found between adaptive functioning and processing speed (PS; r = .52), immediate memory (IM; r = .43), and delayed memory (DM; r = .32). In a regression model with IM and DM predicting daily functioning, only IM significantly explained daily functioning (rsp = .24, p = .009). A multiple regression revealed daily functioning was significantly and uniquely associated with IM (rsp = .28, p < .001) and PS (rsp = .41, p < .001). This was qualified by a significant interaction effect (rsp = -.29, p = .001), revealing that IM was only associated with adaptive functioning at PS scores lower than the RBANS normative 20th percentile.

Results suggest that processing speed may be a more sensitive predictor of functional decline than memory among older adults with cognitive disorders. These findings support further investigation into the clinical utility of processing speed tests for predicting functional decline in older adults.

A common assumption in clinical neuropsychology is that cerebrovascular risk is adversely associated with executive function, while Alzheimer’s disease (AD) primarily targets episodic memory. The goal of the present study was to determine the cross-sectional and longitudinal validity of these assumptions using validated markers of cerebrovascular and AD burden.

19271 longitudinally-followed participants from the National Alzheimer Coordinating Center (NACC) database (Mean age= 72.25; SD age= 10.42; 58% women; 51.6% CDR= 0, 33.7% CDR= 0.5, 14.7% CDR> 1) were included. Cognitive outcomes were a composite memory score and an executive function composite score (UDS3-EF; Staffaroni et al., 2020). Baseline presence of cerebrovascular disease was indexed by the presence of moderate to severe white matter hyperintensities or lacunar infarct on brain MRI (yes/no), while baseline AD pathology was indexed by the presence of a positive amyloid PET scan or elevated CSF AD biomarkers (yes/no). We used linear mixed effect models to assess the effects of baseline cerebrovascular disease, baseline AD pathology, and their interactions with time in study (years post baseline) controlling for baseline age, sex, education, and baseline MoCA score.

Baseline cerebrovascular disease was significantly associated with a lower intercept on executive functioning (between-person effect) (p < -0.001, 95% CI -0.37, -0.14) but not memory, while presence of AD biomarkers was associated with a lower memory intercept (p < -0.001, 95% CI -0.52, -0.39) but not executive function. However, only presence of AD pathology at baseline was associated with faster longitudinal decline on both memory and executive functioning over time. Baseline cerebrovascular disease did not independently relate to rate of cognitive decline.

Consistent with widely held assumptions, our between-person analyses showed that MRI evidence of cerebrovascular disease was associated with worse executive functioning but not memory, while biomarker evidence of AD pathology was associated with worse memory but not executive function. Longitudinally, however, AD is the primary driver of decline in both executive and memory function. These results extend our understanding of how pathology impacts cognition in aging cohorts and highlight the importance of using longitudinal models.

Face-to-face administration is the “gold standard” for both research and clinical cognitive assessments. However, many factors may impede or prevent face-to-face assessments, including distance to clinic, limited mobility, eyesight, or transportation. The COVID19 pandemic further widened gaps in access to care and clinical research participation. Alternatives to face-to-face assessments may provide an opportunity to alleviate the burden caused by both the COVID-19 pandemic and longer standing social inequities. The objectives of this study were to develop and assess the feasibility of a telephone- and video-administered version of the Uniform Data Set (UDS) v3 cognitive batteries for use by NIH-funded Alzheimer’s Disease Research Centers (ADRCs) and other research programs.

Ninety-three individuals (M age: 72.8 years; education: 15.6 years; 72% female; 84% White) enrolled in our ADRC were included. Their most recent adjudicated cognitive status was normal cognition (N=44), MCI (N=35), mild dementia (N=11) or other (N=3). They completed portions of the UDSv3 cognitive battery, plus the RAVLT, either by telephone or video-format within approximately 6 months (M:151 days) of their annual in-person visit, where they completed the same in-person cognitive assessments. Some measures were substituted (Oral Trails for TMT; Blind MoCA for MoCA) to allow for phone administration. Participants also answered questions about the pleasantness, difficulty level, and preference for administration mode. Cognitive testers provided ratings of perceived validity of the assessment. Participants’ cognitive status was adjudicated by a group of cognitive experts blinded to most recent inperson cognitive status.

When results from video and phone modalities were combined, the remote assessments were rated as pleasant as the inperson assessment by 74% of participants. 75% rated the level of difficulty completing the remote cognitive assessment the same as the in-person testing. Overall perceived validity of the testing session, determined by cognitive assessors (video = 92%; phone = 87.5%), was good. There was generally good concordance between test scores obtained remotely and in-person (r = .3 -.8; p < .05), regardless of whether they were administered by phone or video, though individual test correlations differed slightly by mode. Substituted measures also generally correlated well, with the exception of TMT-A and OTMT-A (p > .05). Agreement between adjudicated cognitive status obtained remotely and cognitive status based on in-person data was generally high (78%), with slightly better concordance between video/in-person (82%) vs phone/in-person (76%).

This pilot study provided support for the use of telephone- and video-administered cognitive assessments using the UDSv3 among individuals with normal cognitive function and some degree of cognitive impairment. Participants found the experience similarly pleasant and no more difficult than inperson assessment. Test scores obtained remotely correlated well with those obtained in person, with some variability across individual tests. Adjudication of cognitive status did not differ significantly whether it was based on data obtained remotely or in-person. The study was limited by its’ small sample size, large test-retest window, and lack of randomization to test-modality order. Current efforts are underway to more fully validate this battery of tests for remote assessment. Funded by: P30 AG072947 & P30 AG049638-05S1

Associative memory is impacted early in Alzheimer’s disease (AD). Poorer performance on associative memory tests has been related to greater amyloid and regional tau burden in preclinical AD. Our group previously examined the association of brain pathology and performance on the Free and Cued Selective Reminding Test (FCSRT) in Autosomal Dominant Alzheimer’s Disease (ADAD), finding that associative memory summary scores distinguished non-demented mutation carriers from non-carriers several years before clinical onset of cognitive impairment. In the current study, we examined whether FCSRT learning slopes were associated with brain pathology in a sample of ADAD carriers and non-carriers.

There were 119 participants including 57 non-demented carriers of the Colombian kindred with the Presenilin1 E280A mutation and 62 non-carrier family members (mean age= 36.3, 60% female). Participants were administered the Mini-Mental State Examination (MMSE), a measure of global cognitive status, and the FCSRT, which consists of three trials in which participants are asked to freely recall the same list of 16 items. It is a well-established measure known to be sensitive to early changes in AD. A subsample of 69 participants (32 carriers and 37 non-carriers) underwent positron emission tomography (PET) to measure in vivo cortical amyloid-beta (Pittsburgh compound B, PiB), and regional tau (Flortaucipir, FTP) burden in entorhinal and precuneus regions, which are among the earliest sites of tau accumulation in this ADAD population. Mann Whitney U tests, Spearman correlations, and chi-square tests were used to examine group differences and relations among variables of interest. Learning slope was calculated by subtracting the number of items freely recalled in FCSRT Trial 1 from the number of items freely recalled in Trial 3.

Compared to non-carriers, carriers had greater cortical amyloid-ß and regional tau burden, lower MMSE scores (mean [SD]: carriers= 27.5 [2.7]; non-carriers= 28.8 [1.0]), and lower scores on total immediate/ delayed free/ cued recall scores on the FCSRT (all p<.01). The groups did not differ on age, sex, or education level (all p> 0.05). In the whole sample and in carriers only, we found that higher MMSE scores were associated with higher learning slope, meaning faster learning (whole group p= 0.25, p= 0.006; carriers p= 0.30, p=0.029). In the whole sample, we found that lower learning slope was associated with higher levels of amyloid (p=-.34, p=.006) and tau in the left, right, and bilateral precuneus region (p=-.43, p<.001; p=-.46, p<.001; p=-.45, p<.001). In carriers only, lower learning slope was associated with higher tau burden in the left, right, and bilateral precuneus specifically (p=-.43, p=.017; p=-.48, p=.008; p=-.46, p=.010, respectively). No significant associations were found in non-carriers.

These findings suggest that learning curves on an associative memory test may be sensitive to preclinical pathological changes in AD, specifically within the precuneus, a brain region known to be involved in cue reactivity, episodic memory retrieval, and mental imagery strategies. Future studies with larger samples are warranted to further examine associations between the FCSRT learning curves and regional tau accumulation in individuals with ADAD.

Laterality of motor symptom onset in Parkinson’s disease (PD) is well-known and under-appreciated. It is still unclear though if this laterality might have an influence on other symptoms. Specifically, REM sleep behavior disorder has been shown to be a factor that has a high probability to be lined to PD. In this study we analyzed the longitudinal effect of REM symptomatology on brain lateralization in PD.

We used the baseline and 3-year visit data of 116 participants (67 without REM (PD-non-REM), 49 with REM (PD-REM)) aged 37-81 years from the Parkinson’s Progression Markers Initiative (PPMI) dataset. Statistical 3T MRI data (cortical thicknesses, areas, foldings of cortical Desikan atlas and volumes of subcortical regions) were obtained via FreeSurfer 7.1.1. Lateralization was computed using the formula: (left-right)/(lef +right). Mixed ANOVAs were performed on each region of interest.

Our findings showed an increased right asymmetry of the paracentral lobule area and of the pars orbitalis area and volume in PD-REM. There was a reduced right asymmetry of the parietal inferior volume at baseline in PD-REM, whereas REM symptomatology had a stable effect at the 3 years visit. At baseline, there was an increased left asymmetry of the thickness of the caudal anterior cingulate, pars orbitalis and pars triangularis regions in PD-REM. After 3 years, there was an increased right asymmetry in those regions. The precentral, frontal superior and transversal temporal gyri showed inverse results: an increased right asymmetry of the thickness at baseline and an increased left asymmetry after 3 years. Finally, REM symptomatology is associated with more significant increases of the left asymmetry of the frontal superior gyrus volume and of the right asymmetry of the supramarginal gyrus volume after 3 years than at baseline.

These results provide evidence of the modulating effect of the disease progression on the relationship between REM symptoms and brain lateralization in PD.

Huntington’s disease (HD) is a neurodegenerative disease characterised by motor, psychiatric and cognitive decline. Currently, no treatments have been identified in HD for slowing down cognitive decline or improving cognitive function. We are interested in identifying potentially modifiable factors in HD that can be targeted to improve or maintain cognitive function. Sleep and circadian disruption stand out as possible modifiable targets because sleep and circadian symptoms are common in HD, and such disruptions are known to impact cognition in the general population. Despite some emerging evidence that sleep quality correlates with cognition in manifest HD, whether these same relationships exist in the premanifest period is unknown. Further, whether circadian rhythms relate to cognition in premanifest HD remains open. Therefore, we aimed to determine whether sleep and circadian parameters relate to cognitive performance in premanifest HD.

To date, we have recruited 27 premanifest HD participants to a two-week remote sleep study. During the study, participants wore an Actiwatch-2 and completed a sleep diary for 14 consecutive days to assess their sleep and rest-activity patterns. Participants also completed online sleep and mood questionnaires and a cognitive assessment using videoconference. We calculated Pearson correlations to examine whether cognitive performance relates to subjective sleep quality, objective sleep parameters and circadian rest-activity rhythms. Thus far, we have analysed data from 15 female participants with premanifest HD (Mage = 43.20, SD = 11.58).

Preliminary results indicate that measures of subjective sleep quality, insomnia severity, daytime sleepiness, and fatigue severity in premanifest HD do not correlate with cognitive performance. Increases in objectively measured sleep efficiency, however, strongly correlated with better performance on the Hopkins-Verbal Learning Test-Revised (HVLT-R) immediate (r = 0.562, p < 0.05) and delayed recall trials (r = 0.597, p < 0.05) and the Trail Making Test Part B (TMT-B; r = 0.550, p < 0.05). More time spent awake (i.e., wake after sleep onset) was strongly linked to reduced performance on the TMT-B (r = -0.542, p < 0.05) and Symbol Digit Modalities Test (r = -0.556, p < 0.05). Further, increases in total sleep time were associated with better performance on the HVLT-R immediate (r = 0.682, p < 0.05) and delayed recall trial (r = 0.616, p < 0.05). For our circadian parameters, less fragmented day-today rest-activity rhythms (i.e., higher intra-daily variability) strongly correlated with higher scores on the HVLT-R immediate (r = 0.768, p < 0.001) delayed recall trials (r = 0.7276, p < 0.05) and TMT-B (r = 0.516, p < 0.05), whereas consistent and stable day-to-day rest-activity rhythms (i.e., higher inter-daily stability) was associated with poorer performance on ERT (r = -0.587, p < 0.05).

Preliminary results suggest that fragmented sleep, sleep inefficiency, reduced total sleep time, rest-activity rhythm stability and fragmentation relate to poorer cognitive performance in people with premanifest HD. Should analysis of our whole sample confirm these preliminary findings, targeting sleep in HD (e.g., through sleep hygiene and/or psychoeducation) may be a useful strategy to improve or maintain cognition.

To assess the utility of the Mini Mental State Exam (MMSE) and Montreal Cognitive Assessment (MoCA) for tracking cognitive changes Huntington’s Disease.

Currently, the most frequently used brief assessment of global cognitive functioning is the MMSE. Although the MMSE is helpful for distinguishing individuals without significant cognitive impairment from those with dementia, it is not particularly sensitive to more subtle cognitive deficits. The MoCA is another brief cognitive screening tool that has been shown to be more sensitive to mild impairment and may have greater usefulness in subcortical dementias because of its more extensive assessment of executive function. Although the MoCA appears to have high sensitivity and specificity in a variety of neurological populations, there is currently little known about its efficacy in tracking cognitive decline in individuals with HD. We used a mixed effects model to analyze MMSE and MoCA scores collected prospectively during 5 years of follow-up for 163 patients with HD seen at one academic HDSA Center of Excellence. Baseline mean age for the HD cohort was 51.35 years, mean education 14.46 years, and a mean CAG repeat length 43.95. Mean follow-up time was 3.33 years.

Mean MMSE and MoCA scores at baseline were 25.13 (SD=1.66) and 22.76 (SD=3.70) respectively. At baseline, age and gender were not associated with MMSE and MoCA scores, while years of education were. Neither age nor gender predicted rate of decline for the MoCA while years of education predicted rate of decline for the MMSE. For the MMSE, each year of education predicted on average 0.51 points higher score at enrollment; for the MoCA, each year of education predicted on average 0.79 points higher score at enrollment. The mean rates of decline on the MMSE was 0.48 points per year (p<.001) while that on the MoCA was only 0.31 points annually (p<.001) in the first five years of observation.

The MMSE and MoCA decline significantly over time in an unselected HD population. The smaller rate of decline in the MoCA may be due, in part, to the greater variability in baseline, MoCA (SD=3.70) vs MMSE (SD=1.66) scores in our HD cohort. Unlike cortical dementias, such as Alzheimer’s disease (AD), where declines of 2-3 points per year have been described for the MMSE and MoCA, much lower annual rates of decline have been reported in subcortical dementias such as Parkinson’s disease. To our knowledge, this is the first report of rate of cognitive decline on the MMSE and MoCA in HD: such information is vital for adequately preparing patients and families for future needs, in addition to planning for interventional/treatment trials in HD.

Patients with early Alzheimer Disease (AD) and Mild Cognitive Impairment of the Amnestic type (MCI-A) have been reported to show large variability of tapping scores. Factors that contribute to that variability remain undetermined. This preliminary study aimed to identify predictors of finger tapping variability in older adults evaluated for a neurodegenerative memory disorder. Based on earlier research with normally functioning adults, we predicted that the number of “invalid” tapping responses (i.e. failure of the index finger to adequately lift off the tapping key once it is depressed to produce the next number on a mechanical counter) and the female gender would predict finger tapping variability, but age and educational level would not predict variability.

This preliminary study included 4 groups of participants, comprised of 8 healthy controls (HC, 3 males; 73±7years); 12 persons with subjective memory complaints (SMC, 3 males; 69±5 years); 12 with MCI-A (7 males; 76±5 years) and 7 early AD (5 males; 75±6years). All participants were administered a modified version of the Halstead Finger Tapping Test (HFTT). Mean, range of tapping score (i.e. a measure of variability), and number of invalid taps across 7 trials in each hand were calculated. ANOVA was performed for the HFTT metrics with the main effect of group. Tukey HSD tests were used for post hoc comparisons between groups. Multiple regression analysis was performed to determine the degree to which the number of invalid tapping responses, sex, age, and educational level predicted finger tapping variability using all 4 groups.

Mean tapping score did not vary significantly across groups in the dominant [F (3, 35) = 0.633, p = 0.599] or non-dominant [F (3, 35) = 2.345, p = 0.090] hand. Range score approached a significant difference between groups in the dominant hand [F (3, 35) = 2.745, p = 0.058], with a clear significant effect of group on range score in the non-dominant hand [F (3, 35) = 4.078, p = 0.014]. Range score in the nondominant hand was significantly higher in the AD compared to SMC (p = 0.018) and HC (p = 0.024). Regression analysis revealed statistically significant findings for the dominant hand (R2 = 0.327, F (4, 34) = 4.130, p = 0.008) and for the non-dominant hand (R2 = 0.330, F (4, 34) = 4.180, p = 0.007). For both the dominant and non-dominant hands, number of invalid taps significantly predicted range score (ß = 0.453, p = 0.044, and ß = 0.498, p = 0.012, respectively). Sex, age, and education years did not predict range scores.

Variability of finger tapping in patients evaluated for neurodegenerative memory disorders and aged matched controls is predicted by the number of invalid tapping responses (comprising over 30% of the variance), but not by demographic variables in this clinical sample. Neurodegenerative disorders may eliminate a sex effect.

Traumatic brain injury (TBI) and concussion are associated with increased dementia risk. Accurate TBI/concussion exposure estimates are relatively unknown for less common neurodegenerative conditions like frontotemporal dementia (FTD). We evaluated lifetime TBI and concussion frequency in patients diagnosed with a range of FTD spectrum conditions and related prior head trauma to cavum septum pellucidum (CSP) characteristics observable on MRI.

We administered the Ohio State University TBI Identification and Boston University Head Impact Exposure Assessment to 108 patients (age 69.5 ± 8.0, 35% female, 93% white or unknown race) diagnosed at the UCSF Memory and Aging Center with one of the following FTD or related conditions: behavioral variant frontotemporal dementia (N=39), semantic variant primary progressive aphasia (N=16), nonfluent variant PPA (N=23), corticobasal syndrome (N=14), or progressive supranuclear palsy (N=16). Data were also obtained from 217 controls (“HC”; age 76.8 ± 8.0, 53% female, 91% white or unknown race). CSP characteristics were defined based on width or “grade” (0-1 vs. 2+) and length of anterior-posterior separation (millimeters). We first describe frequency of any and multiple (2+) prior TBI based on different but commonly used definitions: TBI with loss of consciousness (LOC), TBI with LOC or posttraumatic amnesia (LOC/PTA), TBI with LOC/PTA or other symptoms like dizziness, nausea, “seeing stars,” etc. (“concussion”). TBI/concussion frequency was then compared between FTD and HC using chi-square. Associations between TBI/concussion and CSP characteristics were analyzed with chi-square (CSP grade) and Mann-Whitney U tests (CSP length). We explored sex differences due to typically higher rates of TBI among males.

History of any TBI with LOC (FTD=20.0%, HC=19.2%), TBI with LOC/PTA (FTD:32.2%, HC=31.5%), and concussion (FTD: 50.0%, HC=44.3%) was common but not different between study groups (p’s>.4). In both FTD and HC, prior TBI/concussion was nominally more frequent in males but not significantly greater than females. Frequency of repeat TBI/concussion (2+) also did not differ significantly between FTD and HC (repeat TBI with LOC: 6.7% vs. 3.3%, TBI with LOC/PTA: 12.2% vs. 10.3%, concussion: 30.2% vs. 28.7%; p’s>.2). Prior TBI/concussion was not significantly related to CSP grade or length in the total sample or within the FTD or HC groups.

TBI/concussion rates depend heavily on the symptom definition used for classifying prior injury. Lifetime symptomatic TBI/concussion is common but has an unclear impact on risk for FTD-related diagnoses. Larger samples are needed to appropriately evaluate sex differences, to evaluate whether TBI/concussion rates differ between specific FTD phenotypes, and to understand the rates and effects of more extensive repetitive head trauma (symptomatic and asymptomatic) in patients with FTD.

Findings from cognitive screenings have resulted in lower-than-expected scores amongst late-career physicians (Moutier et al., 2013). Similar to healthy aging samples and those with mild cognitive impairment, inconsistencies in self-report and objective neuropsychological functioning have been noted in physicians (Nasreddine et al., 2005). Little research has focused on neuropsychological functioning of other highly educated groups, including PhD and JD degrees. We addressed a lack of normative cognitive performance data for populations with advanced degrees by exploring cognitive test scores in a mixed clinical sample of adults.

Archival data are from 208 neuropsychology clinic outpatients with 20 years of education (Mage=67.7, SDage=12.3; 25% female; 95% White). Academic degrees were PhD (35.6%), JD (28.4%), MD/DO (21.6%), and 6% other. Referrals sources were physicians (93.8%), licensing boards/employers (3.8%), self-referrals (1.4%), and attorneys (1.0%). Employment status was 55.3% employed and 44.7% not employed. Final DSM-5 neurocognitive diagnosis (NCD) status was: no NCD (45.2%), mild NCD (35.6%), and major NCD (19.2%). Etiologies were: possible Alzheimer’s disease (41.2%), unspecified (13.2%), and possible vascular (12.3%). Chi-square tests denoted diagnostic status differences between degree type and employment status. ANOVAs denoted differences in global cognitive and intellectual functioning (on the Repeatable Battery for Neuropsychological Status [RBANS] Total Index, Weschler Adult Intelligence Scale-IV (WAIS-IV), Weschler Abbreviated Scale of Intelligence-II [WASI-II] FSIQ-4 and FSIQ-2) between degree types. Cumulative frequency rates for low scores in the entire sample on normally distributed tests of general intellectual and cognitive functioning were computed for -1.0, -1.5, -2.0, and -2.5 standard deviations (SDs) at or below the population mean.

NCD diagnosis did not differ by degree (X2[14]=8.73, p=.848) but did differ by employment status (x2[2]=40.98, p<.001, cp=0.44). Employment rate was highest for the no NCD group (66.0%), followed by mild NCD (37.8%), and major NCD (7.5%). For cases below retirement age (<65 years), employment status did not significantly differ between NCD diagnostic groups (x2[2]=5.97, p=.050). Low scores on an FSIQ measure were: -1 SD (7.0%), -1.5 SD (2.6%), -2.0 SD (0.9%), and -2.5 SD (0.0%) compared to general cognitive test scores which demonstrated 42.5% at -1 SD, 30.5% at -1.5 SD, 19.0% at -2.0 SD, and 9.2% at -2.5 SD below the population mean.

The high-education literature is limited to medical degree samples. This sample included multiple degree types. Unsurprisingly, employment rates were higher for healthy versus impaired samples; however, employment rates were similar across these groups for people below retirement age. Our findings suggest that cognitively impaired people with 20 years of education often perform at or near the general population average on tests of general intellectual functioning but below the general population average on tests of general cognitive functioning. Future work should include base rates of low scores on a broader array of cognitive tests across diagnostic groups.

The Texas Functional Living Scale (TFLS) is a measure of adaptive functioning commonly utilized across the geriatric population. Current research suggests that those with Alzheimer’s disease and other dementias perform poorly on the TFLS, compared to those with mild cognitive impairment (MCI) and normal cognition (Cullum et al., 2001). Additional research is needed to examine the influence anxiety and depressive symptoms have on activities of daily living (ADLS) in individuals being evaluated for memory disorders. This study will examine the effects of anxiety and depression on adaptive functioning across all patients, and within samples of those with dementia and MCI. It is hypothesized that higher reported anxiety and depressive symptoms will predict lower scores of ADLS.

Patients at a memory disorder clinic (N = 756; 58.2% female) were screened for cognitive impairment using the Montreal Cognitive Assessment (MoCA). A brief neuropsychological evaluation (BNE) was then conducted in which the TFLS, Geriatric Depression Scale (GDS), and Geriatric Anxiety Inventory (GAI) were administered, among other measures.

A stepwise hierarchical regression was conducted on the entire sample to examine the effects of anxiety and depressive symptoms on TFLS performance, controlling for cognitive impairment using the MoCA. Lower MoCA scores explained a significant amount of variance in TFLS performance (R2 = 0.456, F(1, 754) = 632.78, p < .001). MoCA scores (b = 1.27, p < .001), the GAI (b = 0.14, p = .019), and the GDS (b = 0.10, p = 0.039) were significant predictors of poor TFLS performance across the entire sample. Although the MoCA, GDS, and GAI were each significant predictors of the TFLS, the increased variance explained by the GDS and GAI individually was incremental (AR2 = 0.003, F(1, 752) = 3.90, p = .049). Stepwise hierarchical regressions were also conducted on subsamples diagnosed with MCI (N = 171) and dementia (N = 394). For those with MCI, MoCA scores explained a significant amount of variance in TFLS performance (R2 = 0.044, F(1, 169) = 7.80, p = .006). Neither the GAI nor GDS explained significant additional variance. Only MoCA scores (b = .30, p =.006) predicted TFLS performance. For those with dementia, MoCA scores explained significant variance in TFLS scores (R2 = 0.338, F(1, 392) = 200.47, p < .001). The GAI explained additional significant variance when added (AR2 = 0.009, F(1, 391) = 5.26, p = .022). The GDS did not explain any additional variance. Both the MoCA (b = 1.29, p < .001) and the GAI (b = -0.15, p = .002) significantly predicted TFLS performance.

While results suggest that anxiety and depressive symptoms alone do not explain a significant degree of variance within scores of adaptive functioning across the entire sample, elevated ratings of anxiety and depressive symptoms were significant predictors of lower scores of ADLS, suggesting some support for our hypothesis. Additionally, anxiety symptoms significantly explained increased variance in TFLS scores for those diagnosed with dementia, suggesting a potential relationship between anxiety levels and poor adaptive functioning for dementia patients.

Spinocerebellar ataxia type one (SCA1) is an autosomal dominant neurodegenerative disease caused by an expanded CAG repeat that encodes glutamine (polyQ) in the affected ATXN1 gene. SCA1 pathology is commonly characterized by the degeneration of the cerebellar Purkinje cells (PC) and brainstem. Symptoms include motor dysfunction, cognitive impairments, bulbar dysfunction, and premature death. Atxn1175Q/2Q knock-in mice were previously developed to model SCA1 by inserting 175 expanded CAG repeats into one allele of the Atxn1 gene, producing mice expressing ATXN1 throughout the brain and displaying SCA1 symptoms. Previous research has indicated the role of localization of the ATXN1 protein to the nucleus in pathology. Therefore, the Atxn1175QK772T/2Q mouse model was created by disrupting the NLS in the expanded Atxn1175Q/2Q mice by replacing lysine with threonine at position 772 in the nuclear localization sequence (NLS). Since this amino acid change previously blocked PC disease in another mouse model, the Atxn1175QK772T/2Q mice were created to examine how the NLS mutation affects neuronal cells. RNA sequencing analysis was previously performed and found differentially expressed genes (DEG) with Atxn1175Q/2Q downregulated compared to Atxn1175QK772T/2Q and Atxn12Q/2Q in the cerebellum, medulla, cortex, hippocampus, and striatum. The aim was to analyze these brain regions to validate the RNAseq differential gene expression at a protein level.

Therefore, western blots were performed on the following mouse models (n=12): wild type mice (Atxn12Q/2Q), mice with the nuclear localization sequence mutation (Atxn12QK772T/2Q), and mice with 175 expanded CAG repeats (Atxn1175/2Q). Based off the RNAseq data, the cerebellum was tested with ion channel genes (Cav3.1, Kcnma1, and Trpc3) and the striatum was tested with a gene found in medium-spiny neurons (DARPP-32).

In the cerebellum, Atxn1175/2Q was significantly downregulated compared to Atxn1175QK772T/2Q in Cav3.1, Trpc3, and Kcnma1. Atxn1175Q/2Q was significantly downregulated compared to Atxn12Q/2Q in Trpc3 and Kcnma1. Atxn1175QK772T/2Q was significantly downregulated compared to Atxn12Q/2Q in Trpc3. In the striatum, there was significantly reduced DARPP-32 expression found between Atxn12Q/2Q and Atxn1175QK772T/2Q, Atxn12Q/2Q and Atxn1175Q/2Q, and Atxn1175Q/2Q and Atxn1175QK772T/2Q.

Therefore, the significantly reduced gene expression at the protein level in the cerebellum and striatum validate RNAseq differentially expressed genes. Additionally, the downregulation of both the Atxn1175Q/2Q and Atxn1175QK772TQ/2Q compared to Atxn12Q/2Q in the striatum supports the lack of learning of those mouse models on the rotarod, suggesting that the nuclear localization mutation does not rescue learning. Interestingly, the downregulation of Atxn1175Q/2Q compared to Atxn1175QK772TQ/2Q likely supports the age-related motor decline rescue in the rotarod seen in Atxn1175QK772T/2Q and not Atxn1175Q/2Q.

Parkinson’s disease (PD) is one of the most prevalent neurodegenerative conditions that leads to progressive degeneration in areas of the brain that control movement. As the disease progresses, cognition is also frequently affected, primarily executive functioning. Multiple factors may be involved in the relationship between PD and cognitive dysfunction. This study seeks to determine the association between disease duration (i.e., years since PD diagnosis), vascular comorbidities, and cognitive reserve (CR) and their relationship with executive functioning, in a clinic-referred PD population.

Participants included English-speaking subjects with a diagnosis of PD made by the patient’s treating neurologist (i.e., movement disorders specialist) who received their neurological care and had undergone a comprehensive neuropsychological evaluation at Thomas Jefferson University Hospital in Philadelphia, PA over the past five years. The sample consists of 67 patients. Comprehensive medical and psychiatric histories were obtained, and individuals with severe psychopathology (e.g., bipolar disorder or schizophrenia), medical or other neurological disorders (e.g., seizure disorder, stroke, documented head injury that was more severe than a mild TBI or intracranial bleeding) that could account entirely for cognitive impairment were excluded. An overall domain score of executive functioning was calculated by averaging each participant’s T-scores for the individual neuropsychological tests. Regression analysis was utilized to explore the relationship between number of vascular comorbidities, disease duration, and CR, as measured by a composite of formal education and literacy level, with executive functioning performance on neuropsychological testing for this sample.

The model explains 12.1% of the variance of executive functioning performance (F (3, 66) = 2.883, p = 0.043). A significant positive relationship was found between CR and executive functioning (b = .335, p = 0.008). No significant relationships were found between vascular comorbidities or disease duration with executive functioning. The relationship between CR and each neuropsychological measure was explored independently using Pearson correlation (2-tailed). Significant positive correlations were found between CR and WAIS-IV or WASI-II Similarities (r = .49, p < .001), CR and WAIS-IV or WASI-II Matrix Reasoning (r = .46, p = .001), and CR and FAS (r = .26, p = .037). No significant relationships were found between CR and TMT-B (r = .07, p = .565) or CR and Stroop Color and Word Interference (r = .17, p = .240).

Results suggest that CR may be a better predictor of executive functioning in patients with PD than number of vascular comorbidities or disease duration. Stronger premorbid cognitive functioning and better cognitive efficiency may be neuroprotective and stave off cognitive decline in Parkinson’s disease.

Mild cognitive impairment (MCI) in Parkinson’s disease (PD) is a critical state to consider. In fact, PD patients with MCI are more likely to develop dementia than the general population. Thus, identifying the risk factors for developing MCI in patients with PD could help with disease prevention. We aim to use the Cox regression model to identify the variables involved in the development of MCI in healthy controls (HC) and in a PD cohort.

The Parkinson’s Progressive Markers Initiative (PPMI) database was used to analyze data from 166 HC and 365 patients with PD. They were analyzed longitudinally, at baseline and at 3-year follow up. Both HC and PD were further divided in 2 groups based on the presence or absence of MCI. Conversion to MCI was defined as the first detection of MCI. For all participants, we extracted the (1) Neuropsychiatric symptoms (anxiety, impulsive-compulsive disorders and sleep impairment), (2) 3T MRI-based data (cortical and subcortical brain volumes based on the Desikan atlas, using FreeSurfer 7.1.1) and (3) genetic markers (MAPT and APOE £4 genes). We used Python 3.9 to perform three Cox proportional hazard models (PD-HC, HC only and PD only) and to model the risk of conversion to MCI, attributable to neuropsychiatric symptoms and cortical brain parameters. We included as covariates: age, sex, education, and disease duration (for the PD group). Hazard ratios (HRs) along with their 95% confidence intervals (CIs) are reported.

When including both HC and PD in the model, Cox regression analyses showed that age of onset, diagnosis, the State-Trait Anxiety Inventory (STAI) and sleep impairment are variables that are associated with a greater risk of conversion to MCI (p<.005). For HC, only the STAI and the genetic marker MAPT were significantly associated with a risk of cognitive decline (p<.05). These results further indicated that a greater anxiety score at the STAI leads to a greater chance of developing a MCI whereas being a carrier of the MAPT gene reduces the risk of MCI. Regarding analysis on PD, results revealed that the STAI and the cortical volumes of the frontal dorsolateral and temporal regions are involved with a greater risk of developing a MCI (p<.05).

These analyses show that the neuropsychiatric symptom of anxiety seem to play an important role in the development of a MCI (significant in all three analyses). For patients with PD, cortical volumes of the frontal dorsolateral and temporal regions are significantly related to risk of MCI. This study highlights the importance of considering neuropsychiatric symptoms as well as cerebral volumes as key factors in the development of MCI in PD.

Cognitive tests on which performance is unrelated to brain pathology are considered “hold” tests and are often used to estimate cognitive abilities prior to injury or disease. Amongst the most commonly used “hold” tests are measures of irregular word reading, such as the Test of Premorbid Functioning (TOPF). Measures of irregular word reading assess ability to accurately pronounce phonetic irregularities based on prior experience and word knowledge, and tend to be insensitive to most forms of brain pathology (Lezak, 2012). However, research examining whether a relationship exists between neurodegenerative diseases and decline in irregular word reading is limited. The few studies completed have demonstrated a decline in irregular word reading in neurodegenerative disease in general (Berg, Durant, Banks, & Miller, 2016) and Alzheimer’s dementia specifically (McFarlane, Welch, & Rodgers, 2006). However, no known research has been published examining whether irregular word reading and TOPF scores differ depending on cognitive classifications commensurate with DSM-V diagnoses (i.e., mild or major neurocognitive disorder, etc.), or presumed neurological etiology.

Patients were enrolled from the University of Colorado Hospital Neuropsychology Clinic. This study was a retrospective review of consecutive referrals over the age of 65 to the University of Colorado Hospital Neuropsychology Clinic from 2019 to present. The TOPF was administered along with a full neuropsychological battery and patients were clinically classified by severity of cognitive impairment (e.g., Normal, Mild Neurocognitive Disorder, Major Neurocognitive Disorder) and presumed neurologic etiology (e.g., Alzheimer’s disease (AD), Parkinson’s disease (PD), vascular cognitive impairment (VCI), and mixed dementia (AD and VCI). TOPF Raw scores were used for all analyses. Correlation analysis was conducted to determine significant relationships between various demographic variables and TOPF performance. ANCOVA analyses were conducted to examine differences on TOPF performance by diagnostic classification and differences on TOPF performance by presumed neurologic etiology.

Correlation determined a significant relationship between TOPF performance and education (r = .51, p < .001), but not age (p = .092) or gender (p = .680). ANCOVA revealed a significant effect of TOPF performance on diagnostic group classification after controlling for education, F(2, 504)= 26.45, p < .001. Post hoc analysis revealed that those diagnosed with Major Neurocognitive Disorder performed the worst on the TOPF (M=39.801 ± .958), followed by those diagnosed with Mild Neurocognitive Disorder (M= 45.371 ± .767), while those diagnosed as cognitively normal performed the best (M= 49.826 ± .993). Additional ANCOVA analysis revealed a significant effect of TOPF performance on presumed neurologic etiology after controlling for education, F(3,148)=6.07, p = .001. Post hoc analyses revealed that participants with suspected AD (M= 40.728 ± 1.613) and those with suspected VCI (M= 32.804 ± 3.480) performed worse on the TOPF compared to those with suspected PD (M=46.964 ± 1.506), (p=.042 and p = .004, respectively).

Results suggest that TOPF performance in older individuals is sensitive to cognitive impairment. Furthermore, these results suggest that this sensitivity may be further influenced by presumed neurologic etiology. These findings are consistent with prior studies which demonstrated a decline in irregular word reading in individuals with neurodegenerative diseases.

Former professional American football players have a high relative risk for neurodegenerative diseases like chronic traumatic encephalopathy (CTE). Interpreting low cognitive test scores in this population occasionally is complicated by performance on validity testing. Neuroimaging biomarkers may help inform whether a neurodegenerative disease is present in these situations. We report three cases of retired professional American football players who completed comprehensive neuropsychological testing, but “failed” performance validity tests, and underwent multimodal neuroimaging (structural MRI, Aß-PET, and tau-PET).

Three cases were identified from the Focused Neuroimaging for the Neurodegenerative Disease Chronic Traumatic Encephalopathy (FIND-CTE) study, an ongoing multimodal imaging study of retired National Football League players with complaints of progressive cognitive decline conducted at Boston University and the UCSF Memory and Aging Center. Participants were relatively young (age range 55-65), had 16 or more years of education, and two identified as Black/African American. Raw neuropsychological test scores were converted to demographically-adjusted z-scores. Testing included standalone (Test of Memory Malingering; TOMM) and embedded (reliable digit span, RDS) performance validity measures. Validity cutoffs were TOMM Trial 2 < 45 and RDS < 7. Structural MRIs were interpreted by trained neurologists. Aß-PET with Florbetapir was used to quantify cortical Aß deposition as global Centiloids (0 = mean cortical signal for a young, cognitively normal, Aß negative individual in their 20s, 100 = mean cortical signal for a patient with mild-to-moderate Alzheimer’s disease dementia). Tau-PET was performed with MK-6240 and first quantified as standardized uptake value ratio (SUVR) map. The SUVR map was then converted to a w-score map representing signal intensity relative to a sample of demographically-matched healthy controls.

All performed in the average range on a word reading-based estimate of premorbid intellect. Contribution of Alzheimer’s disease pathology was ruled out in each case based on Centiloids quantifications < 0. All cases scored below cutoff on TOMM Trial 2 (Case #1=43, Case #2=42, Case #3=19) and Case #3 also scored well below RDS cutoff (2). Each case had multiple cognitive scores below expectations (z < -2.0) most consistently in memory, executive function, processing speed domains. For Case #1, MRI revealed mild atrophy in dorsal fronto-parietal and medial temporal lobe (MTL) regions and mild periventricular white matter disease. Tau-PET showed MTL tau burden modestly elevated relative to controls (regional w-score=0.59, 72nd%ile). For Case #2, MRI revealed cortical atrophy, mild hippocampal atrophy, and a microhemorrhage, with no evidence of meaningful tau-PET signal. For Case #3, MRI showed cortical atrophy and severe white matter disease, and tau-PET revealed significantly elevated MTL tau burden relative to controls (w-score=1.90, 97th%ile) as well as focal high signal in the dorsal frontal lobe (overall frontal region w-score=0.64, 74th%ile).

Low scores on performance validity tests complicate the interpretation of the severity of cognitive deficits, but do not negate the presence of true cognitive impairment or an underlying neurodegenerative disease. In the rapidly developing era of biomarkers, neuroimaging tools can supplement neuropsychological testing to help inform whether cognitive or behavioral changes are related to a neurodegenerative disease.

Among individuals with Parkinson’s Disease (PD), visual hallucinations (VH) and mild cognitive impairment (MCI) are highly prevalent and often co-occur. Atrophy in similar brain regions [e.g. cholinergic basal forebrain (BF) nuclei] as well as specific cognitive difficulties (e.g. posterior-cortical abilities such as semantic fluency and visuoperception) have been associated with the presentation of each symptom type. While there are separate lines of evidence implicating BF volume in MCI and VH, no study to date has examined BF integrity in patients with concurrent MCI and VH symptomology. Furthermore, no prior studies examining BF integrity in MCI and VH have accounted for the potential confounding effects of dopaminergic medications which are known to exacerbate both symptom types. The aims of this study were to harmonize or bridge the two bodies of literature to determine the common neural substrate of PD-VH and PD-MCI (with an emphasis on the BF), to examine the confounding effects of dopaminergic pharmacotherapy, and to examine whether nondopaminergic “posterior” cognitive abilities differ between PD-MCI with versus without VH.

This study used a clinical chart review and MRI data to examine the associations between BF volume in a large group (n=296) of advanced PD patients (∼10 years disease duration) with and without each VH and MCI, covarying the effect of dopaminergic therapy. A two-way ANCOVA was run on total and regional BF volumes (i.e., total BF volume, and four nuclei including Ch4, Ch4p, Ch1-2, Ch3) using VH and MCI as independent variables, while covarying for dopaminergic medication. Using Mann-Whitney U tests, we compared the performance of individuals with MCI-VH versus that of individuals with MCI-noVH on tasks of semantic verbal fluency and of visuoperceptual skills (e.g., judgement of line orientation, object decision, and silhouettes).

There were two major findings: (1) atrophy of the Ch4 region in the BF was associated with MCI with VH while Ch1-2 was associated with MCI regardless of VH status, and (2) patients with both MCI and VH had poorer performance than individuals with MCI without VH on tasks measuring object recognition but not on tasks of visuospatial perception or semantic verbal fluency. These results remained stable regardless of whether or not dopaminergic medication was included in the model.

PD is a heterogeneous disease with different subtypes reflecting both dopaminergic and cholinergic dysfunction. Our findings suggest further dissociations within the cholinergic system. First, atrophy in Ch4, which projects to the cortical mantle, was preferentially associated with VH symptoms and object-based visuoperception deficits. This is consistent with proposals that VH are real-world manifestations of visuoperceptual deficits. Second, Ch1-2 atrophy, which projects primarily to the hippocampus, was associated with MCI regardless of VH. Future research will extend this work to other cognitive abilities such as memory, to analyses of brain networks that implicate the BF, and to the investigation of the relationship between anti-cholinergic medications and symptom presentation in PD.

Executive function (EF) abilities tend to decline with age, and disproportionately so for people with neurodegenerative disorders such as Parkinson’s Disease (PD), where EF deficits are commonly seen in the early stages of the disease. Due to their nature, EF are essential for performing tasks of daily life, particularly for the more complex instrumental activities of daily living (IADL), and deficits can impair the ability to execute IADL in PD participants. The aim of this study was to examine how EF impairments relate to IADL deficits in both healthy elderly controls and PD participants.

Seventy-four participants with idiopathic PD and 66 elderly controls were recruited. All participants were non-demented. A comprehensive neuropsychological assessment was administered including the following measures of EF: Hayling Sentence Completion, Brixton Spatial Anticipation, Trail Making Test A and B, Stroop Color-Word Test, Symbol Span (Wechsler Memory Scale-III), Digit Span (Wechsler Adult Intelligence Scale-III), F-A-S test, and Semantic Fluency (Animals and Actions). Z scores were calculated from respective test manuals. Independence was measured using the 8-item Lawton IADL Scale where items are coded from 0 (dependent) to 1 (independent) and the total score ranges from 0 to 8. Motor impairments were assessed using Part III of the Movement Disorder Society Unified Parkinson’s Disease Rating Scale. Regression models were run with each cognitive measure as the dependent variable, with group (control vs. PD), age, sex, education, and motor severity as predictors, to examine the effect of group on each cognitive variable. Correlations were then run between the total IADL score, demographic variables, and cognitive variables for each participant group separately to identify the relationship between IADL and EF measures.

PD participants were predominantly males (n=51, 68.9%), with an average age of 70.64±6.03 and 15.22±2.78 education years. Controls were predominantly female (n=34, 51.5%) and had an average age of 71.19±7.75 and 15.85±2.82 education years. Regarding IADL function, all participants were relatively independent in their IADLs (PD: 7.72±0.69, range 4-8, Controls: 7.98±0.13, range 7-8). The most difficult IADL items for PD participants were shopping (8.2% dependent) and food preparation (12.2% dependent). When correcting for age, education, sex, and motor severity, only the Stroop Interference z-score was significant for participant group (b=0.44, t=2.14, p=0.034), where controls had slightly lower scores (-0.33±0.77) than PD participants (-0.31±0.91). Correlations in controls were significant between IADL total score and Hayling trials 1 (r=0.35, p=0.005) and 2 (r=0.33, p=0.008), and semantic fluency actions trial (r=0.34, p=0.006). In PD participants, IADL total score was only correlated with semantic fluency (animals trial, r=0.26, p=0.028).

There were only weak associations between EF abilities and IADL in both healthy controls and PD participants, suggesting that impairments in EF do not necessarily translate into worse ability to execute IADL in PD. More correlations were found in the control group, which may be confounded by the inclusion (in both groups) of participants who already had cognitive impairment. This highlights a further need to examine whether EF impairments in people with PD influence IADL functioning above and beyond normal aging and whether specific deficits have more real-life consequences not attainable through IADL questionnaires.

Semantic variant primary progressive aphasia (svPPA) is a progressive neurodegenerative syndrome characterized by prominent impairments in naming, conceptual knowledge, and comprehension, in the setting of preserved fluency, memory, and visuospatial perception. Generally, svPPA is caused by underlying TDP-43 neuropathology. In contrast, the clinical syndrome of Lewy Body Disease (LBD) is characterized by the presence of parkinsonism and prominent attentional and visuo-spatial deficits, with relative preservation of language skills and visual hallucinations. The underlying neuropathology is Lewy bodies. Here, we describe three unique cases from the UT Health San Antonio Brain Bank of patients with clinical diagnoses of svPPA, but primary neuropathological diagnoses of LBD.

We present three cases who had clinical presentations of svPPA but were found to have LB pathology as opposed to the expected TDP-43 or FTLD pathology. We studied demographic variables in these three patients, along with neuroimaging, clinical symptoms, and patterns of neuropathology, in order to demonstrate and further understand the similarities and connections between LBD and semantic deficits.

In Case 1, the patient exhibited fluent but empty speech with profound anomia. Symptoms started in his late 50s and progressed until he lost all purposeful capacity for language before his death at age 66. DaT scan was normal and brain MRI was unremarkable. Underlying neuropathology revealed diffuse LBD throughout the neocortex with intermediate Alzheimer’s disease neuropathic change (ADNC), and moderate cerebrovascular disease. In Case 2, the patient exhibited language comprehension difficulties with symptom onset in his early 70s before passing away at age 76. The patient also developed changes in judgment and trouble with activities of daily living. MRI revealed left more than right mesial temporal atrophy, left more than right mild to moderate frontal and insular atrophy, and moderate small vessel disease. FDG-PET was significant for hypometabolism in the left mid-frontal region and in the bilateral anterior cingulate and medial prefrontal cortices. Neuropathology revealed diffuse LBD throughout the neocortex with a high level of ADNC, along with limbic-predominant age-related TDP-43 encephalopathy (LATE) stage 1 and moderate cerebrovascular disease. In Case 3, the patient displayed dysgraphia and anomia, starting in his mid-50s, as well as REM behavior sleep disorder. The patient’s neuropathology revealed a high level of ADNC with diffuse LBD throughout the neocortex, and moderate, non-occlusive cerebrovascular disease. None of the patients exhibited the typical Parkinsonism symptoms associated with LBD, but all had prominent visual hallucinations.

This small case series illustrates that a small portion of subjects with underlying LBD pathology may exhibit profound language disturbance suggestive of svPPA. Additional study is warranted, and future endeavors will explore larger pathologically-confirmed samples of subjects with clinical svPPA and high degree of underlying LBD pathology.