Subthalamic nucleus-language network connectivity predicts dopaminergic modulation of speech function in Parkinson's disease.

Speech impediments are a prominent yet understudied symptom of Parkinson's disease (PD). While the subthalamic nucleus (STN) is an established clinical target for treating motor symptoms, these interventions can lead to further worsening of speech. The interplay between dopaminergic medication, STN circuitry, and their downstream effects on speech in PD is not yet fully understood. Here, we investigate the effect of dopaminergic medication on STN circuitry and probe its association with speech and cognitive functions in PD patients. We found that changes in intrinsic functional connectivity of the STN were associated with alterations in speech functions in PD. Interestingly, this relationship was characterized by altered functional connectivity of the dorsolateral and ventromedial subdivisions of the STN with the language network. Crucially, medication-induced changes in functional connectivity between the STN's dorsolateral subdivision and key regions in the language network, including the left inferior frontal cortex and the left superior temporal gyrus, correlated with alterations on a standardized neuropsychological test requiring oral responses. This relation was not observed in the written version of the same test. Furthermore, changes in functional connectivity between STN and language regions predicted the medication's downstream effects on speech-related cognitive performance. These findings reveal a previously unidentified brain mechanism through which dopaminergic medication influences speech function in PD. Our study sheds light into the subcortical-cortical circuit mechanisms underlying impaired speech control in PD. The insights gained here could inform treatment strategies aimed at mitigating speech deficits in PD and enhancing the quality of life for affected individuals.

Clinical utility of self- and informant-reported memory, attention, and spatial navigation in detecting biomarkers associated with Alzheimer disease in clinically normal adults.

OBJECTIVE: Preclinical Alzheimer disease (AD) has been associated with subtle changes in memory, attention, and spatial navigation abilities. The current study examined whether self- and informant-reported domain-specific cognitive changes are sensitive to AD-associated biomarkers. METHOD: Clinically normal adults aged 56-93 and their informants completed the memory, divided attention, and visuospatial abilities (which assesses spatial navigation) subsections of the Everyday Cognition Scale (ECog). Reliability and validity of these subsections were examined using Cronbach's alpha and confirmatory factor analysis. Logistic regression was used to examine the ability of ECog subsections to predict AD-related biomarkers (cerebrospinal fluid (CSF) ptau181/Aß42 ratio (N = 371) or hippocampal volume (N = 313)). Hierarchical logistic regression was used to examine whether the self-reported subsections continued to predict biomarkers when controlling for depressive symptomatology if available (N = 197). Additionally, logistic regression was used to examine the ability of neuropsychological composites assessing the same or similar cognitive domains as the subsections (memory, executive function, and visuospatial abilities) to predict biomarkers to allow for comparison of the predictive ability of subjective and objective measures. RESULTS: All subsections demonstrated appropriate reliability and validity. Self-reported memory (with outliers removed) was the only significant predictor of AD biomarker positivity (i.e., CSF ptau181/Aß42 ratio; p = .018) but was not significant when examined in the subsample with depressive symptomatology available (p = .517). Self-reported memory (with outliers removed) was a significant predictor of CSF ptau181/Aß42 ratio biomarker positivity when the objective memory composite was included in the model. CONCLUSIONS: ECog subsections were not robust predictors of AD biomarker positivity.

Alzheimer disease biomarkers are associated with decline in subjective memory, attention, and spatial navigation ability in clinically normal adults.

OBJECTIVE: Subtle changes in memory, attention, and spatial navigation abilities have been associated with preclinical Alzheimer disease (AD). The current study examined whether baseline AD biomarkers are associated with self- and informant-reported decline in memory, attention, and spatial navigation. METHOD: Clinically normal (Clinical Dementia Rating Scale (CDR®) = 0) adults aged 56-93 (N = 320) and their informants completed the memory, divided attention, and visuospatial abilities (which assesses spatial navigation) subsections of the Everyday Cognition Scale (ECog) annually for an average of 4 years. Biomarker data was collected within (±) 2 years of baseline (i.e., cerebrospinal fluid (CSF) p-tau181/Aß42 ratio and hippocampal volume). Clinical progression was defined as CDR > 0 at time of final available ECog. RESULTS: Self- and informant-reported memory, attention, and spatial navigation significantly declined over time (ps < .001). Baseline AD biomarkers were significantly associated with self- and informant-reported decline in cognitive ability (ps < .030), with the exception of p-tau181/Aß42 ratio and self-reported attention (p = .364). Clinical progression did not significantly moderate the relationship between AD biomarkers and decline in self- or informant-reported cognitive ability (ps > .062). Post-hoc analyses indicated that biomarker burden was also associated with self- and informant-reported decline in total ECog (ps < .002), and again clinical progression did not significantly moderate these relationships (ps > .299). CONCLUSIONS: AD biomarkers at baseline may indicate risk of decline in self- and informant-reported change in memory, attention, and spatial navigation ability. As such, subjectively reported decline in these domains may have clinical utility in tracking the subtle cognitive changes associated with the earliest stages of AD.

Episodic memory deficit in HIV infection: common phenotype with Parkinson's disease, different neural substrates.

Episodic memory deficits occur in people living with HIV (PLWH) and individuals with Parkinson's disease (PD). Given known effects of HIV and PD on frontolimbic systems, episodic memory deficits are often attributed to executive dysfunction. Although executive dysfunction, evidenced as retrieval deficits, is relevant to mnemonic deficits, learning deficits may also contribute. Here, the California Verbal Learning Test-II, administered to 42 PLWH, 41 PD participants, and 37 controls, assessed learning and retrieval using measures of free recall, cued recall, and recognition. Executive function was assessed with a composite score comprising Stroop Color-Word Reading and Backward Digit Spans. Neurostructural correlates were examined with MRI of frontal (precentral, superior, orbital, middle, inferior, supplemental motor, medial) and limbic (hippocampus, thalamus) volumes. HIV and PD groups were impaired relative to controls on learning and free and cued recall trials but did not differ on recognition or retention of learned material. In no case did executive functioning solely account for the observed mnemonic deficits or brain-performance relations. Critically, the shared learning and retrieval deficits in HIV and PD were related to different substrates of frontolimbic mnemonic neurocircuitry. Specifically, diminished learning and poorer free and cued recall were related to smaller orbitofrontal volume in PLWH but not PD, whereas diminished learning in PD but not PLWH was related to smaller frontal superior volume. In PD, poorer recognition correlated with smaller thalamic volume and poorer retention to hippocampal volume. Although memory deficits were similar, the neural correlates in HIV and PD suggest different pathogenic mechanisms.

Limited Longitudinal Change in Self-reported Spatial Navigation Ability in Preclinical Alzheimer Disease.

Subtle changes in objective spatial navigation ability have been observed in the preclinical stage of Alzheimer disease (AD) cross-sectionally and have been found to predict clinical progression. However, longitudinal change in self-reported spatial navigation ability in preclinical AD has yet to be examined. The current study examined whether AD biomarkers suggestive of preclinical AD at baseline spatial navigation assessment and APOE genotype predicted decline in self-reported spatial navigation ability and whether APOE genotype moderated the association of AD biomarkers with change in self-reported spatial navigation. Clinically normal (Clinical Dementia Rating Scale=0) adults aged 56 to 90 completed the Santa Barbara Sense of Direction Scale (SBSOD) annually for an average of 2.73 years. Biomarker data was collected within +/-2 years of baseline (ie, cerebrospinal fluid Aß42, p-tau181, p-tau181/Aß42 ratio, positron emission tomography imaging with Florbetapir or Pittsburgh Compound-B, and hippocampal volume). APOE genotyping was obtained for all participants. SBSOD demonstrated a nonsignificant trend toward a decline over time (P=0.082). AD biomarkers did not predict change in self-reported spatial navigation (all Ps>0.163). APOE genotype did not moderate the relationship between AD biomarkers and self-reported spatial navigation in planned analyses (all Ps>0.222). Results suggest that self-reported spatial navigation ability, as estimated with the SBSOD, may be limited as a measure of subtle cognitive change in the preclinical stage of AD.

Cognitive impairment in Parkinson's disease is associated with Default Mode Network subsystem connectivity and cerebrospinal fluid Aß.

INTRODUCTION: To identify clinically implementable biomarkers of cognitive impairment in Parkinson's Disease (PD) derived from resting state-functional MRI (rs-fMRI) and CSF protein analysis. METHODS: In this single-center longitudinal cohort study, we analyzed rs-fMRI and CSF biomarkers from 50 PD patients (23 cognitively normal, 18 mild cognitive impairment, 9 dementia) and 19 controls, who completed comprehensive neuropsychological testing. A subgroup of participants returned for follow-up cognitive assessments three years later. From rs-fMRI, we studied the connectivity within two distinct Default Mode Network subsystems: left-to-right hippocampus (LHC-RHC) and medial prefrontal cortex-to-posterior cingulate cortex (mPFC-PCC). We used regression analyses to determine whether imaging (LHC-RHC, mPFC-PCC), clinical (CSF Aß-42:40, disease duration), and demographic (age, sex, education) variables were associated with global and domain-specific cognitive impairments. RESULTS: LHC-RHC (F3,67 = 3.41,p=0.023) and CSF Aß-42:40 (χ2(3) = 8.77,p = 0.033) were reduced across more cognitively impaired PD groups. Notably, LHC-RHC connectivity was significantly associated with all global and domain-specific cognitive impairments (attention/executive, episodic memory, visuospatial, and language) at the baseline visit. In an exploratory longitudinal analysis, mPFC-PCC was associated with future global and episodic memory impairment. CONCLUSION: We used biomarker techniques that are readily available in clinical and research facilities to shed light on the pathophysiologic basis of cognitive impairment in PD. Our findings suggest that there is a functionally distinct role of the hippocampal subsystem within the DMN resting state network, and that intrinsic connectivity between the hippocampi is critically related to a broad range of cognitive functions in PD.

Cognitive and motor deficits in older adults with HIV infection: Comparison with normal ageing and Parkinson's disease.

Despite the life-extending success of antiretroviral pharmacotherapy in HIV infection (HIV), the prevalence of mild cognitive impairment in HIV remains high. Near-normal life expectancy invokes an emerging role for age-infection interaction and a potential synergy between immunosenescence and HIV-related health factors, increasing risk of cognitive and motor impairment associated with degradation in corticostriatal circuits. These neural systems are also compromised in Parkinson's disease (PD), which could help model the cognitive deficit pattern in HIV. This cross-sectional study examined three groups, age 45-79 years: 42 HIV, 41 PD, and 37 control (CTRL) participants, tested at Stanford University Medical School and SRI International. Neuropsychological tests assessed executive function (EF), information processing speed (IPS), episodic memory (MEM), visuospatial processing (VSP), and upper motor (MOT) speed and dexterity. The HIV and PD deficit profiles were similar for EF, MEM, and VSP. Although only the PD group was impaired on MOT compared with CTRL, MOT scores were related to cognitive scores in HIV but not PD. Performance was not related to depressive symptoms, socioeconomic status, or CD4+ T-cell counts. The overlap of HIV-PD cognitive deficits implicates frontostriatal disruption in both conditions. The motor-cognitive score relation in HIV provides further support for the hypothesis that these processes share similar underlying mechanisms in HIV infection possibly expressed with or exacerbated by ageing.

White Matter Hyperintensities Related to Parkinson's Disease Executive Function.

BACKGROUND: People with Parkinson's disease (PD) can develop multidomain cognitive impairments; however, it is unclear whether different pathologies underlie domain-specific cognitive dysfunction. OBJECTIVES: We investigated the contribution of vascular copathology severity and location, as measured by MRI white matter hyperintensities (WMHs), to domain-specific cognitive impairment in PD. METHODS: We studied 85 PD (66.6 ± 9.2 years) and 18 control (65.9 ± 6.6) participants. Using the Fazekas scale for rating the severity of WMH, we subdivided PD into 14 PD-WMH+ and 71 PD-WMH-. Participants underwent global, executive, visuospatial, episodic memory, and language testing. We performed nonparametric permutation testing to create WMH probability maps based on PD-WMH group and cognitive test performance. RESULTS: The PD-WMH+ group showed worse global and executive cognitive performance than the PD-WMH- group. On individual tests, the PD-WMH+ group showed worse Montreal Cognitive Assessment (MoCA), Stroop, Symbol Digit Modalities Test (SDMT), and Digit Span scores. WMH probability maps showed that in the PD-WMH+ group, worse Stroop was associated with lesions centered around the corticospinal tract (CST), forceps major, inferior-fronto-occipital fasciculus, and superior longitudinal fasciculus; worse SDMT with lesions around the CST, forceps major, and posterior corona radiata; worse Digit Span with lesions around the posterior corona radiata; and worse MoCA with lesions around the CST. CONCLUSIONS: We found that WMH severity was associated with PD executive dysfunction, including worse attention, working memory, and processing speed. Disruption of key white matter tracts in proximity to vascular lesions could contribute to these specific cognitive impairments. Early treatment of vascular disease might mitigate some executive dysfunction in a subset of patients with PD.

Spatial navigation ability predicts progression of dementia symptomatology.

INTRODUCTION: Spatial navigation deficits are observed in Alzheimer's disease cross-sectionally, but prediction of longitudinal clinical decline has been less examined. METHODS: Cognitive mapping (CM) was assessed in 95 participants and route learning (RL) was assessed in 65 participants at baseline. Clinical progression over an average of 4 to 5 years was assessed using the clinical dementia rating (CDR) scale. Relative predictive ability was compared to episodic memory, hippocampus, and cerebrospinal fluid biomarkers (phosphorylated tau/amyloid ß 42 (ptau181 /Aß42 ) ratio). RESULTS: CM and RL were predictors of clinical progression (P's < 0.032). All measures, except RL-Learning remained predictors with episodic memory in models (P's < 0.048). Only RL-Retrieval remained a predictor when ptau181 /Aß42 was included (P < 0.001). CM interacted with hippocampus and ptau181 /Aß42 in prediction (P's < 0.013). CM, RL, and episodic memory evidenced strong diagnostic accuracy (area under the curve (AUC) = 0.894, 0.794, and 0.735, respectively); CM tended to perform better than episodic memory (P = 0.056). DISCUSSION: Baseline spatial navigation performance may be appropriate for assessing risk of clinical progression.