Apathy Scores Research Articles

Magnetic Resonance Imaging Biomarkers of Punding in Parkinson's Disease.

Punding is a rare condition triggered by dopaminergic therapy in Parkinson's disease (PD), characterized by a complex, excessive, repetitive, and purposeless abnormal movement, and its pathogenesis remains unclear. We aimed to assess the brain structure alterations related to punding by using multipametric magnetic resonance imaging (MRI). Thirty-eight PD patients (19 with punding and 19 without punding) from the Parkinson's Progression Marker Initiative (PPMI) were included in this study. Cortical thickness was assessed with FreeSurfer, and the integrity of white matter fiber tracts and network topologies were analyzed by using FMRIB Software Library (FSL) and Pipeline for Analyzing braiN Diffusion imAges (PANDA). PD patients with punding showed a higher apathy score and more severe cortical atrophy in the left superior parietal, right inferior parietal, and right superior frontal gyrus, and worse integrity of the right cingulum cingulate tract compared to those without punding. On the other hand, no significant difference in structural network topologies was detected between the two groups. These data suggest that the specific area of destruction may be an MRI biomarker of punding risk, and these findings may have important implications for understanding the neural mechanisms of punding in PD.

Motivational and cognitive predictors of apathy after subthalamic nucleus stimulation in Parkinson's disease.

Postoperative apathy is a frequent symptom in Parkinson's disease patients who have undergone bilateral deep brain stimulation of the subthalamic nucleus. Two main hypotheses for postoperative apathy have been suggested: (i) dopaminergic withdrawal syndrome relative to postoperative dopaminergic drug tapering; and (ii) direct effect of chronic stimulation of the subthalamic nucleus. The primary objective of our study was to describe preoperative and 1-year postoperative apathy in Parkinson's disease patients who underwent chronic bilateral deep brain stimulation of the subthalamic nucleus. We also aimed to identify factors associated with 1-year postoperative apathy considering: (i) preoperative clinical phenotype; (ii) dopaminergic drug management; and (iii) volume of tissue activated within the subthalamic nucleus and the surrounding structures. We investigated a prospective clinical cohort of 367 patients before and 1 year after chronic bilateral deep brain stimulation of the subthalamic nucleus. We assessed apathy using the Lille Apathy Rating Scale and carried out a systematic evaluation of motor, cognitive and behavioural signs. We modelled the volume of tissue activated in 161 patients using the Lead-DBS toolbox and analysed overlaps within motor, cognitive and limbic parts of the subthalamic nucleus. Of the 367 patients, 94 (25.6%) exhibited 1-year postoperative apathy: 67 (18.2%) with 'de novo apathy' and 27 (7.4%) with 'sustained apathy'. We observed disappearance of preoperative apathy in 22 (6.0%) patients, who were classified as having 'reversed apathy'. Lastly, 251 (68.4%) patients had neither preoperative nor postoperative apathy and were classified as having 'no apathy'. We identified preoperative apathy score [odds ratio (OR) 1.16; 95% confidence interval (CI) 1.10, 1.22; P < 0.001], preoperative episodic memory free recall score (OR 0.93; 95% CI 0.88, 0.97; P = 0.003) and 1-year postoperative motor responsiveness (OR 0.98; 95% CI 0.96, 0.99; P = 0.009) as the main factors associated with postoperative apathy. We showed that neither dopaminergic dose reduction nor subthalamic stimulation were associated with postoperative apathy. Patients with 'sustained apathy' had poorer preoperative fronto-striatal cognitive status and a higher preoperative action initiation apathy subscore. In these patients, apathy score and cognitive status worsened postoperatively despite significantly lower reduction in dopamine agonists (P = 0.023), suggesting cognitive dopa-resistant apathy. Patients with 'reversed apathy' benefited from the psychostimulant effect of chronic stimulation of the limbic part of the left subthalamic nucleus (P = 0.043), suggesting motivational apathy. Our results highlight the need for careful preoperative assessment of motivational and cognitive components of apathy as well as executive functions in order to better prevent or manage postoperative apathy.

Subacute alpha frequency (10Hz) subthalamic stimulation for emotional processing in Parkinson's disease

BackgroundPsychiatric comorbidities are common in Parkinson's disease (PD) and may change with high-frequency stimulation targeting the subthalamic nucleus. Numerous accounts indicate subthalamic alpha-frequency oscillation is implicated in emotional processing. While intermittent alpha-frequency (10Hz) stimulation induces positive emotional effects, with more ventromedial contacts inducing larger effects, little is known about the subacute effect of ventral 10Hz subthalamic stimulation on emotional processing. Objective/HypothesisTo evaluate the subacute effect of 10Hz stimulation at bilateral ventral subthalamic nucleus on emotional processing in PD patients using an affective task, compared to that of clinical-frequency stimulation and off-stimulation. MethodsTwenty PD patients with bilateral subthalamic deep brain stimulation for more than six months were tested with the affective task under three stimulation conditions (10Hz, 130Hz, and off-stimulation) in a double-blinded randomized design. ResultsWhile 130Hz stimulation reduced arousal ratings in all patients, 10Hz stimulation increased arousal selectively in patients with higher depression scores. Furthermore, 10Hz stimulation induced a positive shift in valence rating to negative emotional stimuli in patients with lower apathy scores, and 130Hz stimulation led to more positive valence to emotional stimuli in the patients with higher apathy scores. Notably, we found correlational relationships between stimulation site and affective rating: arousal ratings increase with stimulation from anterior to posterior site, and positive valence ratings increase with stimulation from dorsal to ventral site of the ventral subthalamic nucleus. ConclusionsOur findings highlight the distinctive role of 10Hz stimulation on subjective emotional experience and unveil the spatial organization of the stimulation effect.

Unawareness of Apathy in Parkinson's Disease: The Role of Executive Dysfunction on Symptom Recognition.

Altered self-awareness or anosognosia may impact patients' everyday life by interfering with their safe and independent functioning. Symptom awareness has been linked to executive dysfunctions caused by damage to frontal regions. Apathy is a frequent neuropsychiatric manifestation of Parkinson's disease (PD) and is considered a consequence of altered functioning of cortico-subcortical circuitries connecting the prefrontal cortex (PFC) with the basal ganglia. Thus, apathetic PD patients may be not be fully aware of their condition due to shared neuropathophysiological mechanisms. The present study aimed to explore the awareness of apathy in PD patients by comparing the self-reported evaluations with their caregivers' ratings. Moreover, we explored the clinical predictors of possible discrepancies and their consequences on patients' self-reported evaluation of quality of life (QoL). We found a fair agreement between patients' self-reports and caregivers' ratings on apathy scores, with patients reporting less severe apathetic symptoms, especially those related to executive and auto-activation processing, compared to their caregivers' reports. Executive functioning was found to mediate the relationship between disease stage and awareness of the apathetic state. Awareness of executive apathy impacted patients' self-reported QoL. Therefore, PD patients might be unaware of their apathetic symptoms, especially those with worse executive functioning, which plays a key role in metacognitive processes such as self-monitoring and error detection. Anosognosia for apathy in PD patients may affect their QoL perception and leads to misleading self-report evaluations that delay diagnosis and treatment.

Cognitive and emotional theory of mind in dementia. Impact on real life behaviors

AbstractBackgroundTheory of mind (ToM) is a core cognitive process that allows regular socioemotional interaction in everyday life. ToM deficits may explain some essential behavior alterations in dementia, particularly in Alzheimer’s disease (AD) and frontotemporal dementia (FTD). This study aimed to (1) identify ToM differences across dementia syndromes and (2) determine if ToM scores predict neuropsychiatric function.MethodWe evaluated 304 participants (age 64.07±9.2) divided into six groups (healthy control, NC = 41; AD = 34; behavioral variant FTD = 96; semantic aphasia; svPPA = 38, nonfluent aphasia; nfvPPA = 47, and progressive supranuclear palsy; PSP = 48) using the UCSF Emotional and Cognitive ToM Test on the TabCAT platform and comprehensive neuropsychological and neuropsychiatric testing. Pa Patients were early in their disease (Clinical Dementia Rating: 0.80±0.53). We compared ToM between groups and used regression models controlling by age and sex to determine if ToM predicted neuropsychiatric symptoms.ResultCognitive ToM was impaired in AD, bvFTD, svPPA, and PSP (p&lt;0.0001), and all groups had impaired emotional ToM (p&lt;0.0001). Both cToM and eToM performance predicted a real‐life neuropsychiatric behavior syndrome, including anxiety, apathy, disinhibition, and aberrant motor subscales scores on the Neuropsychiatric Inventory questionnaire, even after controlling for the influence of bvFTD diagnosis.ConclusionCognitive and Emotional ToM are affected early in diverse dementia syndromes, and impaired ToM test performance can predict a real‐life neuropsychiatric behavior. Assessment of ToM and other aspects of social cognition can be beneficial for the early identification of behavioral alterations in dementia cases.

Brain‐derived neurotrophic factor genes are associated with neuropsychiatric symptom progression in dementia. The Cache county dementia progression study

AbstractBackgroundPolymorphisms in genes coding for the neurotrophin, brain‐derived neurotrophic factor (BDNF) or its receptors, have been associated with Alzheimer’s disease and related disorders (ADRD), with sex‐dependent effects. Associations with neuropsychiatric symptom (NPS) progression after dementia onset has been largely unexplored. In a population‐based cohort, we examined the relationships between BDNF gene single‐nucleotide polymorphisms (SNPs) and NPS progression after dementia onset.Method880 participants [61.3% female; mean (SD) age = 82.0 (71) years] with dementia [68.2% AD; 13.5% Vascular Dementia (VaD); 18.3% other dementia (OD)] were assessed on the Neuropsychiatric Inventory (NPI) every six‐to‐18 months. Mean(SD) baseline dementia duration was 2.9(2.7) years. The following SNPs were examined as predictors of NPI scores over time in linear mixed‐effects models: rs6265 (BDNF G196A/Val66Met), rs56164415 (BDNF C270T), rs2289656 (NTRK2 receptor TrkB), and rs2072446 (NGFR p75NTR). Covariates included age of dementia onset, education, apolipoprotein E genotype, and dementia type and duration at baseline.ResultSex‐dependent effects were found for two SNPs. Compared to those with major alleles, males with the rs56164415 minor allele exhibited a lower initial Apathy score, that increased over time (C/t*sex*time2:b = ‐0.063, SE = 0.029, p = .033); by contrast, females showed no differences by SNP alleles. Females homozygous for the rs2289656 minor allele exhibited a rapid increase in Anxiety that decreased over time (t/t*sex*time2: b = ‐0.145, SE = 0.054, p = .0073). For both sexes, presence of minor alleles for BDNF polymorphisms rs6265 (G/a*time2: b = ‐0.017, SE = 0.004, p &lt; .001; a/a*time2: b = ‐0.035, SE = 0.013, p = .006) and rs56164415 (C/t*time2: b = 0.019, SE = 0.005, p &lt; .001) was associated with increased NPI Agitation/Aggression well after baseline. Rs6265 minor allele homozygotes (a/a*time2: b = ‐0.049, SE = 0.013, p &lt; .001) and rs2072446 minor allele carriers (Ct/tt*time2: b = ‐0.012, SE = 0.005, p = .025) exhibited initial increases in Delusions, which diminished approximately 5 years thereafter.ConclusionSpecific BDNF genotypes were associated with NPS presentation after dementia onset, with some sex‐dependent effects. Future research on enhancing BDNF signaling may present possible targets for intervention.

Psychobehavioural profile in narcolepsy type 1 with and without REM sleep behaviour disorder.

REM sleep behaviour disorder (RBD) is common in narcolepsy type 1 (NT1). Abnormalities in the reward system have been observed in NT1, possibly related to impaired orexin projections towards the mesolimbic reward system, but also in RBD when associated with Parkinson's disease. Our study aimed to explore the psychobehavioural profile of NT1 patients with and without RBD compared with healthy controls (HC). Forty patients with NT1 were compared with 20 sex- and age-matched HC. All patients with NT1 underwent a video-polysomnography including a measure of REM sleep without atonia (RSWA). The following neuropsychobehavioural variables were assessed: apathy, impulsivity, depression, cognition, subjective and objective attention, sensation-seeking, and behavioural addictions. The patient population included 22 patients with NT1-RBD and 18 patients with NT1-noRBD. Compared with the healthy controls, patients with NT1 had higher scores of apathy, impulsivity, and depression; a lower score on global cognition, and poorer self-perceived attention. No differences were found between patients with NT1 with and without RBD in all neuropsychological variables, except for impaired objective attention in patients with NT1-RBD. In patients with NT1, a positive correlation was observed between RSWA and both apathy and impulsivity subscale. Moreover, in patients with NT1-RBD, RSWA was positively correlated with depression. Patients with NT1 showed higher depression, apathy, and impulsivity compared with controls. These measures correlate with the severity of RSWA, suggesting a transdiagnostic association between RBD and abnormalities of the reward system at least for patients with NT1.

Impaired Awareness in People with Severe Alcohol-Related Cognitive Deficits Including Korskoff's Syndrome: A Network Analysis.

Impaired awareness of one's own functioning is highly common in people with Korsakoff's syndrome (KS). However, it is currently unclear how awareness relates to impairments in daily functioning and quality of life (QoL). We assessed how impaired awareness relates to cognitive, behavioral, physical, and social functioning and QoL by applying a network analysis. We used cross-sectional data from 215 patients with KS or other severe alcohol-related cognitive deficits living in Dutch long-term care facilities (LTCFs). Apathy has the most central position in the network. Higher apathy scores relate positively to reduced cognition and to a greater decline in activities of daily living and negatively to social participation and the use of antipsychotic drugs. Impaired awareness is also a central node. It is positively related to a higher perceived QoL, reduced cognition and apathy, and negatively to social participation and length of stay in the LTCF. Mediated through apathy and social participation, impaired awareness is indirectly related to other neuropsychiatric symptoms. Impaired awareness is closely related to other domains of daily functioning and QoL of people with KS or other severe alcohol-related cognitive deficits living in LTCFs. Apathy plays a central role. Network analysis offers interesting insights to evaluate the interconnection of different symptoms and impairments in brain disorders such as KS.

Altered nucleus accumbens functional connectivity precedes apathy in Parkinson's disease.

Work in animal and human neuroscience has identified neural regions forming a network involved in the production of motivated, goal-directed behaviour. In particular, the nucleus accumbens and anterior cingulate cortex are recognized as key network nodes underlying decisions of whether to exert effort for reward, to drive behaviour. Previous work has convincingly shown that this cognitive mechanism, known as effort-based decision making, is altered in people with Parkinson's disease with a syndrome of reduced goal-directed behaviour-apathy. Building on this work, we investigated whether the neural regions implementing effort-based decision-making were associated with apathy in Parkinson's disease, and more importantly, whether changes to these regions were evident prior to apathy development. We performed a large, multimodal neuroimaging analysis in a cohort of people with Parkinson's disease (n = 199) with and without apathy at baseline. All participants had ∼2-year follow-up apathy scores, enabling examination of brain structure and function specifically in those with normal motivation who converted to apathy by ∼2-year follow-up. In addition, of the people with normal motivation, a subset (n = 56) had follow-up neuroimaging data, allowing for examination of the 'rate of change' in key nodes over time in those who did, and did not, convert to apathy. Healthy control (n = 54) data were also included to aid interpretation of findings. Functional connectivity between the nucleus accumbens and dorsal anterior cingulate cortex was higher in people with normal motivation who later converted to apathy compared to those who did not, whereas no structural differences were evident between these groups. In contrast, grey matter volume in these regions was reduced in the group with existing apathy. Furthermore, of those with normal motivation who had undergone longitudinal neuroimaging, converters to apathy showed a higher rate of change in grey matter volume within the nucleus accumbens. Overall, we show that changes in functional connectivity between nucleus accumbens and anterior cingulate cortex precedes apathy in people with Parkinson's disease, with conversion to apathy associated with higher rate of grey matter volume loss in nucleus accumbens, despite no baseline differences. These findings significantly add to an accumulating body of transdiagnostic evidence that apathy arises from disruption to key nodes within a network in which normal goal-directed behaviour is instantiated, and raise the possibility of identifying those at risk for developing apathy before overt motivational deficits have arisen.

Mental health outcomes in older breast cancer survivors: Five-year follow-up from the CLIMB study

BackgroundThere is a lack of information on mental health outcomes for the increasing older population. Therefore, the aim of the current study is to assess depressive symptoms, loneliness, and apathy in older patients with breast cancer within the first 5 years after diagnosis. MethodsWomen aged ≥70 years with early-stage breast cancer were included. Multivariate linear mixed models were used to assess longitudinal changes in symptoms of depression (according to the 15-item Geriatric Depression Scale), loneliness (according to the De Jong Gierveld Loneliness Scale) and apathy (according to the Starkstein Apathy Scale) over time at 3, 9, 15, 27 and 60 months follow-up. ResultsIn total, 299 patients were included (mean [standard deviation (SD)] age: 75.8 [5.2] years). At 3 months follow-up, shortly after the acute treatment, 10% of patients had significant depressive symptoms, while loneliness and apathy were present in 31% and 41% of all patients, respectively. Depression, loneliness and apathy scores showed no clinically relevant changes over time in the whole cohort. Patients who received adjuvant systemic therapies (i.e. endocrine therapy and/or chemotherapy and/or targeted therapy (trastuzumab)) had similar mental health outcomes as those who did not. However, frail patients had more symptoms (p < 0.001) and were more prone to develop depressive symptoms over time than non-frail patients (p = 0.002). DiscussionDepression, loneliness and apathy were frequently observed in older women with breast cancer and did not change over time. Patients who received adjuvant systemic therapies had similar mental health outcomes as those who did not. However, frail patients were at higher risk to experience these symptoms.

507 Apathy Following Bilateral Subthalamic Deep Brain Stimulation for Parkinson’s Disease: The INTREPID Randomized Controlled Trial

INTRODUCTION: Motivational disturbances including apathy have been reported following bilateral subthalamic deep brain stimulation (STN-DBS). Many studies suggest apathy is associated with dopaminergic denervation and can be unmasked by drug withdrawal and by aggressive drug tapering following surgery. Additionally, it is suspected that stimulation of the limbic-associative sub-regions of STN might serve as a catalyst, an independent cause, or possibly act synergistically with dopaminergic medication reduction. METHODS: INTREPID (NCT01839396) is a multi-center, prospective, double-blinded RCT. Participants with advanced Parkinson's disease (PD) received bilateral STN-DBS and completed a neuropsychological battery at screening (prior to DBS) and at follow up (12-months). Apathy was assessed using the Starkstein Apathy Scale (SAS). Demographic and clinical data including age, gender, disease duration, levodopa-equivalent daily dose (LEDD), and imaging correlates of DBS (including location and volume of stimulated tissue) were analyzed. RESULTS: There were a total of 160 subjects evaluated at 1-year following STN-DBS, 44 (27.5%) reported an improvement in apathy scores of at least 5-points, and 7 (4.4%) an improvement &gt;10 points. Eighteen (11.3%) participants had worsening apathy scores &gt;5 points, and 8 (5%) reported worsening &gt;10 points. Aggregation of stimulation field models (SFM) across the cohorts, indicated that worsening of apathy was associated with activation of limbic and associative areas of the STN. CONCLUSIONS: Bilateral STN-DBS in this prospective dataset revealed both improvement and worsening of apathy at 1-year follow-up visits. Further analysis of LEDD, dopamine agonist use, and volume of tissue activation may help us to understand the clinical factors underpinning apathy following DBS. Appropriate counseling preoperatively coupled with post-operative monitoring is important for setting expectations and for employing appropriate treatment when necessary.

Apathy and depression in mild cognitive impairment: distinct longitudinal trajectories and clinical outcomes.

Apathy is a common symptom in mild cognitive impairment (MCI) and may predict progression to dementia. Little research, however, has investigated the longitudinal trajectory of apathy in patients with MCI or controlled for depression, which can mimic apathy, when examining its clinical correlates. The current study sought to address these issues. A prospective longitudinal study was conducted over 3 years. Nine memory clinics around Australia. One hundred and eighty-five patients with MCI at baseline. Measures of cognition, function, neuropsychiatric symptoms, caregiver burden, and medication use were completed annually with additional assessments at 3 and 6 months. Patients were also assessed for dementia by expert clinicians at these time points. Of 164 patients who completed measures of neuropsychiatric symptoms, 59 (36.0%) had apathy and 61 (37.2%) had depression. The proportion affected by apathy and overall apathy scores increased over time, in contrast to measures of depression, which remained relatively stable. Apathy was associated with incident dementia and worse cognition, function, neuropsychiatric symptoms, and caregiver burden independent of both depression and incident dementia. Depression was associated with worse function, albeit to lesser degree than apathy, and neuropsychiatric symptoms. Apathy increases in MCI and is associated with worse clinical outcomes. These findings provide further evidence for apathy as a marker of clinical decline in older people and poorer outcomes across neurocognitive disorders.

The Impact of Subthalamic Deep Brain Stimulation on Apathy in Parkinson's Disease Patients.

To investigate the impact of subthalamic deep brain stimulation (STN DBS) on apathy and the possible relationship between apathy, depression, and levodopa equivalent dosage (LED) in Parkinson's Disease (PD) patients. A total of 26 patients have been evaluated via the Unified Parkinson Disease Rating Scale (UPDRS), Beck Depression Inventory (Beck D), and Beck Anxiety Inventory (Beck A), Montreal Cognitive Assessment (MoCA), Parkinson Disease Questionnaire (PDQ-39) just before and 6 months after DBS. Apathy scores (AES) showed a slight decrease from 54.00 ± 10.30 to 52.69 ± 8.88 without any statistical significance (p=0.502) after DBS therapy. No correlation was detected between the post-treatment changes in apathy and UPDRS scores, Beck D, Beck A. Although the direction of the correlation between changes in AES scores and LED values was negative, the results did not reach statistical significance. STN DBS therapy does not have a negative effect on apathy in PD Patients. Despite the satisfactory motor improvement, conservative dopaminergic dose reduction after surgery seems to be the main point to prevent apathy increase in PD patients after STN DBS.

Are neuropsychiatric symptoms a marker of small vessel disease progression in older adults? Evidence from the Lothian Birth Cohort 1936.

Neuropsychiatric symptoms could form part of an early cerebral small vessel disease prodrome that is detectable before stroke or dementia onset. We aimed to identify whether apathy, depression, anxiety, and subjective memory complaints associate with longitudinal white matter hyperintensity (WMH) progression. Community-dwelling older adults from the observational Lothian Birth Cohort 1936 attended three visits at mean ages 73, 76, and 79years, repeating MRI, Mini-Mental State Examination, neuropsychiatric (Dimensional Apathy Scale, Hospital Anxiety and Depression Scale), and subjective memory symptoms. We ran regression and mixed-effects models for symptoms and normalised WMH volumes (cube root of WMH:ICV×10). At age 73, 76, and 79, m=672, n=476, and n=382 participants attended MRI respectively. Worse apathy at age 79 was associated with WMH volume increase (β=0.27, p=0.04) in the preceding 6years. A 1SD increase in apathy score at age 79 associated with a 0.17 increase in WMH (β=0.17 normalised WMH percent ICV, p=0.009). In apathy subscales, executive (β=0.13, p=0.05) and emotional (β=0.13, p=0.04) scores associated with increasing WMH more than initiation scores (β=0.11, p=0.08). Increasing WMH also associated with age (β=0.40, p=0.002) but not higher depression (β=-0.01, p=0.78), anxiety (β=0.05, p=0.13) scores, or subjective memory complaints (β=1.12, p=0.75). Apathy independently associates with preceding longitudinal WMH progression, while depression, anxiety, and subjective memory complaints do not. Patients with apathy should be considered for enrolment to small vessel disease trials.

Mild behavioral impairment symptom severity predicts tau hyperphosphorylation assessed by plasma p‐tau181 across the Alzheimer’s disease spectrum

AbstractBackgroundMild behavioral impairment (MBI) is a neurobehavioral syndrome characterized by the emergence of persistent non‐cognitive neuropsychiatric symptoms (NPS) in older adults, representing an at‐risk state for dementia and a potential marker of Alzheimer’s disease (AD). However, few studies have investigated associations between MBI and plasma biomarkers of AD pathophysiology, specifically tau hyperphosphorylation.MethodIndividuals across the AD spectrum (cognitively unimpaired (CU) and impaired (CI)) were selected from the Translational Biomarkers of Aging and Dementia (TRIAD) cohort. MBI was assessed using the MBI‐Checklist (MBI‐C), which assesses NPS severity in five subdomains: decreased motivation (apathy), emotional dysregulation (mood/anxiety symptoms), impulse dyscontrol (agitation, impulsivity, abnormal reward salience), social inappropriateness (impaired social cognition), and abnormal thoughts/perception (psychosis). Plasma levels of p‐tau181 were quantified in all individual, and log‐transformed due to right skew. Spearman correlation analysis investigated cross‐sectional associations between plasma p‐tau181 and MBI‐C scores, and between baseline plasma p‐tau181 and annual change in MBI‐C. Multivariable linear regression analyses assessed the ability of cross‐sectional and longitudinal MBI‐C scores to predict plasma p‐tau181, adjusting for age, sex, education, and diagnostic group (CU/CI, Aβ +/‐).ResultCross‐sectional MBI data were available for 211 individuals, with longitudinal data available for 128 individuals (). Significant correlations were found between plasma p‐tau181 and MBI‐C total and apathy scores in the cross‐sectional sample (Figure A). Further, significant correlations were found with plasma p‐tau181 and the annual change in MBI‐C total and apathy scores (Figure B). These associations were corroborated by significant standardized and adjusted regression coefficients from multivariate regression models, which showed that baseline and longitudinal MBI‐C total and apathy score predicted plasma level of p‐tau181 (Figure C).ConclusionOur study provides novel findings on the association between MBI and tau hyperphosphorylation assessed using plasma biomarkers in an AD cohort. These results add to the existing evidence for MBI as a clinical manifestation of AD pathology and support the use of the MBI‐C as an enrichment tool for clinical trial enrollment and therapeutic intervention.

Neuropsychiatric symptoms and functional connectivity of neurotransmitter producing nuclei in MCI and mild dementia in Alzheimer’s disease

AbstractBackgroundThere is evidence that neurotransmitter producing nuclei are impaired in Alzheimer's disease (AD). Recent studies suggest that locus coeruleus and ventral tegmental area, main producers of noradrenaline and dopamine, respectively, are affected before the onset of amyloid‐beta deposition in the entorhinal cortex. Dysfunction of these nuclei seem to contribute especially to the manifestation of neuropsychiatric symptoms (NPS), which tend to aggravate as the disease progresses. As such, we aimed to correlate the functional connectivity (FC) maps of basal nucleus of Meynert (BNM), locus coeruleus (LC) and ventral tegmental area (VTA) to NPS in patients with mild cognitive impairment (MCI) and mild dementia in Alzheimer’s disease.MethodWe analyzed data from 43 subjects with altered amyloid‐beta in the cerebrospinal fluid (23 MCI; 20 mild dementia). Participants underwent rs‐fMRI and full neuropsychological evaluation, including Neuropsychiatric Inventory (NPI). FC maps were generated (UF²C‐toolbox) using the BNM, LC and the VTA as seeds separately. We correlated the NPI syndromes (apathy, hyperactivity, affective syndrome and psychosis) scores with the individual FC maps generated with each seed and group regressing for age and years of education variables (SPM12‐toolbox). The significance level was defined as p&lt;0.05 FWE corrected, with subsequent cluster‐level FDR correction p&lt;0.05. In addition, only anatomical regions with more than 10 voxels were described.ResultSignificant correlations were found exclusively with scores from hyperactivity subsyndrome (agitation, irritability, aberrant motor behavior, euphoria and disinhibition). Regarding right VTA we noticed an increased FC mainly with right and left subcallosal area (volumes 177.92 and 211.68mm³, respectively, Figure 1) and left medial orbital gyrus (volume 162.88). We found a similar pattern in the left VTA (Figure 2) and the right LC (Figure 3), showing increased FC predominantly with right subcallosal area (volumes 151.2 and 91.04mm³, respectively) and left subcallosal area (volumes 110.72 and 97.52mm³, respectively). When looking at BNM FC, there were no between‐group changes that reached statistical significance.ConclusionHyperactivity symptoms in AD correlate to changes in noradrenergic and dopaminergic‐producing nuclei‐FC to subcallosal area/left medial orbital gyrus. These findings may support new research for NPS therapies.

Neuropsychiatric symptoms and functional connectivity of neurotransmitter producing nuclei in MCI and mild dementia in Alzheimer’s disease

AbstractBackgroundThere is evidence that neurotransmitter producing nuclei are impaired in Alzheimer's disease (AD). Recent studies suggest that locus coeruleus and ventral tegmental area, main producers of noradrenaline and dopamine, respectively, are affected before the onset of amyloid‐beta deposition in the entorhinal cortex. Dysfunction of these nuclei seem to contribute especially to the manifestation of neuropsychiatric symptoms (NPS), which tend to aggravate as the disease progresses. As such, we aimed to correlate the functional connectivity (FC) maps of basal nucleus of Meynert (BNM), locus coeruleus (LC) and ventral tegmental area (VTA) to NPS in patients with mild cognitive impairment (MCI) and mild dementia in Alzheimer’s disease.MethodWe analyzed data from 43 subjects with altered amyloid‐beta in the cerebrospinal fluid (23 MCI; 20 mild dementia). Participants underwent rs‐fMRI and full neuropsychological evaluation, including Neuropsychiatric Inventory (NPI). FC maps were generated (UF²C‐toolbox) using the BNM, LC and the VTA as seeds separately. We correlated the NPI syndromes (apathy, hyperactivity, affective syndrome and psychosis) scores with the individual FC maps generated with each seed and group regressing for age and years of education variables (SPM12‐toolbox). The significance level was defined as p&lt;0.05 FWE corrected, with subsequent cluster‐level FDR correction p&lt;0.05. In addition, only anatomical regions with more than 10 voxels were described.ResultSignificant correlations were found exclusively with scores from hyperactivity subsyndrome (agitation, irritability, aberrant motor behavior, euphoria and disinhibition). Regarding right VTA we noticed an increased FC mainly with right and left subcallosal area (volumes 177.92 and 211.68mm³, respectively, Figure 1) and left medial orbital gyrus (volume 162.88). We found a similar pattern in the left VTA (Figure 2) and the right LC (Figure 3), showing increased FC predominantly with right subcallosal area (volumes 151.2 and 91.04mm³, respectively) and left subcallosal area (volumes 110.72 and 97.52mm³, respectively). When looking at BNM FC, there were no between‐group changes that reached statistical significance.ConclusionHyperactivity symptoms in AD correlate to changes in noradrenergic and dopaminergic‐producing nuclei‐FC to subcallosal area/left medial orbital gyrus. These findings may support new research for NPS therapies.

Comparison of the effect of computerized multidomain cognitive training and pen‐and‐paper educational program in older adults with mild cognitive impairment: a preliminary randomized controlled trial

AbstractBackgroundCognitive intervention is accepted as a potential therapy to prevent the incident dementia. It was found that computerized cognitive training might be effective for older adults with mild cognitive impairment (MCI) in previous studies. We aimed to find the effect of multidomain cognitive training using tablet computer on the cognitive and psychological function in patients with MCI.MethodParticipants in training group (n = 15) conducted a multidomain cognitive training program using table computer and those in control group (n = 13) conducted an educational book reading twice a week for eight weeks. They were evaluated of their cognitive and psychiatric function before and after the program. The differences of the pre‐ and post‐ scores were compared between training and control groups.ResultParticipants in training group showed improvement in cognitive domains such as language (p = 0.012), memory (p = 0.050), and frontal executive function (p = 0.017), and psychiatric symptoms such as apathy (p = 0.001) and quality of life (p = 0.035) after the training. Control group participants showed improvements in frontal executive function (p = 0.013), positive affect (p = 0.019), apathy (p = 0.022) and mild behavioral impairment score (p = 0.049). Between group comparison of the pre‐ and post‐training difference showed significant improvement in training group compared to control group in memory (p = 0.020), frontal executive function (p = 0.024), positive affect (p = 0.037), apathy (p = 0.048), and quality of life (p = 0.047).ConclusionWe found the effect of multidomain cognitive training using tablet computer in cognitive domain including memory and executive function, positive affect, apathy, and quality of life in MCI patients. Tablet computer cognitive training may be effective in multidomain cognitive training with transfer effect in the prodromal stage of dementia. Future trials with larger sample size and various devices would find the effect of the computerized cognitive training.

Heterogeneity of response to methylphenidate in apathetic patients in the ADMET 2 Trial

AbstractBackgroundApathy is the most common neuropsychiatric symptom in Alzheimer’s disease (AD), however there are no approved treatments. In the recent Apathy in Dementia Methylphenidate Trial 2 (ADMET 2), methylphenidate treatment resulted in a significant reduction in apathy with a small to medium effect size. Given these results and the clinical heterogeneity of apathetic AD patients, we assessed the heterogeneity of response to methylphenidate in ADMET 2 to identify individuals who may benefit particularly from this treatment.MethodIn this multicenter, randomized, placebo‐controlled clinical trial of 177 AD patients with clinically significant apathy, participants were randomized to receive methylphenidate or placebo for 6 months. Twenty‐one unplanned potential predictors of treatment outcomes were assessed. Predictors were chosen for multivariate modeling based on estimated effect difference, difference of change in the Neuropsychiatric Inventory (NPI)‐apathy subscale of two or more at the 6 month visit. Participants were then grouped into 10 subgroups by their index scores, which were constructed based on the predictors with the biggest difference in effect.ResultOf the 21 predictors, six were chosen for multivariate modelling based on having an effect difference of 2 or more in the NPI apathy score. Four of these predictors had a significant interaction with the treatment. Methylphenidate was more effective in participants less likely to have baseline anxiety (‐3.1, 95% CI ‐5.7 ‐ ‐0.5, p = 0.023) or agitation (‐3.6, 95% CI ‐6.1 ‐ ‐1.1, p = 0.005) as measured by the NPI, taking a cholinesterase inhibitor (‐4.1, 95% CI ‐6.7 ‐ ‐1.3, p = 0.004), taking at least one AD medication (‐4.0, 95% CI ‐6.9 ‐ ‐1.1, p = 0.008), highly educated (‐2.1, 95% CI ‐5.4 – 1.3, p = 0.231), and low functional capacity (‐2.6, 95% CI ‐5.55 – 0.26, p = 0.076) as measured by the Activities of Daily Living scale.ConclusionIndividuals who were less anxious or agitated, more highly educated, on treatment for Alzheimer’s disease, and with low functional capabilities were more likely to benefit from methylphenidate when compared to placebo. Consistent with its potential activating effects, methylphenidate may be particularly beneficial for subgroup of apathetic AD participants with lower baseline anxiety and agitation.

Effectiveness of life story book intervention on apathy and verbal fluency in people with dementia

ABSTRACT Objectives This study determined whether the individual intervention of using life story books (LSBs) improves apathy and verbal fluency in people with dementia (PWD). Methods The intervention group (n = 43) underwent 3 interviews in the 10 weeks following an initial assessment. Based on the information obtained, LSBs were developed; participants received individual interventions weekly, five times for four weeks. They also received a final assessment 12 weeks after the end of the intervention. Primary outcome measures comprised the Categorical Verbal Fluency Test (CFT) and the Neuropsychiatric Inventory–Nursing Home Apathy sub-item. The control group (n = 32) underwent initial and final assessments at intervals of 28 weeks while receiving the best care services. Results CFT scores for participants with mild to moderate dementia increased from 4.3 to 5.3 (P < .05) and the interaction effect of group and data collection timing was significant (p < .05). Apathy score for participants with severe dementia also improved from 4.5 to 2.5 (P < .05) immediately after the intervention period. Conclusions LSB is a comprehensive communication tool that encourages apathy and verbal fluency. Clinical implications The use of LSB may allow caregivers to achieve intervention effects on apathy and verbal fluency in PWD.