Latent Cognitive Phenotypes in De Novo Parkinson's Disease: A Person-Centered Approach.

OBJECTIVES: Cognitive impairment is an important aspect of Parkinson's disease (PD), but there is considerable heterogeneity in its presentation. This investigation aims to identify and characterize latent cognitive phenotypes in early PD. METHODS: Latent class analysis, a data-driven, person-centered, cluster analysis was performed on cognitive data from the Parkinson's Progressive Markers Initiative baseline visit. This analytic method facilitates identification of naturally occurring endophenotypes. Resulting classes were compared across biomarker, symptom, and demographic data. RESULTS: Six cognitive phenotypes were identified. Three demonstrated consistent performance across indicators, representing poor ("Weak-Overall"), average ("Typical-Overall"), and strong ("Strong-Overall") cognition. The remaining classes demonstrated unique patterns of cognition, characterized by "Strong-Memory," "Weak-Visuospatial," and "Amnestic" profiles. The Amnestic class evidenced greater tremor severity and anosmia, but was unassociated with biomarkers linked with Alzheimer's disease. The Weak-Overall class was older and reported more non-motor features associated with cognitive decline, including anxiety, depression, autonomic dysfunction, anosmia, and REM sleep behaviors. The Strong-Overall class was younger, more female, and reported less dysautonomia and anosmia. Classes were unrelated to disease duration, functional independence, or available biomarkers. CONCLUSIONS: Latent cognitive phenotypes with focal patterns of impairment were observed in recently diagnosed individuals with PD. Cognitive profiles were found to be independent of traditional biomarkers and motoric indices of disease progression. Only globally impaired class was associated with previously reported indicators of cognitive decline, suggesting this group may drive the effects reported in studies using variable-based analysis. Longitudinal and neuroanatomical characterization of classes will yield further insight into the evolution of cognitive change in the disease. (JINS, 2017, 23, 551-563).

Dissociation of Executive and Attentional Elements of the Digit Span Task in a Population of Older Adults: A Latent Class Analysis.

The prevailing model for working memory proposes the existence of a "central executive" responsible for coordinating and prioritizing incoming information from sensory and association cortices. The Digit Span task is commonly used by clinicians to parse attentional and executive components of working memory; however, the interrelatedness of these constructs in the context of advanced age and neurodegenerative disease remains an area of active investigation. The current study details a procedure and rationale for the use of latent class analysis, a data-driven, person-centered method, in the investigation of older adults and dementia. Class analysis of digit span performance in older adults (n = 874) drawn from a specialty clinic revealed four classes with distinct performance across task subcomponents. In three of the classes, attentional and executive elements demonstrated similar performance. The fourth class and implications of class structure are discussed in the context of aging.

Neural correlates of distinct cognitive phenotypes in early Parkinson's disease.

OBJECTIVE: Cognitive decline is common in Parkinson's disease (PD), but changes can occur in a variety of cognitive domains. The lack of a single cognitive phenotype complicates diagnosis and tracking. In an earlier study we used a data-driven approach to identify distinct cognitive phenotypes of early PD. Here we identify the morphometric brain differences between those different phenotypes compared with cognitively normal PD participants. METHODS: Six different cognitive classes were included (Weak, Typical, Weak-Visuospatial/Strong-Memory, Weak-Visuospatial, Amnestic, Strong). Structural differences between each class and the Typical class were assessed by deformation-based morphometry. RESULTS: The different groups evidenced different patterns of atrophy. Weak class had frontotemporal and insular atrophy; Weak-Visuospatial/Strong-Memory class had frontotemporal, insular, parietal, and putamen atrophy; Weak-Visuospatial class had Rolandic operculum; Amnestic class had left frontotemporal, occipital, parietal and insular atrophy when compared to the Typical class. The Strong class did not have any atrophy but had significant differences in left temporal cortex in comparison to the Typical class. CONCLUSIONS: Structural neuroimaging differences are evident in PD patients with distinct cognitive phenotypes even very early in the disease process prior to the emergence of frank cognitive impairment. Future studies will elucidate whether these have prognostic value in identifying trajectories toward dementia, or if they represent groups sensitive to different treatments.

Non-motor predictors of freezing of gait in Parkinson's disease.

BACKGROUND: The etiology of freezing of gait in Parkinson's disease (PD) is yet to be clarified. Non-motor risk factors including cognitive impairment, sleep disturbance and mood disorders have been shown in freezing of gait. RESEARCH QUESTION: We aimed to determine the predictive value of non-motor features in freezing of gait development. METHODS: Data were obtained from the Parkinson's Progression Markers Initiative. Fifty PD patients with self-reported freezing of gait, and 50 PD patients without freezing of gait at the fourth year visit were included. Groups were matched for Movement Disorders Society-Unified Parkinson's Disease Rating Scale Part III scores. Several cognitive and non-cognitive tests were used for non-motor features at baseline and over time. Executive function, visuospatial function, processing speed, learning and memory tests were used for cognition. Non-cognitive tests included sleepiness, REM sleep behavior disorder, depression and anxiety scales. RESULTS: Patients with freezing of gait had higher scores on sleepiness, REM sleep behavior disorder, depression and anxiety scales. However, predictor model analysis revealed that baseline processing speed, learning and sleepiness scores were predictive of self-reported freezing of gait development over time. SIGNIFICANCE: Our findings suggest that specific cognitive deficits and sleep disorders are predictive of future freezing of gait. These features may be helpful in identifying underlying networks in freezing of gait and should be further investigated with neuroimaging studies.

Food restriction alters neuronal morphology in the hypothalamic ventromedial nucleus of male rats.

Several lines of evidence have implicated the hypothalamic ventromedial nucleus (VMH) in the control of caloric homeostasis. For example, the activity of VMH neurons depends on energy availability. We tested the hypothesis that energy balance may involve the remodeling of the dendritic arbor of VMH neurons. We compared two groups of animals: one group had ad libitum access to food, and the other experienced 10-d restricted access to food. As expected, the food-deprived group lost body weight and had reduced levels of glucose, insulin, and leptin. VMH neurons were visualized after Golgi impregnation, and dendrite length was measured. Food deprivation had differential effects on VMH neurons. In particular, within the ventrolateral VMH, for neurons with long primary dendrites (LPDs) that extended in the lateral, but not medial, direction, the LPDs were 31% shorter. These same neurons exhibited a 32% reduction in the number of other dendrites without a change in soma size. In contrast, within the dorsomedial VMH, for neurons with medially, but not laterally, extended LPDs, the soma area was reduced by 28%. However, neurons in the dorsomedial VMH did not display a change in the length or number of dendrites, regardless of LPD direction. Thus, although structural changes during calorie depletion occur in both the dorsomedial and ventrolateral VMH, only the latter exhibits a remodeled dendritic arbor. These results also suggest that the direction of the LPD may be an important marker of neuronal function in the VMH.

Affective Disruption from Social Rhythm and Behavioral Approach System (BAS) Sensitivities: A Test of the Integration of the Social Zeitgeber and BAS Theories of Bipolar Disorder.

The Behavioral Approach System (BAS)/Reward Hypersensitivity Theory and the Social Zeitgeber Theory are two biopsychosocial theories of bipolar spectrum disorders (BSD) that may work together to explain affective dysregulation. The present study examined whether BAS sensitivity is associated with affective symptoms via a) increased social rhythm disruption in response to BAS-relevant life events, or b) greater exposure to BAS events leading to social rhythm disruption and subsequent symptoms. Results indicated that high BAS individuals were more likely to experience social rhythm disruption following BAS-relevant events. Social rhythm disruption mediated the association between BAS-relevant events and symptoms (hypothesis a). High BAS individuals experienced significantly more BAS-relevant events, which predicted greater social rhythm disruption, which predicted greater levels of affective symptoms (hypothesis b). Individuals at risk for BSD may be sensitive to BAS-relevant stimuli, experience more BAS-relevant events, and experience affective dysregulation due to the interplay of the BAS and circadian rhythms.

Kindling of life stress in bipolar disorder: comparison of sensitization and autonomy models.

Research on life stress in bipolar disorder largely fails to account for the possibility of a dynamic relationship between psychosocial stress and episode initiation. The kindling hypothesis (Post, 1992) states that over the course of recurrent affective disorders, there is a weakening temporal relationship between major life stress and episode initiation that could reflect either a progressive sensitization or progressive autonomy to life stress. The present study involved a comprehensive and precise examination of the kindling hypothesis in 102 participants with bipolar II disorder that allowed for a direct comparison of sensitization and autonomy models. Polarity-specific tests were conducted across the continuum of event severity with respect to impact and frequency of life events. Hypotheses were polarity- and event-valence specific and were based on the stress sensitization model. Results were only partially consistent with the sensitization model: Individuals with more prior mood episodes had an increased frequency of minor negative events before depression and of minor positive events before hypomania. However, the number of past episodes did not moderate relationships between life events and time until prospective onset of mood episodes. These results are more consistent with a sensitization than an autonomy model, but several predictions of the sensitization model were not supported. Methodological strengths, limitations, and implications are discussed regarding putative changes in stress reactivity that may occur with repeated exposure to mood episodes in bipolar II disorder.

Associations between sleep disturbance, cognitive functioning and work disability in Bipolar Disorder.

Bipolar Disorder (BD) is associated with impairment in a number of areas including poor work functioning, often despite the remission of mood symptoms. The present study aimed to examine the role of sleep disturbance and cognitive functioning in occupational impairment in BD. Twenty-four euthymic BD participants and 24 healthy control participants completed a week of prospective assessment of sleep disruption via self-report and actigraphy, a battery of neuropsychological tests of executive functioning, working memory, and verbal learning, and assessments of work functioning. BD participants experienced significantly poorer cognitive functioning as well as greater months of unemployment and greater incidence of being fired than controls. Moderation analyses revealed that both poor sleep and cognitive functioning were associated with poor work performance in BD participants, but not control participants. Sleep and cognitive functioning may be impaired in euthymic BD and are associated with poor work functioning in this population. More research should be conducted to better understand how sleep and cognitive functioning may interact in BD.

Behavioral approach system sensitivity and risk taking interact to predict left-frontal EEG asymmetry.

The Behavioral Approach System (BAS) hypersensitivity theory of bipolar disorder (BD; Alloy & Abramson, 2010; Depue & Iacono, 1989) suggests that hyperreactivity in the BAS results in the extreme fluctuations of mood characteristic of BD. In addition to risk conferred by BAS hypersensitivity, cognitive and personality variables may play a role in determining risk. We evaluated relationships among BAS sensitivity, risk taking, and an electrophysiological correlate of approach motivation, relative left-frontal electroencephalography (EEG) asymmetry. BAS sensitivity moderated the relationship between risk taking and EEG asymmetry. More specifically, individuals who were high in BAS sensitivity showed left-frontal EEG asymmetry regardless of their level of risk-taking behavior. However, among individuals who were moderate in BAS sensitivity, risk taking was positively associated with asymmetry. These findings suggest that cognitive and personality correlates of bipolar risk may evidence unique contributions to a neural measure of trait-approach motivation. Clinical implications of these findings are discussed.

Life events and social rhythms in bipolar spectrum disorders: an examination of social rhythm sensitivity.

OBJECTIVES: To examine the presence of an underlying social rhythm sensitivity in individuals with bipolar spectrum disorders. METHODS: The present study examined the impact of life events on sleep loss and social rhythm disruption in 184 individuals with bipolar spectrum disorders (BSD) compared to 197 demographically similar normal controls (NC) drawn from the Longitudinal Investigation of Bipolar Spectrum Disorders (LIBS) project. Life events data were obtained at three time points, each spaced four months apart, and included information on the intensity of the event (high or low), valence (negative or positive), and levels of sleep loss and social rhythm disruption brought about the event. We hypothesized that BSD participants would exhibit higher levels of social rhythm disruption and sleep loss than normal controls as a consequence of the same life events. RESULTS: BSD participants experienced significantly more social rhythm disruption and sleep loss following all classes of life events. LIMITATIONS: The cross-sectional design of this study limits the strength of the conclusions that can be drawn, primarily cause and effect relationships between social rhythms and symptoms. CONCLUSIONS: Findings support the presence of an underlying social rhythm sensitivity in individuals with bipolar spectrum disorders. An additive effect of sleep loss and social rhythm disruption may contribute to subsequent mood symptomatology. Results from this study may inform early psychosocial interventions for at-risk individuals.

Genetic and dietary effects on dendrites in the rat hypothalamic ventromedial nucleus.

Both genetic and environmental factors contribute to individual differences in body weight regulation. The present study examined a possible role for the dendritic arbor of hypothalamic ventromedial nucleus (VMH) neurons in a model of diet-induced obesity (DIO) in male rats. Rats were screened and selectively bred for being either susceptible, i.e., exhibiting DIO, or diet resistant (DR) when exposed to a 31% fat diet. A 2x2 experimental design was used, based on these two strains of rats and exposure to rat chow versus the 31% fat diet for seven weeks. Golgi-impregnated neurons were measured for soma size and dendrite parameters, including number, length, and direction. As previously observed, each VMH neuron had a single long primary dendrite. Genetic background and diet did not affect soma size or the number of dendrites of VMH neurons. However, genetic background exerted a main effect on the length of the long primary dendrites. In particular, the long primary dendrites were approximately 12.5% shorter on the VMH neurons in the DIO rats compared with DR rats regardless of diet. This effect was isolated to the long primary dendrites extending in the dorsolateral direction, with these long primary dendrites 19% shorter for the DIO group compared with the DR group. This finding implicates the connectivity of the long primary dendrites on VMH neurons in the control of energy balance. The functional significance of these shortened dendrites and their afferents warrants further study.