Decline in semantic cognition in early stages of Parkinson's disease (PD) is a leading risk factor for future dementia, yet the underlying neural mechanisms are not understood. The present study addressed this gap by investigating the functional connectivity of regions involved in semantic recollection. We further examined whether microtubule-associated protein tau (MAPT) risk variants, which may accelerate cognitive decline, altered the strength of regional functional connections. Cognitively normal PD and healthy elder controls underwent fMRI while performing a fame-discrimination task, which activates the semantic network. Analyses focused on disturbances in fame-modulated functional connectivity in PD for regions that govern semantic recollection and interrelated processes. Group differences were found in multiple connectivity features, which were reduced into principal components that reflected the strength of fame-modulated regional couplings with other brain areas. Despite the absence of group differences in semantic cognition, two aberrant connectivity patterns were uncovered in PD. One pattern was related to a loss in frontal, parietal, and temporal connection topologies that governed semantic recollection in older controls. Another pattern was characterized by functional reconfiguration, wherein frontal, parietal, temporal and caudate couplings were strengthened with areas that were not recruited by controls. Correlations between principal component scores and cognitive measures suggested that reconfigured frontal coupling topologies in PD supported compensatory routes for accessing semantic content, whereas reconfigured parietal, temporal, and caudate connection topologies were detrimental or unrelated to cognition. Increased tau transcription diminished recruitment of compensatory frontal topologies but amplified recruitment of parietal topologies that were unfavorable for cognition. Collectively, the findings provide a new understanding of early vulnerabilities in the functional architecture of regional connectivity during semantic recollection in cognitively normal PD. The findings also have implications for tracking cognitive progression and selecting patients who stand to benefit from therapeutic interventions.

The role of motor activity ipsilateral to movement remains a matter of debate, due in part to discrepancies among studies in the localization of this activity, when observed, and uncertainty about its time course. The present study used magnetoencephalography (MEG) to investigate the spatial localization and temporal dynamics of contralateral and ipsilateral motor activity during the preparation of unilateral finger movements. Eight right-handed normal subjects carried out self-paced finger-lifting movements with either their dominant or nondominant hand during MEG recordings. The Multi-Start Spatial Temporal multi-dipole method was used to analyze MEG responses recorded during the movement preparation and early execution stage (-800 msec to +30 msec) of movement. Three sources were localized consistently, including a source in the contralateral primary motor area (M1) and in the supplementary motor area (SMA). A third source ipsilateral to movement was located significantly anterior, inferior, and lateral to M1, in the premotor area (PMA) (Brodmann area [BA] 6). Peak latency of the SMA and the ipsilateral PMA sources significantly preceded the peak latency of the contralateral M1 source by 60 msec and 52 msec, respectively. Peak dipole strengths of both the SMA and ipsilateral PMA sources were significantly weaker than was the contralateral M1 source, but did not differ from each other. Altogether, the results indicated that the ipsilateral motor activity was associated with premotor function, rather than activity in M1. The time courses of activation in SMA and ipsilateral PMA were consistent with their purported roles in planning movements.

Background

Spatial cognition deteriorates in Parkinson's disease (PD), but the neural substrates are not understood, despite the risk for future dementia. It is also unclear whether deteriorating spatial cognition relates to changes in other cognitive domains or contributes to motor dysfunction.

Objective

This study aimed to identify functional connectivity abnormalities in cognitively normal PD (PDCN) in regions that support spatial cognition to determine their relationship to interfacing cognitive functions and motor disability, and to determine if they predict cognitive and motor progression 2 years later in a PDCN subsample.

Methods

Sixty-three PDCN and 43 controls underwent functional MRI while judging whether pictures, rotated at various angles, depicted the left or right hand. The task activates systems that respond to increases in rotation angle, a proxy for visuospatial difficulty. Angle-modulated functional connectivity was analyzed for frontal cortex, posterior cortex, and basal ganglia regions.

Results

Two aberrant connectivity patterns were found in PDCN, which were condensed into principal components that characterized the strength and topology of angle-modulated connectivity. One topology related to a marked failure to amplify frontal, posterior, and basal ganglia connectivity with other brain areas as visuospatial demands increased, unlike the control group (control features). Another topology related to functional reorganization whereby regional connectivity was strengthened with brain areas not recruited by the control group (PDCN features). Functional topologies correlated with diverse cognitive domains at baseline, underscoring their influences on spatial cognition. In PDCN, expression of topologies that were control features predicted greater cognitive progression longitudinally, suggesting inefficient communications within circuitry normally recruited to handle spatial demands. Conversely, stronger expression of topologies that were PDCN features predicted less longitudinal cognitive decline, suggesting functional reorganization was compensatory. Parieto-occipital topologies (control features) had different prognostic implications for longitudinal changes in motor disability. Expression of one topology predicted less motor decline, whereas expression of another predicted increased postural instability and gait disturbance (PIGD) feature severity. Concurrently, greater longitudinal decline in spatial cognition predicted greater motor and PIGD feature progression, suggesting deterioration in shared substrates.

Conclusion

These novel discoveries elucidate functional mechanisms of visuospatial cognition in PDCN, which foreshadow future cognitive and motor disability.

Behaviours that appear to depend on processing temporal information are frequently disrupted after cerebellar damage. The present study examined the role of the cerebellum in explicit timing and its relationship to other psychological processes. We hypothesized that if the cerebellum regulates timekeeping operations then cerebellar damage should disrupt the perception and the reproduction of intervals, since both are thought to be supported by a common timekeeper mechanism. Twenty-one patients with cerebellar damage from stroke and 30 normal controls performed time perception and time reproduction tasks. In the time reproduction task, timing variability was decomposed into a central timing component (clock variability) and a motor component (motor implementation variability). We found impairments only in time reproduction (increased clock variability) in patients with medial and lateral damage involving the middle- to superior-cerebellar lobules. To explore potential reasons for the temporal processing deficits, time reproduction and perception performance were correlated with independent measures of attention, working memory, sensory discrimination and processing speed. Poorer working memory correlated with increased variability in the 'clock' component of time reproduction. In contrast, processing speed correlated best with time perception. The results did not support a role for the cerebellum in timekeeping operations. Rather, deficits in timing movements may be related to a disruption in acquiring sensory and cognitive information relevant to the task, coupled with an additional impairment in the motor-output system.

In Parkinson's disease (PD) functional changes in the brain occur years before significant cognitive symptoms manifest yet core large-scale networks that maintain cognition and predict future cognitive decline are poorly understood. The present study investigated internetwork functional connectivity of visual (VN), anterior and posterior default mode (aDMN, pDMN), left/right frontoparietal (LFPN, RFPN), and salience (SN) networks in 63 cognitively normal PD (PDCN) and 43 healthy controls who underwent resting-state functional MRI. The functional relevance of internetwork coupling topologies was tested by their correlations with baseline cognitive performance in each group and with 2-year cognitive changes in a PDCN subsample. To disentangle heterogeneity in neurocognitive functioning, we also studied whether α-synuclein (SNCA) and microtubule-associated protein tau (MAPT) variants alter internetwork connectivity and/or accelerate cognitive decline. We found that internetwork connectivity was largely preserved in PDCN, except for reduced pDMN-RFPN/LFPN couplings, which correlated with poorer baseline global cognition. Preserved internetwork couplings also correlated with domain-specific cognition but differently for the two groups. In PDCN, stronger positive internetwork coupling topologies correlated with better cognition at baseline, suggesting a compensatory mechanism arising from less effective deployment of networks that supported cognition in healthy controls. However, stronger positive internetwork coupling topologies typically predicted greater longitudinal decline in most cognitive domains, suggesting that they were surrogate markers of neuronal vulnerability. In this regard, stronger aDMN-SN, LFPN-SN, and/or LFPN-VN connectivity predicted longitudinal decline in attention, working memory, executive functioning, and visual cognition, which is a risk factor for dementia. Coupling strengths of some internetwork topologies were altered by genetic variants. PDCN carriers of the SNCA risk allele showed amplified anticorrelations between the SN and the VN/pDMN, which supported cognition in healthy controls, but strengthened pDMN-RFPN connectivity, which maintained visual memory longitudinally. PDCN carriers of the MAPT risk allele showed greater longitudinal decline in working memory and increased VN-LFPN connectivity, which in turn predicted greater decline in visuospatial processing. Collectively, the results suggest that cognition is maintained by functional reconfiguration of large-scale internetwork communications, which are partly altered by genetic risk factors and predict future domain-specific cognitive progression.

The orienting of attention to different locations in space is fundamental to most organisms and occurs in all sensory modalities. Orienting has been extensively studied in vision, but to date, few studies have investigated neuronal networks underlying automatic orienting of attention and inhibition of return to auditory signals. In the current experiment, functional magnetic resonance imaging and behavioral data were collected while healthy volunteers performed an auditory orienting task in which a monaurally presented tone pip (cue) correctly or incorrectly cued the location of a target tone pip. The stimulus onset asynchrony (SOA) between the cue and target was 100 or 800 msec. Behavioral results were consistent with previous studies showing that valid auditory cues produced facilitation at the short SOA and inhibition of return at the long SOA. Functional results indicated that the reorienting of attention (100 msec SOA) and inhibition of return (800 msec SOA) were mediated by both common and distinct neuronal structures. Both attention mechanisms commonly activated a network consisting of fronto-oculomotor areas, the left postcentral gyrus, right premotor area, and bilateral tonsil of the cerebellum. Several distinct areas of frontal and parietal activation were identified for the reorienting condition, whereas the right inferior parietal lobule was the only structure uniquely associated with inhibition of return.

Normal brain aging is characterized by declining neuronal integrity, yet it remains unclear how microstructural injury influences cognitive aging and whether such mechanisms differ between sexes. Using restriction spectrum imaging (RSI), we examined sex differences in associations between brain microstructure and cognitive function in 147 community-dwelling older men and women (56-99 years). Gray and white matter microstructure correlated with global cognition, executive function, visuospatial memory, episodic memory, and logical memory, with the strongest associations for restricted, hindered and free isotropic diffusion. Associations were stronger for women than for men, a difference likely due to greater age-related variability in cognitive scores and microstructure in women. Isotropic diffusion mediated effects of age on cognition for both sexes, though distinct mediation patterns were present for women and men. For women, hippocampal and corpus callosum microstructure mediated age effects on verbal and visuospatial memory, respectively, whereas for men fiber microstructure (mainly fornix and corpus callosum) mediated age effects on executive function and visuospatial memory. These findings implicate sex-specific pathways by which changing brain cytoarchitecture contributes to cognitive aging, and suggest that RSI may be useful for evaluating risk for cognitive decline or monitoring efficacy of interventions to preserve brain health in later life.

A 50-year-old male immigrant from Ethiopia presented for consultation after 3 years of hematochezia/melena requiring > 25 units of blood transfusions. Physical examination revealed severe proximal muscle wasting and weakness, central obesity, proptosis, and abdominal striae, accompanied by eosinophilia, elevated hemoglobin A1c, elevated 24-hour urinary cortisol, lack of suppression of 8 am cortisol levels by 1 mg dexamethasone, and inappropriately elevated random adrenocorticotropic hormone (ACTH) level. Histopathological examination of gastrointestinal biopsies showed large numbers of Strongyloides stercoralis, indicating Strongyloides hyperinfection. Treatment with 2 days of ivermectin led to resolution of gastrointestinal bleeding. This syndrome was due to chronic immunosuppression from a pituitary ACTH (corticotroph) microadenoma, of which resection led to gradual normalization of urine cortisol, improved glycemic control, resolution of eosinophilia, and no recurrence of infection.

Visuospatial working memory impairments are common in Parkinson's disease (PD), yet the underlying neural mechanisms are poorly understood. The present study investigated abnormalities in context-dependent functional connectivity of working memory hubs in PD. Cognitively normal PD and control participants underwent fMRI while performing a visuospatial working memory task. To identify sources of dysfunction, distraction, and load-modulated connectivity were disentangled for encoding and retrieval phases of the task. Despite normal working memory performance in PD, two features of abnormal connectivity were observed, one due to a loss in normal context-related connectivity and another related to upregulated connectivity of hubs for which the controls did not exhibit context-dependent connectivity. During encoding, striatal-prefrontal coupling was lost in PD, both during distraction and high memory loads. However, long-range connectivity of prefrontal, medial temporal and occipital hubs was upregulated in a context-specific manner. Memory retrieval was characterized by different aberrant connectivity patterns, wherein precuneus connectivity was upregulated during distraction, whereas prefrontal couplings were lost as memory load approached capacity limits. Features of abnormal functional connectivity in PD had pathological and compensatory influences as they correlated with poorer working memory or better visuospatial skills. The results offer new insights into working memory-related signatures of aberrant cortico-cortical and corticostriatal functional connections, which may portend future declines in different facets of working memory.

This study investigated the ability of individuals with Parkinson's disease (PD) to synthesize temporal information across the senses, namely audition and vision. Auditory signals (A) are perceived as lasting longer than visual signals (V) when they are compared together, since attentsion is captured and sustained more easily than for visual information. We used the audiovisual illusion to probe for disturbances in brain networks that govern the resolution of time in two intersensory conditions that putatively differ in their attention demands. PD patients and controls judged the relative duration of successively presented pairs of unimodal (AA, VV) and crossmodal (VA, AV) signals whilst undergoing fMRI. There were four main findings. First, underestimation of time was exaggerated in PD when timing depended on controlled attention (AV), whereas subtle deficits were found when audition dominated and attention was more easily sustained (VA). Second, group differences in regional activation were observed only for the AV-unimodal comparison, where the PD group failed to modulate basal ganglia, anterior insula, and inferior cerebellum activity in accord with the timing condition. Third, the intersensory timing conditions were dissociated by patterns of abnormal functional connectivity. When intersensory timing emphasized controlled attention, patients showed weakened connectivity of the cortico-thalamus-basal ganglia (CTBG) circuit and the anterior insula with widespread cortical regions, yet enhanced cerebellar connectivity. When audition dominated intersensory timing, patients showed enhanced connectivity of CTBG elements, the anterior insula, and the cerebellum with the caudate tail and frontal cortex. Fourth, abnormal connectivity measures showed excellent sensitivity and specificity in accurately classifying subjects. The results demonstrate that intersensory timing deficits in PD were well characterized by context-dependent patterns of functional connectivity within a presumed core timing system (CTBG) and a ventral attention hub (anterior insula), and enhanced cerebellar connectivity irrespective of the hypothesized attention demands of timing.