Visit-To-Visit Blood Pressure Variability and Subthreshold Depressive Symptoms in Older Adults.

OBJECTIVES: Depression is related to increased risk for dementia, possibly through links with cerebrovascular disease. Blood pressure variability is an emerging risk factor for cerebrovascular disease and dementia, but relationships with affective symptoms remain understudied. DESIGN: Retrospective analysis of prospective cohort study. SETTING: Alzheimer's Disease Neuroimaging Initiative. PARTICIPANTS: 505 older adults without history of dementia or recent depression underwent three to four blood pressure measurements over 12 months and completed a self-report measure of depressive symptoms (Geriatric Depression Scale - 15 Item) at study baseline and 24-months follow-up. MEASUREMENTS: Blood pressure variability was calculated as variability independent of mean and maximum minus minimum. Regression models investigated relationships between blood pressure variability and severity of self-reported depressive symptoms at 24-months follow-up after controlling for several variables, including average blood pressure, antihypertensive use, antidepressant use, and baseline depressive symptom severity. RESULTS: Elevated diastolic blood pressure variability was related to greater total depressive symptom score at follow-up (ß = .16 [95% CI 0.02, .30]; p = 0.03), with specific contribution from increased severity of symptoms of dysphoria (odds ratio = 1.35 [95% CI 1.07, 1.75]; p = 0.02). Blood pressure variability was not significantly related to other symptom subscales, including those reflecting life satisfaction or withdrawal. CONCLUSIONS: Findings suggest that elevated diastolic blood pressure variability is related to subthreshold depressive symptomatology in older adults without history of dementia or recent depression, independent of average blood pressure. Blood pressure variability may be an understudied vascular risk factor linked with depression and cognitive impairment, with potential therapeutic implications.

Folic acid is necessary for proliferation and differentiation of C2C12 myoblasts.

Folic acid, a water soluble B vitamin, plays an important role in cellular metabolic activities, such as functioning as a cofactor in one-carbon metabolism for DNA and RNA synthesis as well as nucleotide and amino acid biosynthesis in the body. A lack of dietary folic acid can lead to folic acid deficiency and result in several health problems, including macrocytic anemia, elevated plasma homocysteine, cardiovascular disease, birth defects, carcinogenesis, muscle weakness, and walking difficulty. However, the effect of folic acid deficiency on skeletal muscle development and its molecular mechanisms are unknown. We, therefore, investigated the effect of folic acid deficiency on myogenesis in skeletal muscle cells and found that folic acid deficiency induced proliferation inhibition and cell cycle breaking as well as cellular senescence in C2C12 myoblasts, implying that folic acid deficiency influences skeletal muscle development. Folic acid deficiency also inhibited differentiation of C2C12 myoblasts and induced deregulation of the cell cycle exit and many cell cycle regulatory genes. It inhibited expression of muscle-specific marker MyHC as well as myogenic regulatory factor (myogenin). Moreover, immunocytochemistry and Western blot analyses revealed that DNA damage was more increased in folic acid-deficient medium-treated differentiating C2C12 cells. Furthermore, we found that folic acid resupplementation reverses the effect on the cell cycle and senescence in folic acid-deficient C2C12 myoblasts but does not reverse the differentiation of C2C12 cells. Altogether, the study results suggest that folic acid is necessary for normal development of skeletal muscle cells.

Comprehension of insincere communication in neurodegenerative disease: lies, sarcasm, and theory of mind.

Comprehension of insincere communication is an important aspect of social cognition requiring visual perspective taking, emotion reading, and understanding others' thoughts, opinions, and intentions. Someone who is lying intends to hide their insincerity from the listener, while a sarcastic speaker wants the listener to recognize they are speaking insincerely. We investigated whether face-to-face testing of comprehending insincere communication would effectively discriminate among neurodegenerative disease patients with different patterns of real-life social deficits. We examined ability to comprehend lies and sarcasm from a third-person perspective, using contextual cues, in 102 patients with one of four neurodegenerative diseases (behavioral variant frontotemporal dementia [bvFTD], Alzheimer's disease [AD], progressive supranuclear palsy [PSP], and vascular cognitive impairment) and 77 healthy older adults (normal controls--NCs). Participants answered questions about videos depicting social interactions involving deceptive, sarcastic, or sincere speech using The Awareness of Social Inference Test. All subjects equally understood sincere remarks, but bvFTD patients displayed impaired comprehension of lies and sarcasm compared with NCs. In other groups, impairment was not disease-specific but was proportionate to general cognitive impairment. Analysis of the task components revealed that only bvFTD patients were impaired on perspective taking and emotion reading elements and that both bvFTD and PSP patients had impaired ability to represent others' opinions and intentions (i.e., theory of mind). Test performance correlated with informants' ratings of subjects' empathy, perspective taking and neuropsychiatric symptoms in everyday life. Comprehending insincere communication is complex and requires multiple cognitive and emotional processes vulnerable across neurodegenerative diseases. However, bvFTD patients show uniquely focal and severe impairments at every level of theory of mind and emotion reading, leading to an inability to identify obvious examples of deception and sarcasm. This is consistent with studies suggesting this disease targets a specific neural network necessary for perceiving social salience and predicting negative social outcomes.

Clinicopathological correlations in corticobasal degeneration.

OBJECTIVE: To characterize cognitive and behavioral features, physical findings, and brain atrophy patterns in pathology-proven corticobasal degeneration (CBD) and corticobasal syndrome (CBS) with known histopathology. METHODS: We reviewed clinical and magnetic resonance imaging data in all patients evaluated at our center with either an autopsy diagnosis of CBD (n = 18) or clinical CBS at first presentation with known histopathology (n = 40). Atrophy patterns were compared using voxel-based morphometry. RESULTS: CBD was associated with 4 clinical syndromes: progressive nonfluent aphasia (n = 5), behavioral variant frontotemporal dementia (n = 5), executive-motor (n = 7), and posterior cortical atrophy (n = 1). Behavioral or cognitive problems were the initial symptoms in 15 of 18 patients; less than half exhibited early motor findings. Compared to controls, CBD patients showed atrophy in dorsal prefrontal and perirolandic cortex, striatum, and brainstem (p < 0.001 uncorrected). The most common pathologic substrates for clinical CBS were CBD (35%), Alzheimer disease (AD, 23%), progressive supranuclear palsy (13%), and frontotemporal lobar degeneration (FTLD) with TDP inclusions (13%). CBS was associated with perirolandic atrophy irrespective of underlying pathology. In CBS due to FTLD (tau or TDP), atrophy extended into prefrontal cortex, striatum, and brainstem, whereas in CBS due to AD, atrophy extended into temporoparietal cortex and precuneus (p < 0.001 uncorrected). INTERPRETATION: Frontal lobe involvement is characteristic of CBD, and in many patients frontal, not parietal or basal ganglia, symptoms dominate early stage disease. CBS is driven by medial perirolandic dysfunction, but this anatomy is not specific to a single underlying histopathology. Antemortem prediction of CBD will remain challenging until clinical features of CBD are redefined, and sensitive, specific biomarkers are identified.

Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer's disease.

Resting-state or intrinsic connectivity network functional magnetic resonance imaging provides a new tool for mapping large-scale neural network function and dysfunction. Recently, we showed that behavioural variant frontotemporal dementia and Alzheimer's disease cause atrophy within two major networks, an anterior 'Salience Network' (atrophied in behavioural variant frontotemporal dementia) and a posterior 'Default Mode Network' (atrophied in Alzheimer's disease). These networks exhibit an anti-correlated relationship with each other in the healthy brain. The two diseases also feature divergent symptom-deficit profiles, with behavioural variant frontotemporal dementia undermining social-emotional function and preserving or enhancing visuospatial skills, and Alzheimer's disease showing the inverse pattern. We hypothesized that these disorders would exert opposing connectivity effects within the Salience Network (disrupted in behavioural variant frontotemporal dementia but enhanced in Alzheimer's disease) and the Default Mode Network (disrupted in Alzheimer's disease but enhanced in behavioural variant frontotemporal dementia). With task-free functional magnetic resonance imaging, we tested these ideas in behavioural variant frontotemporal dementia, Alzheimer's disease and healthy age-matched controls (n = 12 per group), using independent component analyses to generate group-level network contrasts. As predicted, behavioural variant frontotemporal dementia attenuated Salience Network connectivity, most notably in frontoinsular, cingulate, striatal, thalamic and brainstem nodes, but enhanced connectivity within the Default Mode Network. Alzheimer's disease, in contrast, reduced Default Mode Network connectivity to posterior hippocampus, medial cingulo-parieto-occipital regions and the dorsal raphe nucleus, but intensified Salience Network connectivity. Specific regions of connectivity disruption within each targeted network predicted intrinsic connectivity enhancement within the reciprocal network. In behavioural variant frontotemporal dementia, clinical severity correlated with loss of right frontoinsular Salience Network connectivity and with biparietal Default Mode Network connectivity enhancement. Based on these results, we explored whether a combined index of Salience Network and Default Mode Network connectivity might discriminate between the three groups. Linear discriminant analysis achieved 92% clinical classification accuracy, including 100% separation of behavioural variant frontotemporal dementia and Alzheimer's disease. Patients whose clinical diagnoses were supported by molecular imaging, genetics, or pathology showed 100% separation using this method, including four diagnostically equivocal 'test' patients not used to train the algorithm. Overall, the findings suggest that behavioural variant frontotemporal dementia and Alzheimer's disease lead to divergent network connectivity patterns, consistent with known reciprocal network interactions and the strength and deficit profiles of the two disorders. Further developed, intrinsic connectivity network signatures may provide simple, inexpensive, and non-invasive biomarkers for dementia differential diagnosis and disease monitoring.