Faculty Bibliography

BACKGROUND: Although cognitive deficits in patients with schizophrenia are rooted early in development, the impact of psychosis on the course of cognitive functioning remains unclear. In this study a nested case-control design was used to examine the relationship between emerging psychosis and the course of cognition in individuals ascertained as clinical high-risk (CHR) who developed psychosis during the study (CHR + T). METHOD: Fifteen CHR + T subjects were administered a neurocognitive battery at baseline and post-psychosis onset (8.04 months, s.d. = 10.26). CHR + T subjects were matched on a case-by-case basis on age, gender, and time to retest with a group of healthy comparison subjects (CNTL, n = 15) and two groups of CHR subjects that did not transition: (1) subjects matched on medication treatment (i.e. antipsychotics and antidepressants) at both baseline and retesting (Meds-matched CHR + NT, n = 15); (2) subjects unmedicated at both assessments (Meds-free CHR + NT, n = 15). RESULTS: At baseline, CHR + T subjects showed large global neurocognitive and intellectual impairments, along with specific impairments in processing speed, verbal memory, sustained attention, and executive function. These impairments persisted after psychosis onset and did not further deteriorate. In contrast, CHR + NT subjects demonstrated stable mild to no impairments in neurocognitive and intellectual performance, independent of medication treatment. CONCLUSIONS: Cognition appears to be impaired prior to the emergence of psychotic symptoms, with no further deterioration associated with the onset of psychosis. Cognitive deficits represent trait risk markers, as opposed to state markers of disease status and may therefore serve as possible predictors of schizophrenia prior to the onset of the full illness.

The World Trade Center (WTC) destruction released dust and fumes into the environment. Although many community members developed respiratory symptoms, screening spirometry was usually normal. We hypothesised that forced oscillation testing would identify functional abnormalities undetected by spirometry and that symptom severity would relate to magnitude of abnormalities measured by oscillometry. A symptomatic cohort (n=848) from the Bellevue Hospital WTC Environmental Health Center was evaluated and compared to an asymptomatic cohort (n=475) from the New York City Department of Health WTC Health Registry. Spirometry and oscillometry were performed. Oscillometry measurements included resistance (R5) and frequency dependence of resistance (R5-20). Spirometry was normal for the majority of subjects (73.2% symptomatic versus 87.6% asymptomatic, p<0.0001). In subjects with normal spirometry, R5 and R5-20 were higher in symptomatic versus asymptomatic subjects (median (interquartile range) R5 0.436 (0.206) versus 0.314 (0.129) kPa.L-1.s-1, p<0.001; R5-20 0.075 (0.085) versus 0.004 (0.042) kPa.L-1.s-1, p<0.0001). In symptomatic subjects, R5 and R5-20 increased with increasing severity and frequency of wheeze (p<0.05). Measurement of R5-20 correlated with the presence and severity of symptoms even when spirometry was within normal limits. These findings are in accord with small airway abnormalities as a potential explanation of the respiratory symptoms.

A major feature of Alzheimer's disease (AD) is the loss of noradrenergic locus coeruleus (LC) projection neurons that mediate attention, memory, and arousal. However, the extent to which the LC projection system degenerates during the initial stages of AD remains unclear. To address this question, we performed tyrosine hydroxylase (TH) immunohistochemistry and unbiased stereology of LC neurons in tissue harvested postmortem from subjects who died with a clinical diagnosis of no cognitive impairment (NCI), amnestic mild cognitive impairment (aMCI, a prodromal AD stage), or mild AD (n = 5-6/group). Stereologic estimates of total LC neuron number revealed a 30-35% decrease in aMCI versus NCI (p < 0.01) and a 45% loss of cells in mild AD compared to NCI (p < 0.01). Furthermore, LC fiber density was selectively reduced in the hippocampus compared to the neocortex of aMCI subjects, suggesting that coeruleohippocampal pathway degeneration marks the transition from normal cognition to prodromal disease. To examine the molecular pathogenic processes underlying LC neurodegeneration in aMCI, we combined laser capture microdissection with custom microarray technology to quantify gene expression patterns in individual TH-immunopositive neurons accessed from LC tissue samples. These studies revealed significant reductions in select functional classes of mRNAs regulating mitochondrial metabolism (e.g., cytochrome c1, cytochrome oxidase subunit 5a, p < 0.01), redox homeostasis (e.g., superoxide dismutase 2, glutathione peroxidase 1, p < 0.01), and cytoskeletal plasticity (e.g., microtubule-associated binding protein 1a, utrophin, p < 0.01) in both aMCI and AD subjects compared to NCI. Taken together, these observations show that LC projection system degeneration is a prominent feature during the transition from NCI to aMCI. In this regard, we are currently examining the extent of LC neuropathology in tissue from "preclinical AD" subjects who died with a clinical diagnosis of NCI but who displayed high postmortem Braak pathology. Targeting the noradrenergic LC system may present a novel disease-modifying strategy for cognitive protection in the elderly

Introduction: Depressive symptoms are common in patients with multiple systematrophy (MSA). We aimed to determine the prevalence of depression in MSA and its impact on quality of life and disease progression. Methods: MSA patients enrolled in a natural history study to determine the natural progression of disease. Patients completed psychiatric (Zung Depression scale, Spielberg's anxiety scale and Body vigilance scale) and autonomic (OHQ, COMPASS, UMSARS-I and II, SCOPA-Autonomic and SF36 Quality of life scale) rating scales, and underwent autonomic and cardiovascular assessments at baseline, and then followed at regular intervals for repeat assessments. Results: Forty-five MSA patients (mean age 61.8 years, 4.3 years disease duration) were included. Thirty patients (67%) scored as having depression on the Zung depression scale (15 mild, 13 moderate, and 2 severe). Seventy-three percent had orthostatic hypotension (OH). Depressed patients had higher trait/state anxiety and body vigilance scores than non-depressed patients. Depressed patients had significantly higher OHQ scores on each of the 6 OHSA items and each of the OHDAS items (OH interference with activities of standing and walking). Trait-anxiety and depression correlated with OHSA and OHDAS items. Depressed patients reported greater OHQscores for the same amount of blood pressure change than non-depressed. Linear regression showed significant effect of depression on progression of UMSARS-II scores. Depression correlated with orthostatic and urinary function symptoms on the COMPASS scale. Conclusions: Depression is common in MSA. It impacts the progression and severity of autonomic symptoms. Recognizing and treating depression may improve quality of life and ameliorate symptoms

Familial dysautonomia (FD) features a unique combination of cardiovascular disturbances not seen in patients with any other chronic disorder of the autonomic nervous system. While blood pressure falls and both heart rate and plasma noradrenaline fail to increase during standing in FD, patients demonstrate significant increases in blood pressure and plasma noradrenaline during episodes of emotional arousal. This indicates that vasoconstrictor neurones can be activated during states of emotional arousal, and that noradrenaline is released. Because constriction of arterioles in skeletal muscle vascular beds is one of the primary determinants of total peripheral resistance and hence of blood pressure, we would expect that muscle sympathetic nerve activity (MSNA) -which is vasoconstrictor in function - would be present in patients with FD. However, given the absence of functional baroreflex afferents we predicted that MSNA would not appear as cardiac-locked bursts. We tested this hypothesis using tungsten microelectrodes inserted percutaneously into muscle or cutaneous fascicles of the nerve in 12 patients with FD. Spontaneous bursts of MSNA were absent in all patients, but in five patients we found evidence of tonically firing sympathetic neurones, with no cardiac rhythmicity, that increased their spontaneous discharge during emotional arousal but not during baroreceptor unloading. Conversely, skin sympathetic nerve activity (SSNA) appeared normal. We conclude that the loss of baroreflex modulation of MSNA contributes to the poor control of blood pressure in FD, and that the increase in tonic firing of muscle vasoconstrictor neurones contributes to the increase in blood pressure during emotional excitement

Background: Clinical distinction between Lewy body disorders (Parkinson disease [PD] and dementia with Lewy bodies [DLB]) and multiple system atrophy (MSA) is sometimes challenging. Aim: We investigated whether activation of afferent and central baroreceptor pathways could differentiate between Lewy body disorders and MSA. Methods: We determined the effect of supine and upright tilt on circulating levels of vasopressin and catecholamines in patients with PD/DLB and MSA. Results: Thirty-five patients with probable MSA (22 MSA-C, 13 MSA-P) and 24 patients with Lewy body disorders (20 with PD, 4 with DLB) were included. All patients had documented neurogenic orthostatic hypotension. In patients with PD and DLB upright tilt induced marked hypotension and a significant increase in plasma vasopressin (from 0.82 +/- 0.77 to 4.85 +/- 13.9 pmol/l in PD (p = 0.0027); from 1.18 +/- 0.81 to 5.1 +/- 3.76 pmol/l in DLB (p = 0.11). In patients with MSA, upright tilt also elicited profound hypotension but circulating levels of vasopressin did not increase significantly (from 0.51+/- 0.08 to 0.70 +/- 0.71 pmol/l, p=0.092). Plasma norepinephrine did not increase significantly on head-tilt in any of the subjects. A plasma vasopressin concentration during upright tilt of <0.6 pmol/l in a patient with neurogenic orthostatic hypotension had a sensitivity of 89% and a specificity of 71% to differentiate between MSA and Lewy bodies disorders. Conclusions: Our results indicate that afferent and central baroreceptor pathways involved in vasopressin release are preserved in patients with Lewy body disorders but are impaired in patients with MSA. Thus, measurement of baroreceptor mediated vasopressin release is helpfulmarker to differentiate between these diagnoses