Isak Prohovnik

Relationship between lifetime occupation and parietal flow Implications for a reserve against Alzheimer's disease pathology

Article abstract-We previously reported an inverse relation between parietal cerebral blood flow and years of education in Alzheimers disease (AD) patients matched for clinical severity. This suggested that the clinical manifestation of advancing AD pathology is delayed in patients with higher educational attainment. Other aspects of life experience may also provide a reserve against the clinical expression of AD. To test this hypothesis, we classified the primary lifetime occupations of 51 AD patients using the Dictionary of Occupational Titles, published by the US Department of Labor, and derived six factor scores describing intellectual, interpersonal, and physical job demands. Regional cerebral blood flow was measured using the xenon-133 inhalation method. After controlling for age, clinical dementia severity, and education, there was less relative perfusion in the parietal region in subjects whose occupations were associated with higher interpersonal skills and physical demands factor scores. We conclude that independent of education, aspects of occupational experience may provide a reserve that delays the clinical manifestation of AD. NEUROLOGY 1995;45: 55-60

Neural correlates of emotion processing in borderline personality disorder

Emotional instability is a hallmark feature of borderline personality disorder (BPD), yet its biological underpinnings are poorly understood. We employed functional magnetic resonance imaging (fMRI) to compare patterns of regional brain activation in BPD patients and healthy volunteers as they process positive and negative social emotional stimuli. fMRI images were acquired while 19 BPD patients and 17 healthy controls (HC) viewed emotion-inducing pictures from the International Affective Pictures System set. Activation data were analyzed with SPM5 ANCOVA models to derive the effects of diagnosis and stimulus type. BPD patients demonstrated greater differences in activation than controls, when viewing negative pictures compared with rest, in the amygdala, fusiform gyrus, primary visual areas, superior temporal gyrus (STG), and premotor areas, while healthy controls showed greater differences than BPD patients in the insula, middle temporal gyrus and dorsolateral prefrontal cortex (BA46). When viewing positive pictures compared with rest, BPD patients showed greater differences in the STG, premotor cortex, and ventrolateral prefrontal cortex. These findings suggest that BPD patients show greater amygdala activity and heightened activity of visual processing regions relative to findings for HC subjects in the processing of negative social emotional pictures compared with rest. The patients activate neural networks in emotion processing that are phylogeneticall older and more reflexive than those activated by HC subjects.

Sickle cell disease: The neurological complications

The genetic cause of sickle cell disease has been known for decades, yet the reasons for its clinical variability are not fully understood. The neurological complications result from one point mutation that causes vasculopathy of both large and small vessels. Anemia and the resultant cerebral hyperemia produce conditions of hemodynamic insufficiency. Sickled cells adhere to the endothelium, contributing to a cascade of activated inflammatory cells and clotting factors, which result in a nidus for thrombus formation. Because the cerebrovascular reserve becomes exhausted, the capacity for compensatory cerebral mechanisms is severely limited. There is evidence of small‐vessel sludging, and a relative deficiency of nitric oxide in these vessels further reduces compensatory vasodilatation. Both clinical strokes and silent infarcts occur, affecting motor and cognitive function. New data suggest that, in addition to sickle cell disease, other factors, both environmental (eg, hypoxia and inflammation) and genetic (eg, mutations resulting in thrombogenesis), may contribute to a patients stroke risk. The stroke risk is polygenic, and sickle cell disease can be considered a model for all cerebrovascular disease. This complex disease underscores the potential intellectual and practical distance between the determination of molecular genetics and effective clinical application and therapeutics.

Cerebral hyperemia, stroke, and transfusion in sickle cell disease

To investigate cerebral hemodynamics in sickle cell disease (SCD), we used the 133Xenon inhalation technique of quantifying cerebral blood flow (CBF) in 67 patients. Clinical examinations and cerebral magnetic resonance imaging also were performed in all patients. Compared with age-matched healthy controls, CBF was elevated by 68% in patients, and inversely related to hematocrit. An experimental index of cerebral blood volume, pr4, was also elevated in the patients in a similar manner. Cerebral blood volume was positively correlated to CBF in SCD patients but not in controls. History of stroke and current neurologic symptoms were associated with lower flow and higher cerebral blood volume. Transfusion therapy reduced the hyperemia, the reduction being greater than expected by hematocrit elevation alone. These findings document a vasodilatory hyperemia in SCD. This dilatation may be a risk factor for ischemic distal-field infarctions, as visualized by MRI, due to a limitation of cerebrovascular reserve capacity.

Dissociation of neuropathology from severity of dementia in late-onset Alzheimer disease

Background: Little is known about Alzheimer disease at advanced ages, although its incidence continues to increase at least through the ninth decade of life. Objective: To examine the effects of age on the relationship between clinical dementia severity and neuropathologic hallmarks in a large sample spanning the full age range. Methods: The authors assessed 81 subjects during life for dementia severity, and examined their brains. They analyzed plaque and tangle burden, as well as the activities of the cholinergic marker enzymes acetylcholinesterase (AChE) and choline acetyltransferase (ChAT), in relation to age at death and the clinical severity of dementia. Results: Dementia severity was strongly related to plaque and tangle burden in relatively young patients (aged <75 years), but this correlation diminished with age and disappeared in the ninth decade of life. Among the oldest patients studied, there was no difference in plaque and tangle load between the mild and severe dementia cases. This interaction (p < 0.0001 for plaque density) was not observed for the cholinergic markers ChAT and AChE. Conclusion: The nature or expression of Alzheimer disease may be different in severely demented older patients, who have equal cholinergic deficits but significantly lower plaque and tangle burden. If confirmed in a prospective study, these findings have diagnostic and therapeutic implications.

Cerebral perfusion as a diagnostic marker of early Alzheimer's disease

Clinical diagnosis of Alzheimers disease (AD) is not fully satisfactory, and laboratory markers of this disease are not yet established. We report substantial regional Cerebral Blood Flow (rCBF) abnormalities in patients with documented early stages of the disease, when differential diagnosis is most critical. Thirty-six patients with carefully documented clinical diagnosis of early AD (mean disease duration, 3.25 ± 1.80 years) and 12 elderly healthy controls participated in rCBF studies using the 133Xe inhalation method. Whole-brain perfusion was significantly (p < 0.001) lower in the AD group, and a characteristic perfusion deficit was consistently found in temporoparietal cortex of the AD patients. Discriminant analyses demonstrated over 90% correct classification of the two groups. Two subgroups of patients with mildest disease manifestations were equally well discriminated. The similarity of these findings to those in late stages, which have been validated neuro-pathologically, offers indirect confirmation of validity and specificity. These results suggest that rCBF procedures may provide an accurate and sensitive laboratory marker for early AD.

Cerebrovascular effects of hemodialysis in chronic kidney disease

Patients with end-stage renal disease (ESRD) undergoing hemodialysis are known to suffer cognitive deficits and stroke of unknown etiology. It has been suspected that the treatment itself may contribute to the syndrome by unknown mechanisms, which we investigated in this study. End-stage renal disease patients on hemodialysis (n = 19) or peritoneal dialysis (PD, n = 5) were compared with 14 healthy controls. Subjects participated in magnetic resonance imaging (MRI) measurements of cerebral atrophy, cerebral blood flow (CBF) arterial spin labeled-MRI (ASL-MRI), quantitative Doppler blood flow through the internal carotid artery, and cerebral oxymetry. The Doppler and oxymetry procedures were also performed at the beginning and end of a single hemodialysis session. End-stage renal disease patients on hemodialysis showed significant cerebral atrophy, associated with longer hemodialysis duration and cognitive deficits, including focal bilateral lesions in the caudate nucleus and midbrain. Cerebral oxygenation was extremely low before dialysis (rSO2 41 ± 13, compared with 70 ± 2 in controls, P < 0.02) and improved only slightly after dialysis. Carotid blood flow was also very low at the start of dialysis (115 ± 28mL/sec, versus 193 ± 56 in controls, P < 0.005) but normalized at the end of the session (181 mL/sec). The PD patients showed intermediate values, between the hemodialysis and controls. Notably, duration of hemodialysis treatment predicted global gray-matter volume (r = −0.74), change of blood flow during dialysis (r = −0.65), and baseline rSO2 (r = −0.65). The findings suggest that ESRD patients on hemodialysis suffer low CBF during the interdialytic cycle. Coupled with low cerebral oxygenation levels and atherosclerosis, this may contribute significantly to the etiology of the observed cerebral atrophy, cognitive deficits, and high stroke prevalence.

Hemodynamic Etiology of Elevated Flow Velocity and Stroke in Sickle-Cell Disease

Elevation of blood flow velocity in the large cerebral vessels is known to be of substantial pathophysiologic and prognostic significance in sickle-cell disease (SCD). Its precise cause is not established, but the two obvious proximal mechanisms are obstructive vascular stenosis and hemodynamic dilatation. Here we revisit this distinction by analyzing cerebrovascular reserve capacity. Forty-two patients with SCD underwent measurements of global cerebral blood flow in grey matter by the 133Xe inhalation method during normocapnia and hypercapnia to quantify cerebrovascular reactivity. Cerebral blood flow was significantly higher in SCD patients (120±31 ml/100 g/min) than in controls (76±20 ml/100 g/min). Reactivity was significantly lower in SCD patients (1.06±1.92 versus 2.16±1.15%/mm Hg). Stepwise multiple regressions within the SCD sample determined that normocapnic cerebral blood flow was largely predicted by hematocrit (r =–0.59; P > 0.0001), whereas hypercapnic reactivity was only predicted by normocapnic flow across all subjects (r =–0.52; P > 0.0001). None of the controls, but 24% of the SCD patients showed ‘steal’ (negative reactivity, χ2 = 6.05; P > 0.02). This impairment of vasodilatory capacity, occurring at perfusion levels above 150 ml/100 g/min, may reflect intrinsic limitations of the human cerebrovascular system and can explain both the elevated blood flow velocities and the high risk of stroke observed in such patients.

Regional cerebral blood flow in mood disorders : IV. Comparison of mania and depression

Cortical regional cerebral blood flow (rCBF) was assessed in minimally medicated, relatively young adults in episodes of either acute mania (n = 11) or major depression (n = 11) and in matched normal control subjects (n = 11), using the 133xenon inhalation method, under eyes-closed, resting conditions. The three groups were equivalent in global CBF. Both patient groups showed significant reductions of rCBF in anterior cortical areas and reduction of the normal anteroposterior gradient. In addition, there was evidence of abnormal, albeit similar, patterns of flow lateralization on a regional basis in both clinical groups compared with normal subjects. An exploratory analysis revealed preliminary evidence of rCBF differences between the clinical groups, localized to the inferior frontal cortex. Otherwise, the evidence in this study suggests that young adult manic and depressed patients are predominantly similar in cortical rCBF parameters.

Cerebral Blood Flow Reactivity to Changes in Carbon Dioxide Calculated Using End-Tidal versus Arterial Tensions

We retrospectively examined arterial and endtidal estimations of CO2 tension used to calculate cerebrovascular reactivity in 68 anesthetized patients. CBF was measured using the intravenous 133Xe technique at mean ± SD Paco2 values of 28.2 ± 5.2 and 38.8 ± 4.8 mm Hg. The correlation between all Paco2 and end-tidal Pco2 (Petco2) values was y = 0.85x −0.49 (r = 0.93, p = 0.0001). There was a moderate correlation between age and the difference between Paco2 and Petco2 (y = 0.11x + 0.79; r = 0.73, p = 0.0001). Cerebrovascular reactivity to changes in CO2 (ml 100 g−1 min−1 mm Hg−1) was similar (p = 0.358) when calculated by using either Paco2 (1.9 ± 0.8) or Petco2 (1.8 ± 0.8) and highly correlated (y = 0.86x + 0.23; r = 0.91, p = 0.0001). The CBF response to changes in CO2 tension can be reliably estimated from noninvasive measurement of Petco2.