Faculty Bibliography

The carnage wrought by systemic racism through social, judicial, and health injustices compels us to work towards a system that is fair and just for patients and colleagues. The evidence that change is necessary in medicine is hiding in plain sight in literature, oral histories, medical records, and news media. Notwithstanding this evidence, changing a system 400 years in the making will require a major paradigm shift. One of the many ways our department sought to catalyze such a shift was through media consumption, reflection, and discussion. Reading and studying literature and humanities in medicine can awaken our consciousness by making medicine an embodied practice that considers the totality of patients' lives in ways that a disembodied, purely scientific approach cannot. Thus, we started a Racial and Social Justice Book Club to normalize discussions about racial and social (in)justice and examine everything through an anti-racist lens. Herein, we describe our experiences in the inaugural year of the Book Club, a space to lend credence and dignity to the voices, experiences, and stories of folks who have long been marginalized by power structures in America, including medicine.

PURPOSE/OBJECTIVE:Prediction of clinical outcomes in patients with primary central nervous system lymphoma (PCNSL) is important for optimization of treatment planning. Quantitative imaging biomarkers for PCNSL have not yet been established. This study evaluated the prognostic value of pretreatment dynamic contrast-enhanced MRI and diffusion-weighted imaging for progression-free survival (PFS) in patients with PCNSL. METHODS:), and apparent diffusion coefficient. Patients were divided into short and long PFS groups based on median PFS. Imaging and clinical variables were correlated with PFS. RESULTS: CONCLUSIONS:derived from dynamic contrast-enhanced MRI may be novel prognostic quantitative imaging biomarkers of progression-free survival in patients with PCNSL. These data should be prospectively validated in larger patient cohorts.

BACKGROUND AND PURPOSE: Glioblastoma and primary CNS lymphoma dictate different neurosurgical strategies; it is critical to distinguish them preoperatively. However, current imaging modalities do not effectively differentiate them. We aimed to examine the use of DWI and T1-weighted dynamic contrast-enhanced-MR imaging as potential discriminative tools. MATERIALS AND METHODS: We retrospectively reviewed 18 patients with primary CNS lymphoma and 36 matched patients with glioblastoma with pretreatment DWI and dynamic contrast-enhanced-MR imaging. VOIs were drawn around the tumor on contrast-enhanced T1WI and FLAIR images; these images were transferred onto coregistered ADC maps to obtain the ADC and onto dynamic contrast-enhanced perfusion maps to obtain the plasma volume and permeability transfer constant. Histogram analysis was performed to determine the mean and relative ADCmean and relative 90th percentile values for plasma volume and the permeability transfer constant. Nonparametric tests were used to assess differences, and receiver operating characteristic analysis was performed for optimal threshold calculations. RESULTS: The enhancing component of primary CNS lymphoma was found to have significantly lower ADCmean (1.1 x 10-3 versus 1.4 x 10-3; P < .001) and relative ADCmean (1.5 versus 1.9; P < .001) and relative 90th percentile values for plasma volume (3.7 versus 5.0; P < .05) than the enhancing component of glioblastoma, but not significantly different relative 90th percentile values for the permeability transfer constant (5.4 versus 4.4; P = .83). The nonenhancing portions of glioblastoma and primary CNS lymphoma did not differ in these parameters. On the basis of receiver operating characteristic analysis, mean ADC provided the best threshold (area under the curve = 0.83) to distinguish primary CNS lymphoma from glioblastoma, which was not improved with normalized ADC or the addition of perfusion parameters. CONCLUSIONS: ADC was superior to dynamic contrast-enhanced-MR imaging perfusion, alone or in combination, in differentiating primary CNS lymphoma from glioblastoma.

BACKGROUND:Genome-wide association studies have revealed a link between essential tremor (ET) and the gene SLC1A2, which encodes excitatory amino acid transporter type 2 (EAAT2). We explored EAAT biology in ET by quantifying EAAT2 and EAAT1 levels in the cerebellar dentate nucleus, and expanded our prior analysis of EAAT2 levels in the cerebellar cortex. OBJECTIVE:To quantify EAAT2 and EAAT1 levels in the cerebellar dentate nucleus and cerebellar cortex of ET cases vs. METHODS:We used immunohistochemistry to quantify EAAT2 and EAAT1 levels in the dentate nucleus of a discovery cohort of 16 ET cases and 16 controls. Furthermore, we quantified EAAT2 levels in the dentate nucleus in a replicate cohort (61 ET cases, 25 controls). Cortical EAAT2 levels in all 77 ET cases and 41 controls were quantified. RESULTS:In the discovery cohort, dentate EAAT2 levels were 1.5-fold higher in 16 ET cases vs. 16 controls (p = 0.007), but EAAT1 levels did not differ significantly (p = 0.279). Dentate EAAT2 levels were 1.3-fold higher in 61 ET cases vs. 25 controls in the replicate cohort (p = 0.022). Cerebellar cortical EAAT2 levels were 20% and 40% lower in ET cases vs. controls in the discovery and the replicate cohorts (respective p values = 0.045 and < 0.001). CONCLUSION:EAAT2 expression is enhanced in the ET dentate nucleus, in contrast to differentially reduced EAAT2 levels in the ET cerebellar cortex, which might reflect a compensatory mechanism to maintain excitation-inhibition balance in cerebellar nuclei.

Based on accumulating post-mortem evidence of abnormalities in Purkinje cell biology in essential tremor, we hypothesized that regressive changes in dendritic morphology would be apparent in the Purkinje cell population in essential tremor cases versus age-matched controls. Cerebellar cortical tissue from 27 cases with essential tremor and 27 age-matched control subjects was processed by the Golgi-Kopsch method. Purkinje cell dendritic anatomy was quantified using a Neurolucida microscopic system interfaced with a motorized stage. In all measures, essential tremor cases demonstrated significant reductions in dendritic complexity compared with controls. Median values in essential tremor cases versus controls were: 5712.1 versus 10 403.2 µm (total dendrite length, P=0.01), 465.9 versus 592.5 µm (branch length, P=0.01), 22.5 versus 29.0 (maximum branch order, P=0.001), and 165.3 versus 311.7 (number of terminations, P=0.008). Furthermore, the dendritic spine density was reduced in essential tremor cases (medians=0.82 versus 1.02 µm(-1), P=0.03). Our demonstration of regressive changes in Purkinje cell dendritic architecture and spines in essential tremor relative to control brains provides additional evidence of a pervasive abnormality of Purkinje cell biology in this disease, which affects multiple neuronal cellular compartments including their axon, cell body, dendrites and spines.

Genetic polymorphisms in Solute carrier family 1 (glial high affinity glutamate transporter), member 2 (SLC1A2) have been linked with essential tremor. SLC1A2 encodes excitatory amino acid transporter type 2 (EAAT2), which clears glutamate from the synaptic cleft. One postulated mechanism for essential tremor is the over-excitation of glutamatergic olivo-cerebellar climbing fibers, leading to excitotoxic death of Purkinje cells. Other glutamatergic excitatory signals are transmitted to Purkinje cells via parallel fibers of cerebellar granule neurons. Therefore, the expression level of glutamate transporters could be important in essential tremor pathogenesis. Using Western blotting, we compared the expression levels of the two main glutamate transporters in the cerebellar cortex, EAAT1 and EAAT2, in postmortem tissue from 16 essential tremor cases and 13 age-matched controls. We also studied the localization of EAAT1 and EAAT2 using immunohistochemistry in 10 essential tremor cases and 12 controls. EAAT1 protein levels were similar in cases and controls (1.12 ± 0.83 vs. 1.01 ± 0.69, p =0.71) whereas EAAT2 protein levels in essential tremor cases were only 1/3 of that in controls (0.35 ± 0.23 vs. 1.00 ± 0.62, p < 0.01). Interestingly, EAAT2, but not EAAT1, was expressed in astrocytic processes surrounding the Purkinje cell axon initial segment, a region of previously observed pathological changes in essential tremor. Our main finding, a significant reduction in cerebellar cortical EAAT2 protein levels in essential tremor, suggests that Purkinje cells in essential tremor might be more vulnerable to excitotoxic damage than those of controls.

BACKGROUND:It would be useful to identify additional postmortem markers of Purkinje cell loss in essential tremor (ET). In hereditary cerebellar ataxia, Purkinje cell loss has been reported to result in a secondary increase in the density of the remaining cell populations in the cerebellar molecular layer. However, this phenomenon has not been studied in ET. We quantified cerebellar molecular layer cellular density in 15 ET cases, 15 controls, and 7 spinocerebellar ataxia (SCA) cases (2:2:1 ratio). METHODS:A standard neocerebellar tissue block was stained with Luxol fast blue Hematoxylin & Eosin. Within 5 selected fields, cell soma (e.g., stellate, basket, and glial cell bodies) were counted. Cellular density was the number of cells/cm(2). RESULTS:The Purkinje cell count differed across the three groups (p < 0.001), with the highest counts in controls, intermediate counts in ET cases and lowest counts in SCA cases. ET cases and controls had similar molecular layer cellular density (p = 0.79) but SCA cases had higher values than both groups (p < 0.01). A robust inverse correlation between Purkinje cell count and molecular layer cellular density (i.e., brains with more Purkinje cell loss had higher molecular layer cellular density), observed in SCA and controls (r = -0.55, p = 0.008), was not observed in ET cases. DISCUSSION/CONCLUSIONS:Although Purkinje cell counts were reduced in ET cases compared to controls, an increase in molecular layer cellular density was not evident in ET. The increase in molecular layer cellular density, observed in SCA cases, may require a more marked loss of PCs than occurs in ET.

Although the number of postmortem studies in essential tremor (ET) has grown in recent years, clinical-pathological correlations remain limited. We are unaware of a study that has assessed whether the pathological changes in ET, if asymmetric, lateralize to the cerebellar hemisphere that is ipsilateral to the arm with more severe action tremor, as one would predict if the lesions were tremor producing. We compared postmortem changes in the right vs. left cerebellar hemispheres in ET and examined how these correlated with asymmetry of tremor on neurological examination. Action tremor in each arm was quantified using a reliable and valid clinical rating scale. Cases were divided into three clinical groups: tremor more severe on right, tremor more severe on left, and tremor symmetric. Calbindin D28k immunohistochemistry was performed on 100 μm vibrotome sections from a standard tissue block of both right and left neocerebellums to quantify Purkinje cell linear density, torpedo counts, and a group of previously described changes in Purkinje cell axonal shape (thickened axonal profiles) and connectivity (axon recurrent collaterals, axonal branching, terminal axonal sprouting, arciform axons, extent of recurrent collateral plexus). ET cases were divided into three postmortem groups: findings greatest on right, findings greatest on left, and findings symmetric. In 18 (72.0 %) of 25 ET cases, clinical and pathological features were concordant (i.e., both clinically and pathologically right-predominant (one case), both clinically and pathologically left-predominant (five cases), or both clinically and pathologically symmetric (12 cases), p = 0.007). In the remaining seven (28.0 %) ET cases, clinical and pathological data were not concordant, and in none were they completely discordant (i.e., tremor was more severe on the right, and postmortem cerebellar changes were paradoxically more severe on the left or vice versa). Among the seven ET cases with >20 % side-to-side difference in tremor severity, six cases (85.7 %) had the expected pathological asymmetry, with quantified postmortem cerebellar changes more marked ipsilateral to the more clinically affected side. We also created continuous measures of asymmetry. For the entire sample, there was a positive correlation between the clinical asymmetry index and the pathological asymmetry index = 0.52, p = 0.01 (i.e., the right-left difference in clinical asymmetry was correlated with the right-left difference in postmortem changes). For the seven ET cases with clear clinical asymmetry, the correlation was even more robust (r = 0.78, p = 0.039). Clinical-pathological correlations are important in terms of understanding the significance of observed pathological changes. The correlation between clinical laterality or symmetry of tremor and pathological changes in the majority of ET cases provides additional evidence that the pathological changes in the cerebellum in ET are of patho-mechanistic importance.

BACKGROUND:In addition to tremor, patients with essential tremor (ET) may exhibit non-motor features, including a range of cognitive deficits. Several prospective, population-based epidemiological studies have reported an association between ET and incident dementia, especially Alzheimer's disease (AD). Moreover, in a brain repository-based study, a larger than expected proportion of ET patients also developed pathological changes characteristic of progressive supranuclear palsy, further suggesting a link between ET and tau pathology. METHODS:We selected a group of ET patients that were free of dementia clinically and without AD on postmortem examination. Our hypothesis was that neuronal tauopathic burden would be higher in the brains of these ET patients compared to controls. We compared Braak stage for neuronal tangles and Consortium to Establish a Registry for Alzheimer's Disease (CERAD) scores for neuritic plaques in the two groups. RESULTS:The two groups were similar in age (82.6 ± 6.0 vs. 80.4 ± 8.1, p = 0.22). The 40 ET patients had a higher Braak neurofibrillary stage than 32 controls (means: 2.2 ± 1.2 vs. 1.2 ± 1.1; medians: 2.0 vs. 1.0, p < 0.001). Meanwhile, CERAD scores for neuritic plaques were similar in patients and controls (means: 0.6 ± 0.9 vs. 0.5 ± 0.6; medians: 0.0 vs. 0.0, p = 0.83). CONCLUSION/CONCLUSIONS:While ET itself is not a tauopathy (i.e., a neurodegenerative disorder among whose main features are accumulation of hyperphosphorylated tau protein), ET may predispose individuals to accumulate more widespread cellular tau aggregates, and thus tau could play a central role in the cognitive impairment that can accompany ET.

Brain donation is an unusual pursuit. It is an aspect of medical research that the lay public may not necessarily know much about. In 2003, to learn more about the underlying pathophysiology of essential tremor (ET), we established the Essential Tremor Brain Repository (ETCBR) at Columbia University, a research effort whose purpose was to enhance understanding of the ET brain (NIH R01 NS042859, Elan D. Louis, principal investigator). Now, at a 10-year point in this endeavor, we pause for a moment to reflect, distill, and share. Why? From the moment potential brain donors first inquire about the possibility of donating their brains to science, all the way through the long course of postmortem brain tissue analyses, health professionals are involved. They experience a range of emotions, thoughts, and reactions, yet we are unaware of any literature that has attempted to capture and record the human elements of this process.