Thomas S. Harris

Tc-99m Hmpao Spect in the Differential Diagnosis of the Dementias With Histopathologic Confirmation

Purpose: The purpose of this study is to determine the value of Tc-99m HMPAO SPECT in the diagnosis of the dementias, with particular reference to Alzheimer disease. Materials and Methods: Tc-99m HMPAO was used with a 3-camera scanner to produce 5 sets of sectional images of the brain. Diagnosis was made by a physician blinded to the clinical diagnosis. Results in 49 subjects were ultimately compared with neuropathologic study of the brain at autopsy. Results: Sensitivity = 86.7% (68.4–95.6%, 95% confidence interval [CI]), specificity = 89.5% (65.5–98.2% CI), positive predictive value = 92.9% (75.0–98.8% CI), negative predictive value = 81% (57.4–93.7% CI), accuracy = 87.8% (74.5–94.9% CI), likelihood ratio = 8.23% (7.09–9.57% CI). Conclusions: Comparison is made with several other SPECT and PET series with histopathologic correlation. Brain blood flow SPECT is useful in the diagnosis and differential diagnosis of the dementias.

Altered Neural Cholinergic Receptor Systems in Cocaine-Addicted Subjects

Changes in the brains cholinergic receptor systems underlie several neuropsychiatric disorders, including Alzheimers disease, schizophrenia, and depression. An emerging preclinical literature also reveals that acetylcoholine may have an important function in addictive processes, including reward, learning, and memory. This study was designed to assess alterations in cholinergic receptor systems in limbic regions of abstinent cocaine-addicted subjects compared with healthy controls. On three separate days, 23 1- to 6-week abstinent, cocaine- (and mostly nicotine-) addicted subjects and 22 sex-, age-, and race-matched control subjects were administered the muscarinic and nicotinic cholinergic agonist physostigmine, the muscarinic antagonist scopolamine, and saline. Regional cerebral blood flow (rCBF) after each infusion was determined using single photon emission-computed tomography. Both cholinergic probes induced rCBF changes (p<0.005) in relatively distinct, cholinergic-rich, limbic brain regions. After physostigmine, cocaine-addicted subjects showed altered rCBF, relative to controls, in limbic regions, including the left hippocampus, left amygdala, and right insula. Group differences in the right dorsolateral prefrontal cortex, posterior cingulate, and middle temporal gyrus were also evident. Scopolamine also revealed group differences in the left hippocampus and right insula as well as the posterior cingulate and middle temporal gyrus. Cocaine addicted and controls differ in their subcortical, limbic, and cortical response to cholinergic probes in areas relevant to craving, learning, and memory. Cholinergic systems may offer a pharmacologic target for cocaine addiction treatment.

Sex Differences in Medial and Lateral Orbitofrontal Cortex Hypoperfusion in Cocaine-Dependent Men and Women

BACKGROUND The different clinical trajectories of cocaine-dependent men and women may be a consequence of distinct neurobiological substrates. Hypoperfusion of the orbitofrontal cortex (OFC) has previously been reported in individuals addicted to cocaine and has been posited as a biological mediator of relapse due to impulsivity or impaired decision making. OBJECTIVE This study assessed regional cerebral blood flow (rCBF) between abstinent cocaine-dependent men and women and sex-matched healthy controls. METHODS Cocaine-dependent subjects were abstinent from cocaine for 11 to 28 days and had no other major mental health or substance use disorders. rCBF was assessed with single photon emission computed tomography after administration of a placebo saline infusion. A resting scan was also obtained in a subset of cocaine-dependent and control men. RESULTS In the 35 cocaine-dependent and 37 healthy control subjects examined, a sex-by-group effect was observed for the left lateral (P=0.001), right lateral (P=0.002), and medial (P<0.02) OFC. Cocaine-dependent men demonstrated significantly lower right and left lateral, but not medial, OFC rCBF compared with sex-matched healthy controls after placebo infusion (P<or=0.001). Similar bilateral OFC decreases were observed in male cocaine-dependent subjects at rest. In contrast, cocaine-dependent women showed lower rCBF in the medial, but not lateral, OFC relative to sex-matched healthy controls after placebo infusion (P<0.01). Male cocaine-dependent subjects also showed decreased rCBF (P<0.01) in the bilateral anterolateral temporal cortex and anterior cingulate, whereas decreased rCBF was observed in female cocaine-dependent subjects in the bilateral superior frontal gyri. Large and diffuse areas of increased rCBF were observed after placebo infusion in cocaine-dependent men, but not in women, relative to sex-matched healthy controls. CONCLUSIONS rCBF appears to be reduced in the bilateral OFC in cocaine-dependent men and in the medial OFC in cocaine-dependent women. Sex differences in the medial and lateral OFC rCBF may be relevant to understanding relapse characteristics differentiating men and women addicted to cocaine.

Activation of the mesostriatal reward pathway with exposure to ultraviolet radiation (UVR) vs. sham UVR in frequent tanners: a pilot study

Frequent and excessive tanning persists despite a growing understanding of its associated morbidity and mortality, suggesting that ultraviolet radiation may impart rewarding effects beyond the assumed cosmetic benefits. To empirically measure putative centrally rewarding properties of ultraviolet radiation (UVR), we assessed the effects of a commercially available tanning bed upon regional cerebral blood flow (rCBF), a measure of brain activity, using single‐photon emission computed tomography (SPECT). Seven frequent salon bed tanners were placed under a UVA/UVB tanning light during two sessions; one session with UVR and the other with filtered UVR (sham UVR). Session order was randomized and subjects were blinded to study order. During the UVR session, relative to sham UVR session, subjects demonstrated a relative increase in rCBF of the dorsal striatum, anterior insula and medial orbitofrontal cortex, brain regions associated with the experience of reward. These changes were accompanied by a decrease in the subjective desire to tan. These findings suggest that UVR may have centrally rewarding properties that encourage excessive tanning.

Convergence of connected language and SPECT in variants of frontotemporal lobar degeneration.

The characterization of frontotemporal lobar degeneration (FTLD) is complicated and not widely recognized. Connected language measures (ie, discourse) and functional neuroimaging may advance knowledge specifying early distinctions among frontal dementias. The present study examined the correspondence of discourse measures with (1) clinical diagnosis and (2) single photon emission computed tomography (SPECT) imaging. Nineteen subjects were selected from Alzheimers Disease Center (ADC) participants if they were diagnosed with early-stage frontotemporal lobar degeneration and also underwent single photon emission computed tomography and discourse evaluation. First, clinical diagnoses given by specialists at an Alzheimers Disease Center were compared with the discourse-based diagnostic profiles. Secondly, compromised brain regions that were predicted from discourse profiles were compared with SPECT findings. Results revealed a significant correspondence between the ADC diagnosis and the discourse-based diagnoses. Also, the discourse profiles across frontotemporal lobar degeneration subtypes were consistently associated with distinctive patterns of SPECT hypometabolism in the right frontal, left frontal, or left temporal lobes. These findings suggest that discourse methods may be systematized to provide an efficient adjunct measure beyond the traditional word and sentential level measures. Objectifying complex language performance may contribute to early detection and differentiation among frontotemporal lobar degeneration variants because consensus in the literature states that language is a core disturbance of frontotemporal lobar degeneration.

Gender differences in limbic responsiveness, by SPECT, following a pharmacologic challenge in healthy subjects

Limbic system functioning is integral to the control and modulation of affect, motivation, reward, and memory. Neuropsychiatric disturbances involving disruptions in these cognitive and emotional dimensions exhibit different prevalence rates for men and women. Gender-specific differences in this integrated brain area may therefore be important in understanding both normal behavioral functioning and the etiologic underpinnings of neuropsychiatric disorders. To further explore such differences in limbic system function, we assessed regional cerebral blood flow, by SPECT, in men and women following the administration of procaine. Procaine is a local anesthetic that preferentially stimulates limbic structures. Psychiatrically and medically healthy, age-matched women (n = 15, 33.2 +/- 6.9 years) and men (n = 15, 32.8 +/- 6.9 years) were administered 1.38 mg/kg procaine or saline intravenously in two separate sessions. Using voxel-based analyses (P < 0.001), males significantly activated the bilateral insular cortex following procaine, whereas females more strongly activated the bilateral anterior and mesial temporal cortex. Both groups demonstrated significant anterior cingulate activation. Subjective responses to procaine did not significantly differ between the men and women. To our knowledge, this is the first report demonstrating gender-specific responses in limbic activation following a pharmacologic challenge. These findings suggest that men and women can activate different limbic structures following the same provocative pharmacologic stimulus, despite sharing a similar subjective experience. Studies assessing pharmacologic challenges of limbic system structures should consider gender as a critical variable in assessing biologic responsiveness.

Pharmacological Enhancement of Aural Habilitation in Adult Cochlear Implant Users

Objective: The purpose of this report was to examine the preliminary data collected under a larger on-going feasibility study conducted with cochlear implant patients exploring the potential benefit of pharmacologically-enhanced aural rehabilitation therapy as a means of increasing speech tracking skills. Design: Eight adult cochlear implant participants participated in a randomized, double-blind study and received either 10 mg d-amphetamine (Treatment group, N = 4) or a placebo (Placebo group, N = 4) 60 minutes prior to a 1.5 hour intensive aural rehabilitation session occurring twice a week for two months. Treatment consisted of a multi-step rehabilitation program individualized for each participant to develop auditory-only speech tracking skills. Prior to and at the conclusion of the therapy sessions, SPECT rCBF imaging and speech tracking assessments were conducted. Results: Speech tracking scores of the placebo and treatment groups were similar before the aural habilitation intervention. In the placebo group, speech tracking performance increased 13.5% for visual plus auditory and auditory only presentations as a function of aural habilitation alone. The 10 mg d-amphetamine-facilitated program resulted in minimal increases in visual plus auditory tracking scores (2%) but led to a 43% increase for auditory-only speech tracking. Regional cerebral blood flow measures indicated no substantial improvement of brain activation in the placebo group while both the extent and magnitude of primary and associative auditory cortex activations increased significantly with the pharmacologically enhanced treatment program. Conclusions: These data support previous studies indicating an accelerated acquisition of speech and language abilities in stroke patients receiving traditional speech therapy in combination with d-amphetamine. Data, however, are preliminary and further study is warranted.

Regional cerebral blood flow in female cocaine-addicted subjects following limbic activation.

BACKGROUND Cocaine dependence follows a different disease course in men and women, possibly as a consequence of sex-specific neurobiologic responses to chronic cocaine use. We have previously reported that male cocaine-dependent subjects demonstrate a significantly different limbic response to the limbic-stimulus procaine, as measured by regional cerebral blood flow (rCBF), compared with male controls. In this study, we assessed the limbic rCBF response to procaine in female cocaine-addicted subjects (n=10) and female controls (n=10). METHODS Subjects were administered 1.38 mg/kg procaine or saline intravenously in two separate sessions. Single photon emission computed tomography (SPECT) was used to compare the rCBF response to procaine. RESULTS Female cocaine-dependent subjects demonstrate a markedly muted, and distinctly different, limbic response to procaine compared with matched healthy controls. CONCLUSIONS The rCBF response to procaine in female cocaine-dependent subjects suggests significant CNS differences compared with non-addicted female controls. Coupled with findings previously observed in male cocaine-dependent subjects, these biologic differences suggest that both male and female subjects experience alterations in limbic responsiveness following the chronic use of cocaine.

Amyloid burden and sleep blood pressure in amnestic mild cognitive impairment

Objective: To determine whether cortical β-amyloid (Aβ) deposition is associated with circadian blood pressure (BP) profiles and dynamic cerebral blood flow (CBF) regulation in patients with amnestic mild cognitive impairment (aMCI). Methods: Forty participants with aMCI were included in this study. Cortical Aβ depositions were measured by 18F-florbetapir PET and expressed as the standardized uptake value ratio (SUVR) relative to the cerebellum. Circadian BP profiles were measured by 24-hour ambulatory monitoring during awake and sleep periods. The dipping status of sleep BP (i.e., the percent changes from the awake BP) was calculated and dichotomized into the dipper (≥10%) and nondipper (<10%) groups. Dynamic CBF regulation was assessed by a transfer function analysis between beat-to-beat changes in BP and CBF velocity measured from the middle cerebral artery during a repeated sit-stand maneuver. Results: Age was positively correlated with a greater Aβ deposition in the posterior cingulate, precuneus, and mean cortex. Accounting for the age effect, attenuated reductions in sleep systolic BP were associated with higher levels of posterior cingulate SUVR. Consistently, the nondippers exhibited a higher SUVR in the posterior cingulate than the dippers. Transfer function gain between changes in BP and CBF velocity was diminished in the nondippers, and moreover those individuals with a lower gain exhibited a higher SUVR in the posterior cingulate. Conclusions: Attenuated reductions in sleep BP are associated with a greater Aβ burden in the posterior cingulate and altered dynamic CBF regulation in patients with aMCI.

Caudolateral orbitofrontal regional cerebral blood flow is decreased in abstinent cocaine-addicted subjects in two separate cohorts

The orbitofrontal cortex (OFC) is crucial for the inhibition of extraneous stimuli, evaluation of aversive information and emotional regulation—all behaviors impaired in cocaine addiction. Previous studies suggest that cocaine‐addicted subjects have decreased basal activity in the OFC. In this study, we examined regional cerebral blood flow (rCBF) during a saline infusion in two independent populations of abstinent cocaine‐ (and mostly nicotine‐) addicted (n = 33 and 26) and healthy control (n = 35 and 20) men and women. Isolated rCBF decreases (P < 0.001) were observed in the left caudolateral OFC, as well as left superior temporal cortex, in cocaine‐addicted subjects relative to controls in both cohorts and bilaterally in the combined cohort. An anatomically defined region of the caudolateral OFC showed similar findings and were evident in both male and female addicted subjects. The reliability of these findings across two cohorts reveals a functional disruption in the lateral OFC, a brain region implicated in the evaluation of behavior‐terminating stimuli. This may contribute to an addicted individuals persistent drug use despite negative consequences.