Neuropsychological, Psychiatric, and Functional Correlates of Clinical Trial Enrollment.

Screen failure rates in Alzheimer's disease (AD) clinical trial research are unsustainable, with participant recruitment being a top barrier to AD research progress. The purpose of this project was to understand the neuropsychological, psychiatric, and functional features of individuals who failed screening measures for AD trials. Previously collected clinical data from 38 patients (aged 50-83) screened for a specific industry-sponsored clinical trial of MCI/early AD (Biogen 221AD302, [EMERGE]) were analyzed to identify predictors of AD trial screen pass/fail status. Worse performance on non-memory cognitive domains like crystalized knowledge, executive functioning, and attention, and higher self-reported anxiety, was associated with failing the screening visit for the EMERGE AD clinical trial, whereas we were not able to detect a relationship between screening status and memory performance, self-reported depression, or self-reported daily functioning. By identifying predictors of AD trial screen passing/failure, this research may influence decision-making about which patients are most likely to successfully enroll in a trial, thereby potentially lowering participant burden, maximizing study resources, and reducing costs.

Designing Trials of Disease Modifying Agents for Early and Preclinical Alzheimer's Disease Intervention: What Evidence is Meaningful to Patients, Providers, and Payers?

BACKGROUND: Drug development for disease modifying agents in Alzheimer's disease (AD) is focused increasingly on targeting underlying pathology in very early stages of AD or in cognitively normal patients at elevated risk of developing dementia due to Alzheimer's. Very early interventional studies of this type have many uncertainties, including whether they can provide the clinical results that payers, providers, and patients will wish to see for decisions. This paper describes an initiative to create greater transparency for researchers to anticipate these decision needs. OBJECTIVE: To create multi-stakeholder-vetted recommendations for the design of studies in later phases of drug development to evaluate the ability of disease modifying agents to delay or prevent the onset of dementia due to Alzheimer's disease (AD). DESIGN: A multi-stakeholder expert workgroup and overseeing steering group were convened to discuss current advances in early interventional clinical trial design and the evidence needs of patients, providers, and payers. Eight teleconferences and one in-person all-day meeting were held. Meetings were recorded and summary notes prepared between sessions. Final conclusions were consolidated by the project team with the workgroup Chair based on these discussions and were reviewed by group members. SETTING: The in-person meeting was held in Baltimore, MD. PARTICIPANTS: In total, 36 stakeholders representing life sciences industry, payers or health technology assessors, patient advocates and research advocacy organizations, regulators, clinical experts and academic or NIH researchers. INTERVENTION: N/A. MEASUREMENTS: N/A. RESULTS: Certain aspects of clinical trial design were deemed important to address stakeholder decision needs for future Alzheimer's prevention drugs even as the field rapidly progresses. These include the need for more robust behavioral and psychological outcome data in early symptomatic disease and the need to update activities of daily living measures to include "digital independence." CONCLUSIONS: Amyloid, tau, and biomarkers of neurodegeneration should be included in trials and studied in relation to other early measures of change meaningful to individuals with AD, their families, and health plans. These measures include early sensitive changes in behavioral and psychological measures and ability to navigate the contemporary digital landscape. Additional work is needed to generate more robust behavioral and psychological outcome data in early symptomatic disease, and to generate multi-stakeholder consensus on early measures of change and magnitudes of change that will be meaningful to patients, providers, and payers.

Increased Functional Connectivity After Listening to Favored Music in Adults With Alzheimer Dementia.

BACKGROUND: Personalized music programs have been proposed as an adjunct therapy for patients with Alzheimer disease related dementia, and multicenter trials have now demonstrated improvements in agitation, anxiety, and behavioral symptoms. Underlying neurophysiological mechanisms for these effects remain unclear. METHODS: We examined 17 individuals with a clinical diagnosis of Alzheimer disease related dementia using functional MRI following a training period in a personalized music listening program. RESULTS: We find that participants listening to preferred music show specific activation of the supplementary motor area, a region that has been associated with memory for familiar music that is typically spared in early Alzheimer disease. We also find widespread increases in functional connectivity in corticocortical and corticocerebellar networks following presentation of preferred musical stimuli, suggesting a transient effect on brain function. CONCLUSIONS: Findings support a mechanism whereby attentional network activation in the brain's salience network may lead to improvements in brain network synchronization.

Short-Term Practice Effects and Amyloid Deposition: Providing Information Above and Beyond Baseline Cognition.

BACKGROUND: Practice effects, which are improvements in cognitive test scores due to repeated exposure to testing materials, may provide information about Alzheimer's disease pathology, which could be useful for clinical trials enrichment. OBJECTIVES: The current study sought to add to the limited literature on short-term practice effects on cognitive tests and their relationship to amyloid deposition on neuroimaging. PARTICIPANTS: Twenty-seven, non-demented older adults (9 cognitively intact, 18 with mild cognitive impairment) received amyloid imaging with 18F-Flutemetamol, and two cognitive testing sessions across one week to determine practice effects. RESULTS: A composite measure of 18F-Flutemetamol uptake correlated significantly with all seven cognitive tests scores on the baseline battery (r's = -0.61 - 0.59, all p's<0.05), with higher uptake indicating poorer cognition. Practice effects significantly added to the relationship (above and beyond the baseline associations) with 18F-Flutemetamol uptake on 4 of the 7 cognitive test scores (partial r's = -0.45 - 0.44, p's<0.05), with higher uptake indicating poorer practice effects. The odds ratio of being "amyloid positive" was 13.5 times higher in individuals with low practice effects compared to high practice effects. CONCLUSIONS: Short-term practice effects over one week may be predictive of progressive dementia and serve as an affordable screening tool to enrich samples for preventative clinical trials in Alzheimer's disease.

Dopamine agonist treatment of schizophrenia with N-propylnorapomorphine.

We administered N-propylnorapomorphine, a potent aporphine-family dopamine (DA) agonist, to schizophrenic patients with active psychotic symptoms. After acute administration a significant antipsychotic action of N-propylnorapomorphine, maximal at an oral dose of 19 mg, was noted. The antipsychotic action predominated in subjects with neuroleptic-responsive symptoms, not in neuroleptic-nonresponders. However, when N-propylnorapomorphine was administered on a subchronic dosage schedule, no antipsychotic effect occurred. These observations suggest a rapid-onset tolerance phenomenon of psychosis to N-propylnorapomorphine and are consistent with results from preclinical experiments. These data support the idea that the acute antipsychotic response of DA agonists is mediated by the DA autoreceptor but fail to provide evidence for the potential clinical usefulness of this treatment approach.

Status of management effort in 153 marine protected areas across the English Channel.

A conceptual framework was developed for assessing the sub-level of protection in 185 multiple-use marine protected areas (MPAs) in the English Channel through a survey on management effort. Data were retrieved from 153 MPAs: 4.56% were assigned low management effort, 83.70% were assigned medium management effort, and 11.76% were assigned high management effort. Overall, French MPAs performed better in terms of management effort than English MPAs and lack of consistency in ratings by different management bodies in England was found. Lack of correlation between management effort and conservation status within an available subset of 13 MPAs suggests that management may not be as influential a factor for the effective conservation of MPAs, especially in marine environments under heavy human pressure such as the English Channel. It is suggested that MPAs in such areas may therefore require an upgrade of their legal level of protection to be effective.

Adiponectin and Insulin in Gray Seals during Suckling and Fasting: Relationship with Nutritional State and Body Mass during Nursing in Mothers and Pups.

Animals that fast during breeding and/or development, such as phocids, must regulate energy balance carefully to maximize reproductive fitness and survival probability. Adiponectin, produced by adipose tissue, contributes to metabolic regulation by modulating sensitivity to insulin, increasing fatty acid oxidation by liver and muscle, and promoting adipogenesis and lipid storage in fat tissue. We tested the hypotheses that (1) circulating adiponectin, insulin, or relative adiponectin gene expression is related to nutritional state, body mass, and mass gain in wild gray seal pups; (2) plasma adiponectin or insulin is related to maternal lactation duration, body mass, percentage milk fat, or free fatty acid (FFA) concentration; and (3) plasma adiponectin and insulin are correlated with circulating FFA in females and pups. In pups, plasma adiponectin decreased during suckling (linear mixed-effects model [LME]: T = 4.49; P < 0.001) and the early postweaning fast (LME: T = 3.39; P = 0.004). In contrast, their blubber adiponectin gene expression was higher during the early postweaning fast than early in suckling (LME: T = 2.11; P = 0.046). Insulin levels were significantly higher in early (LME: T = 3.52; P = 0.004) and late (LME: T = 6.99; P < 0.001) suckling than in fasting and, given the effect of nutritional state, were also positively related to body mass (LME: T = 3.58; P = 0.004). Adiponectin and insulin levels did not change during lactation and were unrelated to milk FFA or percentage milk fat in adult females. Our data suggest that adiponectin, in conjunction with insulin, may facilitate fat storage in seals and is likely to be particularly important in the development of blubber reserves in pups.

The effect of diazepam sedation on cerebral glucose metabolism in Alzheimer's disease as measured using positron emission tomography.

The effect of sedation induced by intravenous diazepam on cerebral glucose metabolic activity was examined with [18F]2-fluoro-2-deoxy-D-glucose (FDG) and positron emission tomography (PET) in five patients with probable Alzheimer's disease. Each subject was studied on 2 separate days: on one occasion at rest with eyes patched and ears open, and on the second when sedated with intravenous diazepam titrated to maintain stage II sleep by clinical and EEG criteria. Similar patterns of glucose uptake were observed in both the presence and the absence of sedation, but overall glucose utilization was depressed an average of 20% and was closely correlated with the amount of diazepam administered prior to the injection of FDG. The predominant temporoparietal hypometabolism and relative sparing of frontal metabolism observed in this disease are therefore not explained by differences in anxiety or activity level in this patient group. Utilization of diazepam sedation for PET study appears to be safe and may permit the study of patients otherwise unable to cooperate with FDG-PET procedures.

Psychiatric disorders in patients with cerebrotendinous xanthomatosis.

Cerebrotendinous xanthomatosis is a familial recessive disorder. Patients with the disorder present with tendon xanthomas, juvenile cataracts, dementia, and pyramidal and cerebellar abnormalities but have normal plasma cholesterol. High plasma cholestanol concentrations and abnormal bile acid metabolism are specific for this disease. The authors describe four patients with cerebrotendinous xanthomatosis and prominent psychiatric symptoms. In three of these patients appropriate diagnosis and treatment were delayed for years because the presence of cerebrotendinous xanthomatosis was not recognized. Early recognition of this potentially lethal disease is important because both the psychiatric and neurological symptoms respond to treatment with chenodeoxycholic acid.

Progressive supranuclear palsy and hyperkalemic periodic paralysis.

A patient with hyperkalemic periodic paralysis experienced the gradual onset of additional and unexpected neurologic abnormalities in middle age, suggestive of progressive supranuclear palsy. Although the concurrence of these findings may be coincidental, these features may evade recognition in other patients by being misattributed to chronic myopathy or depression.

Positron emission tomography measures of benzodiazepine binding in Alzheimer's disease.

OBJECTIVE: To evaluate the integrity of neurons and neuropil in metabolically affected association cortices of patients with Alzheimer's disease by measuring central benzodiazepine binding sites with the use of positron emission tomography. DESIGN: In patients with Alzheimer's disease, we determined the cerebral distribution of flumazenil tagged with carbon 11 ([11C]flumazenil), a ligand that binds to the gamma-aminobutyric acid A (GABAA) receptor complex, and the distribution of fludeoxyglucose tagged with fluorine 18 fludeoxyglucose F 18), a measure of local cerebral glucose metabolism. Tracer kinetic analysis was applied to quantify data in regions of interest. These data were compared with those of normal control subjects. SUBJECTS: Patients with probable Alzheimer's disease ([11C]flumazenil, n = 13; fludeoxyglucose F 18, n = 11) and normal elderly control subjects ([11C]flumazenil, n = 6; fludeoxyglucose F 18, n = 10). RESULTS: Significant decreases of the [11C]flumazenil transport rate were found in hypometabolic parietal and temporal association cortices, but [11C]flumazenil binding was not significantly decreased. CONCLUSIONS: When measured in living patients, association cortical benzodiazepine binding sites are relatively preserved, suggesting structurally intact cortical neuropil underlying the glucose hypometabolism identified in Alzheimer's disease.

Wechsler Adult Intelligence Scale performance. Cortical localization by fluorodeoxyglucose F 18-positron emission tomography.

We compared local cerebral glucose metabolism, as determined by positron emission tomography following administration of fluorodeoxyglucose F 18, with Wechsler Adult Intelligence Scale (WAIS) scores in 22 right-handed persons. Five study subjects were normal volunteers and the remainder had Alzheimer's disease. Subtest scores within the verbal IQ group or the performance IQ group were generally highly interrelated; there was usually no correlation between the verbal and performance subtests. The cortical distribution of regions in which glucose metabolism was most closely associated with verbal subtest scores generally centered in the left parasylvian area. In contrast, scores on the performance subtests mainly localized to the right posterior parietal region. Most WAIS subtests thus appeared to evaluate primarily either verbal or visuospatial cognitive functions and either left parasylvian or right posteroparietal cortical activity.

Mild cognitive impairments predict dementia in nondemented elderly patients with memory loss.

BACKGROUND: Some elderly individuals exhibit significant memory deficits but do not have dementia because their general intellect is preserved and they have no impairments in everyday activities. These symptoms are often a precursor to Alzheimer disease (AD), but sometimes dementia does not occur, even after many years of observation. There is currently no reliable way to distinguish between these 2 possible outcomes in an individual patient. We hypothesized that clear impairments in at least 1 cognitive domain in addition to memory would help identify those who will progress to AD. OBJECTIVE: To determine whether nondemented patients with impairments in memory and other domains are more likely than those with memory impairment alone to develop AD. DESIGN AND METHODS: In a retrospective study, we evaluated 48 nondemented, nondepressed patients with clinical and psychometric evidence of memory impairment who were followed up for 2 or more years. Age-adjusted normative criteria were used to identify whether additional impairments were present in language, attention, motor visuospatial function, and verbal fluency at this initial evaluation. The presence or absence of dementia after 2 years and at the most recent neurological evaluation was compared in subjects with normal scores in all 4 of these cognitive areas apart from memory (M-) and those with impairment in 1 or more of these areas (M+). Outcomes were adjusted for age, intelligence at initial evaluation, and years of education. RESULTS: Of the 48 nondemented patients with memory loss, 17 met M- criteria, leaving 31 in the M+ group. Deficits in block design were the most frequent abnormality other than memory loss. At the 2-year follow-up, 1 M- subject (6%) had progressed to AD, whereas 15 (48%) of the M+ group had progressed to AD (P =.003). At the most recent follow-up (mean +/- SD, 4.0 +/- 2.0 years), 4 (24%) of the M- patients progressed to AD compared with 24 (77%) of the M+ patients (P<.001). CONCLUSIONS: Among nondemented elderly patients, memory loss alone rarely progresses to dementia in the subsequent 2 years. However, the risk of dementia is significantly increased among patients with clear cognitive impairments beyond memory loss. Further study is needed to determine whether patients with impairments limited to memory loss have a distinctive clinical course or pathophysiology.

Divided attention, as measured by dichotic speech performance, in dementia of the Alzheimer type.

To determine if impaired dichotic performance in patients with dementia of the Alzheimer type is due to the inability to divide attention or the inability to perceive degraded auditory stimuli, we measured performance on tasks of both dichotic and degraded monotic speech materials. We also examined whether perception of degraded speech stimuli presented monaurally is related to abnormalities of temporal lobe anatomy and physiology, as we have shown for dichotic performance. Although the patients were impaired on both dichotic and monotic tests, significantly greater impairment was seen on the dichotic test. Our earlier finding of a significant relation between dichotic performance and measures of anterior temporal lobe atrophy and reduced glucose metabolism was replicated, but no significant relation was found between monotic tests and measures to temporal lobe integrity. We conclude that the inability to divide attention, rather than abnormal processing of degraded stimuli per se, is reflected in poor dichotic performance in patients with dementia of the Alzheimer type, and that dichotic performance, unlike degraded monotic perception, depends directly on the integrity of temporal cortex in these patients.

Blood flow imaging of a posterior circulation stroke. Use of technetium Tc 99m hexamethylpropyleneamine oxime and single photon emission computed tomography.

Regional cerebellar perfusion was imaged using technetium Tc 99m hexamethylpropylene amine oxime and single photon emission computed tomography (HM-PAO-SPECT) in a patient with chronic left lateral medullary syndrome with contralateral weakness due to traumatically induced thrombosis of the left vertebral artery. Despite continued neurologic deficits, x-ray transmission computed tomography was normal. However, HM-PAO-SPECT demonstrated that blood flow to the left cerebellar hemisphere was significantly impaired. This abnormality was still apparent after correction for atrophy as estimated by magnetic resonance imaging. Technetium Tc 99m hexamethyl-propyleneamine oxime and single photon emission computed tomography effectively imaged regional blood flow in the vertebrobasilar circulation and appears to more clearly reflect the nature and extent of the neurologic deficit than either x-ray transmission computed tomography or magnetic resonance scanning.

Perceptual analysis of speech disorders in progressive supranuclear palsy.

We used oral motor examinations and quantitative perceptual speech analysis to study deviant speech dimensions in 44 patients with progressive supranuclear palsy (PSP). All patients had dysarthria with variable degrees of spasticity, hypokinesia, and ataxia; 28 patients had all three of these components, and 16 patients had only two components. Twenty-two patients (50%) had predominantly spastic components, 15 (34%) had predominantly hypokinetic components, six (14%) had predominantly ataxic components, and in one (2%) the spastic, hypokinetic, and ataxic components were equal. Stuttering occurred in nine patients (20%) and palilalia in five (11%). The finding of a mixed dysarthria with a combination of spastic, hypokinetic, and ataxic components might assist in diagnosis and is consistent with the widespread neuropathologic changes found in PSP.

Metrizamide ventriculography in syringomyelia.

Computed tomography (CT) both with and without contrast agents has been used to diagnose syringomyelia. We report a case in which the diagnosis was made by injection of metrizamide into a ventriculoperitoneal shunt. Continuity of the syringomyelic cavity with the ventricular system was demonstrated. This case supports the hydrodynamic concept of syringomyelia formation and illustrates a potentially useful approach to its diagnosis.

Spontaneous intracranial hypotension causing reversible frontotemporal dementia.

Spontaneous intracranial hypotension (SIH) causes postural headache and neurologic symptoms owing to traction and brain compression. A 66-year-old man with chronic headache and progressive personality and behavioral changes typical of frontotemporal dementia was examined. He had MRI findings of SIH with low CSF pressure. His headache, dementia, and imaging abnormalities abated after treatment with prednisone. SIH can cause reversible frontotemporal dementia, and should be considered when dementia and behavioral changes are accompanied by headache.

Alzheimer's disease: low cerebral somatostatin levels correlate with impaired cognitive function and cortical metabolism.

Somatostatin-like immunoreactivity in Alzheimer CSF was significantly lower than in that from age-matched controls. The degree of reduction correlated with indices of intellectual impairment and decline in cortical glucose utilization as determined by PET. There was a close association between reduction in CSF somatostatin and glucose hypometabolism in the parietal lobe. In postmortem cortical tissue from Alzheimer patients, somatostatin levels were lower in posterior parietal but not in anterior frontal cortex. Loss of somatostatin-containing neurons, especially in the parietal association cortex, may be a critical determinant for Alzheimer dementia.

THIP treatment of Huntington's disease.

We evaluated the therapeutic efficacy of gamma aminobutyric acid (GABA) system stimulation in four patients with classical Huntington's disease and one with the hypokinetic-rigid form. Orally administered THIP (4,5,6,7-tetrahydroisoxazolo-[5,4,-c] pyridin-3-ol), a novel GABA receptor agonist, failed to improve motor or cognitive function during a 2-week trial. At maximum levels, THIP mimicked another putative GABA agonist, muscimol, in causing unsteadiness of gait, diminished attention to sensory stimuli, and somnolence. These effects suggest that central GABA systems participate in the regulation of some human and behavioral functions. CSF content of homovanillic acid, a major metabolite of dopamine, increased during high-dose THIP therapy, suggesting that augmentation of dopaminergic function may have contributed to the drug's lack of efficacy.