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Background and ObjectivesIn response to the restrictions imposed by the COVID-19 pandemic, the University of California San Francisco Memory and Aging Center (UCSF MAC) has deployed a comprehensive telemedicine model for the diagnosis and management of Alzheimer disease and related dementias. This review summarizes a large academic behavioral neurology clinic's experience transitioning to telemedicine services, including the impact on clinic care indicators, access metrics, and provider's experience. We compared these outcomes from 3 years before COVID-19 to 12 months after the transition to video teleconferencing (VTC) encounters.MethodsPatient demographics and appointment data (dates, visit types, and departments) were extracted from our institution's electronic health record database from January 1, 2017, to May 1, 2021. We present data as descriptive statistics and comparisons using Wilcoxon rank-sum tests and Fisher exact tests. The results of anonymous surveys conducted among the clinic's providers are reported as descriptive findings.ResultsAfter the implementation of telemedicine services, the proportion of clinic encounters completed via VTC increased from 1.9% to 86.4%. There was a statistically significant decline in both the percentage of scheduled appointments that were canceled (32.9% vs 27.9%;p< 0.01) and total cancelations per month (mean 240.3 vs 179.4/mo;p< 0.01). There was an increase in the percentage of completed scheduled appointments (60.2% vs 64.8%;p< 0.01) and an increase in the average estimated commuting distance patients would need to drive for follow-up appointments (mean 49.8 vs 54.7 miles;p< 0.01). The transition to telemedicine services did not significantly affect the clinic's patient population as measured by age, gender, estimated income, area deprivation index, or self-reported racial/ethnic identity. The results of the provider survey revealed that physicians reported a more positive experience relative to neuropsychologists. Both types of providers reported telemedicine services as a reasonable equivalent and acceptable alternative to in-person evaluations with notable caveats.DiscussionUCSF MAC's comprehensive integration of telemedicine services maintained critical ambulatory care to patients living with dementia during the COVID-19 pandemic. The recognized benefits of our care model suggest dementia telemedicine may be used as a feasible and equivalent alternative to in-person ambulatory care in the after COVID-19 era.

Background and Objectives:Synaptic dysfunction and degeneration is a predominant feature of brain aging and synaptic preservation buffers against Alzheimer’s disease (AD) protein-related brain atrophy. We tested whether cerebrospinal fluid (CSF) synaptic protein concentrations similarly moderate the effects of axonal injury, indexed via CSF neurofilament light [NfL], on brain atrophy in clinically normal adults.Methods:Clinically normal older adults enrolled in the observational Hillblom Aging Network study at the UCSF Memory and Aging Center completed baseline lumbar puncture and longitudinal brain MRI (Mean scan [follow-up]=2.6 [3.7 years]). CSF was assayed for synaptic proteins (synaptotagmin-1, synaptosomal-associated protein 2 [SNAP-25], neurogranin, growth associated protein 43 [GAP-43]), axonal injury (NfL), and core AD biomarkers (ptau181/Aβ42 ratio; reflecting AD proteinopathy). Ten bilateral temporo-parietal gray matter ROIs shown to be sensitive to clinical AD were summed to generate a composite temporo-parietal ROI. Linear mixed-effects models tested statistical moderation of baseline synaptic proteins on baseline NfL-related temporo-parietal trajectories, controlling for ptau181/Aβ42 ratios.Results:Forty-six clinically normal older adults (Mean age=70; 43% female) were included. Synaptic proteins exhibited small to medium correlations with NfL (r range: .10 to .36). Higher baseline NfL, but not ptau181/Aβ42 ratios, predicted steeper temporo-parietal atrophy (NfL x time: β=-0.08, pConclusions:The association between baseline CSF NfL and longitudinal temporo-parietal atrophy is accelerated by synaptic dysfunction and buffered by synaptic integrity. Beyond AD proteins, concurrent examination of in vivo axonal and synaptic biomarkers may improve detection of neural alterations that precede overt structural changes in AD-sensitive brain regions.

Objective To determine the effects of ESRT (an iteratively adapted and tailored MBI) on perceived stress, executive cognitive function, psychosocial well-being (ie, burnout, mindfulness), and pro-inflammatory gene expression in surgical (ESRT-1) and mixed specialty (ESRT-2) PGY-1 volunteers. Summary of background and data Tailored MBIs have proven beneficial in multiple high-stress and high-performance populations. In surgeons, tailored MBIs have been shown to be feasible and potentially beneficial, but whether mindfulness-based cognitive training can improve perceived stress, executive function, well-being or physiological distress in surgical and nonsurgical trainees is unknown. Methods In 2 small single-institution randomized clinical trials, ESRT, a tailored mindfulness-based cognitive training program, was administered and iteratively adapted for first-year surgical (ESRT-1, 8 weekly, 2-hour classes, n = 44) and mixed specialty (ESRT-2, 6 weekly, 90-minute classes, n = 45) resident trainees. Primary and secondary outcomes were, respectively, perceived stress and executive function. Other prespecified outcomes were burnout (assessed via Maslach Burnout Inventory), mindfulness (assessed via Cognitive Affective Mindfulness Scale - Revised), and pro-inflammatory gene expression (assessed through the leukocyte transcriptome profile "conserved transcriptional response to adversity"). Results Neither version of ESRT appeared to affect perceived stress. Higher executive function and mindfulness scores were seen in ESRT-1, and lower emotional exhaustion and depersonalization scores in ESRT-2, at pre-/postintervention and/or 50-week follow-up (ESRT-1) or at 32-week follow-up (ESRT-2), compared to controls. Pooled analysis of both trials found ESRT-treated participants had reduced pro-inflammatory RNA expression compared to controls. Conclusions This pilot work suggests ESRT can variably benefit executive function, burnout, and physiologic distress in PGY-1 trainees, with potential for tailoring to optimize effects.

OBJECTIVE: A rare variant in TREM2 (p.R47H, rs75932628) has been consistently reported to increase the risk for Alzheimer’s disease, while mixed evidence has been reported for association of the variant with other neurodegenerative diseases. Here, we investigated the frequency of the R47H variant in a diverse and well-characterized multicenter neurodegenerative disease cohort. METHODS: We examined the frequency of the R47H variant in a diverse neurodegenerative disease cohort, including a total of 3,058 patients clinically diagnosed with Alzheimer’s disease, frontotemporal dementia spectrum syndromes, mild cognitive impairment, progressive supranuclear palsy syndrome, corticobasal syndrome, or amyotrophic lateral sclerosis and 5,089 control subjects. RESULTS: We observed a significant association between the R47H variant and Alzheimer’s disease, while no association was observed with any other neurodegenerative disease included in this study. CONCLUSIONS: Our results support the consensus that the R47H variant is significantly associated with Alzheimer’s disease. However, we did not find evidence for association of the R47H variant with other neurodegenerative diseases.

ObjectiveTo examine clinicopathologic correlations in early vs late age at onset frontotemporal dementia (FTD) and frontotemporal lobar degeneration (FTLD).MethodsAll patients were clinically evaluated and prospectively diagnosed at the UCSF Memory and Aging Center. Two consecutive series were included: (1) patients with a clinically diagnosed FTD syndrome who underwent autopsy (cohort 1) and (2) patients with a primary pathologic diagnosis of FTLD, regardless of the clinical syndrome (cohort 2). These series were divided by age at symptom onset (cutoff 65 years).ResultsIn cohort 1, 48 (25.3%) were 65 years or older at symptom onset. Pathologic causes of behavioral variant FTD (bvFTD) were similar in the early age at onset (EO) and late age at onset (LO) bvFTD groups. In corticobasal syndrome (CBS), however, the most common pathologic substrate differed according to age at onset: progressive supranuclear palsy (42.9%) in LO-CBS and Alzheimer disease (AD; 40.7%) in EO-CBS. In cohort 2, 57 (28.4%) were classified as LO-FTLD. Regarding FTLD major molecular classes, FTLD with transactive response DNA-binding protein of 43 kDa was most common in EO-FTLD (44.4%), whereas FTLD-tau (58.3%) was most common in LO-FTLD. Antemortem diagnosis of a non-FTD syndrome, usually AD-type dementia, was more frequent in LO-FTLD than EO-FTLD (19.3% vs 7.7%, p = 0.017). LO-FTLD was also associated with more prevalent comorbid pathologic changes. Of these, moderate to severe AD neuropathologic change and argyrophilic grain disease were overrepresented among patients who received an antemortem diagnosis of AD-type dementia.ConclusionPatients with FTD and FTLD often develop symptoms after age 65, and age at onset represents an important consideration when making antemortem neuropathologic predictions.

Background Postoperative pain and opioid use are associated with postoperative delirium. We designed a single-center, randomized, placebo-controlled, parallel-arm, double-blinded trial to determine whether perioperative administration of gabapentin reduced postoperative delirium after noncardiac surgery. Methods Patients were randomly assigned to receive placebo (N = 347) or gabapentin 900 mg (N = 350) administered preoperatively and for the first 3 postoperative days. The primary outcome was postoperative delirium as measured by the Confusion Assessment Method. Secondary outcomes were postoperative pain, opioid use, and length of hospital stay. Results Data for 697 patients were included, with a mean ± SD age of 72 ± 6 yr. The overall incidence of postoperative delirium in any of the first 3 days was 22.4% (24.0% in the gabapentin and 20.8% in the placebo groups; the difference was 3.20%; 95% CI, 3.22% to 9.72%; P = 0.30). The incidence of delirium did not differ between the two groups when stratified by surgery type, anesthesia type, or preoperative risk status. Gabapentin was shown to be opioid sparing, with lower doses for the intervention group versus the control group. For example, the morphine equivalents for the gabapentin-treated group, median 6.7 mg (25th, 75th quartiles: 1.3, 20.0 mg), versus control group, median 6.7 mg (25th, 75th quartiles: 2.7, 24.8 mg), differed on the first postoperative day (P = 0.04). Conclusions Although postoperative opioid use was reduced, perioperative administration of gabapentin did not result in a reduction of postoperative delirium or hospital length of stay.

Objective:To determine the association between synaptic functioning as measured via neurogranin in CSF and cognition relative to established Alzheimer disease (AD) biomarkers in neurologically healthy older adults.Methods:We analyzed CSF concentrations of neurogranin, β-amyloid (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau) among 132 neurologically normal older adults (mean 64.5, range 55–85), along with bilateral hippocampal volumes and a measure of episodic memory (Auditory Verbal Learning Test, delayed recall). Univariable analyses examined the relationship between neurogranin and the other AD-related biomarkers. Multivariable regression models examined the relationship between neurogranin and delayed recall, adjusting for age and sex, and interaction terms (neurogranin × AD biomarkers).Results:Higher neurogranin concentrations were associated with older age (ρ = 0.20, p = 0.02), lower levels of p-tau and t-tau, and smaller hippocampal volumes (p < 0.03), but not with CSF Aβ42 (p = 0.18). In addition, CSF neurogranin demonstrated a significant relationship with memory performance independent of the AD-related biomarkers; individuals with the lowest CSF neurogranin concentrations performed better on delayed recall than those with medium or high CSF neurogranin concentrations (p < 0.01). Notably, CSF p-tau, t-tau, and Aβ42 and hippocampal volumes were not significantly associated with delayed recall scores (p > 0.40), and did not interact with neurogranin to predict memory (p > 0.10).Conclusions:Synaptic dysfunction (assessed via neurogranin) may be an early pathologic process in age-related neurodegeneration, and a sensitive marker of age-related cognitive abilities, potentially preceding or even acting independently from AD pathogenesis. Synaptic functioning may be a useful early marker of cognitive aging and possibly a target for future brain aging interventions.

Objective:To identify genetic loci associated with plasma tau concentrations in healthy elders and individuals with Alzheimer disease.Methods:Four hundred sixty-three non-Hispanic white individuals exceeding quality control criteria were included from the Alzheimer's Disease Neuroimaging Initiative (ADNI-1) cohort. Association of plasma tau with genetic polymorphisms was performed with a linear regression model. Significant associations were validated in an independent replication cohort consisting of 431 healthy elders or individuals with mild cognitive impairment recruited from the University of California, San Francisco Memory and Aging Center.Results:The minor allele (A) of rs242557 in the microtubule-associated protein tau gene (MAPT) was associated with higher plasma tau levels at genome-wide significance (p = 4.85 × 10−9, empiric family-wise error corrected p = 0.0024) in a dose-dependent fashion. This association was also observed in the replication cohort (p = 1.0 × 10−5; joint analysis p = 1.2 × 10−12). Single nucleotide polymorphisms near PARK2 (rs2187213) (p = 6.15 × 10−6), IL2RA (rs7072793, rs7073236) (p = 7.89 × 10−6), and an intergenic locus on 9p21.3 (rs7047280) (p = 8.13 × 10−6) were identified as suggestive loci associated with plasma tau levels.Conclusions:MAPT H1c haplotype (rs242557) has previously been identified as a genetic risk factor for progressive supranuclear palsy and corticobasal degeneration. The current findings suggest that plasma tau concentration could be an endophenotype for identifying risk for 4-repeat tauopathies in older individuals.

ObjectiveWhile traumatic brain injury (TBI) is common across the life span, the detailed neurobehavioral characteristics of older adults with prior TBI remain unclear. Our goal was to compare the clinical profile of older independently living veterans with and without prior TBI.SettingTwo veterans' retirement communities.ParticipantsSeventy-five participants with TBI and 71 without (mean age = 78 years).DesignCross-sectional.Main measuresTBI history was determined by the Ohio State University TBI Questionnaire. We assessed psychiatric and medical history via interviews and chart review and conducted measures assessing functional/lifestyle, psychiatric, and cognitive outcomes. Regression analyses (adjusted for demographics, diabetes, prior depression, substance abuse, and site) were performed to compare between TBI and non-TBI participants.ResultsCompared with veterans without TBI, those with TBI had greater functional impairment (adjusted P = .05), endorsed more current depressive (adjusted P = .04) and posttraumatic stress disorder symptoms (adjusted P = .01), and had higher rates of prior depression and substance abuse (both adjusted Ps < .01). While composite memory and language scores did not differ between groups, participants with TBI performed worse on tests of executive functioning/processing speed (adjusted P = .01).ConclusionsOur results suggest that TBI may have adverse long-term neurobehavioral consequences and that TBI-exposed adults may require careful screening and follow-up.

OBJECTIVE We examined verbal list memory in participants with pathology-confirmed or biomarker-supported diagnoses to clarify inconsistencies in comparative memory performance. We hypothesized that Alzheimer disease (AD) participants would show more rapid forgetting, whereas behavioral-variant frontotemporal dementia (bvFTD) participants would show a more dysexecutive pattern. We also explored differences in medial temporal volumes, and relative frontal and medial temporal area contributions to memory consolidation. PARTICIPANTS AND METHODS Participants had clinical diagnoses of AD and bvFTD who were pathologically confirmed at autopsy or supported with Pittsburgh compound B amyloid imaging. We used cognitive and imaging data collected at baseline visits for a sample of 26 participants with AD (mean age=63.7, education=16.2, Clinical Dementia Rating=0.8), 25 participants with bvFTD (mean age=60.7; education=15.7; CRD=1.1), and 25 healthy controls (mean age=65.6; education=17.5; Clinical Dementia Rating=0.2). RESULTS AND CONCLUSIONS AD participants showed more rapid forgetting than bvFTD, and both groups showed more rapid forgetting than controls. In contrast, bvFTD did not conform to a more dysexecutive pattern of performance as patient groups committed similar number of intrusion errors and showed comparably low rates of improvement on cued recall and recognition trials. For patients with neuroimaging, there were no group differences in medial temporal volumes, which was the only significant predictor of consolidation for both dementia groups.

Background and Purpose— The purpose of this study was to investigate whether the Framingham Cardiovascular Risk Profile and carotid artery intima-media thickness are associated with cortical volume and thickness. Methods— Consecutive subjects participating in a prospective cohort study of aging and mild cognitive impairment enriched for vascular risk factors for atherosclerosis underwent structural MRI scans at 3-T and 4-T MRI at 3 sites. Freesurfer (Version 5.1) was used to obtain regional measures of neocortical volumes (mm 3 ) and thickness (mm). Multiple linear regression was used to determine the association of Framingham Cardiovascular Risk Profile and carotid artery intima-media thickness with cortical volume and thickness. Results— One hundred fifty-two subjects (82 men) were aged 78 (±7) years, 94 had a clinical dementia rating of 0, 58 had a clinical dementia rating of 0.5, and the mean Mini-Mental State Examination was 28 ± 2. Framingham Cardiovascular Risk Profile score was inversely associated with total gray matter volume and parietal and temporal gray matter volume (adjusted P P P =0.04). Including history of myocardial infarction or stroke and radiological evidence of brain infarction, or apolipoprotein E genotype did not alter relationships with Framingham Cardiovascular Risk Profile or carotid artery intima-media thickness. Conclusions— Increased cardiovascular risk was associated with reduced gray matter volume and thickness in regions also affected by Alzheimer disease independent of infarcts and apolipoprotein E genotype. These results suggest a “double hit” toward developing dementia when someone with incipient Alzheimer disease also has high cardiovascular risk.

Objective: We sought to determine whether the Val 158 Met polymorphism in the catechol- O -methyltransferase (COMT) gene influences neurodegeneration within dopamine-innervated brain regions. Methods: A total of 252 subjects, including healthy controls and patients with Alzheimer disease, behavioral variant frontotemporal dementia, and semantic dementia, underwent COMT genotyping and structural MRI. Results: Whole-brain voxel-wise regression analyses revealed that COMT Val 158 Met Val allele dosage, known to produce a dose-dependent decrease in synaptic dopamine (DA) availability, correlated with decreased gray matter in the region of the ventral tegmental area (VTA), ventromedial prefrontal cortex, bilateral dorsal midinsula, left dorsolateral prefrontal cortex, and right ventral striatum. Unexpectedly, patients carrying a Met allele showed greater VTA volumes than age-matched controls. Gray matter intensities within COMT-related brain regions correlated with cognitive and behavioral deficits. Conclusions: The results are consistent with the hypothesis that increased synaptic DA catabolism promotes neurodegeneration within DA-innervated brain regions.

Objective: To create and validate a simple, standardized version of the antisaccade (AS) task that requires no specialized equipment for use as a measure of executive function in multicenter clinical studies. Methods: The bedside AS (BAS) task consisted of 40 pseudorandomized AS trials presented on a laptop computer. BAS performance was compared with AS performance measured using an infrared eye tracker in normal elders (NE) and individuals with mild cognitive impairment (MCI) or dementia (n = 33). The neuropsychological domain specificity of the BAS was then determined in a cohort of NE, MCI, and dementia (n = 103) at UCSF, and the BAS was validated as a measure of executive function in a 6-center cohort (n = 397) of normal adults and patients with a variety of brain diseases. Results: Performance on the BAS and laboratory AS task was strongly correlated and BAS performance was most strongly associated with neuropsychological measures of executive function. Even after controlling for disease severity and processing speed, BAS performance was associated with multiple assessments of executive function, most strongly the informant-based Frontal Systems Behavior Scale. Conclusions: The BAS is a simple, valid measure of executive function in aging and neurologic disease.

Neurocognitive symptoms are a prominent feature of nearly all neurodegenerative dementias. Specialized assessment of memory, executive functions, language, and visuospatial skills may aid in the differential diagnosis. This chapter describes the neuropsychological assessment of these domains and provides typical neurocognitive profiles of various dementia types.

This study compared rates of regional atrophy in Alzheimer disease (AD), frontotemporal dementia (FTD), and semantic dementia (SD). Cross-sectional studies have shown that different dementia syndromes are associated with different patterns of regional brain tissue loss. Rates of atrophy over time may be useful for differential diagnosis, and could be used to monitor disease progression, serving as an outcome measure for clinical trials. We studied patients with AD (n=12), FTD (n=13), SD (n=20), and normal controls (n=23) longitudinally with structural magnetic resonance imaging, using BRAINS2 software to measure frontal, temporal, and parietal lobe volumes. In FTD the rate of frontal lobe atrophy over 1 year was greater than in any other group, whereas SD showed the highest rate in the temporal lobes. Atrophy in these regions progressed twice as quickly in FTD and SD compared with AD. Atrophy was not significantly faster for AD in any brain region compared with the other groups. Regional atrophy over time was significantly faster in FTD and SD compared with AD, and the regions of greatest atrophy were specific for each syndrome. Measuring specific regions of cerebral volume changes by serial neuroimaging may serve as a useful biomarker outcome measure for clinical trials in neurodegenerative diseases.

Although early studies on mild cognitive impairment (MCI) focused on memory dysfunction; more recent studies suggest that MCI is clinically heterogeneous. The objective of this study is to examine patterns of cerebral perfusion in anmestic (N=12) and nonamnestic (N=12) single-domain MCI patients from 4 a priori regions of interest: middle and superior frontal cortex, posterior cingulate, and precuneus, to compare them relative to healthy controls (N=12), and to correlate perfusion with neuropsychologic measures. Relative to controls, all MCI patients had hypoperfusion in the posterior cingulate, bilaterally. MCI patients with executive dysfunctions also showed hypoperfusion in bilateral middle frontal cortex and the left precuneus relative to controls and in the left middle frontal cortex, left posterior cingulate, and left precuneus relative to amnestic MCI patients. Perfusion in the posterior cingulate correlated positively with memory performance whereas perfusion in all 4 a priori regions of interest, predominantly on the left side, correlated with executive function performance. The finding that single-domain MCI patients with prominent deficits in different cognitive domains exhibited different patterns of hypoperfusion relative to controls supports the existence of distinct subgroups of MCI. These data further suggest that cognitive impairment in MCI is related to cerebral hypoperfusion.

Background: Measurement of volumetric changes with MR might be a useful surrogate endpoint for clinical trials in frontotemporal lobar degeneration (FTLD). Because there is only limited longitudinal imaging data currently available, we measured the rate of change over 1 year of whole brain volume (WBV) and ventricular volume (VV) in patients with FTLD. Methods: Subjects with an FTLD cognitive syndrome were recruited from five centers using standard clinical diagnostic criteria for behavioral variant frontotemporal dementia (bvFTD), progressive nonfluent aphasia (PNFA), semantic dementia (SMD), and progressive logopenic aphasia. Structural brain imaging, using three-dimensional T1-weighted sequences at 1.5 teslas, and cognitive, behavioral, and functional assessments were performed at baseline and approximately 1 year later. The boundary shift integral algorithm was used to determine change in WBV and VV. Results: There were 76 patients (mean age 64 years; 41 men and 35 women) who had usable baseline and annual scans. The group-wise annualized change was −1.62% (SD 1.03, range +0.69 to −3.6) for WBV and 11.6% (SD 5.9, range −1.3 to 23.9) for VV. Rates of change were similar among bvFTD, PNFA, and SMD groups. Longitudinal changes in WBV and VV were correlated with decline on clinical global and cognitive measures. Conclusions: Multicenter, serial measurements of whole brain volume (WBV) and ventricular volume (VV) from magnetic resonance scans were feasible in patients with frontotemporal lobar degeneration (FTLD). Using WBV or VV as outcome measures would require recruiting (at 80% power) 139 or 55 subjects per group to detect a small (25%) or medium-sized (40%) effect in a randomized, placebo-controlled trial of a putative agent for FTLD.

Background: Primary lateral sclerosis (PLS) is an idiopathic upper motor neuron degenerative disorder. The aim of this study was to compare brain volumes in patients with PLS and controls and determine whether differences were due to loss of gray matter (GM), white matter (WM), or both. Methods: T1-weighted images were acquired in patients with PLS and controls. Freesurfer was used for volumetric segmentation of whole brain, cortical GM, precentral and postcentral cortex, WM, corpus callosum, basal ganglia, thalamus, cerebellum, and CSF. Relationships were sought between disease severity, disease duration, age and brain volumes. Results: Eleven patients with PLS and 10 age-matched healthy controls were included in this study. Compared to control subjects, patients with PLS had significantly smaller whole brain ( p = 0.043), frontal lobe ( p = 0.036), precentral cortex ( p = 0.016), and corpus callosum ( p = 0.036) volumes. There was a trend toward a smaller thalamus ( p = 0.051). Disease severity correlated with ventricular CSF volume (rho = −0.604, p = 0.025) and precentral cortex volume loss (rho = 0.599, p = 0.026). Disease duration tended to correlate with a loss of WM (rho = −0.636, p = 0.063). Conclusions: Our results suggest that there is focal atrophy in patients with primary lateral sclerosis compared with controls especially in the precentral cortex and the corpus callosum, specifically where there is transfer of motor fibers. ALS = amyotrophic lateral sclerosis; ALSFRS-R = ALS Functional Rating Scale; fSPGR = fast spoiled gradient echo sequence; GM = gray matter; PLS = primary lateral sclerosis; TE = echo time; TR = repetition time; WM = white matter.

Putative treatments for the frontotemporal lobar degenerations are likely to become available for testing in clinical trials in the next few years. To design clinical trials for this group of disorders, a number of conceptual, methodologic, and diagnostic issues must be resolved. This presentation reviews diagnostic criteria, instruments for longitudinal study, questions about study duration, and the possible uses of biomarkers in clinical trials. In addition, a multicenter trial is described in which some aspects of diagnosis and longitudinal measurement in the frontotemporal lobar degenerations are being specifically explored.

The most widely established diagnostic criteria for the behavioral variant of frontotemporal dementia have now been in use for almost a decade. Although consensus criteria have provided a much needed standard for frontotemporal dementia research, a growing body of evidence suggests that revisions are needed to improve their applicability. In this article, we discuss the limitations of current diagnostic criteria and propose the establishment of an international consortium to revise diagnostic and research criteria for the behavioral variant of frontotemporal dementia.

Background: Frontotemporal lobar degeneration (FTLD) is associated with a profound de- cline in social and emotional behavior; however, current understanding regarding the specific aspects of emotional functioning that are preserved and disrupted is limited. Objective: To assess preservation of function and deficits in two aspects of emotional processing (emotional reactivity and emotion recognition) in FTLD. Methods: Twenty-eight FTLD patients were compared with 16 controls in emo- tional reactivity (self-reported emotional experience, emotional facial behavior, and autonomic ner- vous system response to film stimuli) and emotion recognition (ability to identify a target emotion of fear, happy, or sad experienced by film characters). Additionally, the neural correlates of emotional reactivity and emotion recognition were investigated. Results: FTLD patients were comparable to con- trols in 1) emotional reactivity to the fear, happy, and sad film clips and 2) emotion recognition for the happy film clip. However, FTLD patients were significantly impaired compared with controls in emotion recognition for the fear and sad film clips. Volumetric analyses revealed that deficits in emo- tion recognition were associated with decreased lobar volumes in the frontal and temporal lobes. Conclusions: The socioemotional decline typically seen in frontotemporal lobar degeneration patients may result more from an inability to process certain emotions in other people than from deficits in emotional reactivity. NEUROLOGY 2007;69:148-155

Frontotemporal dementia (FTD) and Alzheimer disease (AD) can be difficult to clinically differentiate because of overlapping symptoms.1–3 Structural MRI can assess regional patterns of brain pathology and may aid a differential diagnosis between FTD and AD.4–10 However, overlapping of brain tissue loss limits structural MRI to achieve complete separation between FTD and AD. Functional neuroimaging, yielding complementary information to tissue loss, may help the differentiation between FTD and AD. Previous PET and SPECT studies have shown different patterns of metabolism and perfusion reduction in FTD and AD.11–26 However, PET and SPECT have several disadvantages, including injection of radioactive tracers and limited availability in comparison with MRI scanners. Arterial spin labeled perfusion MRI (ASL-MRI) is another method to assess brain perfusion.27 Previous studies found that ASL-MRI detects a regional pattern of hypoperfusion in AD,28,29 similar to PET and SPECT. Therefore, we tested if ASL-MRI detects a regional pattern of hypoperfusion in FTD vs cognitively normal (CN) subjects and patients with AD, similar to PET and SPECT. A complication in interpreting functional imaging data is that brain atrophy and partial volume effects (PVEs) can mimic metabolic and perfusion reductions. Therefore, we also sought to determine if the patterns of hypoperfusion in FTD remain after accounting for PVE. Last, we explored if ASL-MRI can depict the severity of FTD and if PVE-corrected perfusion can improve the separation of FTD from CN and AD over that using structural MRI alone.

Frontotemporal lobar degeneration (FTLD) is a common cause of non-Alzheimer dementia, but its natural history and the factors related to mortality in affected patients are not well understood.This retrospective, longitudinal study compared survival in FTLD (n = 177) with Alzheimer disease (AD; n = 395). Hazards analysis investigated the contribution of various demographic, neuropsychiatric, and neuropsychological variables and associated neurologic and neuropathologic findings.The frontotemporal dementia (FTD) subtype of FTLD progressed faster than AD (median survival from retrospectively determined symptom onset, 8.7 +/- 1.2 vs 11.8 +/- 0.6 years, p0.0001; median survival from initial clinic presentation, 3.0 +/- 0.5 vs 5.7 +/- 0.1 years, p0.0001). Survival was similarly reduced in the related conditions corticobasal degeneration and progressive supranuclear palsy. Survival in the semantic dementia subtype of FTLD (11.9 +/- 0.2 years from onset and 5.3 +/- 0.4 years from presentation), however, was significantly longer than in FTD and did not differ from AD. Hazards analysis to determine factors affecting survival in FTLD showed no effect of age at onset, sex, education, family history, or neuropsychiatric profile. Among neuropsychological measures examined, impaired letter fluency had a significant association with reduced survival. Associated ALS significantly reduced survival in FTLD. The presence of tau-positive inclusions was associated with the slowest progression.Frontotemporal lobar degeneration progresses more rapidly than Alzheimer disease, and the fastest-progressing cases are those with the frontotemporal dementia clinical subtype, coexisting motor neuron disease, or tau-negative neuropathology.

To determine if atrophy rates were higher for entorhinal cortex (ERC) than for hippocampus in Alzheimer disease (AD), to determine the relationship between hippocampal atrophy rate and memory impairment, and to compare atrophy rates of ERC and hippocampus in differentiating between patients with AD and cognitively normal (CN) controls.Twenty patients with AD and 25 CN subjects had MRI scans and clinical evaluations twice approximately 1.9 years apart. ERC volumes were measured manually and hippocampal volumes were measured semiautomatically on volumetric T1-weighted MR images.In AD, the atrophy rate of ERC (7.1 +/- 3.2%/year) was higher (p0.02) than that of hippocampus (5.9 +/- 2.4%/year). Furthermore, memory deficit in mild AD, measured with the Delayed List Verbal Recall test, correlated significantly with atrophy rates of both ERC (r = -0.61) and hippocampus (r = -0.59). Atrophy rates of ERC and hippocampus were comparable in differentiating between AD and CN. Using atrophy rates of ERC or hippocampus to detect a 20% treatment effect with 90% power (p0.05) would require about 100 completed patients per arm in a 2-year study.The finding in AD that the atrophy rate in the entorhinal cortex is higher than in the hippocampus is consistent with the view that AD pathology begins in the entorhinal cortex.

Background: Efforts to characterize changes in social functioning in frontotemporal dementia (FTD) have failed to elicit clear dissociation between frontal and temporal variants of the disease based on behavioral measures. Methods: This study obtained premorbid and current first-degree relative ratings using an established measure of interpersonal functioning, the Interpersonal Adjectives Scales, to measure personality change in 16 patients with frontal variant (FLV) and 13 with temporal variant (TLV) FTD, and in a control group of 16 patients with AD. Results: All three groups showed significant change over time in multiple domains, including increased introversion (FG) and submissiveness (HI). However, patients with both FTD subtypes evidenced significantly greater increases in overall interpersonal pathology vector length [VL] than did patients with AD, who remained within the normal range on all scores. Patients with FLV showed a 2 SD increase in submissiveness (HI), but their cold-heartedness (DE) change scores were not significantly different from those of patients with AD. Conversely, the TLV cold-heartedness (DE) score increased 2 SD compared to minimal change for the AD and FLV groups, yet change in submissiveness (HI) did not differentiate between AD and TLV groups. Conclusions: The Interpersonal Adjectives Scales differentiated both FTD groups from patients with AD on the basis of both degree and direction of personality change. Also, the two subtypes of FTD showed distinctly different patterns of change in social functioning: patients with temporal variant shifted toward severe interpersonal coldness with mild loss of dominance, whereas patients with frontal variant showed the opposite pattern.

Objective: To assess the ability of the current diagnostic criteria for frontotemporal lobar degeneration (FTLD) to differentiate FTLD from AD. Methods: Thirty cases with autopsy-proven FTLD and 30 cases of AD, matched for Mini-Mental State Examination score, were identified from the clinical databases of three dementia subspecialty centers, and their charts were reviewed for the presence of clinical features described in the current criteria for FTLD. The proportion of patients with each clinical feature at the first clinical presentation was compared across groups. Results: A significantly larger proportion of patients with FTLD showed behavioral abnormalities, particularly social and personal conduct disorders and emotional blunting, than patients with AD. Few differences in language features were seen between the groups, and many of the language features detailed in the criteria were found in only a small proportion of patients. In both groups, many patients showed neuropsychological abnormalities, except for perceptual difficulties, which were present in many patients with AD but only in a few patients with FTLD. Extrapyramidal motor symptoms were more likely to be present in FTLD. Logistic regression revealed that five features—social conduct disorders, hyperorality, akinesia, absence of amnesia, and the absence of a perceptual disorder—correctly classified 93% of patients with FTLD and 97% of patients with AD. Conclusion: A combination of behavioral, neuropsychological, and physical findings is most useful in distinguishing FTLD from AD. Future studies should be directed at establishing more objective methods of identifying these clinical features.

Background Erythrocytes are transfused to improve oxygen delivery and prevent or treat inadequate oxygenation of tissues. Acute isovolemic anemia subtly slows human data processing and degrades memory, increases heart rate, and decreases self-assessed energy level. Erythrocyte transfusion is efficacious in reversing these effects of acute anemia. We tested the hypothesis that increasing arterial oxygen pressure (Pao2) to 350 mmHg or greater would supply sufficient oxygen to be equivalent to augmenting hemoglobin concentration by 2-3 g/dl and thus reverse the effects of acute anemia. Methods Thirty-one healthy volunteers, aged 28 +/- 4 yr (mean +/- SD), were tested with verbal memory and standard, computerized neuropsychologic tests before and twice after acute isovolemic reduction of their hemoglobin concentration to 5.7 +/- 0.3 g/dl. Two sets of tests were performed in randomized order at the lower hemoglobin concentration: with the volunteer breathing room air or oxygen. The subject and those administering the tests and recording the results were unaware which gas was administered. As an additional control for duration of the experiment, 10 of these volunteers also completed the same tests on a separate day, without alteration of hemoglobin concentration, at times of the day similar to those on the experimental day. Heart rate, mean arterial blood pressure, and self-assessed sense of energy were recorded at the time of each test. Results Reaction time for digit-symbol substitution test increased, delayed memory was degraded, mean arterial pressure and energy level decreased, and heart rate increased at a hemoglobin concentration of 5.7 g/dl (all P < 0.05). Increasing Pao2 to 406 +/- 47 mmHg reversed the digit-symbol substitution test result and the delayed memory changes to values not different from those at the baseline hemoglobin concentration of 12.7 +/- 1.0 g/dl, and decreased heart rate (P < 0.05). However, mean arterial pressure and energy level changes were not altered with increased Pao2 during acute anemia. Conclusion The authors confirmed that acute isovolemic anemia subtly slows human reaction time, degrades memory, increases heart rate, and decreases energy level. The findings of this study support the hypothesis that increasing Pao2 to 350 mmHg or greater by breathing oxygen reverses all of these effects of acute anemia except for decreased energy.

Background: Frontotemporal dementia (FTD) is associated with a variety of cognitive and behavioral dysfunctions. Symptoms may be influenced by the relative involvement of the right versus the left hemisphere, with left-sided FTD manifesting language changes and right-sided FTD presenting with aggressive, antisocial, and other socially undesirable behaviors. Objective: To test the hypothesis that right-sided FTD is associated with socially undesirable behavior. Methods: The authors assessed 41 patients with FTD diagnosed by the new research criteria for FTD1 including behavioral, neuropsychologic, and neurologic testing as well as SPECT and MRI. Based on visual inspection of SPECT scans, 12 patients were classified as having predominantly right-sided and 19 patients were classified as having predominantly left-sided FTD. A clinician blinded to the imaging data reviewed medical records to tabulate the frequency of the following socially undesirable behaviors: criminal behavior, aggression, loss of job, alienation from family/friends, financial recklessness, sexually deviant behavior, and abnormal response to spousal crisis. Results: Eleven of 12 right-sided and 2 of 19 left-sided FTD patients had socially undesirable behavior as an early presenting symptom (χ = 23.3, p Conclusion: The authors conclude that right-sided frontotemporal degeneration is associated with socially undesirable behavior. The early presence of socially undesirable behavior in FTD differentiates right-sided from left-sided degeneration. The results highlight the importance of the right hemisphere, especially frontotemporal regions, in the mediation of social behavior. The potential mechanism for these social losses with right-sided disease is discussed.

Hippocampal atrophy detected by MRI is a prominent feature of early Alzheimer's disease (AD), but it is likely that MRI underestimates the degree of hippocampal neuron loss, because reactive gliosis attenuates atrophy. We tested the hypothesis that hippocampal N-acetyl aspartate (NAA: a neuronal marker) and volume used together provide greater discrimination between AD and normal elderly than does either measure alone. We used proton MR spectroscopic imaging (1H MRSI) and tissue segmented and volumetric MR images to measure atrophy-corrected hippocampal NAA and volumes in 12 AD patients (mild to moderate severity) and 17 control subjects of comparable age. In AD, atrophy-corrected NAA from the hippocampal region was reduced by 15.5% on the right and 16.2% on the left (both p < 0.003), and hippocampal volumes were smaller by 20.1% (p < 0.003) on the right and 21.8% (p < 0.001) on the left when compared with control subjects. The NAA reductions and volume losses made independent contributions to the discrimination of AD patients from control subjects. When used separately, neither hippocampal NAA nor volume achieved to classify correctly AD patients better than 80%. When used together, however, the two measures correctly classified 90% of AD patients and 94% of control subjects. In conclusion, hippocampal NAA measured by 1H MRSI combined with quantitative measurements of hippocampal atrophy by MRI may improve diagnosis of AD.

Editors' Note: Based on his experience, Dr. Verslegers disagrees with “Long-term use of daily sumatriptan injections in severe drug-resistant chronic cluster headache,” which presented arguments to use sumatriptan injections on a daily basis in refractory patients with cluster headache. Instead, he suggests that ergotamine should be employed when classical treatments fail. Drs. Leone and Proietti Cecchini, authors of the study, argue that ergots are less specific than triptans, have more side effects such as nausea and vomiting, increase the risk of cardiovascular events, and can lead to ergotism when taken frequently. The authors also suggest that neurostimulation procedures can be beneficial in treating intractable chronic cluster headache. Commenting on “Cognition and neuropsychiatry in behavioral variant frontotemporal dementia by disease stage,” Bertoux et al. point to the issue …

Progressive aphasia without dementia is a relatively uncommon neurobehavioral syndrome. The initial presentation of progressive aphasia without cognitive impairment may pose a diagnostic dilemma. The authors report a patient with progressive aphasia. The initial neuro-imaging studies (MRI, CT) were not diagnostically helpful. However, brain SPECT imaging with Tc-99m HMPAO clearly demonstrated a left temporal lobe abnormality. This report discusses the potential clinical usefulness of brain SPECT imaging in the evaluation of neurobehavioral disorders.

Objective: To examine volumetric MRI correlates of longitudinal cognitive decline in normal aging, AD, and subcortical cerebrovascular brain injury (SCVBI). Background: Previous cross-sectional studies examining the relationship between cognitive impairment and dementia have shown that hippocampal and cortical gray matter atrophy are the most important predictors of cognitive impairment, even in cases with SCVBI. The authors hypothesized that hippocampal and cortical gray matter volume also would best predict rate of cognitive decline in cases with and without SCVBI. Methods: Subjects were recruited for a multicenter study of contributions to dementia of AD and SCVBI. The sample (n = 120) included cognitively normal, cognitively impaired, and demented cases with and without lacunes identified by MRI. Cases with cortical strokes were excluded. Average length of follow-up was 3.0 years. Measures of hippocampal volume, volume of cortical gray matter, presence of subcortical lacunes, and volume of white matter hyperintensity were derived from MRI. Random effects modeling of longitudinal data was used to assess effects of baseline MRI variables on longitudinal change in a measure of global cognitive ability. Results: Cortical gray matter atrophy predicted cognitive decline regardless of whether lacunes were present. Hippocampal atrophy predicted decline only in those without lacunes. Neither lacunes nor white matter hyperintensity independently predicted decline. Conclusions: Results suggest that cortical atrophy is an index of disease severity in both AD and subcortical cerebrovascular brain injury and consequently predicts faster progression. Hippocampal volume may index disease severity and predict progression in AD. The absence of this effect in cases with lacunes suggests that this group is etiologically heterogeneous and is not composed simply of cases of AD with incidental stroke.

Objective: To evaluate long-term reliability of intrinsic connectivity analytical strategies in older subjects and their potential use as disease-monitoring biomarkers. Background “Resting-state” or task-free fMRI can assess intrinsic connectivity network (ICN) integrity in health and disease, suggesting a potential for use of these methods as disease-monitoring biomarkers. Numerous analytical options are available, including model-driven ROI-based correlation analysis and model-free, independent component analysis (ICA). High test-retest reliability will be a necessary feature of a successful ICN biomarker, yet available reliability data remains limited. Design/Methods: 24 healthy older controls were recruited through the UCSF Memory and Aging Center and underwent two sessions of task-free functional MR imaging roughly one year apart. One ICN, the salience network, was examined using a series of analytical strategies. Test-retest reliability was measures by intraclass coefficients (ICC) of ICN scores across the two sessions. Results: Most ICN analytical methods proved reliable (ICC > 0.4) and were improved by wavelet analysis. Seed-based ROI correlation analysis showed high map-wise reliability, whereas graph theoretical measures and temporal concatenation group ICA produced the most reliable individual unit-wise outcomes. Including global signal regression in ROI-based correlation analyses reduced reliability. Conclusions: Our study provides a direct comparison between the most commonly used ICN fMRI methods and potential guidelines for measuring intrinsic connectivity in aging control and patient populations over time. Disclosure: Dr. Guo has nothing to disclose. Dr. Kurth has nothing to disclose. Dr. Zhou has nothing to disclose. Dr. Mayer has nothing to disclose. Dr. Eickhoff has nothing to disclose. Dr. Kramer has nothing to disclose. Dr. Seeley has received personal compensation for activities with Korea Novartis.

Summary Background Previous studies have found no association between serum concentrations of total oestradiol and cognitive function, but these measurements may not reflect concentrations of hormone available to the brain. We tested the hypothesis that concentrations of non-protein-bound (free) and loosely bound (bioavailable) sex hormones are associated with cognitive function in older women. Methods We measured cognitive performance with a modified mini mental status examination (mMMSE) at baseline (1986–88) and 6 years later in 425 women (65 years or older). Concentrations of non-protein-bound and bioavailable oestradiol and total and non-protein-bound testosterone were measured by RIA in serum samples taken at baseline. Findings Initial cognitive scores did not differ by tertile of non-protein-bound oestradiol, bioavailable oestradiol, or testosterone. Cognitive impairment (a decrease of 3 points or more in mMMSE score) occurred in five (5%) of 94 women in the high tertile for non-protein-bound oestradiol and in 17 (16%) of 106 in the low tertile (odds ratio 0·3 [95% Cl 0·1–0·8]). After adjustment for age, years of education, body-mass index, current oestrogen use, history of surgical menopause, and baseline mMMSE score, the odds ratio was 0·3 (0·1–0·9). The results were similar for bioavailable oestradiol (five [5%] vs 15 [15%]; adjusted odds ratio 0·3 [0·1–1·0]). There was no association between risk of cognitive impairment and serum testosterone. Interpretation Women with high serum concentrations of non-protein-bound and bioavailable oestradiol, but not testosterone, were less likely to develop cognitive impairment than women with low concentrations. This finding supports the hypothesis that higher concentrations of endogenous oestrogens prevent cognitive decline.

During a 5 1/2 year period 245 patients at Grady Memorial Hospital had cytologic evidence of an active genital herpetic infection. Cervical biopsies obtained in 98 of these patients showed a 23.7% incidence (58 cases) of cervical anaplasia including 4 cases of invasive and 12 cases of in situ squamous cell carcinoma. This is in contrast with the 1.6% overall incidence of cervical anaplasia among a control group of 245 apparently noninfected women of similar age and background and the 2.7% incidence found in the total 56418 women screened during this period. These findings suggest that either similar factors operate independently to produce both conditions or that the venereally transmitted (type 2) genital herpesvirus plays some etiologic role in precancerous and cancerous cervical lesions. Findings supporting 1 or the other theory are presented; however there is no firm conclusion which can be drawn. In either case the results reported here indicate that women with known genital herpetic infection should be followed closely as a special group with an increased risk of developing cervical anaplastic changes. (authors)