Cerebrospinal fluid (CSF) neurofilament light chain (NfL) concentration is elevated in neurological disorders including frontotemporal degeneration (FTD). We investigated the clinical correlates of elevated CSF NfL levels in FTD.
CSF NfL, amyloid-β42 (Aβ42), tau and phosphorylated tau (ptau) concentrations were compared in 47 normal controls (NC), 8 asymptomatic gene carriers (NC2) of FTD-causing mutations, 79 FTD (45 behavioral variant frontotemporal dementia [bvFTD], 18 progressive nonfluent aphasia [PNFA], 16 semantic dementia [SD]), 22 progressive supranuclear palsy, 50 Alzheimer’s disease, 6 Parkinson’s disease and 17 corticobasal syndrome patients. Correlations between CSF analyte levels were performed with neuropsychological measures and the Clinical Dementia Rating scale sum of boxes (CDRsb). Voxel-based morphometry of structural MR images determined the relationship between brain volume and CSF NfL.
Mean CSF NfL concentrations were higher in bvFTD, SD and PNFA than other groups. NfL in NC2 was similar to NC. CSF NfL, but not other CSF measures, correlated with CDRsb and neuropsychological measures in FTD, and not in other diagnostic groups. Analyses in two independent FTD cohorts and a group of autopsy verified or biomarker enriched cases confirmed the larger group analysis. In FTD, gray and white matter volume negatively correlated with CSF NfL concentration, such that individuals with highest NfL levels exhibited the most atrophy.
CSF NfL is elevated in symptomatic FTD and correlates with disease severity. This measurement may be a useful surrogate endpoint of disease severity in FTD clinical trials. Longitudinal studies of CSF NfL in FTD are warranted.
Progressive supranuclear palsy (PSP) has been conceptualized as a large-scale network disruption, but the specific network targeted has not been fully characterized. We sought to delineate the affected network in patients with clinical PSP.
Using task-free fMRI, we mapped intrinsic connectivity to the dorsal midbrain tegmentum (dMT), a region which shows focal atrophy in PSP. Two healthy control groups (1 young, 1 older) were used to define and replicate the normal connectivity pattern, and patients with PSP were compared to an independent matched healthy control group on measures of network connectivity.
Healthy young and older subjects showed a convergent pattern of connectivity to the dMT, including brainstem, cerebellar, diencephalic, basal ganglia, and cortical regions involved in skeletal, oculomotor, and executive control. Patients with PSP showed significant connectivity disruptions within this network, particularly within cortico-subcortical and cortico-brainstem interactions. Patients with more severe functional impairment showed lower mean dMT network connectivity scores.
This study defines a PSP-related intrinsic connectivity network in the healthy brain and demonstrates the sensitivity of network-based imaging methods to PSP-related physiological and clinical changes.
Little is known about how changes in DNA methylation mediate risk for human diseases including dementia. Analysis of genome-wide methylation patterns in patients with two forms of tau-related dementia – progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD) – revealed significant differentially methylated probes (DMPs) in patients versus unaffected controls. Remarkably, DMPs in PSP were clustered within the 17q21.31 region, previously known to harbor the major genetic risk factor for PSP. We identified and replicated a dose-dependent effect of the risk-associated H1 haplotype on methylation levels within the region in blood and brain. These data reveal that the H1 haplotype increases risk for tauopathy via differential methylation at that locus, indicating a mediating role for methylation in dementia pathophysiology.
Progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD) are two neurodegenerative diseases linked, at the pathologic and genetic level, to the microtubule associated protein tau. We studied epigenetic changes (DNA methylation levels) in peripheral blood from patients with PSP, FTD, and unaffected controls. Analysis of genome-wide methylation patterns revealed significant differentially methylated probes in patients versus unaffected controls. Remarkably, differentially methylated probes in PSP vs. controls were preferentially clustered within the 17q21.31 region, previously known to harbor the major genetic risk factor for PSP. We identified and replicated a dose-dependent effect of the risk-associated H1 haplotype on methylation levels within the region in independent datasets in blood and brain. These data reveal that the H1 haplotype increases risk for tauopathy via differential methylation, indicating a mediating role for methylation in dementia pathophysiology.
Frontotemporal Degeneration (FTD) is a common cause of dementia for which there are currently no approved therapies. Over the past decade there has been an explosion of knowledge about the biology and clinical features of FTD that has identified a number of promising therapeutic targets as well as animal models in which to develop drugs. The close association of some forms of FTD with neuropathological accumulation of tau protein or increased neuroinflammation due to progranulin protein deficiency suggests that a drug’s success in treating FTD may predict efficacy in more common diseases such as Alzheimer’s disease (AD). A variety of regulatory incentives, clinical features of FTD, such as rapid disease progression, and relatively pure molecular pathology, suggest that there are advantages to developing drugs for FTD as compared to other more common neurodegenerative diseases such as AD. In March 2011, the Frontotemporal Dementia Treatment Study Group (FTSG) sponsored a conference entitled,“ FTD, the Next Therapeutic Frontier,” focused on pre-clinical aspects of FTD drug development. The goal of the meeting was to promote collaborations between academic researchers and biotechnology and pharmaceutical researchers to accelerate the development of new treatments for FTD. Here we report the key findings from the conference, including the rationale for FTD drug development, epidemiological, genetic and neuropathological features of FTD, FTD animal models and how best to use them and examples of successful drug-development collaborations in other neurodegenerative diseases.
Frontotemporal Degeneration (FTD) encompasses a spectrum of related neurodegenerative disorders with behavioral, language and motor phenotypes for which there are currently no effective therapies. This manuscript is the second of two articles that summarize the presentations and discussions that occurred at two symposia in 2011 sponsored by the Frontotemporal Dementia Treatment Study Group (FTSG), a collaborative group of academic and industry researchers that is devoted to developing treatments for FTD. This manuscript discusses the current status of FTD clinical research that is relevant to the conduct of clinical trials and why FTD research may be an attractive pathway for developing therapies for neurodegenerative disorders. The clinical and molecular features of FTD, including rapid disease progression and relatively pure molecular pathology, suggest that there are advantages to developing drugs for FTD as compared to other dementias. FTD qualifies as orphan indication, providing additional advantages for drug development. Two recent sets of consensus diagnostic criteria will facilitate the identification of patients with FTD, and a variety of neuropsychological, functional and behavioral scales have been shown to be sensitive to disease progression. Moreover, quantitative neuroimaging measurements demonstrate progressive brain atrophy in FTD at rates that may surpass Alzheimer's disease (AD). Finally, the similarities between FTD and other neurodegenerative diseases with drug development efforts already underway suggest that FTD researchers will be able to draw upon this experience to create a roadmap for FTD drug development. We conclude that FTD research has reached sufficient maturity to pursue clinical development of specific FTD therapies.
Behavioral variant frontotemporal dementia and semantic dementia have been associated with striatal degeneration, but few studies have delineated striatal subregion volumes in vivo or related them to clinical phenotype. We traced caudate, putamen, and nucleus accumbens on MR images to quantify volumes of these structures in behavioral variant frontotemporal dementia, semantic dementia, Alzheimer’s disease, and healthy controls (n = 12 per group). We further related these striatal volumes to clinical deficits and neuropathological findings in a subset of patients. Behavioral variant frontotemporal dementia and semantic dementia showed significant overall striatal atrophy compared with controls. Moreover, behavioral variant frontotemporal dementia showed panstriatal degeneration whereas semantic dementia featured a more focal pattern involving putamen and accumbens. Right-sided striatal atrophy, especially in the putamen, correlated with overall behavioral symptom severity and with specific behavioral domains. At autopsy, patients with behavioral variant frontotemporal dementia and semantic dementia showed striking and severe tau or TAR DNA-binding protein of 43 kDa pathology, especially in ventral parts of the striatum. These results demonstrate that ventral striatum degeneration is a prominent shared feature in behavioral variant frontotemporal dementia and semantic dementia and may contribute to social-emotional deficits common to both disorders.
While patients with Alzheimer’s disease (AD) show deficits in attention, manifested by inefficient performance on visual search, new visual talents can emerge in patients with frontotemporal lobar degeneration (FTLD), suggesting that, at least in some of the patients, visual attention is spared, if not enhanced. To investigate the underlying mechanisms for visual talent in FTLD (behavioral variant FTD [bvFTD] and semantic dementia [SD]) patients, we measured performance on a visual search paradigm that includes both feature and conjunction search, while simultaneously monitoring saccadic eye movements. AD patients were impaired relative to healthy controls (NC) and FTLD patients on both feature and conjunction search. BvFTD patients showed less accurate performance only on the conjunction search task, but slower response times than NC on all three tasks. In contrast, SD patients were as accurate as controls and had faster response times when faced with the largest number of distracters in the conjunction search task. Measurement of saccades during visual search showed that AD patients explored more of the image, whereas SD patients explored less of the image before making a decision as to whether the target was present. Performance on the conjunction search task positively correlated with gray matter volume in the superior parietal lobe, precuneus, middle frontal gyrus and superior temporal gyrus. These data suggest that despite the presence of extensive temporal lobe degeneration, visual talent in SD may be facilitated by more efficient visual search under distracting conditions due to enhanced function in the dorsal frontoparietal attention network.
Alzheimer’s disease; frontotemporal dementia; conjunction search; voxel-based morphometry; eye movements
Memantine has been used off-label to treat frontotemporal lobar degeneration (FTD). A previous 26 week open label study suggested a transient, modest benefit on neuropsychiatric symptoms as measured by the Neuropsychiatric Inventory (NPI).
We performed a randomized, parallel group, double blind, placebo controlled trial of 20 mg memantine taken orally daily for 26 weeks in FTD. Participants met Neary criteria for behavioral variant (bvFTD) or semantic dementia (SD) and had characteristic brain atrophy. Use of cholinesterase inhibitors was prohibited. The objective of the study was to determine whether memantine is an effective treatment for FTD. Individuals were randomized to memantine or matched placebo tablets in blocks of two and four. Primary endpoints were the change in total NPI score and Clinical Global Impression of Change (CGIC) scores after 26 weeks. Secondary outcomes included a neuropsychological battery, and other cognitive, global and activity of daily living measures. Clinicaltrials.gov identifier: NCT00545974
100 subjects were screened, 81 were randomized, 5 (6%) discontinued and 76 completed all visits. Enrollment numbers were lower than planned due to many subjects’ preference to take memantine or cholinesterase inhibitors off-label rather than participate in a clinical trial. 39 memantine and 42 placebo subjects entered the primary intent to treat analysis. There was no effect of memantine treatment on either the NPI (mean difference [MD] 2.2, 95%CI: −3.9, 8.3, p = 0.47) or CGIC (MD 0, 95%CI: −0.4, 0.4, p = 0.90) after 26 weeks of treatment. Memantine was generally well tolerated, however there were more frequent cognitive adverse events in the memantine group.
There was no benefit of memantine treatment in bvFTD or SD. These data do not support memantine use in FTD.
Forest Research Institute
To assess the neuropsychological and anatomical correlates of anti-saccade (AS) task performance in normal elders.
The AS task correlates with neuropsychological measures of executive function and frontal lobe volume in neurological diseases, but has not been studied in a well-characterized normal elderly population. Because executive dysfunction can indicate an increased risk for cognitive decline in cognitively normal elders, we hypothesized that AS performance might be a sensitive test of age-related processes that impair cognition.
The percentage of correct AS responses was evaluated in forty-eight normal elderly subjects and compared with neuropsychological test performance using linear regression analysis and gray matter volume measured on MRI scans using voxel-based morphometry.
The percentage of correct AS responses was associated with measures of executive function, including modified trails, design fluency, Stroop inhibition, abstraction, and backward digit span, and correlated with gray matter volume in two brain regions involved in inhibitory control: the left inferior frontal junction and the right supplementary eye field. The association of AS correct responses with neuropsychological measures of executive function was strongest in individuals with fewer years of education.
The AS task is sensitive to executive dysfunction and frontal lobe structural alterations in normal elders.
anti-saccade; normal aging; executive function; frontal lobe; cognitive reserve
Tauopathies represent a group of neurodegenerative disorders characterized by the accumulation of pathological TAU protein in brains. We report a human neuronal model of tauopathy derived from induced pluripotent stem cells (iPSCs) carrying a TAU-A152T mutation. Using zinc-finger nuclease-mediated gene editing, we generated two isogenic iPSC lines: one with the mutation corrected, and another with the homozygous mutation engineered. The A152T mutation increased TAU fragmentation and phosphorylation, leading to neurodegeneration and especially axonal degeneration. These cellular phenotypes were consistent with those observed in a patient with TAU-A152T. Upon mutation correction, normal neuronal and axonal morphologies were restored, accompanied by decreases in TAU fragmentation and phosphorylation, whereas the severity of tauopathy was intensified in neurons with the homozygous mutation. These isogenic TAU-iPSC lines represent a critical advancement toward the accurate modeling and mechanistic study of tauopathies with human neurons and will be invaluable for drug-screening efforts and future cell-based therapies.
•A human neuron model of tauopathy using TAU-A152T-iPSCs•Correction of TAU-A152T mutation eliminates tauopathy•Engineered homozygous TAU-A152T mutation intensifies tauopathy•A152T mutation increases TAU proteolysis, leading to tauopathy
The recently identified GGGGCC repeat expansion in the noncoding region of C9ORF72 is the most common pathogenic mutation in patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS). We generated a human neuronal model and investigated the pathological phenotypes of human neurons containing GGGGCC repeat expansions. Skin biopsies were obtained from two subjects who had >1,000 GGGGCC repeats in C9ORF72 and their respective fibroblasts were used to generate multiple induced pluripotent stem cell (iPSC) lines. After extensive characterization, two iPSC lines from each subject were selected, differentiated into postmitotic neurons, and compared with control neurons to identify disease-relevant phenotypes. Expanded GGGGCC repeats exhibit instability during reprogramming and neuronal differentiation of iPSCs. RNA foci containing GGGGCC repeats were present in some iPSCs, iPSC-derived human neurons and primary fibroblasts. The percentage of cells with foci and the number of foci per cell appeared to be determined not simply by repeat length but also by other factors. These RNA foci do not seem to sequester several major RNA-binding proteins. Moreover, repeat-associated non-ATG (RAN) translation products were detected in human neurons with GGGGCC repeat expansions and these neurons showed significantly elevated p62 levels and increased sensitivity to cellular stress induced by autophagy inhibitors. Our findings demonstrate that key neuropathological features of FTD/ALS with GGGGCC repeat expansions can be recapitulated in iPSC-derived human neurons and also suggest that compromised autophagy function may represent a novel underlying pathogenic mechanism.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-013-1149-y) contains supplementary material, which is available to authorized users.
ALS; Autophagy; C9ORF72; FTD; Hexanucleotide repeats; iPSCs; Neurodegeneration; Neurons; p62; RAN translation; RNA foci
We and others have recently reported an association between ALS and single nucleotide polymorphisms on chromosome 9p21 in several populations. Here we show that the associated haplotype is the same in all populations and that several families previously shown to have genetic linkage to this region also share this haplotype. The most parsimonious explanation of these data is that there is a single founder for this form of disease.
Genetics; amyotrophic lateral sclerosis; frontotemporal dementia; Finland
Patients with corticobasal degeneration (CBD) pathology present with diverse clinical syndromes also associated with other neuropathologies, including corticobasal syndrome, progressive nonfluent aphasia, and an Alzheimer’s-type dementia. Some present with behavioral variant frontotemporal dementia (bvFTD), though this subtype still requires more detailed phenotypic characterization. All patients with CBD pathology and clinical assessment were reviewed (N=17) and selected if they initially met criteria for bvFTD [bvFTD(CBD): N=5]. Available bvFTD patients with Pick’s [bvFTD(Pick’s): N=5] were selected as controls. Patients were also compared to healthy older controls [N=53] on neuropsychological and neuroimaging measures. At initial presentation, bvFTD(CBD) showed few neuropsychological or motor differences from bvFTD(Pick’s). Neuropsychiatrically, they were predominantly apathetic with less florid social disinhibition and eating disturbances, and were more anxious than bvFTD(Pick’s) patients. Voxel-based morphometry revealed similar patterns of predominantly frontal atrophy between bvFTD groups, though overall degree of atrophy was less severe in bvFTD(CBD), who also showed comparative preservation of the frontoinsular rim, with dorsal > ventral frontal atrophy, and sparing of temporal and parietal structures relative to bvFTD(Pick’s) patients. Despite remarkable overlap between the two patient types, bvFTD patients with underlying CBD pathology show subtle clinical features that may distinguish them from patients with Pick’s disease neuropathology.
Corticobasal degeneration; frontotemporal dementia; behavior; neuropsychiatry; neuropsychology; neuropathology
Several families have been reported with autosomal dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here we report an expansion of a non-coding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p. This same repeat expansion was identified in the majority of our families with a combined FTD/ALS phenotype and TDP-43 based pathology. Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (22.5%). The repeat expansion leads to the loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS.
Deficits in the generation and control of saccades have been described in clinically-defined frontotemporal dementia (FTD) and Alzheimer’s disease (AD). Because clinical FTD syndromes can correspond to a number of different underlying neuropathologic FTD and non-FTD diagnoses, we sought to determine the saccade abnormalities associated with autopsy-defined cases of FTLD and AD.
Participants and design
An infrared eye tracker was used to record visually guided saccades to ten degree targets and antisaccades in 28 autopsy-confirmed FTD and 10 AD subjects, an average of 35.6 ± 10 months prior to death and 27 age-matched normal controls (NC). 12 FTD subjects had FTLD-TDP pathology, 15 had FTLD-tau pathology and one showed FTLD-FUS pathology. Receiver operating curve (ROC) statistics were used to determine diagnostic value of oculomotor variables. Neuroanatomical correlates of oculomotor abnormalities were investigated using voxel-based morphometry (VBM).
All FTD and AD subjects were impaired relative to NC on the antisaccade task. However, only FTLD-tau and AD cases displayed reflexive visually-guided saccade abnormalities. AD cases displayed prominent increases in horizontal saccade latency that differentiated them from FTD cases. Impairments in velocity and gain were most severe in individuals with Progressive Supranuclear Palsy (PSP) but were also present in other tauopathies. Vertical and horizontal saccade velocity and gain were able to differentiate PSP cases from other patients. Vertical saccade velocity was strongly correlated with dorsal midbrain volume.
Decreased visually-guided saccade velocity and gain are suggestive of underlying tau pathology in FTD, with vertical saccade abnormalities most diagnostic of PSP.
Frontotemporal Dementia; Corticobasal Degeneration; Progressive Supranuclear Palsy; Ocular Motility
Alzheimer’s disease (AD), frontotemporal dementia (FTD) and semantic dementia (SD) are neurodegenerative diseases that differ in their socioemotional presentations. Mutual gaze (i.e. when two individuals make eye contact) is a building block of social behavior that may be differentially affected by these diseases. We studied 13 AD patients, 11 FTD patients, 9 SD patients and 22 normal controls as they engaged in conversations with partners about relationship conflicts. Physiological reactivity was monitored during the conversations and trained raters coded mutual gaze from videotaped recordings. Results indicated that mutual gaze was preserved in AD couples. Mutual gaze was diminished in FTD couples while SD couples showed evidence of greater mutual gaze. SD couples also showed lower physiological reactivity compared to controls. Across patient groups, reduced mutual gaze was associated with greater behavioral disturbance as measured by the Neuropsychiatric Inventory, especially on the disinhibition and apathy subscales. These results point to subtle differences between the three types of dementia in the social realm that help to illuminate the nature of the disease process and could aid in differential diagnosis.
Alzheimer’s disease; frontotemporal dementia; gaze; social behavior; autonomic nervous system
There is no dedicated therapy for frontotemporal dementia (FTD). In order to treat the often devastating behavioral disturbances that interfere with both normal social functioning and the ability of caregivers to provide needed support, off-label medication usage is frequent. In addition to antidepressant and antipsychotic medications, which afford some benefits, US FDA-approved treatments for Alzheimer’s disease are often used, including both cholinesterase inhibitors and memantine. Here, we review the various clinical manifestations of FTD, a general approach to treatment and the goals of any potential therapies. We review all of the existing literature on the use of cholinesterase inhibitors and memantine in FTD. While cholinesterase inhibitors do not currently have a place in FTD treatment, memantine may be helpful, although the results of two placebo-controlled trials with this agent are not yet available. Finally, we discuss our view that such approaches will probably become supplanted by rational, molecularly-based therapies currently in development.
Alzheimer’s disease; frontotemporal dementia; frontotemporal lobar degeneration; FUS; progressive nonfluent aphasia; semantic dementia; Tau; TDP-43
Frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) is a heritable form of FTD, but the gene(s) responsible for the majority of autosomal dominant FTD-ALS cases have yet to be found. Previous studies have identified a region on chromosome 9p that is associated with FTD and ALS.
The authors report the clinical, volumetric MRI, neuropathological and genetic features of a new chromosome 9p-linked FTD-ALS family, VSM-20.
Ten members of family VSM-20 displayed heterogeneous clinical phenotypes of isolated behavioural-variant FTD (bvFTD), ALS or a combination of the two. Parkinsonism was common, with one individual presenting with a corticobasal syndrome. Analysis of structural MRI scans from five affected family members revealed grey- and white-matter loss that was most prominent in the frontal lobes, with mild parietal and occipital lobe atrophy, but less temporal lobe atrophy than in 10 severity-matched sporadic bvFTD cases. Autopsy in three family members showed a consistent and unique subtype of FTLD-TDP pathology. Genome-wide linkage analysis conclusively linked family VSM-20 to a 28.3 cM region between D9S1808 and D9S251 on chromosome 9p, reducing the published minimal linked region to a 3.7 Mb interval. Genomic sequencing and expression analysis failed to identify mutations in the 10 known and predicted genes within this candidate region, suggesting that next-generation sequencing may be needed to determine the mutational mechanism associated with chromosome 9p-linked FTD-ALS.
Family VSM-20 significantly reduces the region linked to FTD-ALS on chromosome 9p. A distinct pattern of brain atrophy and neuropathological findings may help to identify other families with FTD-ALS caused by this genetic abnormality.
We and others have recently reported an association between amyotrophic lateral sclerosis (ALS) and single nucleotide polymorphisms on chromosome 9p21 in several populations. Here we show that the associated haplotype is the same in all populations and that several families previously shown to have genetic linkage to this region also share this haplotype. The most parsimonious explanation of these data are that there is a single founder for this form of disease.
Genetics; Amyotrophic lateral sclerosis; Frontotemporal dementia; Finland
There are few studies that evaluate the clinical outcomes of individuals with non-amnestic mild cognitive impairment (MCI). The purpose of this study was to evaluate baseline predictors of clinical progression after 2 years for patients with dysexecutive MCI (dMCI), a single-domain non-amnestic MCI subgroup.
We evaluated clinical progression in a sample of 31 older adults with dMCI. Clinical progression was defined as a worsening on the Clinical Dementia Rating sum of boxes at the 2-year visit, whereas patients were classified as stable if the score did not worsen over 2 years. We compared baseline brain MRI, neuropsychological tests, and health risk factors.
Twelve individuals with dMCI progressed clinically, and 19 individuals remained stable over 2 years. Compared to the stable dMCI patients, the dMCI patients who progressed showed brain atrophy in the bilateral insula and left lateral temporal lobe on MRI. dMCI patients who progressed were also older, had lower baseline performance on category fluency and a spatial location task, and reported fewer dysexecutive symptoms. Health risk factors, except hypertension, did not differ between groups.
The results suggest that dMCI patients who progress relatively quickly over 2 years may have unique clinical and brain MRI features.
Executive function; Non-amnestic mild cognitive impairment; Dysexecutive mild cognitive impairment
Importance of the field
Alzheimer’s disease is the leading cause of dementia in the elderly, and there is no disease-modifying therapy yet available. Immunotherapy directed against the β-amyloid peptide may be capable of slowing the rate of disease progression. Bapineuzumab, an anti–β-amyloid monoclonal antibody, will be the first such agent to emerge from Phase III clinical trials.
Areas covered in this review
The primary literature on bapineuzumab from 2009–2010 is reviewed in its entirety, along with the literature on AN1792, a first-generation anti–β-amyloid vaccine, from 2003–2009. Other Alzheimer’s disease immunotherapeutics currently in development, according to www.clinicaltrials.gov, are also discussed.
What the reader will gain
In addition to a critical appraisal of the Phase II trial results for bapineuzumab, this review considers the broader field of immunotherapy for Alzheimer’s disease as a whole, including the challenges ahead.
Take home message
Bapineuzumab appears capable of reducing the cerebral β-amyloid peptide burden in patients with Alzheimer’s disease. However, particularly in APOE ε4 carriers, its ability to slow disease progression remains uncertain, and vasogenic edema — a dose-limiting and potentially severe adverse reaction — may limit its clinical applicability.
Alzheimer’s disease; β-amyloid peptide (amyloid-β Aβ); Bapineuzumab; Immunotherapy (immunization); Monoclonal antibody; Vasogenic edema
There are currently no FDA-approved treatments for frontotemporal lobar degeneration (FTLD). The objectives of this study were to explore the tolerability of memantine treatment in FTLD and to monitor for possible effects on behavior, cognition and function. 43 individuals who met clinical criteria for FTLD (21 with frontotemporal dementia [FTD], 13 with semantic dementia [SD] and 9 with progressive nonfluent aphasia [PA]) received 26 weeks of open label treatment with memantine at a target dose of 20 mg daily. Concurrent treatment with acetylcholinesterase inhibitors was prohibited. Cognitive and functional outcome measures included the MMSE, ADAS-cog, CDR-sum of boxes, NPI, Frontal Behavior Inventory (FBI), Executive Interview (EXIT25), Texas Functional Living Scale (TFLS), Geriatric Depression Scale (GDS) and UPDRS-motor scale. Most subjects were able to tolerate the target dose of memantine. A transient improvement was observed on the total NPI score primarily in the FTD group. Variable declines were observed on the ADAS-cog, EXIT25, FBI, NPI, TFLS and UPDRS scores. The FTD and SD groups declined on most of the cognitive and behavioral outcome measures, but remained stable on the UPDRS, whereas the PA group remained relatively stable on the ADAS-cog, NPI and TFLS, but declined on the UPDRS. Memantine was well tolerated in these subjects. Future placebo-controlled trials of memantine in FTLD are warranted and may have greater power to detect behavioral and cognitive effects if focused on the FTD and SD clinical syndromes.
Frontotemporal dementia; semantic dementia; progressive nonfluent aphasia; memantine; open-label treatment study
There is increasing recognition that set-shifting, a form of cognitive control, is mediated by different neural structures. However, these regions have not yet been carefully identified as many studies do not account for the influence of component processes (e.g., motor speed). We investigated gray matter correlates of set-shifting while controlling for component processes. Using the Design Fluency (DF), Trail Making Test (TMT), and Color Word Interference (CWI) subtests from the Delis-Kaplan Executive Function System (D-KEFS), we investigated the correlation between set-shifting performance and gray matter volume in 160 subjects with neurodegenerative disease, mild cognitive impairment, and healthy older adults using voxel-based morphometry. All three set-shifting tasks correlated with multiple, widespread gray matter regions. After controlling for the component processes, set-shifting performance correlated with focal regions in prefrontal and posterior parietal cortices. We also identified bilateral prefrontal cortex and the right posterior parietal lobe as common sites for set-shifting across the three tasks. There was a high degree of multicollinearity between the set-shifting conditions and the component processes of TMT and CWI, suggesting DF may better isolate set-shifting regions. Overall, these findings highlight the neuroanatomical correlates of set-shifting and the importance of controlling for component processes when investigating complex cognitive tasks.
D-KEFS; Design fluency; Trail making test; Color word interference; Executive function; Voxel-based morphometry
There are no Food and Drug Administration (FDA)-approved medications indicated for the treatment of frontotemporal dementia (FTD). We sought to determine the most commonly used drugs used to treat behavioral variant FTD (bvFTD) in specialized dementia clinics.
Medication and demographic data from the Alzheimer’s Disease Research Centers of California (ARCC) and a multicenter FTD natural history study (NHS) data set were compared in bvFTD and Alzheimer’s disease (AD), and effects of demographic variables were assessed using logistic regression.
Overall, the percentage of patients taking one or more FDA-approved AD or psychiatric medications was similar in bvFTD and AD; however, after controlling for demographic variables, acetylcholinesterase inhibitor (AChI) use was less common in bvFTD, whereas memantine use remained similar in the 2 groups.
Despite lack of evidence for efficacy, the use of AChIs and memantine is common in bvFTD. Clinical trials should be pursued to determine the optimal therapeutic interventions for bvFTD.
frontotemporal dementia; Alzheimer’s disease; treatment; donepezil; memantine; galantamine; antipsychotic agents
The objective of this study was to determine which aspects of executive functions are most affected in behavioral variant frontotemporal dementia (bvFTD) and best differentiate this syndrome from Alzheimer disease (AD).
We compared executive functions in 22 patients diagnosed with bvFTD, 26 with AD, and 31 neurologically healthy controls using a conceptually driven and comprehensive battery of executive function tests, the NIH EXAMINER battery (http://examiner.ucsf.edu).
The bvFTD and the AD patients were similarly impaired compared with controls on tests of working memory, category fluency, and attention, but the patients with bvFTD showed significantly more severe impairments than the patients with AD on tests of letter fluency, antisaccade accuracy, social decision-making, and social behavior. Discriminant function analysis with jackknifed cross-validation classified the bvFTD and AD patient groups with 73% accuracy.
Executive function assessment can support bvFTD diagnosis when measures are carefully selected to emphasize frontally specific functions.