Developmental Pathogenicity of 4-Repeat Human Tau Is Lost with the P301L Mutation in Genetically Matched Tau-Transgenic Mice.

Tau is a microtubule-associated protein that becomes dysregulated in a group of neurodegenerative diseases called tauopathies. Differential tau isoforms, expression levels, promoters, and disruption of endogenous genes in transgenic mouse models of tauopathy make it difficult to draw definitive conclusions about the biological role of tau in these models. We addressed this shortcoming by characterizing the molecular and cognitive phenotypes associated with the pathogenic P301L tau mutation (rT2 mice) in relation to a genetically matched transgenic mouse overexpressing nonmutant (NM) 4-repeat (4R) human tau (rT1 mice). Both male and female mice were included in this study. Unexpectedly, we found that 4R NM human tau (hTau) exhibited abnormal dynamics in young mice that were lost with the P301L mutation, including elevated protein stability and hyperphosphorylation, which were associated with cognitive impairment in 5-month-old rT1 mice. Hyperphosphorylation of NM hTau was observed as early as 4 weeks of age, and transgene suppression for the first 4 or 12 weeks of life prevented abnormal molecular and cognitive phenotypes in rT1, demonstrating that NM hTau pathogenicity is specific to postnatal development. We also show that NM hTau exhibits stronger binding to microtubules than P301L hTau, and is associated with mitochondrial abnormalities. Overall, our genetically matched mice have revealed that 4R NM hTau overexpression is pathogenic in a manner distinct from classical aging-related tauopathy, underlining the importance of assaying the effects of transgenic disease-related proteins at appropriate stages in life.SIGNIFICANCE STATEMENT Due to differences in creation of transgenic lines, the pathological properties of the P301L mutation confers to the tau protein in vivo have remained elusive, perhaps contributing to the lack of disease-modifying therapies for tauopathies. In an attempt to characterize P301L-specific effects on tau biology and cognition in novel genetically matched transgenic mouse models, we surprisingly found that nonmutant human tau has development-specific pathogenic properties of its own. Our findings indicate that overexpression of 4-repeat human tau during postnatal development is associated with excessive microtubule binding, which may disrupt important cellular processes, such as mitochondrial dynamics, leading to elevated stability and hyperphosphorylation of tau, and eventual cognitive impairments.

Impaired Lung Function, Lung Disease, and Risk of Incident Dementia.

Rationale: Growing evidence suggests that compromised lung health may be linked to dementia and worsening cognitive ability. Objectives: To test the hypothesis that impaired lung function or lung disease in midlife is associated with greater risk of incident dementia and mild cognitive impairment (MCI) later in life. Methods: A total of 14,184 Atherosclerosis Risk in Communities study participants who underwent spirometry and were asked about lung health (1987-1989) were followed. Dementia and MCI were defined by hospitalization diagnosis codes (1987-2013) in the whole cohort and with adjudication among 42% who attended a comprehensive neurocognitive examination (2011-2013). Measurements and Main Results: In analysis using adjudicated outcomes, odds of dementia or MCI were higher among participants with restrictive (multivariable-adjusted odds ratio, 1.58; 95% confidence interval, 1.14-2.19) and obstructive lung disease (multivariable-adjusted odds ratio, 1.33; 95% confidence interval, 1.07-1.64), compared with those without disease or respiratory symptoms. Associations were similar in analyses restricted to nonsmokers, and present for both Alzheimer's disease-related dementia and cerebrovascular etiologies. Low FEV1% predicted and FVC% predicted were also associated with increased dementia risk. Conclusions: Midlife lung disease and reduced lung function were associated with modestly increased odds of dementia and MCI later in life. Magnitudes of association were more pronounced for restrictive impairment than for obstructive lung disease. These associations were present in smokers and nonsmokers. If the observed associations are causal, policy and public health efforts to reduce smoking and improve air quality may have the added benefit of preventing the development of dementia and MCI.

Distinct spatiotemporal patterns of neuronal functional connectivity in primary progressive aphasia variants.

Primary progressive aphasia is a syndrome characterized by progressive loss of language abilities with three main phenotypic clinical presentations, including logopenic, non-fluent/agrammatic, and semantic variants. Previous imaging studies have shown unique anatomic impacts within language networks in each variant. However, direct measures of spontaneous neuronal activity and functional integrity of these impacted neural networks in primary progressive aphasia are lacking. The aim of this study was to characterize the spatial and temporal patterns of resting state neuronal synchronizations in primary progressive aphasia syndromes. We hypothesized that resting state brain oscillations will show unique deficits within language network in each variant of primary progressive aphasia. We examined 39 patients with primary progressive aphasia including logopenic variant (n = 14, age = 61 ± 9 years), non-fluent/agrammatic variant (n = 12, age = 71 ± 8 years) and semantic variant (n = 13, age = 65 ± 7 years) using magnetoencephalographic imaging, compared to a control group that was matched in age and gender to each primary progressive aphasia subgroup (n = 20, age = 65 ± 5 years). Each patient underwent a complete clinical evaluation including a comprehensive battery of language tests. We examined the whole-brain resting state functional connectivity as measured by imaginary coherence in each patient group compared to the control cohort, in three frequency oscillation bands-delta-theta (2-8 Hz); alpha (8-12 Hz); beta (12-30 Hz). Each variant showed a distinct spatiotemporal pattern of altered functional connectivity compared to age-matched controls. Specifically, we found significant hyposynchrony of alpha and beta frequency within the left posterior temporal and occipital cortices in patients with the logopenic variant, within the left inferior frontal cortex in patients with the non-fluent/agrammatic variant, and within the left temporo-parietal junction in patients with the semantic variant. Patients with logopenic variant primary progressive aphasia also showed significant hypersynchrony of delta-theta frequency within bilateral medial frontal and posterior parietal cortices. Furthermore, region of interest-based analyses comparing the spatiotemporal patterns of variant-specific regions of interest identified in comparison to age-matched controls showed significant differences between primary progressive aphasia variants themselves. We also found distinct patterns of regional spectral power changes in each primary progressive aphasia variant, compared to age-matched controls. Our results demonstrate neurophysiological signatures of network-specific neuronal dysfunction in primary progressive aphasia variants. The unique spatiotemporal patterns of neuronal synchrony signify diverse neurophysiological disruptions and pathological underpinnings of the language network in each variant.

Clinicopathological correlations in behavioural variant frontotemporal dementia.

Accurately predicting the underlying neuropathological diagnosis in patients with behavioural variant frontotemporal dementia (bvFTD) poses a daunting challenge for clinicians but will be critical for the success of disease-modifying therapies. We sought to improve pathological prediction by exploring clinicopathological correlations in a large bvFTD cohort. Among 438 patients in whom bvFTD was either the top or an alternative possible clinical diagnosis, 117 had available autopsy data, including 98 with a primary pathological diagnosis of frontotemporal lobar degeneration (FTLD), 15 with Alzheimer's disease, and four with amyotrophic lateral sclerosis who lacked neurodegenerative disease-related pathology outside of the motor system. Patients with FTLD were distributed between FTLD-tau (34 patients: 10 corticobasal degeneration, nine progressive supranuclear palsy, eight Pick's disease, three frontotemporal dementia with parkinsonism associated with chromosome 17, three unclassifiable tauopathy, and one argyrophilic grain disease); FTLD-TDP (55 patients: nine type A including one with motor neuron disease, 27 type B including 21 with motor neuron disease, eight type C with right temporal lobe presentations, and 11 unclassifiable including eight with motor neuron disease), FTLD-FUS (eight patients), and one patient with FTLD-ubiquitin proteasome system positive inclusions (FTLD-UPS) that stained negatively for tau, TDP-43, and FUS. Alzheimer's disease was uncommon (6%) among patients whose only top diagnosis during follow-up was bvFTD. Seventy-nine per cent of FTLD-tau, 86% of FTLD-TDP, and 88% of FTLD-FUS met at least 'possible' bvFTD diagnostic criteria at first presentation. The frequency of the six core bvFTD diagnostic features was similar in FTLD-tau and FTLD-TDP, suggesting that these features alone cannot be used to separate patients by major molecular class. Voxel-based morphometry revealed that nearly all pathological subgroups and even individual patients share atrophy in anterior cingulate, frontoinsula, striatum, and amygdala, indicating that degeneration of these regions is intimately linked to the behavioural syndrome produced by these diverse aetiologies. In addition to these unifying features, symptom profiles also differed among pathological subtypes, suggesting distinct anatomical vulnerabilities and informing a clinician's prediction of pathological diagnosis. Data-driven classification into one of the 10 most common pathological diagnoses was most accurate (up to 60.2%) when using a combination of known predictive factors (genetic mutations, motor features, or striking atrophy patterns) and the results of a discriminant function analysis that incorporated clinical, neuroimaging, and neuropsychological data.

Incidence and impact of subclinical epileptiform activity in Alzheimer's disease.

OBJECTIVE: Seizures are more frequent in patients with Alzheimer's disease (AD) and can hasten cognitive decline. However, the incidence of subclinical epileptiform activity in AD and its consequences are unknown. Motivated by results from animal studies, we hypothesized higher than expected rates of subclinical epileptiform activity in AD with deleterious effects on cognition. METHODS: We prospectively enrolled 33 patients (mean age, 62 years) who met criteria for AD, but had no history of seizures, and 19 age-matched, cognitively normal controls. Subclinical epileptiform activity was assessed, blinded to diagnosis, by overnight long-term video-electroencephalography (EEG) and a 1-hour resting magnetoencephalography exam with simultaneous EEG. Patients also had comprehensive clinical and cognitive evaluations, assessed longitudinally over an average period of 3.3 years. RESULTS: Subclinical epileptiform activity was detected in 42.4% of AD patients and 10.5% of controls (p = 0.02). At the time of monitoring, AD patients with epileptiform activity did not differ clinically from those without such activity. However, patients with subclinical epileptiform activity showed faster declines in global cognition, determined by the Mini-Mental State Examination (3.9 points/year in patients with epileptiform activity vs 1.6 points/year in patients without; p = 0.006), and in executive function (p = 0.01). INTERPRETATION: Extended monitoring detects subclinical epileptiform activity in a substantial proportion of patients with AD. Patients with this indicator of network hyperexcitability are at risk for accelerated cognitive decline and might benefit from antiepileptic therapies. These data call for more sensitive and comprehensive neurophysiological assessments in AD patient evaluations and impending clinical trials. Ann Neurol 2016;80:858-870.

Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease.

SEE SARAZIN ET AL DOI101093/BRAIN/AWW041 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: The advent of the positron emission tomography tracer (18)F-AV1451 provides the unique opportunity to visualize the regional distribution of tau pathology in the living human brain. In this study, we tested the hypothesis that tau pathology is closely linked to symptomatology and patterns of glucose hypometabolism in Alzheimer's disease, in contrast to the more diffuse distribution of amyloid-ß pathology. We included 20 patients meeting criteria for probable Alzheimer's disease dementia or mild cognitive impairment due to Alzheimer's disease, presenting with a variety of clinical phenotypes, and 15 amyloid-ß-negative cognitively normal individuals, who underwent (18)F-AV1451 (tau), (11)C-PiB (amyloid-ß) and (18)F-FDG (glucose metabolism) positron emission tomography, apolipoprotein E (APOE) genotyping and neuropsychological testing. Voxel-wise contrasts against controls (at P < 0.05 family-wise error corrected) showed that (18)F-AV1451 and (18)F-FDG patterns in patients with posterior cortical atrophy ('visual variant of Alzheimer's disease', n = 7) specifically targeted the clinically affected posterior brain regions, while (11)C-PiB bound diffusely throughout the neocortex. Patients with an amnestic-predominant presentation (n = 5) showed highest (18)F-AV1451 retention in medial temporal and lateral temporoparietal regions. Patients with logopenic variant primary progressive aphasia ('language variant of Alzheimer's disease', n = 5) demonstrated asymmetric left greater than right hemisphere (18)F-AV1451 uptake in three of five patients. Across 30 FreeSurfer-defined regions of interest in 16 Alzheimer's disease patients with all three positron emission tomography scans available, there was a strong negative association between (18)F-AV1451 and (18)F-FDG uptake (Pearson's r = -0.49 ± 0.07, P < 0.001) and less pronounced positive associations between (11)C-PiB and (18)F-FDG (Pearson's r = 0.16 ± 0.09, P < 0.001) and (18)F-AV1451 and (11)C-PiB (Pearson's r = 0.18 ± 0.09, P < 0.001). Voxel-wise linear regressions thresholded at P < 0.05 (uncorrected) showed that, across all patients, younger age was associated with greater (18)F-AV1451 uptake in wide regions of the neocortex, while older age was associated with increased (18)F-AV1451 in the medial temporal lobe. APOE ϵ4 carriers showed greater temporal and parietal (18)F-AV1451 uptake than non-carriers. Finally, worse performance on domain-specific neuropsychological tests was associated with greater (18)F-AV1451 uptake in key regions implicated in memory (medial temporal lobes), visuospatial function (occipital, right temporoparietal cortex) and language (left > right temporoparietal cortex). In conclusion, tau imaging-contrary to amyloid-ß imaging-shows a strong regional association with clinical and anatomical heterogeneity in Alzheimer's disease. Although preliminary, these results are consistent with and expand upon findings from post-mortem, animal and cerebrospinal fluid studies, and suggest that the pathological aggregation of tau is closely linked to patterns of neurodegeneration and clinical manifestations of Alzheimer's disease.

Brain rhythm attractor breakdown in Alzheimer's disease: Functional and pathologic implications.

This perspective binds emerging evidence on the bidirectional relationship between Alzheimer's disease (AD) and sleep disorders through a model of brain rhythm attractor breakdown. This approach explains behavioral-cognitive changes in AD across the sleep-wake cycle and supports a causal association between early brainstem tau pathology and subsequent cortical amyloid ß accumulation. Specifically, early tau dysregulation within brainstem-hypothalamic nuclei leads to breakdown of sleep-wake attractor networks, with patients displaying an attenuated range of behavioral and electrophysiological activity patterns, a "twilight zone" of constant activity between deep rest and full alertness. This constant cortical activity promotes activity-dependent amyloid ß accumulation in brain areas that modulate their activity across sleep-wake states, especially the medial prefrontal cortex. In addition, the accompanying breakdown of hippocampal-medial prefrontal cortex interplay across sleep stages could explain deficient memory consolidation through dysregulation of synaptic plasticity. Clinical implications include the potential therapeutic benefit of attractor consolidation (e.g., slow-wave sleep enhancers) in delaying AD progression.

Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model.

In light of the rising prevalence of Alzheimer's disease (AD), new strategies to prevent, halt, and reverse this condition are needed urgently. Perturbations of brain network activity are observed in AD patients and in conditions that increase the risk of developing AD, suggesting that aberrant network activity might contribute to AD-related cognitive decline. Human amyloid precursor protein (hAPP) transgenic mice simulate key aspects of AD, including pathologically elevated levels of amyloid-ß peptides in brain, aberrant neural network activity, remodeling of hippocampal circuits, synaptic deficits, and behavioral abnormalities. Whether these alterations are linked in a causal chain remains unknown. To explore whether hAPP/amyloid-ß-induced aberrant network activity contributes to synaptic and cognitive deficits, we treated hAPP mice with different antiepileptic drugs. Among the drugs tested, only levetiracetam (LEV) effectively reduced abnormal spike activity detected by electroencephalography. Chronic treatment with LEV also reversed hippocampal remodeling, behavioral abnormalities, synaptic dysfunction, and deficits in learning and memory in hAPP mice. Our findings support the hypothesis that aberrant network activity contributes causally to synaptic and cognitive deficits in hAPP mice. LEV might also help ameliorate related abnormalities in people who have or are at risk for AD.

ApoE and TDP-43 neuropathology in two siblings with familial FTLD-motor neuron disease.

Frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) is characterized by neuronal cytoplasmic inclusions containing TDP-43. Apolipoprotein E4 (apoE4), derived from the apoE ϵ4 allele, enhances brain atrophy in FTLD through unknown mechanisms. Here, we studied two siblings with C9ORF72-linked familial FTLD-MND, an apoE ϵ4 homozygote and an apoE ϵ3 homozygote. The apoE ϵ4 homozygote had more cognitive-behavioral symptoms, fronto-insulo-temporal atrophy, and apoE fragments and aggregates in the anterior cingulate cortex. ApoE formed complexes with TDP-43 that were more abundant in the apoE ϵ4 homozygote. Although differences seen in a sibling pair could arise due to chance, these findings raise the possibility that apoE4 exacerbates brain pathology in FTLD through formation of neurotoxic apoE fragments and interactions with TDP-43.

Apolipoprotein E epsilon4 is associated with disease-specific effects on brain atrophy in Alzheimer's disease and frontotemporal dementia.

Apolipoprotein epsilon4 (apoE4) has been strongly linked with Alzheimer's disease (AD) and contributes to several other neurological disorders. We investigated the influence of epsilon4 allele carrier status on the pattern of gray matter atrophy and disease severity in 51 patients with probable AD and 31 patients with behavioral variant frontotemporal dementia (bvFTD), compared with 56 healthy controls. Voxel-based morphometry was performed by using statistical parametric mapping. The epsilon4 allele frequency was higher in the AD group (P < 0.001) than the controls but not in the bvFTD group. No differences in demographic or cognitive profiles were observed between epsilon4 allele carriers and noncarriers within any of the diagnostic groups. However, epsilon4 carrier status was associated with more severe brain atrophy in disease-specific regions compared with noncarriers in both AD and bvFTD. AD epsilon4 carriers showed greater atrophy in the bilateral parietal cortex and right hippocampus, and bvFTD epsilon4 carriers demonstrated greater atrophy in the bilateral medial, dorsolateral, and orbital frontal cortex, anterior insula, and cingulate cortex with right predominance. This regional epsilon4 effect is consistent with the hypothesis that apoE may affect the morphologic expression uniquely in different neurodegenerative diseases. The atrophy patterns in epsilon4 carriers may indicate that they are at greater risk for clinical progression.

Dementia in late-onset epilepsy: The Atherosclerosis Risk in Communities study.

OBJECTIVE: To determine the risk of dementia after the development of late-onset epilepsy. METHODS: We used data from the Atherosclerosis Risk in Communities (ARIC) cohort study, which started in 1987 to 1989 with 15,792 mostly Black and White men and women from 4 US communities. We identified late-onset epilepsy (LOE; seizures starting at age 67 or later) from linked Medicare claims data. We used a Cox proportional hazards regression model to evaluate associations between LOE and dementia through 2017 as ascertained from neuropsychological testing, interviews, and hospital discharge surveillance, and we used multinomial logistic regression to assess the risk of dementia and mild cognitive impairment in the subset with full neuropsychological assessments available. We adjusted for demographics and vascular and Alzheimer disease risk factors. RESULTS: Of 9,033 ARIC participants with sufficient Medicare coverage data (4,980 [55.1%] female, 1993 [22.1%] Black), 671 met the definition of LOE. Two hundred seventy-nine (41.6%) participants with and 1,408 (16.8%) without LOE developed dementia (p < 0.001). After a diagnosis of LOE, the adjusted hazard ratio for developing subsequent dementia was 3.05 (95% confidence interval 2.65-3.51). The median time to dementia ascertainment after the onset of LOE was 3.66 years (quartile 1-3, 1.28-8.28 years). INTERPRETATION: The risk of incident dementia is substantially elevated in individuals with LOE. Further work is needed to explore causes for the increased risk of dementia in this growing population.

Neurophysiological signatures in Alzheimer's disease are distinctly associated with TAU, amyloid-ß accumulation, and cognitive decline.

Neural synchrony is intricately balanced in the normal resting brain but becomes altered in Alzheimer's disease (AD). To determine the neurophysiological manifestations associated with molecular biomarkers of AD neuropathology, in patients with AD, we used magnetoencephalographic imaging (MEGI) and positron emission tomography with amyloid-beta (Aß) and TAU tracers. We found that alpha oscillations (8 to 12 Hz) were hyposynchronous in occipital and posterior temporoparietal cortices, whereas delta-theta oscillations (2 to 8 Hz) were hypersynchronous in frontal and anterior temporoparietal cortices, in patients with AD compared to age-matched controls. Regional patterns of alpha hyposynchrony were unique in each neurobehavioral phenotype of AD, whereas the regional patterns of delta-theta hypersynchrony were similar across the phenotypes. Alpha hyposynchrony strongly colocalized with TAU deposition and was modulated by the degree of TAU tracer uptake. In contrast, delta-theta hypersynchrony colocalized with both TAU and Aß depositions and was modulated by both TAU and Aß tracer uptake. Furthermore, alpha hyposynchrony but not delta-theta hypersynchrony was correlated with the degree of global cognitive dysfunction in patients with AD. The current study demonstrates frequency-specific neurophysiological signatures of AD pathophysiology and suggests that neurophysiological measures from MEGI are sensitive indices of network disruptions mediated by TAU and Aß and associated cognitive decline. These findings facilitate the pursuit of novel therapeutic approaches toward normalizing network synchrony in AD.

Long-Term Trazodone Use and Cognition: A Potential Therapeutic Role for Slow-Wave Sleep Enhancers.

BACKGROUND: Recent studies reveal an association between slow-wave sleep (SWS), amyloid-ß aggregation, and cognition. OBJECTIVE: This retrospective study examines whether long-term use of trazodone, an SWS enhancer, is associated with delayed cognitive decline. METHODS: We identified 25 regular trazodone users (mean age 75.4±7.5; 9 women, 16 men) who carried a diagnosis of Alzheimer's dementia, mild cognitive impairment, or normal cognition, and 25 propensity-matched trazodone non-users (mean age 74.5±8.0; 13 women, 12 men), accounting for age, sex, education, type of sleep deficit (hypersomnia, insomnia, parasomnia), diagnosis, and baseline Mini-Mental State Examination (MMSE). Longitudinal group differences in cognitive testing were evaluated through repeated measures tests over an average inter-evaluation interval of four years. RESULTS: Trazodone non-users had 2.6-fold faster decline MMSE (primary outcome) compared to trazodone users, 0.27 (95% confidence interval [CI]: 0.07-0.48) versus 0.70 (95% CI: 0.50-0.90) points per year (p = 0.023). The observed effects were especially associated with subjective improvement of sleep complaints in post-hoc analyses (p = 0.0006). Secondary outcomes of other cognitive and functional scores had variable worsening in non-users and varied in significance when accounting for co-administered medications and multiple comparisons. Trazodone effects on MMSE remained significant within participants with AD-predicted pathology, with 2.4-fold faster decline in non-users (p = 0.038). CONCLUSIONS: These results suggest an association between trazodone use and delayed cognitive decline, adding support for a potentially attractive and cost-effective intervention in dementia. Whether the observed relationship of trazodone to cognitive function is causal or an indirect marker of other effects, such as treated sleep disruption, and if such effects are mediated through SWS enhancement requires confirmation through prospective studies.

Neural correlates of abnormal auditory feedback processing during speech production in Alzheimer's disease.

Accurate integration of sensory inputs and motor commands is essential to achieve successful behavioral goals. A robust model of sensorimotor integration is the pitch perturbation response, in which speakers respond rapidly to shifts of the pitch in their auditory feedback. In a previous study, we demonstrated abnormal sensorimotor integration in patients with Alzheimer's disease (AD) with an abnormally enhanced behavioral response to pitch perturbation. Here we examine the neural correlates of the abnormal pitch perturbation response in AD patients, using magnetoencephalographic imaging. The participants phonated the vowel /α/ while a real-time signal processor briefly perturbed the pitch (100 cents, 400 ms) of their auditory feedback. We examined the high-gamma band (65-150 Hz) responses during this task. AD patients showed significantly reduced left prefrontal activity during the early phase of perturbation and increased right middle temporal activity during the later phase of perturbation, compared to controls. Activity in these brain regions significantly correlated with the behavioral response. These results demonstrate that impaired prefrontal modulation of speech-motor-control network and additional recruitment of right temporal regions are significant mediators of aberrant sensorimotor integration in patients with AD. The abnormal neural integration mechanisms signify the contribution of cortical network dysfunction to cognitive and behavioral deficits in AD.

Relative Incidence of Seizures and Myoclonus in Alzheimer's Disease, Dementia with Lewy Bodies, and Frontotemporal Dementia.

BACKGROUND: Patients with Alzheimer's disease (AD) are more prone to seizures and myoclonus, but relative risk of these symptoms among other dementia types is unknown. OBJECTIVE: To determine incidence of seizures and myoclonus in the three most common neurodegenerative dementias: AD, dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). METHODS: Our institution's medical records were reviewed for new-onset unprovoked seizures and myoclonus in patients meeting criteria for AD (n = 1,320), DLB (n = 178), and FTD (n = 348). Cumulative probabilities of developing seizures and myoclonus were compared between diagnostic groups, whereas age-stratified incidence rates were determined relative to control populations. RESULTS: The cumulative probability of developing seizures after disease onset was 11.5% overall, highest in AD (13.4%) and DLB (14.7%) and lowest in FTD (3.0%). The cumulative probability of developing myoclonus was 42.1% overall, highest in DLB (58.1%). The seizure incidence rates, relative to control populations, were nearly 10-fold in AD and DLB, and 6-fold in FTD. Relative seizure rates increased with earlier age-at-onset in AD (age <50, 127-fold; 50-69, 21-fold; 70+, 2-fold) and FTD (age <50, 53-fold; 50-69, 9-fold), and relative myoclonus rates increased with earlier age-at-onset in all groups. Seizures began an average of 3.9 years after the onset of cognitive or motor decline, and myoclonus began 5.4 years after onset. CONCLUSIONS: Seizures and myoclonus occur with greater incidence in patients with AD, DLB, and FTD than in the general population, but rates vary with diagnosis, suggesting varied pathomechanisms of network hyperexcitability. Patients often experience these symptoms early in disease, suggesting hyperexcitability could be an important target for interventions.

Epileptic activity in Alzheimer's disease: causes and clinical relevance.

Epileptic activity is frequently associated with Alzheimer's disease; this association has therapeutic implications, because epileptic activity can occur at early disease stages and might contribute to pathogenesis. In clinical practice, seizures in patients with Alzheimer's disease can easily go unrecognised because they usually present as non-motor seizures, and can overlap with other symptoms of the disease. In patients with Alzheimer's disease, seizures can hasten cognitive decline, highlighting the clinical relevance of early recognition and treatment. Some evidence indicates that subclinical epileptiform activity in patients with Alzheimer's disease, detected by extended neurophysiological monitoring, can also lead to accelerated cognitive decline. Treatment of clinical seizures in patients with Alzheimer's disease with select antiepileptic drugs (AEDs), in low doses, is usually well tolerated and efficacious. Moreover, studies in mouse models of Alzheimer's disease suggest that certain classes of AEDs that reduce network hyperexcitability have disease-modifying properties. These AEDs target mechanisms of epileptogenesis involving amyloid ß and tau. Clinical trials targeting network hyperexcitability in patients with Alzheimer's disease will identify whether AEDs or related strategies could improve their cognitive symptoms or slow decline.

Abnormal vocal behavior predicts executive and memory deficits in Alzheimer's disease.

Speakers respond automatically and rapidly to compensate for brief perturbations of pitch in their auditory feedback. The specific adjustments in vocal output require integration of brain regions involved in speech-motor-control in order to detect the sensory-feedback error and implement the motor correction. Cortical regions involved in the pitch reflex phenomenon are highly vulnerable targets of network disruption in Alzheimer's disease (AD). We examined the pitch reflex in AD patients (n = 19) compared to an age-matched control group (n = 16). We measured the degree of behavioral compensation (peak compensation) and the extent of the adaptive response (pitch-response persistence). Healthy-controls reached a peak compensation of 18.7 ± 0.8 cents, and demonstrated a sustained compensation at 8.9 ± 0.69 cents. AD patients, in contrast, demonstrated a significantly elevated peak compensation (22.4 ± 1.2 cents, p < 0.05), and a reduced sustained response (pitch-response persistence, 4.5 ± 0.88 cents, p < 0.001). The degree of increased peak compensation predicted executive dysfunction, while the degree of impaired pitch-response persistence predicted memory dysfunction, in AD patients. The current study demonstrates pitch reflex as a sensitive behavioral index of impaired prefrontal modulation of sensorimotor integration, and compromised plasticity mechanisms of memory, in AD.

Cognition and neuropsychiatry in behavioral variant frontotemporal dementia by disease stage.

OBJECTIVE: To characterize the cognitive and neuropsychiatric symptoms of patients with behavioral variant frontotemporal dementia (bvFTD) over the natural course of the disease. METHODS: We examined the initial and subsequent neuropsychological test performance and neuropsychiatric symptoms in a large cohort of patients with bvFTD (n = 204) across progressive stages of disease as measured by the Clinical Dementia Rating (CDR). We also compared cognitive and neuropsychiatric impairments of patients with bvFTD to those of an age-matched cohort with Alzheimer disease (AD) dementia (n = 674). RESULTS: At the earliest stage (CDR = 0.5), patients with bvFTD had profound neuropsychiatric disturbances, insensitivity to errors, slower response times, and poor naming, with intact attention span, memory, and facial affect naming. Tests continuing to show progressive, statistically significant stepwise declines after the CDR = 1 stage included free recall, visuoconstruction, set-shifting, error insensitivity, semantic fluency, design fluency, emotion naming, calculations, confrontation naming, syntax comprehension, and verbal agility. At CDR = 0.5, patients with bvFTD significantly outperformed patients with AD in episodic memory and were faster in set-shifting, while scoring quantitatively worse in lexical fluency, emotion naming, and error sensitivity. The overall rate of disease progression in bvFTD was more rapid than in AD. CONCLUSION: There are distinct patterns of cognitive deficits differentiating the earlier and later disease stages in bvFTD, with the pattern of cognitive decline revealing in greater detail the natural history of the disease. These cognitive symptoms are readily apparent clinical markers of dysfunction in the principal brain networks known to undergo molecular and anatomical changes in bvFTD, thus are important indicators of the evolving pathology in individual patients.

Distinct Subtypes of Behavioral Variant Frontotemporal Dementia Based on Patterns of Network Degeneration.

IMPORTANCE: Clearer delineation of the phenotypic heterogeneity within behavioral variant frontotemporal dementia (bvFTD) will help uncover underlying biological mechanisms and improve clinicians' ability to predict disease course and to design targeted management strategies. OBJECTIVE: To identify subtypes of bvFTD syndrome based on distinctive patterns of atrophy defined by selective vulnerability of specific functional networks targeted in bvFTD using statistical classification approaches. DESIGN, SETTING AND PARTICIPANTS: In this retrospective observational study, 90 patients meeting the Frontotemporal Dementia Consortium consensus criteria for bvFTD underwent evaluation at the Memory and Aging Center of the Department of Neurology at University of California, San Francisco. Patients underwent a multidisciplinary clinical evaluation, including clinical demographics, genetic testing, symptom evaluation, neurologic examination, neuropsychological bedside testing, and socioemotional assessments. All patients underwent structural magnetic resonance imaging at their earliest evaluation at the memory clinic. From each patient's structural imaging scans, the mean volumes of 18 regions of interest (ROI) constituting the functional networks specifically vulnerable in bvFTD, including the salience network (SN), with key nodes in the frontoinsula and pregenual anterior cingulate, and the semantic appraisal network (SAN), anchored in the anterior temporal lobe and subgenual cingulate, were estimated. Principal component and cluster analyses of ROI volumes were used to identify patient clusters with anatomically distinct atrophy patterns. Data were collected from from June 19, 2002, to January 13, 2015. MAIN OUTCOMES AND MEASURES: Evaluation of brain morphology and other clinical features, including presenting symptoms, neurologic examination signs, neuropsychological performance, rate of dementia progression, and socioemotional function, in each patient cluster. RESULTS: Ninety patients (54 men [60%]; 36 women [40%]; mean [SD] age at evaluation, 55.1 [9.7] years) were included in the analysis. Four subgroups of patients with bvFTD with distinct anatomic patterns of network degeneration were identified, including 2 salience network-predominant subgroups (frontal/temporal [SN-FT] and frontal [SN-F]), a semantic appraisal network-predominant group (SAN), and a subcortical-predominant group. Subgroups demonstrated distinct patterns of cognitive, socioemotional, and motor symptoms, as well as genetic compositions and estimated rates of disease progression. CONCLUSIONS AND RELEVANCE: Divergent patterns of vulnerability in specific functional network components make an important contribution to the clinical heterogeneity of bvFTD. The data-driven anatomic classification identifies biologically meaningful anatomic phenotypes and provides a replicable approach to disambiguate the bvFTD syndrome.

Tau reduction prevents Aß-induced axonal transport deficits by blocking activation of GSK3ß.

Axonal transport deficits in Alzheimer's disease (AD) are attributed to amyloid ß (Aß) peptides and pathological forms of the microtubule-associated protein tau. Genetic ablation of tau prevents neuronal overexcitation and axonal transport deficits caused by recombinant Aß oligomers. Relevance of these findings to naturally secreted Aß and mechanisms underlying tau's enabling effect are unknown. Here we demonstrate deficits in anterograde axonal transport of mitochondria in primary neurons from transgenic mice expressing familial AD-linked forms of human amyloid precursor protein. We show that these deficits depend on Aß1-42 production and are prevented by tau reduction. The copathogenic effect of tau did not depend on its microtubule binding, interactions with Fyn, or potential role in neuronal development. Inhibition of neuronal activity, N-methyl-d-aspartate receptor function, or glycogen synthase kinase 3ß (GSK3ß) activity or expression also abolished Aß-induced transport deficits. Tau ablation prevented Aß-induced GSK3ß activation. Thus, tau allows Aß oligomers to inhibit axonal transport through activation of GSK3ß, possibly by facilitating aberrant neuronal activity.