Increased Cortical Thickness in Alzheimer's Disease.

OBJECTIVE: Patients with Alzheimer's disease (AD) have diffuse brain atrophy, but some regions, such as the anterior cingulate cortex (ACC), are spared and may even show increase in size compared to controls. The extent, clinical significance, and mechanisms associated with increased cortical thickness in AD remain unknown. Recent work suggested neural facilitation of regions anticorrelated to atrophied regions in frontotemporal dementia. Here, we aim to determine whether increased thickness occurs in sporadic AD, whether it relates to clinical symptoms, and whether it occur in brain regions functionally connected to-but anticorrelated with-locations of atrophy. METHODS: Cross-sectional clinical, neuropsychological, and neuroimaging data from the Alzheimer's Disease Neuroimaging Initiative were analyzed to investigate cortical thickness in AD subjects versus controls. Atrophy network mapping was used to identify brain regions functionally connected to locations of increased thickness and atrophy. RESULTS: AD patients showed increased thickness in the ACC in a region-of-interest analysis and the visual cortex in an exploratory analysis. Increased thickness in the left ACC was associated with preserved cognitive function, while increased thickness in the left visual cortex was associated with hallucinations. Finally, we found that locations of increased thickness were functionally connected to, but anticorrelated with, locations of brain atrophy (r = -0.81, p < 0.05). INTERPRETATION: Our results suggest that increased cortical thickness in Alzheimer's disease is relevant to AD symptoms and preferentially occur in brain regions functionally connected to, but anticorrelated with, areas of brain atrophy. Implications for models of compensatory neuroplasticity in response to neurodegeneration are discussed. ANN NEUROL 2024;95:929-940.

Measuring Antisocial Behaviors in Behavioral Variant Frontotemporal Dementia With a Novel Informant-Based Questionnaire.

OBJECTIVE: Antisocial behaviors are common and problematic among patients with behavioral variant frontotemporal dementia (bvFTD). In the present study, the investigators aimed to validate an informant-based questionnaire developed to measure the extent and severity of antisocial behaviors among patients with dementia. METHODS: The Social Behavior Questionnaire (SBQ) was developed to measure 26 antisocial behaviors on a scale from absent (0) to very severe (5). It was administered to 23 patients with bvFTD, 19 patients with Alzheimer's disease, and 14 patients with other frontotemporal lobar degeneration syndromes. Group-level differences in the presence and severity of antisocial behaviors were measured. Psychometric properties of the SBQ were assessed by using Cronbach's alpha, exploratory factor analysis, and comparisons with a psychopathy questionnaire. Cluster analysis was used to determine whether the SBQ identifies different subgroups of patients. RESULTS: Antisocial behaviors identified by using the SBQ were common and severe among patients with bvFTD, with at least one such behavior endorsed for 21 of 23 (91%) patients. Antisocial behaviors were more severe among patients with bvFTD, including the subsets of patients with milder cognitive impairment and milder disease severity, than among patients in the other groups. The SBQ was internally consistent (Cronbach's α=0.81). Exploratory factor analysis supported separate factors for aggressive and nonaggressive behaviors. Among the patients with bvFTD, the factor scores for aggressive behavior on the SBQ were correlated with those for antisocial behavior measured on the psychopathy scale, but the nonaggressive scores were not correlated with psychopathy scale measures. The k-means clustering analysis identified a subset of patients with severe antisocial behaviors. CONCLUSIONS: The SBQ is a useful tool to identify, characterize, and measure the severity of antisocial behaviors among patients with dementia.

Anosognosia and Memory Encoding in Huntington Disease.

BACKGROUND: Anosognosia can manifest as an unawareness of neurobehavioral symptoms in individuals with Huntington disease (HD). Measurement of anosognosia is challenging, but the Anosognosia Scale (AS) represents a brief option with promising findings in small samples. OBJECTIVE: To replicate application of the AS in a larger HD sample than previous studies in order to assess psychometrics and demographic correlates and to investigate the genetic, motor, and neuropsychological correlates of the AS in individuals with HD. METHOD: We retrospectively reviewed the AS ratings of 74 genetically confirmed Huntington gene carriers, nearly all early motor manifest, who had been referred for clinical neuropsychological assessment. Concurrent clinical neurologic examination and neuropsychometric assessment data were compiled, where available (ns = 35-74). The severity of the anosognosia per AS ratings was characterized for the HD sample. RESULTS: The AS ratings did not correlate with demographic variables, genetic markers, or motor dysfunction severity. Correlation analyses revealed that higher AS ratings correlated with worse recognition-discrimination memory performance (r = 0.38, P < 0.05) but not cognitive control on executive functioning performance or on collateral-reported frontal-behavioral symptoms. Higher AS ratings also correlated with fewer patient-reported depressive symptoms (r = -0.38, P < 0.01) and diurnal hypersomnia symptoms (r = -0.44, P < 0.01). CONCLUSION: Anosognosia (per AS) is associated with recognition-discrimination deficits and fewer self-reported neuropsychiatric symptoms in individuals with pre-to-early manifest HD, though not with HD severity per genetic or motor markers, nor to executive dysfunction or collateral-reported frontal-behavioral symptoms.

Network localization of clinical, cognitive, and neuropsychiatric symptoms in Alzheimer's disease.

There is both clinical and neuroanatomical variability at the single-subject level in Alzheimer's disease, complicating our understanding of brain-behaviour relationships and making it challenging to develop neuroimaging biomarkers to track disease severity, progression, and response to treatment. Prior work has shown that both group-level atrophy in clinical dementia syndromes and complex neurological symptoms in patients with focal brain lesions localize to brain networks. Here, we use a new technique termed 'atrophy network mapping' to test the hypothesis that single-subject atrophy maps in patients with a clinical diagnosis of Alzheimer's disease will also localize to syndrome-specific and symptom-specific brain networks. First, we defined single-subject atrophy maps by comparing cortical thickness in each Alzheimer's disease patient versus a group of age-matched, cognitively normal subjects across two independent datasets (total Alzheimer's disease patients = 330). No more than 42% of Alzheimer's disease patients had atrophy at any given location across these datasets. Next, we determined the network of brain regions functionally connected to each Alzheimer's disease patient's location of atrophy using seed-based functional connectivity in a large (n = 1000) normative connectome. Despite the heterogeneity of atrophied regions at the single-subject level, we found that 100% of patients with a clinical diagnosis of Alzheimer's disease had atrophy functionally connected to the same brain regions in the mesial temporal lobe, precuneus cortex, and angular gyrus. Results were specific versus control subjects and replicated across two independent datasets. Finally, we used atrophy network mapping to define symptom-specific networks for impaired memory and delusions, finding that our results matched symptom networks derived from patients with focal brain lesions. Our study supports atrophy network mapping as a method to localize clinical, cognitive, and neuropsychiatric symptoms to brain networks, providing insight into brain-behaviour relationships in patients with dementia.

Lesion network localization of free will.

Our perception of free will is composed of a desire to act (volition) and a sense of responsibility for our actions (agency). Brain damage can disrupt these processes, but which regions are most important for free will perception remains unclear. Here, we study focal brain lesions that disrupt volition, causing akinetic mutism (n = 28), or disrupt agency, causing alien limb syndrome (n = 50), to better localize these processes in the human brain. Lesion locations causing either syndrome were highly heterogeneous, occurring in a variety of different brain locations. We next used a recently validated technique termed lesion network mapping to determine whether these heterogeneous lesion locations localized to specific brain networks. Lesion locations causing akinetic mutism all fell within one network, defined by connectivity to the anterior cingulate cortex. Lesion locations causing alien limb fell within a separate network, defined by connectivity to the precuneus. Both findings were specific for these syndromes compared with brain lesions causing similar physical impairments but without disordered free will. Finally, our lesion-based localization matched network localization for brain stimulation locations that disrupt free will and neuroimaging abnormalities in patients with psychiatric disorders of free will without overt brain lesions. Collectively, our results demonstrate that lesions in different locations causing disordered volition and agency localize to unique brain networks, lending insight into the neuroanatomical substrate of free will perception.

Lesion network localization of criminal behavior.

Following brain lesions, previously normal patients sometimes exhibit criminal behavior. Although rare, these cases can lend unique insight into the neurobiological substrate of criminality. Here we present a systematic mapping of lesions with known temporal association to criminal behavior, identifying 17 lesion cases. The lesion sites were spatially heterogeneous, including the medial prefrontal cortex, orbitofrontal cortex, and different locations within the bilateral temporal lobes. No single brain region was damaged in all cases. Because lesion-induced symptoms can come from sites connected to the lesion location and not just the lesion location itself, we also identified brain regions functionally connected to each lesion location. This technique, termed lesion network mapping, has recently identified regions involved in symptom generation across a variety of lesion-induced disorders. All lesions were functionally connected to the same network of brain regions. This criminality-associated connectivity pattern was unique compared with lesions causing four other neuropsychiatric syndromes. This network includes regions involved in morality, value-based decision making, and theory of mind, but not regions involved in cognitive control or empathy. Finally, we replicated our results in a separate cohort of 23 cases in which a temporal relationship between brain lesions and criminal behavior was implied but not definitive. Our results suggest that lesions in criminals occur in different brain locations but localize to a unique resting state network, providing insight into the neurobiology of criminal behavior.

Cortical lesions causing loss of consciousness are anticorrelated with the dorsal brainstem.

Brain lesions can provide unique insight into the neuroanatomical substrate of human consciousness. For example, brainstem lesions causing coma map to a specific region of the tegmentum. Whether specific lesion locations outside the brainstem are associated with loss of consciousness (LOC) remains unclear. Here, we investigate the topography of cortical lesions causing prolonged LOC (N = 16), transient LOC (N = 91), or no LOC (N = 64). Using standard voxel lesion symptom mapping, no focus of brain damage was associated with LOC. Next, we computed the network of brain regions functionally connected to each lesion location using a large normative connectome dataset (N = 1,000). This technique, termed lesion network mapping, can test whether lesions causing LOC map to a connected brain circuit rather than one brain region. Connectivity between cortical lesion locations and an a priori coma-specific region of brainstem tegmentum was an independent predictor of LOC (B = 1.2, p = .004). Connectivity to the dorsal brainstem was the only predictor of LOC in a whole-brain voxel-wise analysis. This relationship was driven by anticorrelation (negative correlation) between lesion locations and the dorsal brainstem. The map of regions anticorrelated to the dorsal brainstem thus defines a distributed brain circuit that, when damaged, is most likely to cause LOC. This circuit showed a slight posterior predominance and had peaks in the bilateral claustrum. Our results suggest that cortical lesions causing LOC map to a connected brain circuit, linking cortical lesions that disrupt consciousness to brainstem sites that maintain arousal.

Network localization of heterogeneous neuroimaging findings.

Studies of the same disease often implicate different brain regions, contributing to a perceived reproducibility crisis in neuroimaging. Here, we leverage the normative human brain connectome to test whether seemingly heterogeneous neuroimaging findings localize to connected brain networks. We use neurodegenerative disease, and specifically Alzheimer's disease, as our example as it is one of the diseases that has been studied the most using neuroimaging. First, we show that neuroimaging findings in Alzheimer's disease occur in different brain regions across different studies but localize to the same functionally connected brain network. Second, we show that neuroimaging findings across different neurodegenerative diseases (Alzheimer's disease, frontotemporal dementia, corticobasal syndrome, and progressive non-fluent aphasia) localize to different disease-specific brain networks. Finally, we show that neuroimaging findings for a specific symptom within a disease (delusions in Alzheimer's disease) localize to a symptom-specific brain network. Our results suggest that neuroimaging studies that appear poorly reproducible may identify different regions within the same connected brain network. Human connectome data can be used to link heterogeneous neuroimaging findings to common neuroanatomy, improving localization of neuropsychiatric diseases and symptoms.

Network localization of cervical dystonia based on causal brain lesions.

Cervical dystonia is a neurological disorder characterized by sustained, involuntary movements of the head and neck. Most cases of cervical dystonia are idiopathic, with no obvious cause, yet some cases are acquired, secondary to focal brain lesions. These latter cases are valuable as they establish a causal link between neuroanatomy and resultant symptoms, lending insight into the brain regions causing cervical dystonia and possible treatment targets. However, lesions causing cervical dystonia can occur in multiple different brain locations, leaving localization unclear. Here, we use a technique termed 'lesion network mapping', which uses connectome data from a large cohort of healthy subjects (resting state functional MRI, n = 1000) to test whether lesion locations causing cervical dystonia map to a common brain network. We then test whether this network, derived from brain lesions, is abnormal in patients with idiopathic cervical dystonia (n = 39) versus matched controls (n = 37). A systematic literature search identified 25 cases of lesion-induced cervical dystonia. Lesion locations were heterogeneous, with lesions scattered throughout the cerebellum, brainstem, and basal ganglia. However, these heterogeneous lesion locations were all part of a single functionally connected brain network. Positive connectivity to the cerebellum and negative connectivity to the somatosensory cortex were specific markers for cervical dystonia compared to lesions causing other neurological symptoms. Connectivity with these two regions defined a single brain network that encompassed the heterogeneous lesion locations causing cervical dystonia. These cerebellar and somatosensory regions also showed abnormal connectivity in patients with idiopathic cervical dystonia. Finally, the most effective deep brain stimulation sites for treating dystonia were connected to these same cerebellar and somatosensory regions identified using lesion network mapping. These results lend insight into the causal neuroanatomical substrate of cervical dystonia, demonstrate convergence across idiopathic and acquired dystonia, and identify a network target for dystonia treatment.

A network-based response to the two-factor theory of delusion formation.

In response to Dr. Corlett's paper regarding the two factor theory of delusional misidentifications, I discuss further evidence that VMPFC damaged patients do not have an isolated factor 1 defect. I then discuss more broadly the limitations in the modular view of brain function that leads to the 2-factor theory. Finally, I propose a connectionist based interpretation of delusional misidentifications that better fits with the clinical data from patients with focal brain lesions showing how these lesion locations relate to complex brain networks.

Neuroimaging Abnormalities in Neurological Patients with Criminal Behavior.

PURPOSE OF REVIEW: Criminal behavior occurs in previously law-abiding neurological patients, including patients with traumatic brain injury, focal brain lesions, and dementia. Neuroimaging abnormalities in these patients allow one to explore the potential neuroanatomical correlates of criminal behavior. However, this process has been challenging because (1) It is difficult to determine the temporal relationship between criminal behavior and neurological disease onset; (2) Abnormalities in several different brain regions have been associated with criminal behavior; and (3) It is difficult to quantify neuroimaging abnormalities in individual subjects. RECENT FINDINGS: Recent studies have begun to address these concerns, showing that neuroimaging abnormalities in patients with criminal behavior localize to a common brain network, rather than a single specific brain region. New methods have been developed to identify atrophy patterns in individual patients, but have not yet been used in neurological patients with criminal behavior. Future advances will be important for making sure that neuroimaging data is used in a responsible manner in legal cases involving criminal behavior.

Finding the imposter: brain connectivity of lesions causing delusional misidentifications.

SEE MCKAY AND FURL DOI101093/AWW323 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Focal brain injury can sometimes lead to bizarre symptoms, such as the delusion that a family member has been replaced by an imposter (Capgras syndrome). How a single brain lesion could cause such a complex disorder is unclear, leading many to speculate that concurrent delirium, psychiatric disease, dementia, or a second lesion is required. Here we instead propose that Capgras and other delusional misidentification syndromes arise from single lesions at unique locations within the human brain connectome. This hypothesis is motivated by evidence that symptoms emerge from sites functionally connected to a lesion location, not just the lesion location itself. First, 17 cases of lesion-induced delusional misidentifications were identified and lesion locations were mapped to a common brain atlas. Second, lesion network mapping was used to identify brain regions functionally connected to the lesion locations. Third, regions involved in familiarity perception and belief evaluation, two processes thought to be abnormal in delusional misidentifications, were identified using meta-analyses of previous functional magnetic resonance imaging studies. We found that all 17 lesion locations were functionally connected to the left retrosplenial cortex, the region most activated in functional magnetic resonance imaging studies of familiarity. Similarly, 16 of 17 lesion locations were functionally connected to the right frontal cortex, the region most activated in functional magnetic resonance imaging studies of expectation violation, a component of belief evaluation. This connectivity pattern was highly specific for delusional misidentifications compared to four other lesion-induced neurological syndromes (P < 0.0001). Finally, 15 lesions causing other types of delusions were connected to expectation violation (P < 0.0001) but not familiarity regions, demonstrating specificity for delusion content. Our results provide potential neuroanatomical correlates for impaired familiarity perception and belief evaluation in patients with delusional misidentifications. More generally, we demonstrate a mechanism by which a single lesion can cause a complex neuropsychiatric syndrome based on that lesion's unique pattern of functional connectivity, without the need for pre-existing or hidden pathology.

Effects of cognitive reserve depend on executive and semantic demands of the task.

BACKGROUND: Cognitive reserve (CR) is one factor that helps to maintain cognitive function in patients with Alzheimer's disease (AD). Whether the effects of CR depend on the semantic/executive components of the task remains unknown. METHODS: 470 patients (138 with AD, 332 with mild cognitive impairment (MCI)) were selected from the Alzheimer's Disease Neuroimaging Initiative database. Linear regression models were used to determine the effects of CR (years of education) on cognitive performance after controlling for demographic factors and regional cortical atrophy. First, we assessed memory tasks with low (Auditory Verbal Learning Test (AVLT) discriminability), moderate (AVLT delayed recall) and high (Logical Memory Test (LMT) delayed recall) executive/semantic components. Next, we assessed tasks with lower (digit span forward, Trails A) or higher (digit span backwards, Trails B) executive demands, and lower (figure copying) or higher (naming, semantic fluency) semantic demands. RESULTS: High CR was significantly associated with performance on the LMT delayed recall, approached significance in the AVLT delayed recall and was not significantly associated with performance on AVLT discriminability. High CR was significantly associated with performance on the Trails B and digit span backwards, mildly associated with Trails A performance and was not associated with performance on digit span forwards. High CR was associated with performance on semantic but not visuospatial tasks. High CR was associated with semantic tasks in patients with both MCI and AD, but was only associated with executive functions in patients with MCI. CONCLUSION: CR may relate to executive functioning and semantic knowledge, leading to preserved cognitive performance in patients with AD pathology.

"Cat-gras" delusion: a unique misidentification syndrome and a novel explanation.

ABSRACT Capgras syndrome is a distressing delusion found in a variety of neurological and psychiatric diseases where a patient believes that a family member, friend, or loved one has been replaced by an imposter. Patients recognize the physical resemblance of a familiar acquaintance but feel that the identity of that person is no longer the same. Here we describe a 73-year-old male with right posterior frontal and bilateral anterior-medial frontal damage from prior brain trauma with a similar delusion of an imposter replacing his pet cat. Misidentification syndromes for animals, as opposed to humans, have been rarely reported. Neuropsychological testing showed deficits in executive processing and memory retrieval with prominent intrusions and false positive responses. The delusional belief content in Capgras syndrome has been hypothesized to result from loss of an emotional or autonomic response to familiar stimuli, from theory of mind deficits, or from loss of self-environment distinctions. We instead propose that Capgras delusions result from a dysfunction in linking external stimuli with retrieved internal autobiographical memories pertaining to that object. This leads to an erroneously learned identity that persists as a specific delusional belief.

Forensic Neurology and the Role of Neurologists in Forensic Evaluations.

Forensic psychiatrists may be asked to opine on neurological evidence or neurological diseases outside the scope of their expertise. This article discusses the value of involving experts trained in behavioral neurology in such cases. First, we describe the field of behavioral neurology and neuropsychiatry, the subspecialty available to both neurologists and psychiatrists focused on the behavioral, cognitive, and neuropsychiatric manifestations of neurological diseases. Next, we discuss the added value of behavioral neurologists in forensic cases, including assisting in the diagnostic evaluation for complex neuropsychiatric diseases, using expertise in localization to provide a strong scientific basis for linking neurodiagnostic testing to relevant neuropsychiatric symptoms, and assisting in relating these symptoms to the relevant legal question in cases where such symptoms may be less familiar to forensic psychiatrists, such as frontal lobe syndromes. We discuss approaches to integrating behavioral neurology with forensic psychiatry, highlighting the need for collaboration and mentorship between disciplines. Finally, we discuss several forensic cases highlighting the additional value of experts trained in behavioral neurology. We conclude that forensic psychiatrists should involve behavioral neurology experts when encountering neurological evidence that falls outside their scope of expertise, and the need for further cross-disciplinary collaboration and training.

Forensic neurology: a distinct subspecialty at the intersection of neurology, neuroscience and law.

Neurological evidence is increasingly used in criminal cases to argue that a defendant is less responsible for their behaviour, is not competent to stand trial or should receive a reduced punishment for the crime. Unfortunately, neurologists are rarely involved in such cases despite having the expertise to help to inform these decisions in court. In this Perspective, we advocate for the development of 'forensic neurology', a subspecialty of neurology focused on using neurological clinical and scientific expertise to address legal questions for the criminal justice system. We review literature suggesting that the incidence of criminal behaviour is higher in people with certain neurological disorders than the general public and that undiagnosed neurological abnormalities are common in people who commit crimes. We discuss the need for forensic neurologists in criminal cases to provide an opinion on what neurological diagnoses are present, the resulting symptoms and ultimately whether the symptoms affect legal determinations such as criminal responsibility or competency.

Forensic Neurology: Practice Considerations and Training Opportunities.

Neurologic evidence, including MRI, PET, and EEG, has been introduced in more than 2,800 criminal cases in the past decade, including 12% of all murder trials and 25% of death penalty trials, to argue whether neurologic diseases are present, contribute to criminal behavior, and ultimately whether the defendant is less criminally responsible, competent to stand trial, or should receive a reduced punishment for his or her crime. Unfortunately, neurologists are often not involved in these criminal cases despite being the medical specialty with the most relevant training and expertise to address these issues for the court. Reasons for the absence of neurologists in criminal cases include a lack of awareness from lawyers, judges, and other expert witnesses on the value of including neurologists in forensic evaluations, and the lack of experience, training, and willingness of neurologists to work as expert witnesses in criminal cases. Here, we discuss forensic neurology, a field bridging the gap between neurology, neuroscience, and the law. We discuss the process of performing forensic evaluations, including answering 3 fundamental questions: the neurologic diagnostic question, the behavioral neurology/neuropsychiatry question, and the forensic neurology question. We discuss practical aspects of performing forensic expert witness work and important ethical differences between the neurologist's role in treatment vs forensic settings. Finally, we discuss the currently available pathways for interested neurologists to receive additional training in forensic assessments.

Examining Associations Between Smartphone Use and Clinical Severity in Frontotemporal Dementia: Proof-of-Concept Study.

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged <65 years. Several challenges to conducting in-person evaluations in FTLD illustrate an urgent need to develop remote, accessible, and low-burden assessment techniques. Studies of unobtrusive monitoring of at-home computer use in older adults with mild cognitive impairment show that declining function is reflected in reduced computer use; however, associations with smartphone use are unknown. OBJECTIVE: This study aims to characterize daily trajectories in smartphone battery use, a proxy for smartphone use, and examine relationships with clinical indicators of severity in FTLD. METHODS: Participants were 231 adults (mean age 52.5, SD 14.9 years; n=94, 40.7% men; n=223, 96.5% non-Hispanic White) enrolled in the Advancing Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL study) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS study) Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Mobile App study, including 49 (21.2%) with mild neurobehavioral changes and no functional impairment (ie, prodromal FTLD), 43 (18.6%) with neurobehavioral changes and functional impairment (ie, symptomatic FTLD), and 139 (60.2%) clinically normal adults, of whom 55 (39.6%) harbored heterozygous pathogenic or likely pathogenic variants in an autosomal dominant FTLD gene. Participants completed the Clinical Dementia Rating plus National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains (CDR+NACC FTLD) scale, a neuropsychological battery; the Neuropsychiatric Inventory; and brain magnetic resonance imaging. The ALLFTD Mobile App was installed on participants' smartphones for remote, passive, and continuous monitoring of smartphone use. Battery percentage was collected every 15 minutes over an average of 28 (SD 4.2; range 14-30) days. To determine whether temporal patterns of battery percentage varied as a function of disease severity, linear mixed effects models examined linear, quadratic, and cubic effects of the time of day and their interactions with each measure of disease severity on battery percentage. Models covaried for age, sex, smartphone type, and estimated smartphone age. RESULTS: The CDR+NACC FTLD global score interacted with time on battery percentage such that participants with prodromal or symptomatic FTLD demonstrated less change in battery percentage throughout the day (a proxy for less smartphone use) than clinically normal participants (P<.001 in both cases). Additional models showed that worse performance in all cognitive domains assessed (ie, executive functioning, memory, language, and visuospatial skills), more neuropsychiatric symptoms, and smaller brain volumes also associated with less battery use throughout the day (P<.001 in all cases). CONCLUSIONS: These findings support a proof of concept that passively collected data about smartphone use behaviors associate with clinical impairment in FTLD. This work underscores the need for future studies to develop and validate passive digital markers sensitive to longitudinal clinical decline across neurodegenerative diseases, with potential to enhance real-world monitoring of neurobehavioral change.

Reliability and Validity of Smartphone Cognitive Testing for Frontotemporal Lobar Degeneration.

Importance: Frontotemporal lobar degeneration (FTLD) is relatively rare, behavioral and motor symptoms increase travel burden, and standard neuropsychological tests are not sensitive to early-stage disease. Remote smartphone-based cognitive assessments could mitigate these barriers to trial recruitment and success, but no such tools are validated for FTLD. Objective: To evaluate the reliability and validity of smartphone-based cognitive measures for remote FTLD evaluations. Design, Setting, and Participants: In this cohort study conducted from January 10, 2019, to July 31, 2023, controls and participants with FTLD performed smartphone application (app)-based executive functioning tasks and an associative memory task 3 times over 2 weeks. Observational research participants were enrolled through 18 centers of a North American FTLD research consortium (ALLFTD) and were asked to complete the tests remotely using their own smartphones. Of 1163 eligible individuals (enrolled in parent studies), 360 were enrolled in the present study; 364 refused and 439 were excluded. Participants were divided into discovery (n = 258) and validation (n = 102) cohorts. Among 329 participants with data available on disease stage, 195 were asymptomatic or had preclinical FTLD (59.3%), 66 had prodromal FTLD (20.1%), and 68 had symptomatic FTLD (20.7%) with a range of clinical syndromes. Exposure: Participants completed standard in-clinic measures and remotely administered ALLFTD mobile app (app) smartphone tests. Main Outcomes and Measures: Internal consistency, test-retest reliability, association of smartphone tests with criterion standard clinical measures, and diagnostic accuracy. Results: In the 360 participants (mean [SD] age, 54.0 [15.4] years; 209 [58.1%] women), smartphone tests showed moderate-to-excellent reliability (intraclass correlation coefficients, 0.77-0.95). Validity was supported by association of smartphones tests with disease severity (r range, 0.38-0.59), criterion-standard neuropsychological tests (r range, 0.40-0.66), and brain volume (standardized ß range, 0.34-0.50). Smartphone tests accurately differentiated individuals with dementia from controls (area under the curve [AUC], 0.93 [95% CI, 0.90-0.96]) and were more sensitive to early symptoms (AUC, 0.82 [95% CI, 0.76-0.88]) than the Montreal Cognitive Assessment (AUC, 0.68 [95% CI, 0.59-0.78]) (z of comparison, -2.49 [95% CI, -0.19 to -0.02]; P = .01). Reliability and validity findings were highly similar in the discovery and validation cohorts. Preclinical participants who carried pathogenic variants performed significantly worse than noncarrier family controls on 3 app tasks (eg, 2-back ß = -0.49 [95% CI, -0.72 to -0.25]; P < .001) but not a composite of traditional neuropsychological measures (ß = -0.14 [95% CI, -0.42 to 0.14]; P = .32). Conclusions and Relevance: The findings of this cohort study suggest that smartphones could offer a feasible, reliable, valid, and scalable solution for remote evaluations of FTLD and may improve early detection. Smartphone assessments should be considered as a complementary approach to traditional in-person trial designs. Future research should validate these results in diverse populations and evaluate the utility of these tests for longitudinal monitoring.