Dr. Younes is a fellowship-trained, board-certified neurologist and a clinical assistant professor in the Department of Neurology at Stanford University School of Medicine.

His areas of expertise include the diagnosis and treatment of Alzheimer’s disease, frontotemporal dementia, primary progressive aphasia, Lewy body dementia, normal pressure hydrocephalus and cognitive and behavioral impairments. For each patient, Dr. Younes develops a personalized plan of care. A plan may include his close collaboration with experts from psychiatry, nursing, pharmacy, genetic counseling, and other specialties. His goal is to ensure that each patient receives care that is both comprehensive and compassionate.

To help lead advances and innovations in his field, Dr. Younes conducts extensive research. He is studying the clinical, neuropsychological, socioemotional, genetic, and pathological features when a patient experiences degeneration of the right anterior temporal lobe area of the brain. This disorder can affect a person’s ability to process emotions and person-specific knowledge.

He also is researching how multimodal brain imaging, including magnetic resonance imaging (MRI) and Positron Emission Tomography (PET) combined with machine learning can help improve the detection of neurodegenerative diseases. In other research, he has participated in clinical trials of new drug therapies for Alzheimer’s disease.

Dr. Younes has presented research findings at meetings of the American Neurological Association, American Academy of Neurology, and American Psychiatric Association. Topics have included predictors of cognitive performance in dementia.

He has co-authored research articles published in the American Journal of Psychiatry, Annals of Clinical and Translational Neurology, Journal of Neuroimaging, and elsewhere. Subjects of these articles have included guidelines for diagnosing the effects of right anterior temporal lobe degeneration on behavior, treatment for symptoms of encephalitis, and the impact of mild traumatic brain injury on healthy older adults.

Dr. Younes has written chapters on frontotemporal dementia for Psychiatric Clinics as well as the epilepsy, coma, acute ischemic stroke, meningitis and encephalitis chapters for the textbook The Little Black Book of Neurology.

He is a member of the American Academy of Neurology, American Neurological Association, Alzheimer’s Association, and International Society for Frontotemporal Dementias.

Clinical Focus

  • Neurology
  • Cognitive Dysfunction
  • Alzheimer’s Disease
  • Frontotemporal Dementia
  • Primary Progressive Aphasia
  • Lewy Body Dementia
  • Normal Pressure Hydrocephalus

Academic Appointments

Professional Education

  • Residency: University of Texas Health Science Center (2018) TX
  • Fellowship: UCSF Dept of Neurology (2021) CA
  • Board Certification: American Board of Psychiatry and Neurology, Neurology (2018)
  • Medical Education: University of Damascus, Faculty of Medicine (2013) Syria

Clinical Trials

  • Bumetanide in Patients With Alzheimer's Disease Recruiting

    This study aims to investigate bumetanide in patients with biologically confirmed Alzheimer's disease (AD). Bumetanide is a potent diuretic administered orally and is FDA approved for the treatment of edema and hypertension. Repurposing bumetanide as a medication for AD has been proposed based on data that demonstrated its ability to "flip" the APOE genotype-dependent transcriptomic signatures in AD mouse and cell culture models. Critically, this discovery was subsequently explored in Electronic Health Record cohorts, which revealed that among individuals over the age of 65, bumetanide exposure was significantly associated with a lower prevalence of AD in three independent datasets. Primary Objective: To evaluate the safety and tolerability of bumetanide when administered to participants with biomarker-confirmed Alzheimer's disease. Secondary Objective: To evaluate the clinical and biomarker effects of bumetanide in participants with mild cognitive impairment or mild dementia due to Alzheimer's disease.

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All Publications

  • Diminished baseline autonomic outflow in semantic dementia relates to left-lateralized insula atrophy. NeuroImage. Clinical Hua, A. Y., Roy, A. R., Kosik, E. L., Morris, N. A., Chow, T. E., Lukic, S., Montembeault, M., Borghesani, V., Younes, K., Kramer, J. H., Seeley, W. W., Perry, D. C., Miller, Z. A., Rosen, H. J., Miller, B. L., Rankin, K. P., Gorno-Tempini, M. L., Sturm, V. E. 2023; 40: 103522


    In semantic dementia (SD), asymmetric degeneration of the anterior temporal lobes is associated with loss of semantic knowledge and alterations in socioemotional behavior. There are two clinical variants of SD: semantic variant primary progressive aphasia (svPPA), which is characterized by predominant atrophy in the anterior temporal lobe and insula in the left hemisphere, and semantic behavioral variant frontotemporal dementia (sbvFTD), which is characterized by predominant atrophy in those structures in the right hemisphere. Previous studies of behavioral variant frontotemporal dementia, an associated clinical syndrome that targets the frontal lobes and anterior insula, have found impairments in baseline autonomic nervous system activity that correlate with left-lateralized frontotemporal atrophy patterns and disruptions in socioemotional functioning. Here, we evaluated whether there are similar impairments in resting autonomic nervous system activity in SD that also reflect left-lateralized atrophy and relate to diminished affiliative behavior. A total of 82 participants including 33 people with SD (20 svPPA and 13 sbvFTD) and 49 healthy older controls completed a laboratory-based assessment of respiratory sinus arrhythmia (RSA; a parasympathetic measure) and skin conductance level (SCL; a sympathetic measure) during a two-minute resting baseline period. Participants also underwent structural magnetic resonance imaging, and informants rated their current affiliative behavior on the Interpersonal Adjective Scale. Results indicated that baseline RSA and SCL were lower in SD than in healthy controls, with significant impairments present in both svPPA and sbvFTD. Voxel-based morphometry analyses revealed left-greater-than-right atrophy related to diminished parasympathetic and sympathetic outflow in SD. While left-lateralized atrophy in the mid-to-posterior insula correlated with lower RSA, left-lateralized atrophy in the ventral anterior insula correlated with lower SCL. In SD, lower baseline RSA, but not lower SCL, was associated with lower gregariousness/extraversion. Neither autonomic measure related to warmth/agreeableness, however. Through the assessment of baseline autonomic nervous system physiology, the present study contributes to expanding conceptualizations of the biological basis of socioemotional alterations in svPPA and sbvFTD.

    View details for DOI 10.1016/j.nicl.2023.103522

    View details for PubMedID 37820490

  • Loop diuretics association with Alzheimer's disease risk. Frontiers in aging Graber-Naidich, A., Lee, J., Younes, K., Greicius, M. D., Le Guen, Y., He, Z. 2023; 4: 1211571


    Objectives: To investigate whether exposure history to two common loop diuretics, bumetanide and furosemide, affects the risk of developing Alzheimer's disease (AD) after accounting for socioeconomic status and congestive heart failure. Methods: Individuals exposed to bumetanide or furosemide were identified in the Stanford University electronic health record using the de-identified Observational Medical Outcomes Partnership platform. We matched the AD case cohort to a control cohort (1:20 case:control) on gender, race, ethnicity, and hypertension, and controlled for variables that could potentially be collinear with bumetanide exposure and/or AD diagnosis. Among individuals older than 65 years, 5,839 AD cases and 116,103 matched controls were included. A total of 1,759 patients (54 cases and 1,705 controls) were exposed to bumetanide. Results: After adjusting for socioeconomic status and other confounders, the exposure of bumetanide and furosemide was significantly associated with reduced AD risk (respectively, bumetanide odds ratio [OR] = 0.23; 95% confidence interval [CI], 0.15-0.36; p = 4.0 × 10-11; furosemide OR = 0.42; 95% CI, 0.38-0.47; p < 2.0 × 10-16). Discussion: Our study replicates in an independent sample that a history of bumetanide exposure is associated with reduced AD risk while also highlighting an association of the most common loop diuretic (furosemide) with reduced AD risk. These associations need to be additionally replicated, and the mechanism of action remains to be investigated.

    View details for DOI 10.3389/fragi.2023.1211571

    View details for PubMedID 37822457

    View details for PubMedCentralID PMC10563814

  • The pathotome and precision health. Brain : a journal of neurology Younes, K., Mormino, E. 2023

    View details for DOI 10.1093/brain/awad154

    View details for PubMedID 37150902

  • The MVP or the tombstone: is tau the correct target to treat Alzheimer's disease? Brain : a journal of neurology Younes, K., Sha, S. J. 2023

    View details for DOI 10.1093/brain/awad151

    View details for PubMedID 37150887

  • Performance of a fully-automated Lumipulse plasma phospho-tau181 assay for Alzheimer's disease. Alzheimer's research & therapy Wilson, E. N., Young, C. B., Ramos Benitez, J., Swarovski, M. S., Feinstein, I., Vandijck, M., Le Guen, Y., Kasireddy, N. M., Shahid, M., Corso, N. K., Wang, Q., Kennedy, G., Trelle, A. N., Lind, B., Channappa, D., Belnap, M., Ramirez, V., Skylar-Scott, I., Younes, K., Yutsis, M. V., Le Bastard, N., Quinn, J. F., van Dyck, C. H., Nairn, A., Fredericks, C. A., Tian, L., Kerchner, G. A., Montine, T. J., Sha, S. J., Davidzon, G., Henderson, V. W., Longo, F. M., Greicius, M. D., Wagner, A. D., Wyss-Coray, T., Poston, K. L., Mormino, E. C., Andreasson, K. I. 2022; 14 (1): 172


    BACKGROUND: The recent promise of disease-modifying therapies for Alzheimer's disease (AD) has reinforced the need for accurate biomarkers for early disease detection, diagnosis and treatment monitoring. Advances in the development of novel blood-based biomarkers for AD have revealed that plasma levels of tau phosphorylated at various residues are specific and sensitive to AD dementia. However, the currently available tests have shortcomings in access, throughput, and scalability that limit widespread implementation.METHODS: We evaluated the diagnostic and prognostic performance of a high-throughput and fully-automated Lumipulse plasma p-tau181 assay for the detection of AD. Plasma from older clinically unimpaired individuals (CU, n = 463) and patients with mild cognitive impairment (MCI, n = 107) or AD dementia (n = 78) were obtained from the longitudinal Stanford University Alzheimer's Disease Research Center (ADRC) and the Stanford Aging and Memory Study (SAMS) cohorts. We evaluated the discriminative accuracy of plasma p-tau181 for clinical AD diagnosis, association with amyloid beta peptides and p-tau181 concentrations in CSF, association with amyloid positron emission tomography (PET), and ability to predict longitudinal cognitive and functional change.RESULTS: The assay showed robust performance in differentiating AD from control participants (AUC 0.959, CI: 0.912 to 0.990), and was strongly associated with CSF p-tau181, CSF Abeta42/Abeta40 ratio, and amyloid-PET global SUVRs. Associations between plasma p-tau181 with CSF biomarkers were significant when examined separately in Abeta+ and Abeta- groups. Plasma p-tau181 significantly increased over time in CU and AD diagnostic groups. After controlling for clinical diagnosis, age, sex, and education, baseline plasma p-tau181 predicted change in MoCA overall and change in CDR Sum of Boxes in the AD group over follow-up of up to 5 years.CONCLUSIONS: This fully-automated and available blood-based biomarker assay therefore may be useful for early detection, diagnosis, prognosis, and treatment monitoring of AD.

    View details for DOI 10.1186/s13195-022-01116-2

    View details for PubMedID 36371232

  • Right temporal lobe and socioemotional semantics: semantic behavioural variant frontotemporal dementia. Brain : a journal of neurology Younes, K., Borghesani, V., Montembeault, M., Spina, S., Mandelli, M. L., Welch, A. E., Weis, E., Callahan, P., Elahi, F. M., Hua, A. Y., Perry, D. C., Karydas, A., Geschwind, D., Huang, E., Grinberg, L. T., Kramer, J. H., Boxer, A. L., Rabinovici, G. D., Rosen, H. J., Seeley, W. W., Miller, Z. A., Miller, B. L., Sturm, V. E., Rankin, K. P., Luisa Gorno-Tempini, M. 2022


    Focal anterior temporal lobe (ATL) degeneration often preferentially affects the left or right hemisphere. While patients with left-predominant ATL (lATL) atrophy show severe anomia and verbal semantic deficits and meet criteria for semantic variant primary progressive aphasia (svPPA) and semantic dementia, patients with early right ATL (rATL) atrophy are more difficult to diagnose as their symptoms are less well understood. Focal rATL atrophy is associated with prominent emotional and behavioral changes, and patients often meet, or go on to meet, criteria for behavioral variant frontotemporal dementia (bvFTD). Uncertainty around early symptoms and absence of an overarching clinicoanatomical framework continue to hinder proper diagnosis and care of patients with rATL disease. Here, we examine a large, well-characterized, longitudinal cohort of patients with rATL-predominant degeneration and propose new criteria and nosology. We identified individuals from our database with a clinical diagnosis of bvFTD or svPPA and a structural MRI (n=478). Based on neuroimaging criteria, we defined three patient groups: rATL-predominant atrophy with relative sparing of the frontal lobes (n=46), frontal-predominant atrophy with relative sparing of the rATL (n=79), and lATL-predominant atrophy with relative sparing of the frontal lobes (n=75). We compared the clinical, neuropsychological, genetic, and pathological profiles of these groups. In the rATL-predominant group, the earliest symptoms were loss of empathy (27%), person-specific semantic impairment (23%), and complex compulsions and rigid thought process (18%). On testing, this group exhibited greater impairments in Emotional Theory of Mind, recognition of famous people (from names and face), and facial affect naming (despite preserved face perception) than the frontal- and lATL-predominant groups. The clinical symptoms in the first three years of the disease alone were highly sensitive (81%) and specific (84%) differentiating rATL-predominant from frontal-predominant groups. FTLD-TDP (84%) was the most common pathology of the rATL-predominant group. rATL-predominant degeneration is characterized by early loss of empathy and person-specific knowledge, deficits that are caused by progressive decline in semantic memory for concepts of socioemotional relevance. Guided by our results, we outline new diagnostic criteria and propose the name, "semantic behavioral variant frontotemporal dementia" (sbvFTD), which highlights the underlying cognitive mechanism and the predominant symptomatology. These diagnostic criteria will facilitate early identification and care of patients with early, focal rATL degeneration as well as in vivo prediction of FTLD-TDP pathology.

    View details for DOI 10.1093/brain/awac217

    View details for PubMedID 35731122

  • Divergent Cortical Tau Positron Emission Tomography Patterns Among Patients With Preclinical Alzheimer Disease. JAMA neurology Young, C. B., Winer, J. R., Younes, K., Cody, K. A., Betthauser, T. J., Johnson, S. C., Schultz, A., Sperling, R. A., Greicius, M. D., Cobos, I., Poston, K. L., Mormino, E. C., Alzheimers Disease Neuroimaging Initiative and the Harvard Aging Brain Study, Weiner, M. W., Aisen, P., Petersen, R., Jack, C. R., Jagust, W., Trojanowki, J. Q., Toga, A. W., Beckett, L., Green, R. C., Saykin, A. J., Morris, J. C., Perrin, R. J., Shaw, L. M., Khachaturian, Z., Carrillo, M., Potter, W., Barnes, L., Bernard, M., Gonzalez, H., Ho, C., Hsiao, J. K., Jackson, J., Masliah, E., Masterman, D., Okonkwo, O., Ryan, L., Silverberg, N., Fleisher, A., Sacrey, D. T., Fockler, J., Conti, C., Veitch, D., Neuhaus, J., Jin, C., Nosheny, R., Ashford, M., Flenniken, D., Kormos, A., Montine, T., Rafii, M., Raman, R., Jimenez, G., Donohue, M., Gessert, D., Salazar, J., Zimmerman, C., Cabrera, Y., Walter, S., Miller, G., Coker, G., Clanton, T., Hergesheimer, L., Smith, S., Adegoke, O., Mahboubi, P., Moore, S., Pizzola, J., Shaffer, E., Harvey, D., Forghanian-Arani, A., Borowski, B., Ward, C., Schwarz, C., Jones, D., Gunter, J., Kantarci, K., Senjem, M., Vemuri, P., Reid, R., Fox, N. C., Malone, I., Thompson, P., Thomopoulos, S. I., Nir, T. M., Jahanshad, N., DeCarli, C., Knaack, A., Fletcher, E., Tosun-Turgut, D., Chen, S. R., Choe, M., Crawford, K., Yuschkevich, P. A., Das, S., Koeppe, R. A., Reiman, E. M., Chen, K., Mathis, C., Landau, S., Cairns, N. J., Householder, E., Franklin, E., Bernhardt, H., Taylor-Reinwald, L., Korecka, M., Figurski, M., Neu, S., Nho, K., Risacher, S. L., Apostolova, L. G., Shen, L., Foroud, T. M., Nudelman, K., Faber, K., Wilmes, K., Thal, L., Johnson, K. A., Sperling, R. A. 2022


    Importance: Characterization of early tau deposition in individuals with preclinical Alzheimer disease (AD) is critical for prevention trials that aim to select individuals at risk for AD and halt the progression of disease.Objective: To evaluate the prevalence of cortical tau positron emission tomography (PET) heterogeneity in a large cohort of clinically unimpaired older adults with elevated beta-amyloid (A+).Design, Setting, and Participants: This cross-sectional study examined prerandomized tau PET, amyloid PET, structural magnetic resonance imaging, demographic, and cognitive data from the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study from April 2014 to December 2017. Follow-up analyses used observational tau PET data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Harvard Aging Brain Study (HABS), and the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center (together hereinafter referred to as Wisconsin) to evaluate consistency. Participants were clinically unimpaired at the study visit closest to the tau PET scan and had available amyloid and tau PET data (A4 Study, n=447; ADNI, n=433; HABS, n=190; and Wisconsin, n=328). No participants who met eligibility criteria were excluded. Data were analyzed from May 11, 2021, to January 25, 2022.Main Outcomes and Measures: Individuals with preclinical AD with heterogeneous cortical tau PET patterns (A+T cortical+) were identified by examining asymmetrical cortical tau signal and disproportionate cortical tau signal relative to medial temporal lobe (MTL) tau. Voxelwise tau patterns, amyloid, neurodegeneration, cognition, and demographic characteristics were examined.Results: The 447 A4 participants (A+ group, 392; and normal beta-amyloid group, 55), with a mean (SD) age of 71.8 (4.8) years, included 239 women (54%). A total of 36 individuals in the A+ group (9% of the A+ group) exhibited heterogeneous cortical tau patterns and were further categorized into 3 subtypes: asymmetrical left, precuneus dominant, and asymmetrical right. A total of 116 individuals in the A+ group (30% of the A+ group) showed elevated MTL tau (A+T MTL+). Individuals in the A+T cortical+ group were younger than those in the A+T MTL+ group (t61.867=-2.597; P=.03). Across the A+T cortical+ and A+T MTL+ groups, increased regional tau was associated with reduced hippocampal volume and MTL thickness but not with cortical thickness. Memory scores were comparable between the A+T cortical+ and A+T MTL+ groups, whereas executive functioning scores were lower for the A+T cortical+ group than for the A+T MTL+ group. The prevalence of the A+T cortical+ group and tau patterns within the A+T cortical+ group were consistent in ADNI, HABS, and Wisconsin.Conclusions and Relevance: This study suggests that early tau deposition may follow multiple trajectories during preclinical AD and may involve several cortical regions. Staging procedures, especially those based on neuropathology, that assume a uniform trajectory across individuals are insufficient for disease monitoring with tau imaging.

    View details for DOI 10.1001/jamaneurol.2022.0676

    View details for PubMedID 35435938

  • Selective vulnerability to atrophy in sporadic Creutzfeldt-Jakob disease ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY Younes, K., Rojas, J. C., Wolf, A., Sheng-Yang, G. M., Paoletti, M., Toller, G., Caverzasi, E., Mandelli, M., Illan-Gala, I., Kramer, J. H., Cobigo, Y., Miller, B. L., Rosen, H. J., Geschwind, M. D. 2021; 8 (6): 1183-1199


    Identification of brain regions susceptible to quantifiable atrophy in sporadic Creutzfeldt-Jakob disease (sCJD) should allow for improved understanding of disease pathophysiology and development of structural biomarkers that might be useful in future treatment trials. Although brain atrophy is not usually present by visual assessment of MRIs in sCJD, we assessed whether using voxel-based morphometry (VBM) can detect group-wise brain atrophy in sCJD.3T brain MRI data were analyzed with VBM in 22 sCJD participants and 26 age-matched controls. Analyses included relationships of regional brain volumes with major clinical variables and dichotomization of the cohort according to expected disease duration based on prion molecular classification (i.e., short-duration/Fast-progressors (MM1, MV1, and VV2) vs. long-duration/Slow-progressors (MV2, VV1, and MM2)). Structural equation modeling (SEM) was used to assess network-level interactions of atrophy between specific brain regions.sCJD showed selective atrophy in cortical and subcortical regions overlapping with all but one region of the default mode network (DMN) and the insulae, thalami, and right occipital lobe. SEM showed that the effective connectivity model fit in sCJD but not controls. The presence of visual hallucinations correlated with right fusiform, bilateral thalami, and medial orbitofrontal atrophy. Interestingly, brain atrophy was present in both Fast- and Slow-progressors. Worse cognition was associated with bilateral mesial frontal, insular, temporal pole, thalamus, and cerebellum atrophy.Brain atrophy in sCJD preferentially affects specific cortical and subcortical regions, with an effective connectivity model showing strength and directionality between regions. Brain atrophy is present in Fast- and Slow-progressors, correlates with clinical findings, and is a potential biomarker in sCJD.

    View details for DOI 10.1002/acn3.51290

    View details for Web of Science ID 000647027700001

    View details for PubMedID 33949799

    View details for PubMedCentralID PMC8164858

  • Diagnostic Utility of Measuring Cerebral Atrophy in the Behavioral Variant of Frontotemporal Dementia and Association With Clinical Deterioration JAMA NETWORK OPEN Illan-Gala, I., Falgas, N., Friedberg, A., Castro-Suarez, S., Keret, O., Rogers, N., Oz, D., Nigro, S., Quattrone, A., Quattrone, A., Wolf, A., Younes, K., Santos-Santos, M., Borrego-Ecija, S., Cobigo, Y., Dols-Icardo, O., Llado, A., Sanchez-Valle, R., Clarimon, J., Blesa, R., Alcolea, D., Fortea, J., Lleo, A., Grinberg, L. T., Spina, S., Kramer, J. H., Rabinovici, G. D., Boxer, A., Gorno Tempini, M., Miller, B. L., Seeley, W. W., Rosen, H. J., Perry, D. C. 2021; 4 (3): e211290


    The presence of atrophy on magnetic resonance imaging can support the diagnosis of the behavioral variant of frontotemporal dementia (bvFTD), but reproducible measurements are lacking.To assess the diagnostic and prognostic utility of 6 visual atrophy scales (VAS) and the Magnetic Resonance Parkinsonism Index (MRPI).In this diagnostic/prognostic study, data from 235 patients with bvFTD and 225 age- and magnetic resonance imaging-matched control individuals from 3 centers were collected from December 1, 1998, to September 30, 2019. One hundred twenty-one participants with bvFTD had high confidence of frontotemporal lobar degeneration (FTLD) (bvFTD-HC), and 19 had low confidence of FTLD (bvFTD-LC). Blinded clinicians applied 6 previously validated VAS, and the MRPI was calculated with a fully automated approach. Cortical thickness and subcortical volumes were also measured for comparison. Data were analyzed from February 1 to June 30, 2020.The main outcomes of this study were bvFTD-HC or a neuropathological diagnosis of 4-repeat (4R) tauopathy and the clinical deterioration rate (assessed by longitudinal measurements of Clinical Dementia Rating Sum of Boxes). Measures of cerebral atrophy included VAS scores, the bvFTD atrophy score (sum of VAS scores in orbitofrontal, anterior cingulate, anterior temporal, medial temporal lobe, and frontal insula regions), the MRPI, and other computerized quantifications of cortical and subcortical volumes. The areas under the receiver operating characteristic curve (AUROC) were calculated for the differentiation of participants with bvFTD-HC and bvFTD-LC and controls. Linear mixed models were used to evaluate the ability of atrophy measures to estimate longitudinal clinical deterioration.Of the 460 included participants, 296 (64.3%) were men, and the mean (SD) age was 62.6 (11.4) years. The accuracy of the bvFTD atrophy score for the differentiation of bvFTD-HC from controls (AUROC, 0.930; 95% CI, 0.903-0.957) and bvFTD-HC from bvFTD-LC (AUROC, 0.880; 95% CI, 0.787-0.972) was comparable to computerized measures (AUROC, 0.973 [95% CI, 0.954-0.993] and 0.898 [95% CI, 0.834-0.962], respectively). The MRPI was increased in patients with bvFTD and underlying 4R tauopathies compared with other FTLD subtypes (14.1 [2.0] vs 11.2 [2.6] points; P < .001). Higher bvFTD atrophy scores were associated with faster clinical deterioration in bvFTD (1.86-point change in Clinical Dementia Rating Sum of Boxes score per bvFTD atrophy score increase per year; 95% CI, 0.99-2.73; P < .001).Based on these study findings, in bvFTD, VAS increased the diagnostic certainty of underlying FTLD, and the MRPI showed potential for the detection of participants with underlying 4R tauopathies. These widely available measures of atrophy can also be useful to estimate longitudinal clinical deterioration.

    View details for DOI 10.1001/jamanetworkopen.2021.1290

    View details for Web of Science ID 000627897500006

    View details for PubMedID 33704477

    View details for PubMedCentralID PMC7953307

  • Association of remote mild traumatic brain injury with cortical amyloid burden in clinically normal older adults BRAIN IMAGING AND BEHAVIOR Asken, B. M., Mantyh, W. G., La Joie, R., Strom, A., Casaletto, K. B., Staffaroni, A. M., Apple, A. C., Lindbergh, C. A., Iaccarino, L., You, M., Grant, H., Fonseca, C., Windon, C., Younes, K., Tanner, J., Rabinovici, G. D., Kramer, J. H., Gardner, R. C. 2021


    We investigated whether clinically normal older adults with remote, mild traumatic brain injury (mTBI) show evidence of higher cortical Aβ burden. Our study included 134 clinically normal older adults (age 74.1 ± 6.8 years, 59.7% female, 85.8% white) who underwent Aβ positron emission tomography (Aβ-PET) and who completed the Ohio State University Traumatic Brain Injury Identification questionnaire. We limited participants to those reporting injuries classified as mTBI. A subset (N = 30) underwent a second Aβ-PET scan (mean 2.7 years later). We examined the effect of remote mTBI on Aβ-PET burden, interactions between remote mTBI and age, sex, and APOE status, longitudinal Aβ accumulation, and the interaction between remote mTBI and Aβ burden on memory and executive functioning. Of 134 participants, 48 (36%) reported remote mTBI (0, N = 86; 1, N = 31, 2+, N = 17; mean 37 ± 23 years since last mTBI). Effect size estimates were small to negligible for the association of remote mTBI with Aβ burden (p = .94, η2 < 0.01), and for all interaction analyses. Longitudinally, we found a non-statistically significant association of those with remote mTBI (N = 11) having a faster rate of Aβ accumulation (B = 0.01, p = .08) than those without (N = 19). There was no significant interaction between remote mTBI and Aβ burden on cognition. In clinically normal older adults, history of mTBI is not associated with greater cortical Aβ burden and does not interact with Aβ burden to impact cognition. Longitudinal analyses suggest remote mTBI may be associated with more rapid cortical Aβ accumulation. This finding warrants further study in larger and more diverse samples with well-characterized lifelong head trauma exposure.

    View details for DOI 10.1007/s11682-020-00440-1

    View details for Web of Science ID 000607018500002

    View details for PubMedID 33432536

  • Right Anterior Temporal Degeneration, Emotions, and Loss of Nonverbal Semantics: Guidelines for Diagnosis of the Emotional Semantic Variant Frontotemporal Dementia MedRxiv Younes, K., Borghesani, V., Montembeault, M., Spina, S., Mandelli, M., Welch, A., Weis, E., Callahan, P., Elahi, F., Hua, A., Perry, D., Karydas, A., Geschwind, D., Huang, E., Grinberg, L., Kramer, J., Boxer, A., Rabinovici, G., Rosen, H., Seeley, W., Miller, Z., Miller, B., Sturm, V., Rankin, K., Gorno-Tempini, M. 2021
  • Topiramate as Possible Treatment for Catatonia in Anti-NMDA Receptor Encephalitis Melicher, T., Younes, K. The American Journal of Psychiatry. 2021


    Anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis is a disorder characterized by the presence of pathological auto-antibodies, frequently paraneoplastic, and presenting primarily in young women. The condition has a variable neuropsychiatric presentation, with symptoms frequently including agitation, psychotic symptoms, behavioral changes, generalized or partial seizures, autonomic abnormalities, and hypoventilation. Catatonic symptoms are also frequently present. Catatonia is a syndrome of unclear pathophysiology, hypothesized to be caused by an underlying dysfunction in the GABA­ergic system and typically treated with the benzodiazepine lorazepam or electroconvulsive therapy (ECT). However, there is also evidence for the involvement of glutamate in catatonia, as well as the efficacy of glutamatergic agents, including amantadine, memantine, and topiramate. Here, the authors present the case of a 20-year-old female patient who was admitted with a severe catatonia in the setting of anti-NMDA receptor encephalitis. Because of concerns for side effects of lorazepam and ECT, the patient elected to try a different treatment. Topiramate was chosen due to its good tolerability, prior evidence of efficacy in catatonia (though not in cases of anti-NMDA receptor encephalitis), and its mechanism of action on both GABA receptors and on kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. The patient improved rapidly with the treatment. To the authors' knowledge, this is the first published case of successful treatment of catatonia in anti-NMDA receptor encephalitis with topiramate.

  • Regional and hemispheric susceptibility of the temporal lobe to FTLD-TDP type C pathology NEUROIMAGE-CLINICAL Borghesani, V., Battistella, G., Mandelli, M. L., Welch, A., Weis, E., Younes, K., Neuhaus, J., Grinberg, L. T., Seeley, W. M., Spina, S., Miller, B., Miller, Z., Gorno-Tempini, M. L. 2020; 28: 102369


    Post-mortem studies show that focal anterior temporal lobe (ATL) neurodegeneration is most often caused by frontotemporal lobar degeneration TDP-43 type C pathology. Clinically, these patients are described with different terms, such as semantic variant primary progressive aphasia (svPPA), semantic dementia (SD), or right temporal variant frontotemporal dementia (FTD) depending on whether the predominant symptoms affect language, semantic knowledge for object or people, or socio-emotional behaviors. ATL atrophy presents with various degrees of lateralization, with right-sided cases considered rarer even though estimation of their prevalence is hampered by the paucity of studies on well-characterized, pathology-proven cohorts. Moreover, it is not clear whether left and right variants show a similar distribution of atrophy within the ATL cross-sectionally and longitudinally. Here we study the largest cohort to-date of pathology-proven TDP-43-C cases diagnosed during life as svPPA, SD or right temporal variant FTD. We analyzed clinical, cognitive, and neuroimaging data from 30 cases, a subset of which was followed longitudinally. Guided by recent structural and functional parcellation studies, we constructed four bilateral ATL regions of interest (ROIs). The computation of an atrophy lateralization index allowed the comparison of atrophy patterns between the two hemispheres. This led to an automatic, imaging-based classification of the cases as left-predominant or right-predominant. We then compared the two groups in terms of regional atrophy patterns within the ATL ROIs (cross-sectionally) and atrophy progression (longitudinally). Results showed that 40% of pathology proven cases of TDP-43-C diagnosed with a temporal variant presented with right-lateralized atrophy. Moreover, the findings of our ATL ROI analysis indicated that, irrespective of atrophy lateralization, atrophy distribution within both ATLs follows a medial-to-lateral gradient. Finally, in both left and right cases, atrophy appeared to progress to the contralateral ATL, and from the anterior temporal pole to posterior temporal and orbitofrontal regions. Taken together, our findings indicate that incipient right predominant ATL atrophy is common in TDP-43-C pathology, and that distribution of damage within the ATLs appears to be the same in left- and right- sided variants. Thus, regardless of differences in clinical phenotype and atrophy lateralization, both temporal variants of FTD should be viewed as a spectrum presentation of the same disease.

    View details for DOI 10.1016/j.nicl.2020.102369

    View details for Web of Science ID 000600619100013

    View details for PubMedID 32798912

    View details for PubMedCentralID PMC7426562

  • Hepatic Encephalopathy Mimicking Acute Dominant Middle Cerebral Artery Ischemic Stroke: A Case Report CASE REPORTS IN NEUROLOGY Younes, K., Gonzales, N., Sarraj, A., Bonfante, E., Jagolino-Cole, A. 2019; 11 (3): 304-311


    Hepatic encephalopathy and hyperammonemia are common in the setting of liver disease and have been associated with both generalized and focal neurological deficits. We report a case of hepatic encephalopathy with transaminitis in the setting of hyperammonemia clinically mimicking acute dominant middle cerebral artery (MCA) syndrome. A 59-year-old right-handed woman had new-onset expressive aphasia, left gaze deviation, and right hemiparesis consistent with MCA stroke. Her symptoms began 12 h after transarterial chemoembolization, a procedure to embolize blood supply and provide cytotoxic agents to a hepatocellular carcinoma tumor. Thrombocytopenia and age-indeterminate hypodensities on brain CT precluded intravenous thrombolytic administration. MRI revealed predominantly dominant hemisphere subcortical restricted diffusion with no cortical involvement. Due to a mismatch between the MRI findings and the neurological symptoms, she underwent digital subtraction cerebral angiography to assess candidacy for intra-arterial thrombectomy, which revealed completely patent MCAs with intact filling of the distal branches. Liver enzymes and ammonia were elevated. The patient was treated with lactulose and intravenous fluids. After normalization of liver enzymes, the patient's neurological deficits resolved. Reversal of this patient's focal symptoms with medical management could potentially be explained by the recovery of blood flow-metabolic demand mismatch caused by worsening liver dysfunction and hyperammonemia. As acute stroke therapies and interventions increase in utility for large artery acute ischemic stroke, it is vital to recognize hepatic encephalopathy and liver failure as part of the differential diagnosis for patients presenting with MCA syndrome.

    View details for DOI 10.1159/000504017

    View details for Web of Science ID 000506585600009

    View details for PubMedID 31824285

    View details for PubMedCentralID PMC6902223

  • Verbal semantics and the left dorsolateral anterior temporal lobe: a longitudinal case of bilateral temporal degeneration APHASIOLOGY Vonk, J. J., Borghesani, V., Battistella, G., Younes, K., DeLeon, J., Welch, A., Hubbard, H., Miller, Z. A., Miller, B. L., Gorno-Tempini, M. 2020; 34 (7): 865-885


    Semantic variant primary progressive aphasia (svPPA), a clinical syndrome characterized by loss of semantic knowledge, is associated with neurodegeneration that starts in the anterior temporal lobe (ATL) and gradually spreads towards posterior temporal and medial frontal areas. At the earliest stages, atrophy may be predominantly lateralized to either the left or right ATL, leading to different clinical profiles with greatest impairment of word comprehension or visual/social semantics, respectively.We report the in-depth longitudinal investigation of cognitive and neuroanatomical features of JB, an unusual case of ATL neurodegeneration with relative sparing of left lateral ATL regions.Over the course of nine years, neurodegeneration progressed to involve bilateral temporo-lateral and frontal regions, resulting in a relatively symmetric and diffuse frontotemporal atrophy pattern. In parallel, JB developed greater behavioral, cognitive, and language impairments, as well as signs of motor neuron disease at her last evaluation. Episodic memory and socio-emotional processing deficits arose, likely secondary to semantic verbal deficits, while visuospatial processing, executive function, and non-semantic language abilities remained largely unaffected throughout the course of the disease.The details of this rare case of early medial more than lateral ATL degeneration are consistent with a bilateral organization of the semantic system and, crucially, with a functional dissociation between medial paralimbic and lateral neocortical temporal regions. Cases of frontotemporal dementia (FTD) such as JB, who initially do not meet current clinical criteria for svPPA and instead present with some features of behavioral variant FTD, highlight the need for specific criteria for the right temporal variant of FTD that we propose could be called semantic variant FTD.

    View details for DOI 10.1080/02687038.2019.1659935

    View details for Web of Science ID 000484996000001

    View details for PubMedID 33012947

    View details for PubMedCentralID PMC7529336

  • Diffusion Tensor Imaging of the Superior Thalamic Radiation and Cerebrospinal Fluid Distribution in Idiopathic Normal Pressure Hydrocephalus JOURNAL OF NEUROIMAGING Younes, K., Hasan, K. M., Kamali, A., McGough, C. E., Keser, Z., Hasan, O., Melicher, T., Kramer, L. A., Schulz, P. E., Alzheimer's Dis Neuroimaging Initi 2019; 29 (2): 242-251


    Ventricular enlargement in elderly raises a challenging differential diagnosis to physicians. While Alzheimer's disease is the most common form of dementia, idiopathic normal pressure hydrocephalus (iNPH) constitutes a potentially reversible syndrome. iNPH has a unique pathophysiology pertaining to cerebrospinal fluid (CSF) dynamics and periventricular white matter. We aimed to determine the effects of iNPH on periventricular white matter bundles and to further characterize its ventricular and sulcal CSF distribution by using diffusion tensor tractography (DTT) and CSF volumetrics on high resolution T1-weighted magnetic resonance imaging data.Deterministic DTT and validated volumetric parcellation were performed on 20 healthy elderly, 13 Alzheimer's disease (AD), and 9 iNPH patients. The superior thalamic radiation, corticospinal tract, and dentatorubrothalamic tract were traced and quantified using DTI studio software. Cloud-based volumetric parcellation was also performed on 138 healthy subjects across the lifespan, 13 AD, and 9 iNPH-patients. Ventricular and sulcal CSF volumes in the three groups were compared.Combining increased mean diffusivity of the superior thalamic radiation with ventricular volume resulted in clear separation of iNPH from the AD and age-matched healthy subject groups. Additionally, ventricular to sulcal CSF ratio, utilizing fully automated methods, was significantly greater in the iNPH patients compared to AD and healthy age-matched controls.Combined microstructural (DTT) and macrostructural (ventricular volume) changes is a promising radiological approach in studying ventriculomegaly. Automated estimation of the disproportionate ventricular and sulcal CSF ratio in patients presenting with ventriculomegaly may be important as radiologic markers in differentiating iNPH from other causes of ventriculomegaly.

    View details for DOI 10.1111/jon.12581

    View details for Web of Science ID 000460474700013

    View details for PubMedID 30461106

  • Yakovlev's Basolateral Limbic Circuit in Multiple Sclerosis Related Cognitive Impairment JOURNAL OF NEUROIMAGING Keser, Z., Kamali, A., Younes, K., Schulz, P. E., Nelson, F. M., Hasan, K. M. 2018; 28 (6): 596-600


    In 1948, Paul Yakovlev described an additional limbic circuit located basolateral to James Papez's circuit (1937) and included orbitofrontal cortex, amygdala, and dorsomedial nucleus of thalamus. This circuit is shown to be an important component of subcortical cognitive abilities. We aimed to demonstrate this circuit in a multiple sclerosis (MS) cohort using diffusion tensor imaging (DTI) and evaluate its role in MS-related cognitive impairment (CI).We enrolled cognitively intact (n = 10) and impaired (n = 36) MS patients who underwent a comprehensive cognitive assessment; the minimal assessment of cognitive function in MS (MACFIMS) and structural magnetic resonance imaging. Correlation analyses between volumetric and DTI-derived values of the orbitofrontothalamic (OFT), amygdalothalamic tracts (ATTs), and dorsomedial nucleus of thalamus and CI index derived from MACFIMS were computed after adjustment for age, education, and lesion load.We observed a consistent trend between CI index and bilateral dorsomedial nucleus' mean diffusivity (MD) (r = .316; P = .02), left OFT Fractional anisotropy (FA) (r = -.302; P = .02), MD (r = .380; .006), and radial diffusivities (RDs) (r = .432; P = .002), also with right ATT FA (r = -.475; P = .0006) and left ATT FA ( = -.487; P = .0005). After Bonferroni correction, correlations of left OFT RD and right and left ATT FA with CI were found to be significant.Our study provides in vivo DTI delineation of Yakovlev's historical basolateral limbic circuit and establishes a role in MS-related CI. These findings may potentially pave the way for future clinical studies using targeted invasive and noninvasive neurostimulation modalities for CI in MS.

    View details for DOI 10.1111/jon.12531

    View details for Web of Science ID 000449993400004

    View details for PubMedID 29893064

    View details for PubMedCentralID PMC6212307

  • Revealing the cerebello-ponto-hypothalamic pathway in the human brain NEUROSCIENCE LETTERS Kamali, A., Karbasian, N., Rabiei, P., Cano, A., Riascos, R. F., Tandon, N., Arevalo, O., Ocasio, L., Younes, K., Khayat-khoei, M., Mirbagheri, S., Hasan, K. M. 2018; 677: 1-5


    The cerebellum is shown to be involved in some limbic functions of the human brain such as emotion and affect. The major connection of the cerebellum with the limbic system is known to be through the cerebello-hypothalamic pathways. The consensus is that the projections from the cerebellar nuclei to the limbic system, and particularly the hypothalamus, or from the hypothalamus to the cerebellar nuclei, are through multisynaptic pathways in the bulbar reticular formation. The detailed anatomy of the pathways responsible for mediating these responses, however, is yet to be determined. Diffusion tensor imaging may be helpful in better visualizing the surgical anatomy of the cerebello-ponto-hypothalamic (CPH) pathway. This study aimed to investigate the utility of high-spatial-resolution diffusion tensor tractography for mapping the trajectory of the CPH tract in the human brain. Fifteen healthy adults were studied. We delineated, for the first time, the detailed trajectory of the CPH tract of the human brain in fifteen normal adult subjects using high-spatial-resolution diffusion tensor tractography. We further revealed the close relationship of the CPH tract with the optic tract, temporo-pontine tract, amygdalofugal tract and the fornix in the human brain.

    View details for DOI 10.1016/j.neulet.2018.04.024

    View details for Web of Science ID 000436220200001

    View details for PubMedID 29673951

  • Decreased Fractional Anisotropy as a Marker of Aberrant White Matter Integrity in Unaffected Offspring of Patients With Bipolar Disorder Melicher, T., Mwangi, B., Wu, M., Cao, B., Zeni, C., Younes, K., Zunta-Soares, G., Hasan, K., Soares, J. ELSEVIER SCIENCE INC. 2018: S176
  • Auto-antibodies against P/Q- and N-type voltage-dependent calcium channels mimicking frontotemporal dementia SAGE OPEN MEDICAL CASE REPORTS Younes, K., Lepow, L. A., Estrada, C., Schulz, P. E. 2018; 6: 2050313X17750928


    The behavioral variant of frontotemporal dementia is usually a sporadic and progressive neurodegenerative disorder. Here, we report the subacute onset of a frontotemporal dementia phenotype with a treatable etiology. The patient has a history of rheumatoid arthritis, episcleritis, and thyroid eye disease on immunosuppressive therapy. He experienced a rapid personality change, including inappropriate behavior, which suggested frontotemporal dementia. Results of imaging and neuropsychological testing also suggested frontotemporal dementia. Because of his autoimmune diseases and unusually short onset of symptoms, serum paraneoplastic panel and cerebrospinal fluid were analyzed and revealed elevated P/Q- and N-type calcium channel antibodies. Treatment with therapeutic plasma exchange resulted in a rapid improvement of his behavior and cognition. This case suggests that there may be some treatable causes of frontotemporal dementia symptomatology, that is, paraneoplastic antibodies. In the context of atypical features of frontotemporal dementia, practitioners should maintain a high index of suspicion.

    View details for DOI 10.1177/2050313X17750928

    View details for Web of Science ID 000450966100001

    View details for PubMedID 29662677

    View details for PubMedCentralID PMC5896852

  • Quantitative limbic system Mapping of Main cognitive Domains in Multiple sclerosis FRONTIERS IN NEUROLOGY Keser, Z., Hasan, K. M., Mwangi, B., Younes, K., Khayat-Khoei, M., Kamali, A., Lincoln, J. A., Nelson, F. M. 2018; 9: 132


    Cognitive impairment (CI) is common in multiple sclerosis (MS), but underlying mechanisms and their imaging correlates are not completely understood. The gray and white matter structures of the limbic system (LS) play crucial roles in different aspects of cognition. To investigate their role in MS related CI, and since a detailed evaluations are lacking in the literature, we used a comprehensive neuroimaging approach to evaluate CI's correlations with the main components of the LS.Ten non-cognitively impaired MS patients and 30 MS patients with diagnosed CI, who underwent a comprehensive neuropsychological evaluation were included in the analysis. Microstructural integrity, volumetry of main limbic gray and white matter structures and cortical thickness were assessed for associations with CI.Fornix and cingulum/cingulate cortices were found to be the strongest correlates of CI in MS. As expected, LS' gray and white matter structures were involved in various cognitive functions. Uncinate fasciculi showed significant correlation with verbal and visuospatial learning and memory, phonemic and semantic fluency; hippocampi with visuospatial skills, phonemic and semantic fluency, executive functions, and processing speed; thalami with verbal learning, visuospatial skills, semantic fluency; and amygdala with verbal recognition discrimination.This comprehensive neuroimaging approach elucidated the role of the main limbic structures in cognitive functions associated with MS-related CI.

    View details for DOI 10.3389/fneur.2018.00132

    View details for Web of Science ID 000427182000003

    View details for PubMedID 29593633

    View details for PubMedCentralID PMC5857595

  • Micro and Macrostructural Limbic System Correlates of Comprehensive Cognitive Symptomatology in Multiple Sclerosis using Quantitative MRI and DTI (P3.358) Neurology Keser, Z., Hasan, K., Mwangi, B., Kamali, A., Younes, K., Lincoln, J., Nelson, F. 2018
  • Diffusion tensor tractography of the mammillothalamic tract in the human brain using a high spatial resolution DTI technique Kamali, A., Zhang, C., Riascos, R., Tandon, N., Bonafante-Mejia, E., Patel, R., Lincoln, J., Rabiei, P., Ocasio, L., Younes, K., Hasan , K. Scientific Reports. 2018


    The mammillary bodies as part of the hypothalamic nuclei are in the central limbic circuitry of the human brain. The mammillary bodies are shown to be directly or indirectly connected to the amygdala, hippocampus, and thalami as the major gray matter structures of the human limbic system. Although it is not primarily considered as part of the human limbic system, the thalamus is shown to be involved in many limbic functions of the human brain. The major direct connection of the thalami with the hypothalamic nuclei is known to be through the mammillothalamic tract. Given the crucial role of the mammillothalamic tracts in memory functions, diffusion tensor imaging may be helpful in better visualizing the surgical anatomy of this pathway noninvasively. This study aimed to investigate the utility of high spatial resolution diffusion tensor tractography for mapping the trajectory of the mammillothalamic tract in the human brain. Fifteen healthy adults were studied after obtaining written informed consent. We used high spatial resolution diffusion tensor imaging data at 3.0 T. We delineated, for the first time, the detailed trajectory of the mammillothalamic tract of the human brain using deterministic diffusion tensor tractography.

  • Ictal motor sequences: Lateralization and localization values EPILEPSIA Marashly, A., Ewida, A., Agarwal, R., Younes, K., Lueders, H. O. 2016; 57 (3): 369-375


    To determine the lateralization and localization values of ictal motor sequences in the setting of focal epilepsy ending with a secondarily generalized motor seizure.Retrospectively, the ictal motor sequences were analyzed in patients with focal epilepsy ending with a secondarily generalized motor seizure by three readers blinded to all clinical and electrographic data. One representative seizure per patient was selected. Prevalence, positive predictive value (PPV), and Fleiss Kappa for the following motor signs were calculated: version, unilateral limb tonic posturing, unilateral limb clonic seizure, figure-of-4, M2e, hand dystonia, clonic asymmetric ending, and Todd's paralysis. Sequences of signs with a PPV ≥ 80% were then analyzed to determine their lateralization and localization values.A total of 47 seizures were studied. The "reliable" motor signs with a robust lateralizing value (PPV > 80%) were version, unilateral tonic posturing, M2e, unilateral clonic seizure, asymmetric clonic ending, and Todd's paralysis. Figure-of-4 and hand dystonia had a relatively low PPV, and therefore were not included in the following sequence analysis, which included only 38 patients with two or more motor signs of high PPV. Multiple combinations of temporal progression of motor signs were seen in these 38 patients, with version being the most common initial motor sign (29 of 38 patients) usually followed by M2e (15 of 29 patients), and/or a focal tonic seizure (7 of 29 patients). Accurate lateralization of the epileptogenic zone (EZ) with a PPV of 100% can be predicted when two or more reliable motor signs point to the same side. However, the various sequences of reliable motor signs did not differentiate between temporal and extratemporal epilepsy.The presence of reliable ictal motor signs in focal epilepsy is extremely valuable in lateralizing the EZ, but not in determining the localization of the EZ. This is especially useful when epilepsy surgery is indicated.

    View details for DOI 10.1111/epi.13322

    View details for Web of Science ID 000371998800009

    View details for PubMedID 26864781