The severity of neuropsychiatric symptoms is higher in early-onset than late-onset Alzheimer’s disease
Neus Falgàs
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Global Brain Health Institute, University of California, San Francisco, California, USA
Alzheimer’s Disease and Other Cognitive Disorders Unit, Hospital Clínic de Barcelona. Barcelona, Catalonia, Spain
Contribution: Conceptualization (lead), Formal analysis (lead), Investigation (lead), Methodology (equal), Writing - original draft (lead), Writing - review & editing (lead)
Search for more papers by this authorIsabel E. Allen
Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA
Contribution: Formal analysis (equal), Methodology (equal), Writing - review & editing (supporting)
Search for more papers by this authorSalvatore Spina
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Contribution: Methodology (equal), Writing - review & editing (equal)
Search for more papers by this authorHarli Grant
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Contribution: Project administration (equal), Writing - review & editing (supporting)
Search for more papers by this authorStefanie D. Piña Escudero
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Global Brain Health Institute, University of California, San Francisco, California, USA
Contribution: Data curation (supporting), Writing - review & editing (supporting)
Search for more papers by this authorJennifer Merrilees
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Contribution: Methodology (supporting), Writing - review & editing (supporting)
Search for more papers by this authorRosalie Gearhart
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Contribution: Methodology (supporting), Writing - review & editing (supporting)
Search for more papers by this authorHoward J. Rosen
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Global Brain Health Institute, University of California, San Francisco, California, USA
Contribution: Methodology (supporting), Writing - review & editing (supporting)
Search for more papers by this authorJoel H. Kramer
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Global Brain Health Institute, University of California, San Francisco, California, USA
Contribution: Methodology (supporting), Writing - review & editing (supporting)
Search for more papers by this authorWilliam W. Seeley
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Contribution: Methodology (supporting), Writing - review & editing (supporting)
Search for more papers by this authorThomas C. Neylan
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Department of Psychiatry, University of California, San Francisco, California, USA
Contribution: Conceptualization (supporting), Funding acquisition (equal), Writing - review & editing (equal)
Search for more papers by this authorBruce L. Miller
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Contribution: Funding acquisition (equal), Writing - review & editing (supporting)
Search for more papers by this authorGil D. Rabinovici
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Global Brain Health Institute, University of California, San Francisco, California, USA
Search for more papers by this authorLea T. Grinberg
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Global Brain Health Institute, University of California, San Francisco, California, USA
Department of Pathology, University of Sao Paulo Medical School, Sao Paulo, Brazil
Department of Pathology, University of California, San Francisco, California, USA
Contribution: Conceptualization (equal), Funding acquisition (equal), Writing - review & editing (supporting)
Search for more papers by this authorCorresponding Author
Christine M. Walsh
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Correspondence
Christine M. Walsh, Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, 675 Nelson Rising Lane, Suite 190, San Francisco, CA 94158, USA.
Email: [email protected]
Contribution: Conceptualization (lead), Supervision (lead), Writing - original draft (equal), Writing - review & editing (equal)
Search for more papers by this authorNeus Falgàs
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Global Brain Health Institute, University of California, San Francisco, California, USA
Alzheimer’s Disease and Other Cognitive Disorders Unit, Hospital Clínic de Barcelona. Barcelona, Catalonia, Spain
Contribution: Conceptualization (lead), Formal analysis (lead), Investigation (lead), Methodology (equal), Writing - original draft (lead), Writing - review & editing (lead)
Search for more papers by this authorIsabel E. Allen
Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA
Contribution: Formal analysis (equal), Methodology (equal), Writing - review & editing (supporting)
Search for more papers by this authorSalvatore Spina
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Contribution: Methodology (equal), Writing - review & editing (equal)
Search for more papers by this authorHarli Grant
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Contribution: Project administration (equal), Writing - review & editing (supporting)
Search for more papers by this authorStefanie D. Piña Escudero
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Global Brain Health Institute, University of California, San Francisco, California, USA
Contribution: Data curation (supporting), Writing - review & editing (supporting)
Search for more papers by this authorJennifer Merrilees
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Contribution: Methodology (supporting), Writing - review & editing (supporting)
Search for more papers by this authorRosalie Gearhart
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Contribution: Methodology (supporting), Writing - review & editing (supporting)
Search for more papers by this authorHoward J. Rosen
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Global Brain Health Institute, University of California, San Francisco, California, USA
Contribution: Methodology (supporting), Writing - review & editing (supporting)
Search for more papers by this authorJoel H. Kramer
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Global Brain Health Institute, University of California, San Francisco, California, USA
Contribution: Methodology (supporting), Writing - review & editing (supporting)
Search for more papers by this authorWilliam W. Seeley
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Contribution: Methodology (supporting), Writing - review & editing (supporting)
Search for more papers by this authorThomas C. Neylan
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Department of Psychiatry, University of California, San Francisco, California, USA
Contribution: Conceptualization (supporting), Funding acquisition (equal), Writing - review & editing (equal)
Search for more papers by this authorBruce L. Miller
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Contribution: Funding acquisition (equal), Writing - review & editing (supporting)
Search for more papers by this authorGil D. Rabinovici
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Global Brain Health Institute, University of California, San Francisco, California, USA
Search for more papers by this authorLea T. Grinberg
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Global Brain Health Institute, University of California, San Francisco, California, USA
Department of Pathology, University of Sao Paulo Medical School, Sao Paulo, Brazil
Department of Pathology, University of California, San Francisco, California, USA
Contribution: Conceptualization (equal), Funding acquisition (equal), Writing - review & editing (supporting)
Search for more papers by this authorCorresponding Author
Christine M. Walsh
Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA
Correspondence
Christine M. Walsh, Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, 675 Nelson Rising Lane, Suite 190, San Francisco, CA 94158, USA.
Email: [email protected]
Contribution: Conceptualization (lead), Supervision (lead), Writing - original draft (equal), Writing - review & editing (equal)
Search for more papers by this authorFunding information
This work was supported by the Global Brain Health Institute, Tau Consortium/Rainwater Charity Foundation, National Institute on Aging grants NIA R01 AG060477, NIA R01 AG064314, K24AG053435, K23-AG031861, K08 AG052648, R01-AG027859, P01-AG1972403 and P50- AG023501, State of California Department of Health Services Alzheimer's Disease Research Center of California grant 04-33516
Abstract
Background and purpose
The faster rates of cognitive decline and predominance of atypical forms in early-onset Alzheimer's disease (EOAD) suggest that neuropsychiatric symptoms could be different in EOAD compared to late-onset AD (LOAD); however, prior studies based on non-biomarker-diagnosed cohorts show discordant results. Our goal was to determine the profile of neuropsychiatric symptoms in EOAD and LOAD, in a cohort with biomarker/postmortem-confirmed diagnoses. Additionally, the contribution of co-pathologies was explored.
Methods
In all, 219 participants (135 EOAD, 84 LOAD) meeting National Institute on Aging and Alzheimer's Association criteria for AD (115 amyloid positron emission tomography/cerebrospinal fluid biomarkers, 104 postmortem diagnosis) at the University of California San Francisco were evaluated. The Neuropsychiatric Inventory—Questionnaire (NPI-Q) was assessed at baseline and during follow-up. The NPI-Q mean comparisons and regression models adjusted by cognitive (Mini-Mental State Examination) and functional status (Clinical Dementia Rating Sum of Boxes) were performed to determine the effect of EOAD/LOAD and amnestic/non-amnestic diagnosis on NPI-Q. Regression models assessing the effect of co-pathologies on NPI-Q were performed.
Results
At baseline, the NPI-Q scores were higher in EOAD compared to LOAD (p < 0.05). Longitudinally, regression models showed a significant effect of diagnosis, where EOAD had higher NPI-Q total, anxiety, motor disturbances and night-time behavior scores (p < 0.05). No differences between amnestics/non-amnestics were found. Argyrophilic grain disease co-pathology predicted a higher severity of NPI-Q scores in LOAD.
Conclusions
Anxiety, night-time behaviors and motor disturbances are more severe in EOAD than LOAD across the disease course. The differential patterns of neuropsychiatric symptoms observed between EOAD/LOAD could suggest a pattern of selective vulnerability extending to the brain's subcortical structures. Further, co-pathologies such as argyrophilic grain disease in LOAD may also play a role in increasing neuropsychiatric symptoms.
Conflict of Interest
Authors declare no conflict of interest.
Open Research
DATA AVALIABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
REFERENCES
- 1Lanctôt KL, Amatniek J, Ancoli-Israel S, et al. Neuropsychiatric signs and symptoms of Alzheimer’s disease: new treatment paradigms. Alzheimers Dement N Y N. 2017; 3(3): 440-449.
- 2Clement A, Wiborg O, Asuni AA. Steps towards developing effective treatments for neuropsychiatric disturbances in Alzheimer’s disease: insights from preclinical models, clinical data, and future directions. Front Aging Neurosci. 2020; 12: 56.
- 3Gatchel JR, Donovan NJ, Locascio JJ, et al. Depressive symptoms and tau accumulation in the inferior temporal lobe and entorhinal cortex in cognitively normal older adults: a pilot study. J Alzheimers Dis. 2017; 59(3): 975-985.
- 4Liguori C, Placidi F, Izzi F, Spanetta M, Mercuri NB, Di Pucchio A. Sleep dysregulation, memory impairment, and CSF biomarkers during different levels of neurocognitive functioning in Alzheimer’s disease course. Alzheimers Res Ther. 2020; 12(1): 5.
- 5Tanaka H, Hashimoto M, Fukuhara R, et al. Relationship between dementia severity and behavioural and psychological symptoms in early-onset Alzheimer’s disease. Psychogeriatrics. 2015; 15(4): 242-247.
- 6Ehrenberg AJ, Suemoto CK, França Resende EDP, et al. Neuropathologic correlates of psychiatric symptoms in Alzheimer’s disease. J Alzheimers Dis. 2018; 66(1): 115-126.
- 7Okuda S, Tetsuka J, Takahashi K, Toda Y, Kubo T, Tokita S. Association between sleep disturbance in Alzheimer’s disease patients and burden on and health status of their caregivers. J Neurol. 2019; 266(6): 1490-1500.
- 8Lyketsos CG, Carrillo MC, Ryan JM, et al. Neuropsychiatric symptoms in Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc. 2011; 7(5): 532-539.
- 9Germain S, Adam S, Olivier C, et al. Does cognitive impairment influence burden in caregivers of patients with Alzheimer’s disease? J Alzheimers Dis JAD. 2009; 17(1): 105-114.
- 10McCleery J, Sharpley AL. Pharmacotherapies for sleep disturbances in dementia. Cochrane Database Syst Rev. 2020; 11: CD009178.
- 11Murray ME, Graff-Radford NR, Ross OA, Petersen RC, Duara R, Dickson DW. Neuropathologically defined subtypes of Alzheimer’s disease with distinct clinical characteristics: a retrospective study. Lancet Neurol. 2011; 10(9): 785-796.
- 12Petersen C, Nolan AL, de Paula França Resende E, et al. Alzheimer’s disease clinical variants show distinct regional patterns of neurofibrillary tangle accumulation. Acta Neuropathol (Berl). 2019; 138(4): 597-612.
- 13Ferreira MDC, Abreu MJ, Machado C, Santos B, Machado Á, Costa AS. Neuropsychiatric profile in early versus late onset Alzheimer’s disease. Am J Alzheimers Dis Other Demen. 2018; 33(2): 93-99.
- 14Baillon S, Gasper A, Wilson-Morkeh F, Pritchard M, Jesu A, Velayudhan L. Prevalence and severity of neuropsychiatric symptoms in early- versus late-onset Alzheimer’s disease. Am J Alzheimers Dis Other Demen. 2019; 34(7–8): 433-438.
- 15Mushtaq R, Pinto C, Tarfarosh SFA, et al. A comparison of the behavioral and psychological symptoms of dementia (BPSD) in early-onset and late-onset Alzheimer’s disease—a study from south east Asia (Kashmir, India). Cureus. 2016; 8(5): e625.
- 16Park HK, Choi SH, Park SA, et al. Cognitive profiles and neuropsychiatric symptoms in Korean early-onset Alzheimer’s disease patients: a CREDOS study. J Alzheimers Dis. 2015; 44(2): 661-673.
- 17Hori K, Oda T, Asaoka T, et al. First episodes of behavioral symptoms in Alzheimer’s disease patients at age 90 and over, and early-onset Alzheimer’s disease: comparison with senile dementia of Alzheimer’s type. Psychiatry Clin Neurosci. 2005; 59(6): 730-735.
- 18Singleton EH, Rijkers C, Groot C, et al. The evolution of neuropsychiatric symptoms in atypical variants of Alzheimer’s disease. Alzheimers Dement. 2020; 16(S6): 1-3. doi:10.1002/alz.045236
10.1002/alz.045236 Google Scholar
- 19Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975; 12(3): 189-198.
- 20Morris JC. The clinical dementia rating (CDR): current version and scoring rules. Neurology. 1993; 43(11): 2412-2414.
- 21Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging—Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc. 2011; 7(3): 270-279.
- 22McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging—Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc. 2011; 7(3): 263-269.
- 23Hyman BT, Phelps CH, Beach TG, et al. National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc. 2012; 8(1): 1-13.
- 24Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging—Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011; 7(3): 270-279.
- 25McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging—Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011; 7: 263-269.
- 26Ossenkoppele R, Pijnenburg YAL, Perry DC, et al. The behavioural/dysexecutive variant of Alzheimer’s disease: clinical, neuroimaging and pathological features. Brain. 2015; 138(9): 2732-2749.
- 27Spina S, La Joie R, Petersen C, et al. Comorbid neuropathological diagnoses in early versus late-onset Alzheimer’s disease. Brain J Neurol. 2021; 144(7): 2186-2198. doi:10.1093/brain/awab099
- 28Kaufer DI, Cummings JL, Ketchel P, et al. Validation of the NPI-Q, a brief clinical form of the neuropsychiatric inventory. J Neuropsychiatry Clin Neurosci. 2000; 12(2): 233-239.
- 29van Vliet D, de Vugt ME, Aalten P, et al. Prevalence of neuropsychiatric symptoms in young-onset compared to late-onset Alzheimer’s disease—part 1: findings of the two-year longitudinal NeedYD-study. Dement Geriatr Cogn Disord. 2012; 34(5–6): 319-327.
- 30Wattmo C, Wallin ÅK. Early- versus late-onset Alzheimer’s disease in clinical practice: cognitive and global outcomes over 3 years. Alzheimers Res Ther. 2017; 9(1): 70.
- 31Smits LL, Pijnenburg YAL, van der Vlies AE, et al. Early onset APOE E4-negative Alzheimer’s disease patients show faster cognitive decline on non-memory domains. Eur Neuropsychopharmacol. 2015; 25(7): 1010-1017.
- 32Marshall GA, Fairbanks LA, Tekin S, Vinters HV, Cummings JL. Early-onset Alzheimer’s disease is associated with greater pathologic burden. J Geriatr Psychiatry Neurol. 2007; 20(1): 29-33.
- 33Middleton LE, Grinberg LT, Miller B, Kawas C, Yaffe K. Neuropathologic features associated with Alzheimer disease diagnosis: age matters. Neurology. 2011; 77(19): 1737-1744.
- 34La Joie R, Visani AV, Baker SL, et al. Prospective longitudinal atrophy in Alzheimer’s disease correlates with the intensity and topography of baseline tau-PET. Sci Transl Med. 2020; 12(524): eaau5732.
- 35Theofilas P, Dunlop S, Heinsen H, Grinberg LT. Turning on the light within: subcortical nuclei of the isodentritic core and their role in Alzheimer’s disease pathogenesis. J Alzheimers Dis. 2015; 46(1): 17-34.
- 36Braak H, Thal DR, Ghebremedhin E, Del Tredici K. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol. 2011; 70(11): 960-969.
- 37Ishii T. Distribution of Alzheimer’s neurofibrillary changes in the brain stem and hypothalamus of senile dementia. Acta Neuropathol (Berl). 1966; 6(2): 181-187.
- 38Oh J, Eser RA, Ehrenberg AJ, et al. Profound degeneration of wake-promoting neurons in Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc. 2019; 15(10): 1253-1263.
- 39Ehrenberg AJ, Nguy AK, Theofilas P, et al. Quantifying the accretion of hyperphosphorylated tau in the locus coeruleus and dorsal raphe nucleus: the pathological building blocks of early Alzheimer’s disease. Neuropathol Appl Neurobiol. 2017; 43(5): 393-408.
- 40Jacobs HIL, Riphagen JM, Ramakers IHGB, Verhey FRJ. Alzheimer’s disease pathology: pathways between central norepinephrine activity, memory, and neuropsychiatric symptoms. Mol Psychiatry. 2021; 26(3): 897-906.
- 41Theofilas P, Ehrenberg AJ, Nguy A, et al. Probing the correlation of neuronal loss, neurofibrillary tangles, and cell death markers across the Alzheimer’s disease Braak stages: a quantitative study in humans. Neurobiol Aging. 2018; 61: 1-12.
- 42Bolton CJ, Tam JW. Differential involvement of the locus coeruleus in early- and late-onset Alzheimer’s disease: a potential mechanism of clinical differences? J Geriatr Psychiatry Neurol. 2021. doi:10.1177/08919887211044755
- 43Falgàs N, Walsh CM, Neylan TC, Grinberg LT. Deepen into sleep and wake patterns across Alzheimer’s disease phenotypes. Alzheimers Dement J Alzheimers Assoc. 2021; 17(8): 1403-1406.
- 44Nagata T, Shinagawa S, Nakajima S, Mimura M, Shigeta M. Association between neuropsychiatric improvement and neurocognitive change in Alzheimer’s disease: analysis of the CATIE-AD study. J Alzheimers Dis. 2018; 66(1): 139-148.
- 45Nagata T, Nakajima S, Shinagawa S, et al. Psychosocial or clinico-demographic factors related to neuropsychiatric symptoms in patients with Alzheimer’s disease needing interventional treatment: analysis of the CATIE-AD study. Int J Geriatr Psychiatry. 2017; 32(12): 1264-1271.
- 46Rouch I, Pongan E, Trombert B, et al. One-year evolution of behavioral and psychological symptoms of dementia in patients initially hospitalized in cognitive behavioral units: the EVITAL prospective cohort. J Alzheimers Dis. 2017; 57(1): 147-155.
- 47Kaiser NC, Liang L-J, Melrose RJ, Wilkins SS, Sultzer DL, Mendez MF. Differences in anxiety among patients with early- versus late-onset Alzheimer’s disease. J Neuropsychiatry Clin Neurosci. 2014; 26(1): 73-80.
- 48Panegyres PK, Chen HY. Coalition against major diseases (CAMD). Early-onset Alzheimer’s disease: a global cross-sectional analysis. Eur J Neurol. 2014; 21(9): 1149-1154, e64–65.
- 49Mendez MF. The relationship between anxiety and Alzheimer’s disease. J Alzheimers Dis Rep. 2021; 5(1): 171-177.
- 50Grinberg LT, Rüb U, Ferretti REL, et al. The dorsal raphe nucleus shows phospho-tau neurofibrillary changes before the transentorhinal region in Alzheimer’s disease. A precocious onset? Neuropathol Appl Neurobiol. 2009; 35(4): 406-416.
- 51Lehrner J, Kogler S, Lamm C, et al. Awareness of memory deficits in subjective cognitive decline, mild cognitive impairment, Alzheimer’s disease and Parkinson’s disease. Int Psychogeriatr. 2015; 27(3): 357-366.
- 52Townley RA, Graff-Radford J, Mantyh WG, et al. Progressive dysexecutive syndrome due to Alzheimer’s disease: a description of 55 cases and comparison to other phenotypes. Brain Commun. 2020; 2(1): fcaa068.
- 53Rodriguez RD, Suemoto CK, Molina M, et al. Argyrophilic grain disease: demographics, clinical, and neuropathological features from a large autopsy study. J Neuropathol Exp Neurol. 2016; 75(7): 628-635.
- 54Rodriguez RD, Grinberg LT. Argyrophilic grain disease: an underestimated tauopathy. Dement Neuropsychol. 2015; 9(1): 2-8.
- 55Naasan G, Shdo SM, Rodriguez EM, et al. Psychosis in neurodegenerative disease: differential patterns of hallucination and delusion symptoms. Brain J Neurol. 2021; 144(3): 999-1012.
- 56Gelman A, Hill J, Yajima M. Why we (usually) don’t have to worry about multiple comparisons. J Res Educ Eff. 2012; 5(2): 189-211.
