AccScience Publishing / AN / Volume 3 / Issue 1 / DOI: 10.36922/an.2232
Cite this article
Journal Browser
Volume | Year
News and Announcements
View All

Unraveling the challenges of diagnosing dementia with Lewy bodies in a patient with alcohol and benzodiazepine misuse: A case study-based review

Kelly Tuchman1* Fraser C. Henderson Sr1,2
Show Less
1 The Metropolitan Neurosurgery Group, LLC, Silver Spring, Maryland, United States of America
2 Department Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
Advanced Neurology 2024, 3(1), 2232
Submitted: 11 November 2023 | Accepted: 15 February 2024 | Published: 13 March 2024
© 2024 by the Author (s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( )

Dementia with Lewy bodies (DLBs) is the second most common cause of neurodegenerative dementia in the United States, after Alzheimer’s disease, and is often misdiagnosed. A history of substance use disorder (SUD) complicates the diagnosis process, and side effects of substance misuse can mirror or mask signs of degenerative dementia. The fluctuating cognition and mobility which would normally point toward DLB are erroneously seen as signs of SUD or polypharmacy. However, a history of SUD should not preclude the diagnosis of DLB or other forms of proteinopathy, as substance misuse can contribute to the development of neurodegenerative dementias. Both alcohol and benzodiazepines have a sedative effect as ligands to gamma-aminobutyric acid (GABA) receptors. Long-term use, misuse, and withdrawals can upset the delicate GABAergic/glutamatergic balance, resulting in adverse neuroimmune and neuroinflammatory responses which contribute to the pathologies seen in degenerative dementias, such as DLB. In this paper, we review the challenges, including limitations of standardized instruments for dementia and the harms of delayed diagnosis, in DLB diagnosis, in combination with our experiences drawn from studying a polypharmacy-practicing 68-year-old man with a 40-year history of benzodiazepine and alcohol use. Understanding the underlying mechanisms of SUD serves to destigmatize the condition to expedite treatment and further our knowledge of the relationship between neuroinflammation and dementia.

Lewy body disease
Substance use disorder
Reactive oxygen species
Alzheimer’s disease
  1. Lewy Body Demenita Association. The LBD Spectrum. Available from: body%20dementia%20(lbd)%20is,parkinson’s%20disease%20 dementia%20(pdd [Last accessed on 2023 Oct 19].


  1. Kane JPM, Surendranthan A, Bentley SAH, et al. Clinical prevalence of Lewy body dementia. Alzheimers Res Ther. 2018;10(1):19. doi: 10.1186/s13195-018-0350-6


  1. McKeith I. Clinical aspects of dementia with Lewy Bodies. Handb Clin Neurol. 2008;89:307-311. doi: 10.1016/S0072-9752(07)01229-8


  1. Bouter C, Hansen N, Timäus C, Wiltfang J, Lange C. Case report: the role of neuropsychological assessment and imaging biomarkers in the early diagnosis of Lewy body dementia in a patient with major depression and prolonged alcohol and benzodiazepine dependence. Front Psychiatry. 2020;11:684. doi: 10.3389/fpsyt.2020.00684


  1. Yamada M, Komatsu J, Nakamura K, et al. Diagnostic criteria for dementia with Lewy bodies: Updates and future directions. J Mov Disord. 2020;13(1):1-10. doi: 10.14802/jmd.19052


  1. McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies. Neurology. 2017;89(1):88-100. doi: 10.1212/WNL.0000000000004058


  1. Stephens DN. A glutamatergic hypothesis of drug dependence: Extrapolations from benzodiazepine receptor ligands. Behav Pharmacol. 1995;6(5 and 6):425-446.


  1. Kaufmann H, Goldstein D. Autonomic dysfunction in Parkinson disease. Handb Clin Neurol. 2013;117:259-278. doi: 10.1016/B978-0-444-53491-0.00021-3


  1. Henderson FC, Rowe P, Narayanan M, et al. Refractory syncope and presyncope associated with atlantoaxial instability: Preliminary evidence of improvement following surgical stabilization. World Neurosurg. 2021;149:e854-e865. doi: 10.1016/j.wneu.2021.01.084


  1. Shin H, Chung S. Drug-induced Parkinsonism. J Clin Neurol. 2012;8(1):15-21. doi: 10.3988/jcn.2012.8.1.15


  1. Crowe SF, Stranks EK. The residual medium and long-term cognitive effects of benzodiazepine use: An updated meta-analysis. Arch Clin Neuropsychol. 2018;33(7):901-911. doi: 10.1093/arclin/acx120


  1. He Q, Chen X, Wu T, Li L, Fei X. Risk of dementia in long-term benzodiazepine users: Evidence from a meta-analysis of observational studies. J Clin Neurol. 2019;15(1):9-19. doi: 10.3988/jcn.2019.15.1.9


  1. Ritchie K, Villebrun D. Epidemiology of alcohol-related dementia. Handb Clin Neurol. 2008;89:845-850. doi: 10.1016/S0072-9752(07)01273-0


  1. Pariente A, Billioti de Gage S, Moore N, Bégaud B. The benzodiazepine-dementia disorders link: Current state of knowledge. CNS Drugs. 2016;30(1):1-7. doi: 10.1007/s40263-015-0305-4


  1. Johnston JA, Ward CL, Kopito RR. Aggresomes: A cellular response to misfolded proteins. J Cell Biol. 1998;143(7):1883-1898. doi: 10.1083/jcb.143.7.1883


  1. Konsman JP. Cytokines in the brain and neuroinflammation: We didn’t starve the fire! Pharmaceuticals (Basel). 2022;15(2):140. doi: 10.3390/ph15020140


  1. Kontic MZ, Dragic M, Martinovic J, et al. Prolonged alprazolam treatment alters components of glutamatergic neurotransmission in the hippocampus of male wistar rats-the neuroadaptive changes following long-term benzodiazepine (Mis)use. Pharmaceuticals (Basel). 2023;16(3):331. doi: 10.3390/ph16030331


  1. Creavin ST, Wisniewski S, Noel-Storr AH, et al. Mini-mental state examination (MMSE) for the detection of dementia in clinically unevaluated people aged 65 and over in community and primary care populations. Cochrane Database Syst Rev. 2016;2016(1):CD011145. doi: 10.1002/14651858.CD011145.pub2


  1. Ramalho J, Castillo M. Dementia resulting from traumatic brain injury. Dement Neuropsychol. 2015;9(4):356-368. doi: 10.1590/1980-57642015DN94000356


  1. Eker SS, Akkaya C, Sarandol A, Cangur S, Sarandol E, Kirli S. Effects of various antidepressants on serum thyroid hormone levels in patients with major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(4):955-961. doi: 10.1016/j.pnpbp.2007.12.029


  1. Mathew CJ, Jose MT, Elshaikh AO, Shah L, Lee R, Cancarevic I. Is hyperthyroidism a possible etiology of early onset dementia? Cureus. 2020;12(9):e10603. doi: 10.7759/cureus.10603


  1. Levine KS, Leonard HL, Blauwendraat C, et al. Virus exposure and neurodegenerative disease risk across national biobanks. Neuron. 2023;111(7):1086-1093.e2. doi: 10.1016/j.neuron.2022.12.029


  1. Jatoi S, Hafeez A, Riaz SU, Ali A, Ghauri MI, Zehra M. Low vitamin B12 levels: An underestimated cause of minimal cognitive impairment and dementia. Cureus. 2020;12(2):e6976. doi: 10.7759/cureus.6976


  1. Zhang X, Bao G, Liu D, et al. The association between folate and Alzheimer’s disease: A systematic review and meta-analysis. Front Neurosci. 2021;15:661198. doi: 10.3389/fnins.2021.661198


  1. Ma LZ, Wang ZX, Wang ZT, et al. Serum calcium predicts cognitive decline and clinical progression of Alzheimer’s disease. Neurotox Res. 2021;39(3):609-617. doi: 10.1007/s12640-020-00312-y


  1. Morris MC, Evans DA, Bienias JL, et al. Dietary niacin and the risk of incident Alzheimer’s disease and of cognitive decline. J Neurol Neurosurg Psychiatry. 2004;75(8):1093-1099. doi: 10.1136/jnnp.2003.025858


  1. Gibson GE, Hirsch JA, Fonzetti P, Jordan BD, Cirio RT, Elder J. Vitamin B1 (thiamine) and dementia. Ann NY Acad Sci. 2016;1367(1):21-30. doi: 10.1111/nyas.13031


  1. Sun R, Wang J, Feng J, Cao B. Zinc in cognitive impairment and aging. Biomolecules. 2022;12(7):1000. doi: 10.3390/biom12071000


  1. Viramontes TS, Truong H, Linnebur SA. Antidepressant-induced hyponatremia in older adults. Consult Pharm. 2016;31(3):139-150. doi: 10.4140/TCP.n.2016.139


  1. Deckers K, Camerino I, van Boxtel MP, et al. Dementia risk in renal dysfunction: A systematic review and meta-analysis of prospective studies. Neurology. 2017;88(2):198-208. doi: 10.1212/WNL.0000000000003482


  1. Butterworth RF. The role of liver disease in alcohol-induced cognitive defects. Alcohol Health Res World. 1995;19(2):122-129.


  1. Jan K. Wernicke encephalopathy: (MRI) picture worth a thousand words. Oxf Med Case Reports. 2018;2018(5):omy013. doi: 10.1093/omcr/omy013


  1. Koenig AM, Nobuhara CK, Williams VJ, Arnold SE. Biomarkers in Alzheimer’s, frontotemporal, lewy body, and vascular dementias. Focus (Am Psychiatr Publ). 2018;16(2):164-172. doi: 10.1176/appi.focus.20170048


  1. Kim HW, Hong J, Jeon JC. Cerebral small vessel disease and Alzheimer’s disease: A review. Front Neurol. 2020;11:927. doi: 10.3389/fneur.2020.00927


  1. Qian X, Xiao S. Peripheral nerve conduction study in early cognitive impairment of Alzheimer’s disease: Neuropsychiatry and behavioral neurology/Mild cognitive impairment/Early symptomatic disease. Alzheimers Dement. 2020;16(s6):e041671. doi: 10.1002/alz.041671


  1. Nakajima M, Kawamura K, Akiba C, et al. Differentiating comorbidities and predicting prognosis in idiopathic normal pressure hydrocephalus using cerebrospinal fluid biomarkers: A review. Croat Med J. 2021;62(4):387-398. doi: 10.3325/cmj.2021.62.387


  1. Janssen JC, Godbolt AK, Ioannidis P, Thompson EJ, Rossor MN. The prevalence of oligoclonal bands in the CSF of patients with primary neurodegenerative dementia. J Neurol. 2004;251(2):184-188. doi: 10.1007/s00415-004-0296-4


  1. Santaella A, Kuiperij HB, van Rumund A, Esselink RAJ, Bloem BR, Verbeek MM. Cerebrospinal fluid myelin basic protein is elevated in multiple system atrophy. Parkinsonism Relat Disord. 2020;76:80-84. doi: 10.1016/j.parkreldis.2020.06.004


  1. De Lorenzi D, Mandara MT. The central nervous system. Can Feline Cytol. 2010:325-365. doi: 10.1016/B978-141604985-2.50019-0


  1. Zetterberg H, Blennow K. Biological CSF markers of Alzheimer’s disease. Handb Clin Neurol. 2008;89:261-268. doi: 10.1016/S0072-9752(07)01224-9


  1. Vanmechelen E, Vanderstichele H, Hulstaert F, et al. Cerebrospinal t and B-amyloid in dementia disorders. Mech Ageing Dev. 2001;122(16):2005-2011. doi: 10.1016/S0047-6374(01)00304-9


  1. Tariciotti L, Casadei M, Honig LS, et al. Clinical experience with cerebrospinal fluid Aβ42, total and phosphorylated tau in the evaluation of 1,016 individuals for suspected dementia. J Alzheimers Dis. 2018;65(4):1417-1425. doi: 10.3233/jad-180548


  1. Kac PR, Gonzalez-Ortiz F, Simrén J, et al. Diagnostic value of serum versus plasma phospho-tau for Alzheimer’s disease. Alzheimers Res Ther. 2022;14(1):65. doi: 10.1186/s13195-022-01011-w


  1. Rodríguez-Blázquez C, Martinez-Martin P, Forjaz M, Kurtis M, Balestrino R. Rating scales in movement disorders. Front Neurol. 2018;9:435. doi: 10.3389/fneur.2018.00435


  1. Nasreddine Z, Phillips N, Bédirian V, et al. The Montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695-699. doi: 10.1111/j.1532-5415.2005.53221.x


  1. Hyman B, Phelps C, Beach T, et al. National institute on aging- Alzheimer’s association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement. 2012;8(1):1-13. doi: 10.1016/j.jalz.2011.10.007


  1. Farrer M. The genetics and molecular biology of alpha-synuclein. Handb Clin Neurol. 2008;89:313-319. doi: 10.1016/S0072-9752(07)01230-4


  1. Braak H, Del Tredici K, Rüb U, de Vos R, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinsons disease. Neurobiol Aging. 2003;24(2):197-211. doi: 10.1016/s0197-4580(02)00065-9


  1. Lowe J. Neuropathy of dementia with lewy bodies. Handb Clin Neurol. 2008;89:321-330. doi: 10.1016/S0072-9752(07)01231-6


  1. Eriksen J, Zehr C, Lewis J. Biological models of neurodegenerative disorders. Handb Clin Neurol. 2008;89:173-188. doi: 10.1016/S0072-9752(07)01216-X


  1. Gomez-Isla T, Spires T, De Calignon A, Hyman B. Neuropathy of Alzheimer’s disease. Handb Clin Neurol. 2008;89:233-243. doi: 10.1016/S0072-9752(07)01222-5


  1. Hardy J, Gwinn-Hardy K. The relationship between nosology, etiology and pathogenesis in neurodegenerative disease. Handb Clin Neurol. 2008;89:189-192. doi: 10.1016/S0072-9752(07)01217-1


  1. Dugger BN, Adler CH, Shill HA, et al. Concomitant pathologies among a spectrum of Parkinsonian disorders. Parkinsonism Relat Disord. 2014;20(5):525-529. doi: 10.1016/j.parkreldis.2014.02.012


  1. Werner CJ, Heyny-von Haussen R, Mall G, Wolf S. Proteome analysis of human substantia nigra in Parkinsons disease. Proteome Sci. 2008;6:8. doi: 10.1186/1477-5956-6-8


  1. Schaser AJ, Osterberg VR, Dent SE, et al. Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders. Sci Rep. 2019;9(1):10919. doi: 10.1038/s41598-019-47227-z


  1. Emanuele M, Chieregatti E. Mechanisms of alpha-synuclein action on neurotransmission: Cell-autonomous and non-cell autonomous role. Biomolecules. 2015;5(2):865-892. doi: 10.3390/biom5020865


  1. Südhof TC, Rizo J. Synaptic vesicle exocytosis. Cold Spring Harb Perspect Biol. 2011;3(12):a005637. doi: 10.1101/cshperspect.a005637


  1. Lücking CB, Brice A. Alpha-synuclein and Parkinson’s disease. Cell Mol Life Sci. 2000;57(13-14):1894-1908. doi: 10.1007/PL00000671


  1. Man WK, Tahirbegi B, Vrettas MD, et al. The docking of synaptic vesicles on the presynaptic membrane induced by α-synuclein is modulated by lipid composition. Nat Commun. 2021;12:927. doi: 10.1038/s41467-021-21027-4


  1. Hettiarachchi NT, Parker A, Dallas ML, et al. alpha-Synuclein modulation of Ca2+ signaling in human neuroblastoma (SH-SY5Y) cells. J Neurochem. 2009;111(5):1192-1201. doi: 10.1111/j.1471-4159.2009.06411.x


  1. Huang M, Wang B, Li X, Fu C, Wang C, Kang X. α-Synuclein: A multifunctional player in exocytosis, endocytosis, and vesicle recycling. Front Neurosci. 2019;13:28. doi: 10.3389/fnins.2019.00028


  1. Hou X, Watzlawik JO, Fiesel FC, Springer W. Autophagy in Parkinson’s disease. J Mol Biol. 2020;432(8):2651-2672. doi: 10.1016/j.jmb.2020.01.037


  1. Dickson DW. Alpha-synuclein and the Lewy body disorders. Curr Opin Neurol. 2001;14(4):423-432. doi: 10.1097/00019052-200108000-00001y


  1. Zou K, Gong JS, Yanagisawa K, Michikawa M. A novel function of monomeric amyloid β-protein serving as an antioxidant molecule against metal-induced oxidative damage. J Neurosci. 2002;22(12):4833-4841. doi: 10.1523/JNEUROSCI.22-12-04833.2002


  1. Surmeier DJ, Obeso JA, Halliday GM. Selective neuronal vulnerability in Parkinson disease. Nat Rev Neurosci. 2017;18(2):101-113. doi: 10.1038/nrn.2016.178


  1. Lautenschläger J, Stephens AD, Fusco G, et al. C-terminal calcium binding of α-synuclein modulates synaptic vesicle interaction. Nat Commun. 2018;9:712. doi: 10.1038/s41467-018-03111-4


  1. Erskine D, Koss D, Korolchuk VI, Outeiro TF, Attems J, McKeith I. Lipids, lysosomes and mitochondria: Insights into Lewy body formation from rare monogenic disorders. Acta Neuropathol. 2021;141(4):511-526. doi: 10.1007/s00401-021-02266-7


  1. Lee HJ, Baek S, Ho DH, et al. Dopamine promotes formation and secretion of non-fibrillar alpha-synuclein oligomers. Exp Mol Med. 2011;43:216-222. doi: 10.3858/emm.2011.43.4.026


  1. King E, O’Brien JT, Donaghy P, et al. Peripheral inflammation in prodromal Alzheimer’s and Lewy body dementias. J Neurol Neurosurg Psychiatry. 2018;89(4):339-345. doi: 10.1136/jnnp-2017-317134


  1. Shams R, Banik NL, Haque A. Calpain in the cleavage of alpha-synuclein and the pathogenesis of Parkinson’s disease. Prog Mol Biol Transl Sci. 2019;167:107-124. doi: 10.1016/bs.pmbts.2019.06.007


  1. Tan LY, Tang KH, Lim LYY, Ong JX, Park H, Jung S. α-synuclein at the presynaptic axon terminal as a double-edged sword. Biomolecules. 2022;12(4):507. doi: 10.3390/biom12040507


  1. Adamczyk A, Strosznajder JB. Alpha-synuclein potentiates Ca2+ influx through voltage-dependent Ca2+ channels. Neuroreport. 2006;17(18):1883-1886. doi: 10.1097/WNR.0b013e3280115185


  1. Loveland PM, Yu JJ, Churilov L, Yassi N, Watson R. Investigation of inflammation in Lewy body dementia: A systematic scoping review. Int J Mol Sci. 2023;24(15):12116. doi: 10.3390/ijms241512116


  1. Myers AJ, Brahimi A, Jenkins IJ, Koob AO. The synucleins and the astrocyte. Biology (Basel). 2023;12(2):155. doi: 10.3390/biology12020155


  1. Scarlata S, Golebiewska U. Linking alpha-synuclein properties with oxidation: A hypothesis on a mechanism underling cellular aggregation. J Bioenerg Biomembr. 2014;46(2):93-98. doi: 10.1007/s10863-014-9540-5


  1. Pacheco C, Aguayo LG, Opazo C. An extracellular mechanism that can explain the neurotoxic effects of α-synuclein aggregates in the brain. Front Physiol. 2012;3:297. doi: 10.3389/fphys.2012.00297


  1. Milanese C, Cerri S, Ulusoy A, et al. Activation of the DNA damage response in vivo in synucleinopathy models of Parkinson’s disease. Cell Death Dis. 2018;9:818. doi: 10.1038/s41419-018-0848-7


  1. Danzer KM, Haasen D, Karow AR, et al. Different species of alpha-synuclein oligomers induce calcium influx and seeding. J Neurosci. 2007;27(34):9220-9232. doi: 10.1523/JNEUROSCI.2617-07.2007


  1. Virdi GS, Choi ML, Evans JR, et al. Protein aggregation and calcium dysregulation are hallmarks of familial Parkinson’s disease in midbrain dopaminergic neurons. NPJ Parkinsons Dis. 2022;8:162. doi: 10.1038/s41531-022-00423-7


  1. Ke PC, Zhou R, Serpell LC, et al. Half a century of amyloids: Past, present and future. Chem Soc Rev. 2020;49(15):5473-5509. doi: 10.1039/c9cs00199a


  1. Tanaka M, Toldi J, Vécsei L. Exploring the etiological links behind neurodegenerative diseases: Inflammatory cytokines and bioactive kynurenines. Int J Mol Sci. 2020;21:2431. doi: 10.3390/ijms21072431


  1. Sastre M, Klockgether T, Heneka MT. Contribution of inflammatory processes to Alzheimer’s disease: Molecular mechanisms. Int J Dev Neurosci. 2006;24(2-3):167-176. doi: 10.1016/j.ijdevneu.2005.11.014


  1. Shahidehpour RK, Higdon RE, Crawford NG, et al. Dystrophic microglia are associated with neurodegenerative disease and not healthy aging in the human brain. Neurobiol Aging. 2021;99:19-27. doi: 10.1016/j.neurobiolaging.2020.12.003


  1. Streit WJ, Xue QS. Microglia in dementia with Lewy bodies. Brain Behav Immun. 2016;55:191-201. doi: 10.1016/j.bbi.2015.10.012


  1. Simon C, Soga T, Ahemad N, Bhuvanendran S, Parhar I. Kisspeptin-10 rescues cholinergic differentiated SHSY-5Y cells from α-synuclein-induced toxicity in vitro. Int J Mol Sci. 2022;23(9):5193. doi: 10.3390/ijms23095193


  1. Cremades N, Cohen SI, Deas E, et al. Direct observation of the interconversion of normal and toxic forms of α-synuclein. Cell. 2012;149(5):1048-1059. doi: 10.1016/j.cell.2012.03.037


  1. Furukawa K, Matsuzaki-Kobayashi M, Hasegawa T, et al. Plasma membrane ion permeability induced by mutant alpha-synuclein contributes to the degeneration of neural cells. J Neurochem. 2006;97(4):1071-1077. doi: 10.1111/j.1471-4159.2006.03803.x


  1. Selkoe DJ. Biochemistry and molecular bilology of amylod B-protein and the mechanism of Alzheimer’s disease. Handb Clin Neurol. 2008;89:245-260. doi: 10.1016/S0072-9752(07)01223-7


  1. Uchicara T, Tsuchiya K. Neuropathology of pick body disease. Handb Clin Neurol. 2008;89:415-430. doi: 10.1016/S0072-9752(07)01238-9


  1. Saxton J, Morrow L. Toxic dementias. Handb Clin Neurol. 2008;89:851-862. doi: 10.1016/S0072-9752(07)01274-2


  1. Pétursson H. The benzodiazepine withdrawal syndrome. Addiction. 1994;89(11):1455-1459. doi: 10.1111/j.1360-0443.1994.tb03743.x


  1. Stewart S. The effects of benzodiazepines on cognition. J Clin Psychiatry. 2005;66 Suppl 2:9-13.


  1. Zetsen SPG, Schellekens AFA, Paling EP, Kan CC, Kessels RPC. Cognitive functioning in long-term benzodiazepine users. Eur Addict Res. 2022;28(5):377-381. doi: 10.1159/000525988


  1. Morin L, Johnell K, Laroche M, Fastbom J, Wastesson JW. The epidemiology of polypharmacy in older adults: register-based prospective cohort study. Clin Epidemiol. 2018;10:289-298. doi: 10.2147/CLEP.S153458


  1. Greene DS, Salazar DE, Dockens RC, Kroboth P, Barbhaiya RH. Coadministration of nefazodone and benzodiazepines: III. A pharmacokinetic interaction study with alprazolam. J Clin Psychopharmacol. 1995;15(6):399-408. doi: 10.1097/00004714-199512000-00003


  1. Volpi-Abadie J, Kaye AM, Kaye AD. Serotonin syndrome. Ochsner J. 2013;13(4):533-540.


  1. Rivasi G, Rafanelli M, Mossello E, Brignole M, Ungar A. Drug-related orthostatic hypotension: Beyond anti-hypertensive medications. Drugs Aging. 2020;37:725-738. doi: 10.1007/s40266-020-00796-5


  1. Doraiswamy PM, Husain MM. Anticholinergic drugs and elderly people: A no brainer? Lancet Neurol. 2006;5(3):379-380. doi: 10.1016/S1474-4422(06)70421-5


  1. National Center for Drug Abuse Statistics. Prescription Drug Abuse Statistics. Available from: https://drugabusestatistics. org/prescription-drug-abuse-statistics [Last accessed on 2023 Oct 19].


  1. Maust DT, Lin LA, Blow FC. Benzodiazepine use and misuse among adults in the united states. Psychiatr Serv. 2019;70(2):97-106. doi: 10.1176/


  1. Kennedy KM, O’Riordan J. Prescribing benzodiazepines in general practice. Br J Gen Pract. 2019;69(680):152-153. doi: 10.3399/bjgp19X701753


  1. Tsuda M, Shimizu N, Yajima Y, Suzuki T, Misawa M. Hypersusceptibility to DMCM-induced seizures during diazepam withdrawal in mice: Evidence for upregulation of NMDA receptors. Naunyn Schmiedebergs Arch Pharmacol. 1998;357(3):309-315. doi: 10.1007/pl00005172


  1. Koob GF, Le Moal M. Plasticity of reward neurocircuitry and the “dark side” of drug addiction. Nat Neurosci. 2005;8(11):1442-1444. doi: 10.1038/nn1105-1442


  1. Volkow ND, Koob GF, McLellan AT. Neurobiologic advances from the brain disease model of addiction. N Engl J Med. 2016;374(4):363-371. doi: 10.1056/NEJMra1511480


  1. Tanaka M, Tóth F, Polyák H, et al. Immune influencers in action: Metabolites and enzymes of the tryptophan-kynurenine metabolic pathway. Biomedicines. 2021;9(7):734. doi: 10.3390/biomedicines9070734


  1. Britt JP, Bonci A. Optogenetic interrogations of the neural circuits underlying addiction. Curr Opin Neurobiol. 2013;23(4):539-545. doi: 10.1016/j.conb.2013.01.010


  1. Allison C, Pratt JA. Neuroadaptive processes in GABAergic and glutamatergic systems in benzodiazepine dependence. Pharmacol Ther. 2003;98(2):171-195. doi: 10.1016/s0163-7258(03)00029-9


  1. Edinoff AN, Nix CA, Hollier J, et al. Benzodiazepines: Uses, dangers, and clinical considerations. Neurol Int. 2021;13(4):594-607. doi: 10.3390/neurolint13040059


  1. U.S. Food and Drug Administration. FDA Requiring Boxed Warning Updated to Improve Safe Use of Benzodiazepine Drug Class. Available from: drug-safety-and-availability/fda-requiring-boxed-warning-updated-improve-safe-use-benzodiazepine-drug-class [Last accessed on 2023 Oct 19].


  1. American Addictions Centers. 6 of the Hardest Drugs to Quit. Available from: https://americanaddictioncenters. org/adult-addiction-treatment-programs/hardest-quit [Last accessed on 2023 Oct 19].


  1. Brett J, Murnion B. Management of benzodiazepine misuse and dependence. Aust Prescr. 2015;38(5):152-155. doi: 10.18773/austprescr.2015.055


  1. Schoch P, Richards JG, Häring P, et al. Co-localization of GABA receptors and benzodiazepine receptors in the brain shown by monoclonal antibodies. Nature. 1985;314:168-171. doi: 10.1038/314168a0


  1. Tietz EI, Rosenberg HC, Chiu TH. Autoradiographic localization of benzodiazepine receptor downregulation. J Pharmacol Exp Ther. 1986;236(1):284-292.


  1. Vinkers CH, Olivier B. Mechanisms underlying tolerance after long-term benzodiazepine use: A future for subtype-selective GABAA receptor modulators? Adv Pharmacol Sci. 2102;2012:416864. doi: 10.1155/2012/416864


  1. Izzo E, Auta J, Impagnatiello F, Pesold C, Guidotti A, Costa E. Glutamic acid decarboxylase and glutamate receptor changes during tolerance and dependence to benzodiazepines. Proc Natl Acad Sci U S A. 2001;98(6):3483-3488. doi: 10.1073/pnas.051628698


  1. Van Sickle BJ, Cox AS, Schak K, Greenfield LJ Jr., Tietz EI. Chronic benzodiazepine administration alters hippocampal CA1 neuron excitability: NMDA receptor function and expression(1). Neuropharmacology. 2002;43(4):595-606. doi: 10.1016/s0028-3908(02)00152-1


  1. Gravielle MC. Activation-induced regulation of GABAA receptors: Is there a link with the molecular basis of benzodiazepine tolerance? Pharmacol Res. 2016;109:92-100. doi: 10.1016/j.phrs.2015.12.030


  1. Tehrani MH, Barnes EM Jr. Sequestration of gamma-aminobutyric acid A receptors on clathrin-coated vesicles during chronic benzodiazepine administration in vivo. J Pharmacol Exp Ther. 1997;283(1):384-390.


  1. Bonavita C, Ferrero A, Cereseto M, et al. Adaptive changes in the rat hippocampal glutamatergic neurotransmission are observed during long-term treatment with lorazepam. Psychopharmacology (Berl). 2003;166(2):163-167. doi: 10.1007/s00213-002-1373-y


  1. Allison C, Pratt J. Differential effects of two chronic diazepam treatment regimes on withdrawal anxiety and AMPA receptor characteristics. Neuropsychopharmacol. 2006;31:602-619. doi: 10.1038/sj.npp.1300800


  1. Henry ME, Jensen JE, Licata SC, et al. The acute and late CNS glutamine response to benzodiazepine challenge: A pilot pharmacokinetic study using proton magnetic resonance spectroscopy. Psychiatry Res. 2010;184(3):171-176. doi: 10.1016/j.pscychresns.2010.08.003


  1. Bateson AN. Basic pharmacologic mechanisms involved in benzodiazepine tolerance and withdrawal. Curr Pharm Des. 2002;8(1):5-21. doi: 10.2174/1381612023396681


  1. Bauer ME, Teixeira AL. Inflammation in psychiatric disorders: What comes first? Ann N Y Acad Sci. 2019;1437(1):57-67. doi: 10.1111/nyas.13712


  1. Whitman BA, Knapp DJ, Werner DF, Crews FT, Breese GR. The cytokine mRNA increase induced by withdrawal from chronic ethanol in the sterile environment of brain is mediated by CRF and HMGB1 release. Alcohol Clin Exp Res. 2013;37(12):2086-2097. doi: 10.1111/acer.12189


  1. Knapp DJ, Harper KM, Whitman BA, Zimomra Z, Breese GR. Stress and withdrawal from chronic ethanol induce selective changes in neuroimmune mRNAs in differing brain sites. Brain Sci. 2016;6(3):25. doi: 10.3390/brainsci6030025


  1. Lobo IA, Harris RA. GABAA receptors and alcohol. Pharmacol Biochem Behav. 2008;90(1):90-94. doi: 10.1016/j.pbb.2008.03.006


  1. Barker JS, Hines RM. Regulation of GABAA receptor subunit expression in substance use disorders. Int J Mol Sci. 2020;21(12):4445. doi: 10.3390/ijms21124445


  1. Swift KM, Gross BA, Frazer MA, et al. Abnormal locus coeruleus activity during sleep alters sleep signatures of memory consolidation and impairs place cell stability and spatial memory. Curr Biol. 2018; 28(22):3599-3609.e4. doi: 10.1016/j.cub.2018.09.054


  1. Mather M, Harley CW. The locus coeruleus: Essential for maintaining cognitive function and the aging brain. Trends Cogn Sci. 2016;20(3):214-226. doi: 10.1016/j.tics.2016.01.001


  1. Van Bockstaele EJ, Reyes B, Valentino RJ. The locus coeruleus: A key nucleus where stress and opioids intersect to mediate vulnerability to opiate abuse. Brain Res. 2010;16:1314:162-174. doi: 10.1016/j.brainres.2009.09.036


  1. Morikawa H, Paladini CA. Dynamic regulation of midbrain dopamine neuron activity: Intrinsic, synaptic, and plasticity mechanisms. Neuroscience. 2011;198:95-111. doi: 10.1016/j.neuroscience.2011.08.023


  1. Samuels ER, Szabadi E. Functional neuroanatomy of the noradrenergic locus coeruleus: Its roles in the regulation of arousal and autonomic function part I: Principles of functional organisation. Curr Neuropharmacol. 2008;6(3):235-253. doi: 10.2174/157015908785777229


  1. By BruceBlaus. Own Work. CC BY-SA 4.0. Available from: php?curid=44968541 [Last accessed on 2023 Oct 19.


  1. Harper C. Neuropathology of alcohol-related cognitive alterations. Alcohol Alcohol. 2009;44(2):136-140. doi: 10.1093/alcalc/agn102


  1. Lewerenz J, Maher P. Chronic glutamate toxicity in neurodegenerative diseases-what is the evidence? Front Neurosci. 2015;9:469. doi: 10.3389/fnins.2015.00469


  1. Hartwick ATE, Hamilton CM, Baldridge WH. Glutamatergic calcium dynamics and deregulation of rat retinal ganglion cells. J Physiol. 2008;586(14):3425-3446. doi: 10.1113/jphysiol.2008.154609


  1. Görlach A, Bertram K, Hudecova S, Krizanova O. Calcium and ROS: A mutual interplay. Redox Biol. 2015;6:260-271. doi: 10.1016/j.redox.2015.08.010


  1. Schrank S, Barrington N, Stutzmann GE. Calcium-handling defects and neurodegenerative disease. Cold Spring Harb Perspect Biol. 2020;12(7):a035212. doi: 10.1101/cshperspect.a035212


  1. Silva-Peña D, García-Marchena N, Alén F, et al. Alcohol-induced cognitive deficits are associated with decreased circulating levels of the neurotrophin BDNF in humans and rats. Addict Biol. 2019;24(5):1019-1033. doi: 10.1111/adb.12668


  1. Tilleux S, Hermans E. Neuroinflammation and regulation of glial glutamate uptake in neurological disorders. J Neurosci Res. 2007;85(10):2059-2070. doi: 10.1002/jnr.21325


  1. Liddelow SA, Guttenplan KA, Clarke LE, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541(7638):481-487. doi: 10.1038/nature21029


  1. Morcuende A, Navarrete F, Nieto E, Manzanares J, Femenía T. Inflammatory biomarkers in addictive disorders. Biomolecules. 2021;11(12):1824. doi: 10.3390/biom11121824


  1. Amor S, Peferoen LAN, Vogel DYS, et al. Inflammation in neurodegenerative diseases--an update. Immunology. 2014;142(2):151-166. doi: 10.1111/imm.12233


  1. Zhang LS, Davies SS. Microbial metabolism of dietary components to bioactive metabolites: Opportunities for new therapeutic interventions. Genome Med. 2016;8(1):46. doi: 10.1186/s13073-016-0296-x


  1. Chyan YJ, Poeggeler B, Omar RA, et al. Potent neuroprotective properties against the Alzheimer beta-amyloid by an endogenous melatonin-related indole structure, indole-3-propionic acid. J Biol Chem. 1999;274(31):21937-2142. doi: 10.1074/jbc.274.31.21937


  1. Navarrete F, García-Gutiérrez MS, Gasparyan A, et al. Biomarkers of the endocannabinoid system in substance use disorders. Biomolecules. 2022;12(3):396. doi: 10.3390/biom12030396


  1. Li D, Yu S, Long Y, et al. Tryptophan metabolism: Mechanism-oriented therapy for neurological and psychiatric disorders. Front Immunol. 2022;13:985378. doi: 10.3389/fimmu.2022.985378


  1. Németh H, Toldi J, Vécsei L. Kynurenines, Parkinson’s Disease and Other Neurodegenerative Disorders: Preclinical and Clinical Studies; 2006. p. 285-304. Available from: https://link.springer. com/book/10.1007/978-3-211-45295-0?page=3#toc doi: 10.1007/978-3-211-45295-0_45


  1. Tanaka M, Bohár Z, Martos D, Telegdy G, Vécsei L. Antidepressant-like effects of kynurenic acid in a modified forced swim test. Pharmacol Rep. 2020;72(2):449-455. doi: 10.1007/s43440-020-00067-5


  1. Mechtcheriakov S, Gleissenthall GV, Geisler S, et al. Tryptophan-kynurenine metabolism during acute alcohol withdrawal in patients with alcohol use disorder: The role of immune activation. Alcohol Clin Exp Res. 2022;46(9):1648-1656. doi: 10.1111/acer.14920


  1. Montesinos J, Alfonso-Loeches S, Guerri C. Impact of the innate immune response in the actions of ethanol on the central nervous system. Alcohol Clin Exp Res. 2016;40(11):2260-2270. doi: 10.1111/acer.13208


  1. Alfonso-Loeches S, Pascual-Lucas M, Blanco AM, Sanchez-Vera I, Guerri C. Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage. J Neurosci. 2010;30(24):8285-8295. doi: 10.1523/JNEUROSCI.0976-10.2010


  1. Porrini V, Pilotto A, Vezzoli M, et al. NF-κB/c-Rel DNA-binding is reduced in substantia nigra and peripheral blood mononuclear cells of Parkinson’s disease patients. Neurobiol Dis. 2023;180:106067. doi: 10.1016/j.nbd.2023.106067


  1. Mincheva-Tasheva S, Soler RM. NF-κB signaling pathways: Role in nervous system physiology and pathology. Neuroscientist. 2013;19(2):175-174. doi: 10.1177/1073858412444007


  1. Lippai D, Bala S, Petrasek J, et al. Alcohol-induced IL-1β in the brain is mediated by NLRP3/ASC inflammasome activation that amplifies neuroinflammation. J Leukoc Biol. 2013;94(1):171-182. doi: 10.1189/jlb.1212659


  1. Nennig SE, Schank JR. The role of NFkB in drug addiction: Beyond inflammation. Alcohol Alcohol. 2017;52(2):172-179. doi: 10.1093/alcalc/agw098


  1. He J, Crews FT. Increased MCP-1 and microglia in various regions of the human alcoholic brain. Exp Neurol. 2008;210(2):349-358. doi: 10.1016/j.expneurol.2007.11.017


  1. Fernandez-Lizarbe S, Pascual M, Guerri C. Critical role of TLR4 response in the activation of microglia induced by ethanol. J Immunol. 2009;183(7):4733-4744. doi: 10.4049/jimmunol.0803590


  1. Qin L, Crews FT. NADPH oxidase and reactive oxygen species contribute to alcohol-induced microglial activation and neurodegeneration. J Neuroinflammation. 2012;9:5. doi: 10.1186/1742-2094-9-5


  1. Erickson EK, Grantham EK, Warden AS, Harris RA. Neuroimmune signaling in alcohol use disorder. Pharmacol Biochem Behav. 2019;177:34-60. doi: 10.1016/j.pbb.2018.12.007


  1. Sun E, Motolani A, Campos L, Lu T. The pivotal role of NF-KB in the pathogenesis and therapeutics of Alzheimer’s disease Int. J Mol Sci. 2022;23(16):8972. doi: 10.3390/ijms23168972


  1. Starr JM, Whalley LJ. Drug-induced dementia. Incidence, management and prevention. Drug Saf. 1994;11:310-317. doi: 10.2165/00002018-199411050-00003


  1. Albert M. Neuropsychology of Alzheimer’s disease. Handb Clin Neurol. 2008;88:511-525. doi: 10.1016/S0072-9752(07)88027-4


  1. Kipps CM, Knibb JA, Patterson K, Hodges JR. Neuropsychology of frontotemporal dementia. Handb Clin Neurol. 2008;88:527-548. doi: 10.1016/S0072-9752(07)88028-6


  1. Marshall GA, Cummings JL. Neuropsychological evaluation in dementia. Handb Clin Neurol. 2008;89:53-61. doi: 10.1016/S0072-9752(07)01204-3


  1. Costa A, Bagoj E, Monaco M, et al. Mini mental Parkinson test standardization and normative data on an Italian sample. Neurol Sci. 2013;34(10):1797-1803. doi: 10.1007/s10072-013-1342-8


  1. Hadar U, Rose FC. Neuropsychological assessment of cognitive change in dementia. Neuroepidemiology. 1990;9(4):189-192. doi: 10.1159/000110772


  1. Lucca JM, Ramesh M, Parthasarathi G, Raman R. An adverse drug interaction of haloperidol with Levodopa. Indian J Psychol Med. 2015;37(2):220-222. doi: 10.4103/0253-7176.155636


  1. Gomperts SN. Lewy body dementias: Dementia with lewy bodies and Parkinson disease dementia. Continuum (Minneap Minn). 2016;22(2):435-463. doi: 10.1212/CON.0000000000000309


  1. Armstrong MJ, Daniel Weintraub D. The case for antipsychotics in dementia with lewy bodies. Mov Disord Clin Pract. 2016;4(1):32-35. doi: 10.1002/mdc3.12383


  1. Cohen MR, Smetzer JL. Delayed administration and contraindicated drugs place hospitalized Parkinson’s disease patients at risk; doxorubicin liposomal mix-up; Avoid mix-ups between hydroxyprogesterone and medroxyprogesterone. Hosp Pharm. 2015;50(7):559-563. doi: 10.1310/hpj5007-559
Conflict of interest
The authors declare that they have no competing interests.
Back to top
Advanced Neurology, Electronic ISSN: 2810-9619 Published by AccScience Publishing