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Cited by 204Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

The DOI matches its Crossref record; 172 of the 172 references it cites were found in a registry or an index.

Does Alzheimer's disease begin in the brainstem?

Open access
Simic, G., Stanic, G., Mladinov, M., Jovanov‐Milosevic, N., Kostovic, I., Hof, P. R.·2009·Neuropathology and Applied Neurobiology
DOI 10.1111/j.1365-2990.2009.01038.xPMC PMC2787819
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Abstract

Although substantial evidence indicates that the progression of pathological changes of the neuronal cytoskeleton is crucial in determining the severity of dementia in Alzheimer's disease (AD), the exact causes and evolution of these changes, the initial site at which they begin, and the neuronal susceptibility levels for their development are poorly understood. The current clinical criteria for diagnosis of AD are focused mostly on cognitive deficits produced by dysfunction of hippocampal and high‐order neocortical areas, whereas noncognitive, behavioural and psychological symptoms of dementia such as disturbances in mood, emotion, appetite, and wake–sleep cycle, confusion, agitation and depression have been less considered. The early occurrence of these symptoms suggests brainstem involvement, and more specifically of the serotonergic nuclei. In spite of the fact that the Braak and Braak staging system and National Institutes of Aging – Reagan Institute (NIA‐RI) criteria do not include their evaluation, several recent reports drew attention to the possibility of selective and early involvement of raphe nuclei, particularly the dorsal raphe nucleus (DRN), in the pathogenesis of AD. Based on these findings of differential susceptibility and anatomical connectivity, a novel pathogenetic scheme of AD progression was proposed. Although the precise mechanisms of neurofibrillary degeneration still await elucidation, we speculated that cumulative oxidative damage may be the main cause of DRN alterations, as the age is the main risk factor for sporadic AD. Within such a framework, β‐amyloid production is considered only as one of the factors (although a significant one in familial cases) that promotes molecular series of events underlying AD‐related neuropathological changes.

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Crossref · 10.1111/j.1365-2990.2009.01038.x

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  • The olfactory bulb, entorhinal cortex and hippocampal formation (all olfactory structures), as well as the brainstem, are the CNS regions that exhibit the earliest signs of pathology in both late-onset dementia and familial Alzheimer's disease.

    “Interestingly, the olfactory bulb, entorhinal cortex and hippocampal formation (all olfactory structures), as well as the brainstem, are the CNS regions that exhibit the earliest signs of pathology in both late-onset dementia and familial Alzheimer’s disease21–23.”

    From Chlamydia pneumoniae can infect the central nervous system via the olfactory and trigeminal nerves and contributes to Alzheimer’s disease risk (2022) · cites this paper as [23]

    The section on early dorsal raphe nucleus involvement (page not provided) describes early brainstem pathology and proposes a sequence from the dorsal raphe nucleus to the entorhinal cortex and hippocampal formation. It does not establish the olfactory bulb as an earliest-affected region or establish this regional sequence for both late-onset dementia and familial Alzheimer’s disease. (LLM, conf=0.88)

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  • NFTs are also very common in certain brainstem nuclei in subjects without dementia.

    “Recently, it has been reported that NFTs are also very common in certain brainstem nuclei in subjects without dementia (39-44).”

    From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [43]

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Citations

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Research works printed but not linked: 8

  1. Simic G, 2003, Tau phosphorylation and selective neuronal vulnerability in Alzheimer's disease, Neurol Croat, 52, 87
  2. Simic G, 1998, Cytoskeletal changes as an alternative view on pathogenesis of Alzheimer's disease, Period Biol, 100, 165
  3. 10.1111/j.1750-3639.1998.tb00160.x · DOI
  4. 10.1111/j.1440-1789.2006.00722.x · DOI
  5. American Psychiatric Association, 2000, Diagnostic and Statistical Manual of Mental Disorders (IV‐TR)
  6. World Health Organization, 2004, ICD‐10: International Statistical Classification of Diseases and Related Health Problems
  7. Diana A, 2008, Mitochondria morphology and DNA content upon sublethal exposure to β‐amyloid1‐42 peptide, Coll Antropol, 32, 51
  8. Van DomburgP.Human brainstem monoaminergic structures in Parkinson's disease and Alzheimer's disease. Thesis University of Nijmegen 1990

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Metadata

Authors
Simic, G., Stanic, G., Mladinov, M., Jovanov‐Milosevic, N., Kostovic, I., & Hof, P. R.
Affiliations
  • Hrvatski institut za istraživanje mozga (HR)
  • Icahn School of Medicine at Mount Sinai (US)
ORCID
Mladinov, M.
Venue
Neuropathology and Applied Neurobiology
Publisher
Wiley
Published
2009-11
Volume
35
Issue
6
Pages
532-554
ISSN
  • 0305-1846 (ISSN-L)
  • 1365-2990
DOI
10.1111/j.1365-2990.2009.01038.x
PMC
PMC2787819
OpenAlex
W2129951633
Cited by
204
References
172
Citations by year
2026: 3 · 2025: 11 · 2024: 12 · 2023: 17 · 2022: 12 · 2021: 20 · 2020: 7 · 2019: 14 · 2018: 13 · 2017: 11 · 2016: 13 · 2015: 14 · 2014: 15 · 2013: 13 · 2012: 7
FWCI
6.43
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Neuropathology and Applied Neurobiology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute on Aging (AG-02219, AG 05138, P50AG005138, P01AG002219)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, brainstem, dorsal raphe nucleus, neurofibrillary degeneration, neuronal cytoskeleton, behavioral and psychological symptoms of dementia, oxidative damage, amyloid-beta, Braak staging, pathogenesis
MeSH terms
Age Factors, Alzheimer Disease, Brain Stem, Cytoskeleton, Humans, Models, Neurological, Neuronal Plasticity, Neuropsychological Tests, Raphe Nuclei, Neuroimmunomodulation, Amyloid beta-Peptides, Neurofibrillary Tangles, tau Proteins, Oxidative Stress, Disease Progression

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