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Advanced Neurology Dementia with Lewy bodies and substance misuse

3.3. Clinical applications

Benzodiazepine use and misuse have been known to
be linked with cognitive deficits, even dementia, for
decades. 14,17,90,162 A meta-analysis by He et al. showed a
significant risk of dementia faced by elderly benzodiazepine
users, which increased with a longer half-life (>20 h) and
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longer use (>3 years). The patient described in this paper
had been taking prescription benzodiazepines for over
30 years and had been taking them at a higher dose than
recommended for years. His concurrent use of alcohol and
the potentiating effects of some of his other medications
Figure 5. GABA receptor. Benzodiazepine and alcohol ligands bind to increased his risk for harm. Periodic withdrawals of
GABA receptors, opening ligand-gated chloride channels and decreasing different substances could have added to his inflammatory
nerve cell firing rates. Excitatory processes, reflected by glutamatergic 7,81,123-125
activity, increase to compensate for the GABAergic inhibition. Image burden through the process of kindling. The
is reproduced from By BruceBlaus. Own Work distributed under CC neuropsychological profile of alcohol and benzodiazepine
133
BY-SA 4.0. misuse is very similar to that of DLB, making detection on
Abbreviation: GABA=Gamma-aminobutyric acid. neuropsychological tests difficult. The improvement in the
patient’s language and memory, with continued deficits in
as brain-derived neurotrophic factor, are decreased. visuoconstructional and executive function and worsening
139
Gliotic astrocytes which process the glutamate and of MMSE following withdrawal from his benzodiazepines
microglia become dysfunctional and lose their ability to and sobriety, suggested a degenerative proteinopathy
promote neuronal survival, outgrowth, synaptogenesis, rather than a simple alcohol-related dementia/Wernicke–
and phagocytosis and instead release pro-inflammatory Korsakoff syndrome or cognitive impairment from
3
cytokines, generating more ROS. 140-143 In addition benzodiazepine withdrawal syndrome. His normal
to contributing to the formation of proteinopathies, thiamine, hepatic panel, and lack of encephalopathy
increased neuroinflammation activates the tryptophan- findings on MRI also excluded Wernicke’s. 27,32 The lack
kynurenine (KYN) metabolic pathway. KYN can be of extensive deep white matter hyperintensities helped
metabolized into either neuroprotective kynurenic acid to rule out VD; however, there can be overlap with
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(KYNA) or in an environment of high ROS, neurotoxic some white matter diseases later in the course of DLB.
quinolinic acid (QA). 144-146 KYNA modulates glutamate Visuoconstructional deficits are more common early in the
course of DLB compared to AD or FTD.
163,164
receptors, while QA causes glutamate excitotoxicity,
cytoskeletal instability, disruption of the blood–brain One of the weaknesses of the current criteria for
barrier, mitochondrial dysfunction, promotion of tau the diagnosis of many proteinopathies is the stringent
protein phosphorylation, disruption of autophagy, and requirement of dementia as detected on standardized
generation of more ROS. 105,147-149 A shift to QA from instruments. Executive dysfunctions can be present in
KYNA has been seen in low-grade immune activation by the prodromal phase of the disease, which are debilitating
substances such as alcohol. The products of QA and other enough to severely impact ADLs and work. Tests such
150
neuroinflammatory factors, such as TLR4, can activate as the MMSE rely heavily on memory and the ability to
nuclear factor kappa B/RelA, increasing expression of follow simple directions, which can be helpful for tracking
pro-inflammatory factors and glutamate excitotoxicity, decline and the presence of more severe dementias but fail
creating a cycle of inflammation, cell death, and additional to give enough weight to the severe deficits reported by
proteinopathy formation 142,150-161 (Figure 6). Other sources families or the patients themselves. The Neuropsychiatric
of inflammation and ROS include repeated traumatic Inventory helps identify the disabling neuropsychological
brain injury (TBIs), psychological and social stress, and symptoms, which accompany suspected prodromal
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the byproducts produced by latent viruses, which can stay dementias, and may help differentiate among them. The
in the brain for long periods of time. 15,16 Mini–Mental Parkinson Test (MMP) has been developed
to test cognitive decline in those with Parkinson’s
Alcohol, benzodiazepines, and other toxins can generate disease and would be better suited for measuring
harmful ROS and pro-inflammatory factors in the brain. visuoconstructional and executive dysfunctions than the
Other sources, such as repeated TBIs and viral byproducts, MMSE. It is also possible to make adjustments for age and
can also directly cause ROS and pro-inflammatory factors. level of education with the MMP. The testing ceiling
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Volume 3 Issue 1 (2024) 9 https://doi.org/10.36922/an.2232