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| Home > Publications database > Alzheimer-typical temporo-parietal atrophy and hypoperfusion are associated with a more significant cholinergic impairment in amnestic neurodegenerative syndromes |
| Typ | Amount | VAT | Currency | Share | Status | Cost centre |
| Hybrid-OA | 325.00 | 0.00 | EUR | 100.00 % | (Zahlung erfolgt) | 40200 |
| Sum | 325.00 | 0.00 | EUR | |||
| Total | 325.00 |
| Journal Article | FZJ-2025-01978 |
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2025
IOS Press
Amsterdam
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Please use a persistent id in citations: doi:10.1177/13872877251324080 doi:10.1177/13872877251324080 doi:10.34734/FZJ-2025-01978
Abstract: BackgroundTo date, cholinomimetics remain central in the pharmacotherapy of Alzheimer's disease (AD) dementia. However, postmortem investigations indicate that the AD-typical progressive amnestic syndrome may also result from predominantly limbic non-AD neuropathology such as TDP-43 proteinopathy and argyrophilic grain disease. Experimental evidence links a beneficial response to cholinomimetics in early AD to reduced markers of cholinergic neurotransmission. However, the cholinergic impairment varies among patients with a clinical AD presentation, likely due to non-AD (co)-pathologies.ObjectiveThis study examines whether AD-typical atrophy and hypoperfusion can provide information about the cholinergic system in clinically diagnosed AD.MethodsThirty-two patients with amnestic mild cognitive impairment or mild dementia due to AD underwent positron emission tomography (PET) with the tracer N-methyl-4-piperidyl-acetate (MP4A) to estimate acetylcholinesterase (AChE) activity, neurological examinations, cerebral magnetic resonance imaging (MRI) and neuropsychological assessment. The ‘cholinergic deficit’ was computed as the deviation of AChE activity from cognitively normal controls across the cerebral cortex and correlated gray matter (GM) and perfusion of temporo-parietal cortices typically affected by AD and basal forebrain (BF) GM.ResultsTemporo-parietal perfusion and GM, as well as the inferior temporal to medial temporal ratio of perfusion correlated negatively with the ‘cholinergic deficit’. A smaller Ch4p area of the BF was associated with a more significant ‘cholinergic deficit’, albeit to a lesser degree than cortical measures.ConclusionsIn clinically diagnosed AD, temporo-parietal GM and perfusion are more closely associated with the ‘cholinergic deficit’ than BF volumes, making them possible markers for cholinergic treatment response in amnestic neurodegeneration.IntroductionAlzheimer's disease (AD), biologically characterized by the accumulation of amyloid and tau pathologies and subsequent neurodegeneration,1 typically first presents with slowly progressive memory impairment. The observation of particularly severe degeneration of the cholinergic basal forebrain in AD led to the use of cholinomimetics, which to date are central to AD pharmacotherapy.2,3 However, the effects of these medications are limited and vary considerably across patients, while side-effects often limit their use. Nonetheless, cholinergic pharmacotherapy is likely to remain relevant despite the introduction of anti-amyloid medications, given the moderate effects, side-effects, and contraindications of current anti-amyloid therapies and the lack of alternatives.4 Given the enormous burden of AD and other amnestic neurodegenerative syndromes on patients and caregivers and the risk of side-effects in the often geriatric patients, it is therefore crucial to identify factors that will allow a targeted use of cholinergic medications and ensure an appropriate risk-benefit balance for each patient.An explanation for the variable treatment response and limited group level effects of cholinomimetics may be, that a relevant ‘cholinergic deficit’ is required for patients to benefit from these medications and that the degree of cholinergic degeneration varies considerably across patients. Supporting this idea, we previously observed that even patients with mild cognitive impairment (MCI) due to AD may benefit from cholinergic stimulation, but the treatment response depended on the degree of cholinergic impairment.5 Interestingly, even in this relatively homogenous group, the cortical levels of acetylcholinesterase (AChE), a critical enzyme of cholinergic neurotransmission, varied substantially between patients.6 There is also evidence for more severe cholinergic impairment in patients with early-onset than late-onset AD.6–8A cause of the variability in cholinergic degeneration and, consequently, response to cholinergic treatment could be the heterogeneity of underlying neuropathology. Trials examining the efficacy of cholinergic medications recruited patients based purely on a clinical AD diagnosis.9–11 However, it has become clear, that the AD-typical amnestic syndrome may also be caused by non-AD pathologies.12 Non-AD pathological change is common and can be observed as co-pathology in up to half of the patients with molecular evidence of AD-pathology, especially with increasing age.12–14 It remains unclear, how limbic predominant non-AD pathologies, such as limbic-predominant age-associated TDP-43 encephalopathy (LATE) and argyrophilic grain disease, affect the cholinergic system. Basal forebrain atrophy has been linked to amyloid and Lewy-body pathology rather than LATE.15 Furthermore, the basal forebrain does not appear particularly susceptible to the TDP-43 pathology observed in frontotemporal lobar degeneration,16 and total basal forebrain volumes measured using MRI did not differ between patients with pure-AD and pure LATE neuropathological change.17Specific molecular markers of cholinergic neurotransmission, such as the activity of critical enzymes, transporters, and receptors, can be quantified in vivo using positron emission tomography (PET).18–20 However, these techniques are resource-intensive, and their use, hence, remains restricted to specialized centers, limiting their utility in large-scale studies of treatment response. However, AD and non-AD (co)-pathologies are associated with specific hypometabolism and atrophy patterns:13,21–25 The common non-AD pathologies predominantly affect the medial temporal lobe, whereas AD also affects lateral temporal and parietal cortices. Furthermore, the volume of basal forebrain structures, which are the source of cholinergic input to the cerebral cortex, can be assessed with MRI methods similar to those routinely used in the clinical setting.6,26,27 Therefore, these markers, thought to reflect different underlying pathologies, might be suitable for indirectly assessing the degree of cholinergic dysfunction in vivo.Hence, we here examined putative structural (MRI) and metabolic (PET) imaging markers that could provide insights regarding the integrity of the cortical cholinergic system in patients with a clinical diagnosis of AD. Specifically, based on our prior work, we hypothesized (1) that the volume of the posterior basal forebrain (Ch4p region) would be more closely correlated with levels of cortical AChE activity than that of the whole basal forebrain. Furthermore, we hypothesized (2) that the inferior temporal gyrus to medial temporal (ITM) ratio of cerebral perfusion, which contrasts perfusion in areas of AD- and non-AD-degeneration,13,21 and perfusion of temporo-parietal cortices, serving as markers of AD-specific degeneration, would also be correlated with cortical AChE activity.
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