Palmqvist S, Rossi M, Hall S, Quadalti C, Mattsson-Carlgren N, Dellavalle S, Tideman P, Pereira JB, Nilsson MH, Mammana A, Janelidze S, Baiardi S, Stomrud E, Parchi P, Hansson O. Cognitive effects of Lewy body pathology in clinically unimpaired individuals. Nat Med. 2023 Aug;29(8):1971-1978. Epub 2023 Jul 18 PubMed.

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  1. The remarkable ability of seed amplification assays (SAA), such as RT-QuIC, to detect pathological α-synuclein in CSF has enabled many interesting clinical questions to be addressed, in particular, those related to early diagnosis of synuclein disorders. The pair of recent papers from the BioFINDER cohort applied RT-QuIC to a large set of CSF samples. In cognitively unimpaired people (Palmqvist et al.) about 8 percent were positive, with greater likelihood related to age, male sex, positive AD (amyloid biomarkers) and, notably, olfactory loss. Long-term follow-up data showed a striking increased risk for RT-QuIC positive people to develop a clinical synucleinopathy, such as Parkinson’s Disease or DLB, as well as a risk for worsening of cognition.

    The study of cognitively impaired people suggests that SAAs can be used to identify people at risk for synucleinopathies, as is being implemented at scale by the Parkinson’s Progression Markers Initiative. This may pave the way for prevention studies but we will need a less-invasive approach than CSF sampling for screening or enriching populations. The recent study of SAA using serum (Okuzumi et al., 2023) suggests that blood screening may become feasible in future. Combining SAA with olfactory screening may be a useful way to identify people at risk.

    In people with MCI or mild dementia (Quadalti et al.), more than 20 percent had positive RT-QUiC tests, with a similar increased risk in people with amyloid co-pathology. The clinical phenotype at baseline did not always indicate DLB—sometimes hallucinations were present, although Parkinsonism was not assessed using a structured examination—but people with positive RT-QuIC had faster progression on tests of executive and visuospatial abilities. In symptomatic MCI or mild dementia, the rate of cognitive decline was faster in people who were SAA positive, particularly for the combination of A+S+. These findings support RT-QuIC as a way to identify DLB early in its clinical course, and extend many prior studies showing that people with AD and concomitant LB pathology progress faster.

    With the approval of amyloid immunotherapy for AD, the effects and benefits of this treatment in patients who have AD plus positive SAA should be formally studied; it will be of interest to see whether anti-amyloid antibodies have weaker clinical effects in such patients, or whether their use attenuates synuclein pathology. The Palmqvist and Quadalti papers further the concept of using a panel of biomarkers to identify specific brain pathology to improve personalized predictions of clinical progression.

    References:

    Okuzumi A, Hatano T, Matsumoto G, Nojiri S, Ueno SI, Imamichi-Tatano Y, Kimura H, Kakuta S, Kondo A, Fukuhara T, Li Y, Funayama M, Saiki S, Taniguchi D, Tsunemi T, McIntyre D, Gérardy JJ, Mittelbronn M, Kruger R, Uchiyama Y, Nukina N, Hattori N. Propagative α-synuclein seeds as serum biomarkers for synucleinopathies. Nat Med. 2023 Jun;29(6):1448-1455. Epub 2023 May 29 PubMed.

    View all comments by Douglas Galasko

  2. For decades, the link between Lewy body (LB) pathology with parkinsonism and cognitive impairment has been known. Most commonly LB pathology clinically manifests as Parkinson’s disease dementia or dementia with Lewy bodies. Subsequent studies have highlighted the heightened clinical aggressiveness and accelerated decline observed in individuals whose brains exhibit both LB pathology and Alzheimer's disease pathology. This stands in contrast to those with singular pathologies, be it pure Alzheimer's (AD) or pure Lewy bodies. This evidence has largely been based on postmortem autopsy studies and preclinical animal data. Excitingly, contemporary advances now empower us to assess LB pathology in vivo through α-synuclein-seed amplification assays, such as real-time, quaking-induced conversion assay (RT-QuIC). Several recent studies from different laboratories have shown the very high sensitivity and specificity of RT-QUIC for PD and DLB, including prodromal DLB.

    In the Swedish BioFinder study, a large cohort of people, with and without cognitive impairment, has provided CSF and other biomarkers and is being followed longitudinally. Palmqvist et al. demonstrated that individuals categorized as AD–/LB+ or AD+/LB– exhibited notably inferior performance in baseline global cognition and memory compared to their AD–/LB– counterparts.

    Similarly, the study conducted by Quadalti et al. yielded significant insights. It revealed that while Aβ and tau showed no direct correlation, LB pathology displayed a robust association with hallucinations, as well as impaired attention, executive function, visuospatial skills, and motor abilities. Notably, LB pathology emerged as a pivotal factor in accelerating longitudinal decline, autonomously impacting this decline trajectory without being contingent on Aβ or tau.

    The quantification of LB pathology in vivo holds dual relevance—one within a clinical framework, offering improved individualized prognostic insights, and the other in the context of clinical trials for all neurodegenerative disorders, where a substantial number of cases are marked by the presence of LB pathology. Together, these studies underline the importance of α-synuclein pathology also outside of typical Lewy body disease, and suggest that the novel technology might become a relevant screening test in memory clinics together with the traditional AD biomarkers.

    View all comments by Maria Camila Gonzalez Velez

  3. Intraneuronal aggregates of α-synuclein (αSyn) are the hallmark of pathology in Lewy body diseases (LBD), including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) (Henderson et al., 2019). Diffuse cortical spread of αSyn pathology correlates strongly with cognitive decline in LBD with PD dementia (PDD) and in DLB, being nearly indistinguishable at autopsy (Kövari et al., 2003; Hurtig et al., 2000). There is a significant population of normal and cognitively impaired individuals who at autopsy have concurrent AD and LBD pathology. Over 25 percent of these individuals have primary LBD pathology meeting criteria for AD neuropathologic diagnosis, and up to 60 percent of them have primary AD pathology with concomitant LBD neuropathology (Hepp et al., 2016; Irwin et al., 2012). However, the interplay between Alzheimer’s and LBD pathology has been difficult to study in living individuals until the advent of seed aggregation assays (SAAs) as a biomarker for αSyn pathology. These studies from Palmqvist et al. and Quadalti et al. use novel αSyn SAAs to characterize cognitive trajectories as they relate to underlying AD and LBD pathology in cognitively unimpaired individuals and in those with mild impairment (Quadalti et al., 2023). 

    First, these studies reinforce the utility of aSyn SAA as a biomarker, given that only SAA+ individuals progressed to clinical LBD and their significant association with hyposmia, a known prodromal symptom in LBD. Notably, SAA-positivity was a better predictor of conversion to clinical LBD than a smell test. Second, the presence of LB pathology was associated with worse baseline cognition and memory and with worse longitudinal cognitive decline, implicating both an independent and synergistic effect with AD pathology. Interestingly, in the populations with cognitive impairment, people in the AD+LBD- biomarker group had a higher proportion of progression to a clinical diagnosis (50 percent to 93 percent AD, 0.5 to 0.8 percent DLB/PD) relative to those in the AD-LBD+ (8 percent to 14 percent AD, 31 percent to 46 percent DLB/PD) or AD+LBD+ (46 percent to 75 percent AD, 9 percent to 16 percent DLB/PD) groups. Whether these findings are due to length of follow-up (mean of four years in these studies), due to diagnosis setting (memory clinic rather than movement disorders clinic), or other factors remains to be seen. The heterogeneity of clinical diagnosis in the AD+LBD+ cohort suggests pathways to a diversity of clinical phenotypes.

    The availability and clinical use of biomarkers for amyloid, tau, and αSyn pathology provides the opportunity to understand the interplay between these pathologies that contribute to cognitive decline and neurodegeneration. These studies are novel and exciting because for the first time they characterize early and prodromal populations, using underlying biomarkers, to begin to understand in vivo how LBD pathology interacts with AD pathology as well as to demonstrate the potential for selecting relevant individuals for clinical trials based on underlying pathology. Furthermore, prognostic information based on biomarker data may be useful for individuals who are known to be at high-risk for development of cognitive decline or neurodegeneration, especially with the idea of potentially testing drugs in those with early or prodromal disease. Future studies will need to enroll larger cohorts (given relative paucity of AD and LBD co-pathology) and have longer follow-up to fully understand the synergy of LBD and AD pathology.

    References:

    Henderson MX, Trojanowski JQ, Lee VM. α-Synuclein pathology in Parkinson's disease and related α-synucleinopathies. Neurosci Lett. 2019 Sep 14;709:134316. Epub 2019 Jun 3 PubMed.

    Kövari E, Gold G, Herrmann FR, Canuto A, Hof PR, Bouras C, Giannakopoulos P. Lewy body densities in the entorhinal and anterior cingulate cortex predict cognitive deficits in Parkinson's disease. Acta Neuropathol. 2003 Jul;106(1):83-8. PubMed.

    Hurtig HI, Trojanowski JQ, Galvin J, Ewbank D, Schmidt ML, Lee VM, Clark CM, Glosser G, Stern MB, Gollomp SM, Arnold SE. Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson's disease. Neurology. 2000 May 23;54(10):1916-21. PubMed.

    Hepp DH, Vergoossen DL, Huisman E, Lemstra AW, Netherlands Brain Bank, Berendse HW, Rozemuller AJ, Foncke EM, van de Berg WD. Distribution and Load of Amyloid-β Pathology in Parkinson Disease and Dementia with Lewy Bodies. J Neuropathol Exp Neurol. 2016 Oct;75(10):936-945. Epub 2016 Aug 11 PubMed.

    Irwin DJ, White MT, Toledo JB, Xie SX, Robinson JL, Van Deerlin V, Lee VM, Leverenz JB, Montine TJ, Duda JE, Hurtig HI, Trojanowski JQ. Neuropathologic substrates of Parkinson disease dementia. Ann Neurol. 2012 Oct;72(4):587-98. PubMed.

    Quadalti C, Palmqvist S, Hall S, Rossi M, Mammana A, Janelidze S, Dellavalle S, Mattsson-Carlgren N, Baiardi S, Stomrud E, Hansson O, Parchi P. Clinical effects of Lewy body pathology in cognitively impaired individuals. Nat Med. 2023 Aug;29(8):1964-1970. Epub 2023 Jul 18 PubMed.

    View all comments by George Kannarkat

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