Journal of Parkinson’s Disease xx (2020) x–xx 1 DOI 10.3233/JPD-202323 IOS Press

1 Review

2 Neuropathological and Biomarker Findings

3 in Parkinson’s Disease and Alzheimer’s

4 Disease: From Protein Aggregates to

5 Synaptic Dysfunction

a,b,∗ c,d,e,∗ 6 Yaroslau Compta and Tamas Revesz a 7 Parkinson’s disease & Movement Disorders Unit, Neurology Service, Hospital Cl´ınic / IDIBAPS / CIBERNED, 8 Barcelona, Catalonia, Spain b 9 Institut de Neuroci`encies, Maextu’s excellence center, University of Barcelona, Barcelona, Catalonia, Spain c 10 Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neurosciences, 11 UCL Queen Square Institute of Neurology, University College London, UK d 12 Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, London, UK 13 eDepartment of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College 14 London, UK

Accepted 9 November 2020

15 Abstract. 16 There is mounting evidence that Parkinson’s disease (PD) and Alzheimer’s disease (AD) share neuropathological hallmarks, 17 while similar types of biomarkers are being applied to both. In this review we aimed to explore similarities and differences 18 between PD and AD at both the neuropathology and the biomarker levels, specifically focusing on protein aggregates 19 and synapse dysfunction. Thus, amyloid-␤ peptide (A␤) and tau lesions of the Alzheimer-type are common in PD and 20 ␣-synuclein Lewy-type aggregates are frequent findings in AD. Modern neuropathological techniques adding to routine 21 immunohistochemistry might take further our knowledge of these diseases beyond protein aggregates and down to their 22 presynaptic and postsynaptic terminals, with potential mechanistic and even future therapeutic implications. Translation of 23 neuropathological discoveries to the clinic remains challenging. Cerebrospinal fluid (CSF) and positron emission tomography 24 (PET) markers of A␤ and tau have been shown to be reliable for AD diagnosis. Conversely, CSF markers of ␣-synuclein 25 have not been that consistent. In terms of PET markers, there is no PET probe available for ␣-synuclein yet, while the AD 26 PET markers range from consistent evidence of their specificity (amyloid imaging) to greater uncertainty of their reliability 27 due to off-target binding (tau imaging). CSF synaptic markers are attractive, still needing more evidence, which currently 28 suggests those might be non-specific markers of disease progression. It can be summarized that there is neuropathological

3229 evidence that protein aggregates of AD and PD are present both at the soma and the synapse. Thus, a number of CSF and

3330 PET biomarkers beyond ␣-synuclein, tau and A␤ might capture these different faces of protein-related neurodegeneration. 31 It remains to be seen what the longitudinal outcomes and the potential value as surrogate markers of these biomarkers are.

Keywords: α-Synuclein, alzheimer’s disease, amyloid-␤, biomarkers, cerebrospinal fluid, lewy-type pathology, molecular imaging, Parkinson’s disease, synaptic dysfunction,Uncorrected tau Author Proof

∗Correspondence to: Yaroslau Compta, Parkinson’s disease & Movement Disorders Unit, Neurology Service, Hospital Cl´ınic / Bank for Neurological Disorders, Department of Clinical and IDIBAPS / CIBERNED, Barcelona, Catalonia, Spain. E-mail: Movement Neurosciences, UCL Queen Square Institute of Neurol- [email protected]. and Tamas Revesz, Queen Square Brain ogy, University College London, UK. E-mail: [email protected].

ISSN 1877-7171/20/$35.00 © 2012 – IOS Press and the authors. All rights reserved This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License (CC BY-NC 4.0). 2 Y. Compta and T. Revesz / Neuropathological and Biomarker Findings in Parkinson’s Disease and Alzheimer’s Disease

34 INTRODUCTION pathology and synaptic dysfunction related to PD and 85 AD-related disease proteins (␣-synuclein, A␤ and 86 35 Partly derived from the fact that dementia is very tau), in order to put these in perspective and suggest 87 36 common in Parkinson’s disease (PD) [1], there is future directions. 88 37 mounting neuropathological evidence that PD and 38 Alzheimer’s disease (AD) share several common NEUROPATHOLOGICAL EVIDENCE OF 89 39 features [2, 3]. Traditional post-mortem neuropatho- ASSOCIATION OF ALZHEIMER’S 90 40 logical studies are nowadays supplemented by DISEASE-TYPE PATHOLOGY WITH 91 41 biomarker studies purportedly reflecting the under- LEWY PATHOLOGY IN PARKINSON’S 92 42 lying pathology in vivo, ranging from biochemical DISEASE 93 43 studies in cerebrospinal fluid (CSF) to molecular 44 imaging of proteins deposition such as amyloid-␤ In the pre-␣-synuclein era when assessment of cor- 94 45 (A␤) or tau. Both types of studies have favoured in tical Lewy bodies was possible, but more difficult 95 46 recent years the notion that neurofibrillary tangle- and less reliable, some studies found Alzheimer-type 96 47 type lesions composed of hyperphosphorylated tau lesions as a correlate of dementia in PD [9–12]. 97 48 and, particularly, A␤-containing aggregates are com- With the discovery of ␣-synuclein as a key compo- 98 49 mon in PD and associated with presence and risk of, nent of Lewy bodies, Lewy neurites and other lesion 99 50 as well as timing to, dementia [2, 3]. All this has types [13] the subsequent introduction of ␣-synuclein 100 51 supposed a paradigm shift of sorts, departing from immunohistochemistry, the tide turned, and several 101 52 the general conception at the end of the 20th and studies favoured cortical Lewy pathology as the main 102 53 early 21st century that cortical Lewy pathology alone (and almost sole) neuropathological correlate of cog- 103 54 accounted for dementia in PD, to conceiving that nitive dysfunction in PD. However, in the last decade, 104 55 both Lewy and Alzheimer pathologies are relevant in a number of clinico-pathological studies consistently 105 56 PD-dementia. Additionally, there is also consistent showed that Alzheimer co-pathology is significantly 106 57 data as to the concomitant presence of ␣-synuclein associated with cognitive dysfunction in PD, both in 107 58 containing Lewy-type aggregates in a significant pro- terms of increased risk and shorter time interval from 108 59 portion of both sporadic and familial AD, particularly disease onset to the development of dementia. All 109 60 in the amygdala [4, 5]. these studies have been extensively reviewed [2, 3] 110 61 However, it remains unknown what is the exact and are summarized in Table 1 [9–32]. In short, large 111 62 mechanistic role of co-existing Lewy and Alzheimer studies have identified that, besides cortical Lewy- 112 63 pathologies observed in post-mortem studies, with type pathology, A␤ plaque pathology is a determinant 113 64 common criticism being that these most often reflect of cognitive impairment in PD as A␤ deposition has 114 65 findings in end-stage cases (unless the autopsies are been shown to be associated with the risk and timing 115 66 performed in patients dying prematurely of an unre- of developing dementia [22, 28, 29] and with disease 116 67 lated illness) and that these may not necessarily reflect duration [30]. Others have identified tau pathology 117 68 what originally drove the symptoms (in this case more as the determinant of progression to dementia [32]. 118 69 importantly, but not exclusively, dementia). These discrepancies as to the predominating role of 119 70 As for in vivo biomarker studies-derived evidence A␤ or tau most probably owe to methodological dif- 120 71 of coexistence of both Lewy and Alzheimer patholo- ferences (for instance, including all A␤ plaque forms, 121 72 gies it is yet controversial as it is still not clear such as diffuse and mature plaques [25, 27], vs. only 122 73 whether the used biomarkers actually reflect underly- accounting neuritic plaques as A␤ pathology [31]). 123 74 ing pathology or rather are the consequence of some 75 other molecular processes. Thus, in studies assess- 76 ing CSF biomarkers, the main concern is that these NEUROPATHOLOGICAL EVIDENCE OF 124 77 might be reflecting non-specific alterations (mostly CO-EXISTING LEWY-TYPE LESIONS IN 125 78 axonal loss or neuronal degeneration, in the case of ALZHEIMER’S DISEASE 126 79 tau [6]) or intrinsic processes relatedUncorrected to the soluble Author Proof 80 species of the involved protein (such as synaptic dys- Similar to co-existing AD-type pathology in PD, 127 81 function in the case of A␤ [7] and ␣-synuclein [8]), Lewy-type pathology has also been widely studied 128 82 rather than the respective disease protein aggregates. in AD. Interestingly, the relationship between Lewy 129 83 Here we revisit the neuropathological and bio- pathology and AD attracted the interest of inves- 130 84 marker evidence from recent years focusing in tigators before the actual finding of specific Lewy 131 Y. Compta and T. Revesz / Neuropathological and Biomarker Findings in Parkinson’s Disease and Alzheimer’s Disease 3 -synuclein era ␣ -synuclein Retrospective Pre- Retrospective ␣ Definition of • • • • study (ubiquitin immune-staining) • dementia? immunostaining were not ␤ ␤ highly sensitive → ␤ -synuclein era examples to more recent clinicopathological studies ␣ 5 = not explained by histological4 changes = vascular damage 3 = numerous cortical Lewy bodies 2 = hydrocephalus 9/9 (100%) with severe dementia 3/7 (43%) with mild dementia 3/13 (23%) with no dementia -synuclein+cortical Lewy bodies Plaques & tangles in 15/36→ (42%): → → 23 patients had dementia includingwidespread all cortical 9 A cases with Lewy bodies density correlated withtangles plaques rather than Frontal Lewy bodies = significant predictorimpairment of cognitive AD changes = 6-fold in PD(5.1%) (33&) relative to controls AD changes = shorter survival than no AD changes 5 of 17 controls withdemented widespread cortical A 14 patients with dementia unrelated→ to A → → → 43% of cases with Alzheimer-changes Total cortical Lewy bodies+temporal neurofibrillary tangles associated with cognitive impairment ␣ (91%) and specific (90%) neuropathologicdementia markers in of PD Slightly more sensitive than ubiquitin+corticalbodies Lewy Better indicators of dementia thandystrophic angles, neurites. plaques, or Table 1 -synuclein, ubiquitin and thioflavine S stainings Plaques & tanglesDementia casesPlaques & tangles 33 PD cases with plaques & tangles 9 cases 7 with cases severe dementia with (31%) mild dementia (24%) Dementia cases Plaques & tangles Vascular damage Hydrocephalus Lewy body and Alzheimer type changes 40% of cases with Alzheimer-changes Reisberg’s global deterioration scale (GDS) LewyAlzheimer-changes & in the substantia nigra,hippocampus amygdala, and cortex ␣ with adequate clinical data) 79 controls 22 PDD

Uncorrected Author Proof Boller et al. [10] 1980 36 PD cases (29 ReferenceHakim & Mathieson [9] 1979 34 PD Year Sample Dementia cases Main outcomes 19 PDD cases (56%) Main findings Comments Jendroska et al. [11] 1996 50 PD cases Mattila et al. [14] 2000 45 PD cases Amygdala, hippocampus+6 cortical gyri At least 1 cortical Lewy body in 95% Mattila et al. [12] 1998 44 PD cases CERAD neuropathological assessment At least 1 cortical Lewy body in 93% Hurtig et al. [15] 2000 20 PDND Summary of relevant neuropathological evidence of Alzheimer-type co-pathology in Parkinson’s disease ranging from few pre- 4 Y. Compta and T. Revesz / Neuropathological and Biomarker Findings in Parkinson’s Disease and Alzheimer’s Disease -synuclein -synuclein ␣ Retrospective Prospective ␣ • • immunostaining • • immunostaining ␤ ␤ -synuclein ␣ -synuclein (specifically in the ␣ ␤ scores, but not Braak staging ␤ none met AD neuropathological → -synuclein & tau as well as cortical ␣ diffuse or transitional Lewy bodies → Entorhinal Lewy & plaque densitiesand explained 19.3% 36.2% of CDR variability, respectively Mean cortical & limbic Lewygreater body in counts PDD 10-fold > PDND Cortical Lewy body counts significantlyplaques correlated & to tangles transitional and 8 had neocortical Lewy bodies CDR correlated with entorhinal and area 24 Lewy scores 12 PDD MMSE scores correlated with neuropathologic stages Higher neurofibrillary pathology stages anddeposition A in cognitively impaired cases Few or no cortical Lewy bodiesThe in opposite brains in without brains A with A cingulate cortex) 18 developed PDD definition Cortical Lewy bodies were thecognitive main impairment substrate of associated with less severe cortical pathology and CERAD A Cases with shorter survivals hadpathology more Lewy and plaque PDD+AD subjects were older atprogressed onset faster and to death, dementia; and aboutmet one AD half neuropathological of criteria cases Aß plaque load, and generalizedangiopathy cerebral or amyloid CAA) were significantlysevere higher/more in DLB and PDD than in PD Table 1 Continued -synuclein and tau ␣ immunohistochemistry Braak stages for ␤ immunohistochemistry and ␤ -synuclein and tau immunostainings ␣ CERAD classification and Braak stages for ␤ -synuclein and tau immunostainings Of the 17 patients without cognitive impairment, 9 had -synuclein and A -synuclein and tau -synuclein, tau & A ␣ Lewy bodies, tangles and plaquesand in entorhinal areas cx 9, 21, 24, 40 Hematoxylin-eosin, Bielschowsky and thioflavin S stains+ pathologies ␣ immunoblots ␣ ␣ (21 = cognitive impairment) 12 PDD 52 PDD+ 6 DLB 23 PDD-AD 44 PDD+ 20 DLB

Uncorrected Author Proof Colosimo et al. [17] 2005Kovari et 38 al. PD [18] 2003 22 PD Clinical dementia rating scale (CDR)+quantification of Braak et al. [19] 2005 88 PD MMSE, Braak stages for ReferenceApaydin et al. [16] 2002 9 PDND Year Sample Main outcomes Main findings Comments Pletnikova et al. [20] 2005 21 PD+DLB Aarsland et al. [21] 2005 22 PD A Ballard et al. [22] 2006 28 PDD+29 DLB MMSE & UPDRS Longer time from parkinsonism to dementia was Haliday et al. [23] 2008 29 PDND+ Sabbagh et al. [24] 2009Jellinger & Attems 28 [25] PDD+AD 2008 54 PDND+ Y. Compta and T. Revesz / Neuropathological and Biomarker Findings in Parkinson’s Disease and Alzheimer’s Disease 5 D, Parkinson’s disease -synuclein Retrospective ␣ • • immunostaining had significantly ␤ -synuclein stages, significantly -synuclein scores and shorter ␣ load ␣ ␤ score and older age at onset were ␤ scores were marginal in the ␤ scores & Braak tau stages, but not Lewy +cortical Lew scores+Braak tau stages in ␤ ␤ load correlated with cortical Lewy burden burden was greater in the striatum of PDD than in and tau more prominent in the tectum increasing ␤ ␤ ␤ -synuclein and tau deposition were rare in the striatum -synuclein midbrain scores rose from controls to AD moderate to high A ␣ in both groups A PDND combination predicted better dementia thanseparately each body scores or Braak correlated with MMSE scores associated with a shorter time-to-dementiaCortical period. Lewy scores+APOE4 were thecorrelates stronger of dementia PDD+AD cases were older, hadand more CAA Lewy pathology shorter survival ␣ and then LBD irrespective ofA dementia from controls to LBD (mostlypeaking dementia in cases) AD then Cerebellar A LBD-spectrum (as opposed to AD)trend only towards showing greater a involvement in dementiaGreater cases Alzheimer pathology (chiefly oftype) neurofibrillary implied higher time-to-dementia ␤ ␤ and ␤ Table 1 Continued ) ␤ -synuclein, A ␣ deposition in the caudate, ␤ immunohistochemistry Patients with synucleinopathy+A plaques & CAA scores A plaques & CAA scores Cortical A ␤ ␤ ␤ -synuclein and tau Cortical A ␣ -synuclein, tau, and A -synuclein, tau & A ␣ putamen, and accumbens Braak stages for Semiquantitative A Lewy densities and semiquantitative scores High cortical A Semiquantitative scores for neurofibrillary tangles, A ␣ plaques & Lewy bodies/neurites Semiquantitative scores for neurofibrillary tangles in the midbrain& (substantia tectum)+cerebellum nigra (for A plaques & Lewy bodies/neurites 16 PDD 20 controls Morphometric approach for Lewy pathology This correlation was more marked in cases with 29 PDD 92 PDD 10 PDD 10 DLB 10 AD 10 controls Uncorrected Author Proof ; AD, Alzheimer’s disease; DLB, dementia with Lewy bodies; LBD, Lewy body disorder; PD, Parkinson’s disease; PDD, Parkinson’s disease dementia; PDN ␤ , amyloid- ␤ ReferenceLashley et al. [26] 2008 40 PD Year Sample Semiquantitative A Main outcomes Main findings Comments Kalaitzakis et al. [27] 2009 14 PDND Compta et al. [28] 2011 27 PDND Irwin et al. [29] 2012 48Kotzbauer PDND et al. [30] 2012 32 PDD Sierra et al. [31] 2016 10 PD Irwin et al. [32] 2017 213 LBD Semiquantitative scores for neurofibrillary tangles, A A non-demented. 6 Y. Compta and T. Revesz / Neuropathological and Biomarker Findings in Parkinson’s Disease and Alzheimer’s Disease

132 pathology in AD, since research on the so-called non- presynaptic ␣-synuclein aggregates and visualiza- 179 133 amyloid component of plaques (NACP) [33] started tion and semi-quantitation of post-synaptic dendritic 180 134 long before the identification of alpha-synuclein as spines. For instance, in a study applying the paraffin- 181 135 the main constituent of Lewy bodies [13]. Subse- embedded tissue (PET) blot and the protein aggregate 182 136 quently, several studies have consistently shown that filtration (PAF) assay, Kramer and Schulz-Schaeffer 183 137 both in sporadic and in genetically determined AD observed with the PET blot a large amount of 184 138 (such as in PSEN1 familial AD and in Down’s syn- very small ␣-synuclein aggregates, which, using the 185 139 drome) Lewy pathology is common, particularly in PAF assay, were most frequently found in presy- 186 140 the amygdala, but also in the olfactory bulb, as sum- naptic terminals. This finding was mirrored by an 187 141 marized in Table 2 [34–38]. almost complete loss of postsynaptic dendritic spines, 188 in sharp contrast to the relatively small amount 189 of cortical Lewy bodies, particularly compared to 190 142 SUMMARY OF CO-PATHOLOGY IN the severity of cognitive impairment seen in PDD 191 143 PARKINSON’S DISEASE AND and DLB [41]. Accordingly, these authors proposed 192 144 ALZHEIMER’S DISEASE presynaptic ␣-synuclein aggregates and the loss of 193 dendritic spines as critical events for neurodegenera- 194 145 The concurrence of Alzheimer and Lewy patholo- tion in Lewy-related disorders [41, 42]. 195 146 gies in structures such as the amygdala and the Also focusing on samples of DLB cases, Colom- 196 147 olfactory bulb, which are commonly affected in Cadena and co-workers applied a microscopy 197 148 both conditions (i.e., PD and AD) is scientifically technique called array tomography (which combines 198 149 intriguing, and, as the aforementioned co-existence ultrathin tissue sections with immunofluorescence to 199 150 of Alzheimer and Lewy pathologies, is in keeping visualize and quantify small structures such as the 200 151 with the experimental evidence supportive of patho- synapses) to assess presynaptic phosphorylated ␣- 201 152 logical synergism. Thus, these proteins have been synuclein in the cingulate cortex and striatum from 202 153 shown being capable of cross seeding and promot- 5 DLB cases and compared them to 5 AD and 5 203 154 ing each other’s aggregation [39], most probably not control cases. Hence, the authors found that 19% to 204 155 in all instances, but specifically when some protein 25% of phosphorylated ␣-synuclein aggregates were 205 156 strains are present [40]. While these experimental in presynaptic terminals with synaptic terminals co- 206 157 works are not free of criticism (mostly regarding as localizing with these small aggregates being larger 207 158 to what extent they can translate to what actually hap- than terminals without such aggregates. There was 208 159 pens in humans and in disease), they provide a basis also a gradient in the presence of phosphorylated 209 160 for further studies to understand how these proteins synaptic ␣-synuclein aggregates, with their greater 210 161 form disease-associated aggregates and, ultimately presence presynaptically suggesting a primary role 211 162 test specific anti-protein-aggregation agents. Discus- for the presynaptic compartment [43]. 212 163 sion of such experimental studies is beyond the scope Other authors have aimed at assessing other synap- 213 164 of this review and we refer to reviews published else- tic alterations such as suboptimal energy metabolism, 214 165 where [3]. and oxidative and endoplasmic reticulum stress dam- 215 age in preclinical PD by means of studying incidental 216 166 NEUROPATHOLOGICAL EVIDENCE OF Lewy bodies [44]. Finally, it remains a matter of 217 167 SYNAPTIC DYSFUNCTION IN PD AND AD debate to what extent levodopa influences synaptic 218 dysfunction in PD, as for decades many have made 219 168 Synaptic dysfunction is a relatively new player in observations supportive of the notion that levodopa 220 169 the field, since it is not as easily assessable as pro- is harmful [45], whereas others have not [46]. 221 170 tein aggregation, for which immunohistochemistry Synaptic dysfunction is also considered in the 222 171 provides a robust tool, albeit not devoid of limitations. pathophysiology of AD. In this vein, loss of den- 223 172 Lewy body disorders can be considered as dritic spines has been correlated with loss of synaptic 224 ␤ 173 a clinicopathological spectrum encompassingUncorrected PD, function [47–49]. Author Intriguingly, Proof A , both in its insol- 225 174 PD-dementia (PDD) and dementia with Lewy uble (fibrils and plaques) and its soluble (oligomers) 226 175 bodies (DLB), rather than a group of truly dis- forms, either extra or intracellularly, has been sug- 227 176 tinct conditions. Across this spectrum, the use of gested to precede and lead to dysfunction of dendritic 228 177 non-conventional light microscopy techniques, has spines in experimental and pathological studies by 229 178 allowed for sensitive and selective detection of a number of mechanisms ranging from reduced 230 Y. Compta and T. Revesz / Neuropathological and Biomarker Findings in Parkinson’s Disease and Alzheimer’s Disease 7 -synuclein in ␣ -synuclein ␣ -synuclein ␣ entia with Lewy bodies; fAD, -synuclein studies ␣ -synuclein immunohistochemistry in a First study investigating using ␣ large cohort of fAD First large study using immunohistochemistry in late onset sporadic AD cases First study using immunohistochemistry in Down’s syndrome cases with Alzheimer pathology No direct correlation between Alzheimer and Lewy lesions, but Lewy pathology present even in cases andmore locations severe with tau degeneration (hippocampus) Co-localization of tau and the olfactory bulb Prospective design -synuclein+structures ␣ synuclein ␥ or ␤ -synuclein+Lewy bodies and neurites in 50% of ␣ -synuclein in neurons and neurites of the olfactory Table 2 ␣ -synuclein-immunoreactive Lewy bodies. In 12 of the -synuclein+structures most frequent in the-synuclein+structures amygdala different from Lewy bodies -synuclein pathology detected in the olfactory bulb in significantly with LTS 18 patients had > 1 of13 these of changes them had featured9 rigidity+/- had tremor had a second11 diagnosis (85%) of had PD PD pathologic11 changes cases (55%) showed PDNo changes significant difference in ageAD+PD or vs. symptom AD-PD duration in History of rigidity in 80%AD-PD of AD+PD but only Pre- 14%Tremor of not observed in either AD+PD or AD-PD In at least in 22%␣ of the entire cohort there19 were fAD cases (63%), ininvestigated, which Lewy the bodies amygdala were was found in this structure Many amygdala samples with Alzheimer pathology No positivity for Lewy bodies found in 88/145and (60.7%) 56.8% of of CERAD 95 cases casesThe with amygdala Braak was stage severely 5-6) involved inAbsent all to cases mild Lewy pathology in the substantia nigra 13 of 27 cases (48.2%) had including Lewy bodies Frequency and density of plaquesdiffer and between+and tangles – did cases not ␣ ␣ more frequent in the hippocampus Lewy-related structures even in AD caseswidespread with and numerous tangles ␣ 38/41 AD+ALB (93%) and 4Double of immunolabeling 21 revealed AD-ALB co-localization (19%) ofand tau bulb AD subjects with LTS pathology hadand higher III total UPDRS scores II as wellscores as compared generally to higher AD individual alone Depression scales and Trail-making Test A correlated -synuclein -synuclein ␥ ␥ / / -synuclein ␤ ␤ / / -synuclein ␣ ␣ ␣ ␣ -synuclein pathology in the neurofibrillary tangles in the substantia nigra and gliosis of pigmented nuclei Controlled for use of neuroleptic medication Immunohistochemistry with antibodies to Immunohistochemistry with antibodies to antibodies to pathology and aggregation ␣ olfactory bulb in AD withwithout and ALB Summary of relevant neuropathological evidence of Lewy-type co-pathology in Alzheimer’s disease familial AD syndrome amygdala Lewy bodies (AD-ALB) 21 AD without ALB ADLB, 70 AD, 41 PDD/AD cases Uncorrected Author Proof ReferenceLeverenz et al. [34] 1986 40 sporadic AD Year Sample NeuronalDitter loss, et Lewy al. bodies, [35] or 1987 20 sporadic AD Main outcomes Lewy body formation, neuronal loss, Lippa et al. [4] 1998 74 cases of Main findings Comments Lippa et al. [36] 1999 20 Down’s Arai et al. [5] 2001 27 sporadic AD Relationship between Alzheimer Hamilton et al. [4] 2000 145 sporadic AD Immunohistochemistry with Fujishiro et al. [37] 2008 41AD with Savica et al. [38] 2019 32 DLB/AD, 54 AD, Alzheimer’s disease; AD-ALB, Alzheimer’s disease with amygdala Lewy bodies; ADLB, AD cases with LTS, but not meeting the criteria of DLB; DLB, dem familial Alzheimer’s disease; LTS, Lewy-type synucleinopathy; PD, Parkinson’s disease; PDD, Parkinson’s disease dementia. 8 Y. Compta and T. Revesz / Neuropathological and Biomarker Findings in Parkinson’s Disease and Alzheimer’s Disease

231 spine formation, stability and plasticity (inhib- species in CSF (mostly total and oligomeric) has 280 232 ited long-term potentiation and enhanced long-term rapidly increased, albeit with remarkable inconsis- 281 233 depression), to abnormalities in synaptic scaffold tencies, most likely related to several pre-analytic and 282 234 proteins and impaired organelle transport [50–56]. analytic factors. However, overall the trend is that 283 235 Tau hyperphosphorylation and microglia activation, CSF total ␣-synuclein levels are lowered in PD and 284 236 which according to the amyloid cascade hypothesis other synucleinopathies vs. controls and other neu- 285 237 are events secondary to A␤ pathology, appear to con- rodegenerative conditions [60, 61], with the opposite 286 238 tribute to spine failure in AD as well [57]. Recently occurring with CSF levels of oligomeric ␣-synuclein 287 239 the postsynaptic protein neurogranin has been found [62]. This notwithstanding, the interpretation of CSF 288 240 to be reduced in brain tissue in AD [58]. markers appears to be more difficult in terms of 289 241 Therefore, synaptic dysfunction in PD, DLB and PD-related cognitive impairment. Thus, few studies 290 242 AD, appears to be an attractive target both for have found that CSF levels of oligomeric ␣-synuclein 291 243 improving knowledge of disease mechanism and also tend to increase in PDD and DLB [63, 64] 292 244 developing new therapies, since preserved synaptic (that is, consistent with its trend as a diagnostic 293 245 spines have been in turn linked to resilience against marker), but CSF total ␣-synuclein has shown con- 294 246 neurodegeneration [59]. Should the synaptic fail- flicting results, with a number of cross-sectional and 295 247 ure hypothesis hold true, it would theoretically be longitudinal studies having even suggested that high 296 248 possible to revert it. However, unlike A␤ and tau (instead of low) CSF total ␣-synuclein might be a 297 249 pathologies, its assessment neuropathologically is correlate of cognitive impairment [64–66]. All these 298 250 not straightforward, since this requires the aforemen- findings have led to speculations that low CSF total 299 251 tioned sophisticated methodologies, whereas in terms ␣-synuclein might be a diagnostic marker in the set- 300 252 of biomarkers (see next sections) it faces the contro- ting of either sequestration of ␣-synuclein within the 301 253 versy of whether it is already reflected by available intraneuronal aggregates, or a compensatory reuptake 302 254 biomarkers (such as A␤, tau and ␣-synuclein) due to of the protein to maintain the synaptic homeosta- 303 255 their close correlation, or it needs from more specific sis. Conversely, as disease progresses and there is 304 256 markers (as proper synaptic proteins). Thus, synap- greater neuronal damage and cell death, the levels 305 257 tic dysfunction to date remains investigational and would increase due to the leakage of the proteins from 306 258 awaits further studies, both neuropathologically and the intracellular space to the CSF. How this would 307 259 with biomarkers, particularly in terms of the similar- relate to the CSF levels of the AD-related proteins 308 260 ities that synaptic dysfunction might have between (tau and A␤) in PD is not straightforward. CSF total 309 261 PD and AD. ␣-synuclein has been reported to correlate positively 310 with both CSF A␤ and CSF tau levels [63, 66], but 311 low CSF A␤ has been consistently associated with 312 262 BIOMARKER EVIDENCE OF poor cognitive outcome [67–69], whereas CSF tau 313 263 UNDERLYING PROTEINOPATHY AND has been reported to be either normal or low [63] in 314 264 SYNAPTIC DYSFUNCTION IN PD early disease stages, but increased in a proportion of 315 late stage PDD cases [70, 71]. Therefore, in PD low 316 265 One of the main aims of research in biomark- CSF A␤ levels, as in AD, might reflect sequestra- 317 266 ers in neurodegenerative disorders such as PD and tion of A␤ in extracellular parenchymal A␤ deposits 318 267 AD is that they can make it possible to obtain infor- (senile plaques), while CSF total ␣-synuclein would 319 268 mation about the underlying neuropathology in vivo range from being low to increase paralleling what 320 269 early in the disease process as opposed to traditional happens with CSF tau and reflecting increasing neu- 321 270 post-mortem neuropathological assessments, which ronal loss. 322 271 most often provides information about end stage dis- Alternatively, all these trends and correlations 323 272 ease. There are several different types and sources might be unrelated to aggregation and deposition of 324 273 of biomarkers for both PD and AD, but those that these proteins and their trafficking from the intra or 325 274 most directly reflect (or at least aimUncorrected at reflecting) extracellular Author space to CSF, and Proof rather reflect other 326 275 underlying pathology are CSF and positron emission processes, as for instance synaptic dysfunction, as 327 276 tomography (PET) biomarkers. previously mentioned. Yet, this view would be chal- 328 277 In PD the obvious choice as either CSF or PET mar- lenged by PET marker studies, which are available 329 278 ker is ␣-synuclein. Over the last decade the num- and reasonably reliable for A␤ [72] and tau [73], 330 279 ber of studies on the levels of different ␣-synuclein but not yet for ␣-synuclein. Hence, to date published 331 Y. Compta and T. Revesz / Neuropathological and Biomarker Findings in Parkinson’s Disease and Alzheimer’s Disease 9

332 data of studies on A␤ imaging in PD and DLB have BIOMARKER EVIDENCE OF 383 333 ranged from negligible uptake in PD and moderately UNDERLYING PROTEINOPATHY AND 384 334 increased binding in DLB [74, 75] to more consis- SYNAPTIC DYSFUNCTION IN AD 385 335 tently showing a correlation of A␤ imaging and CSF 336 A␤ levels longitudinally with cognitive outcome in In AD as in PD the accumulated evidence of bio- 386 337 PD [76, 77]. More recently, similar data emerged for markers of ␣-synuclein pathology is indeed restricted 387 338 tau in PD and DLB in two independent studies, albeit to CSF studies, since, as already discussed there 388 339 the tau PET uptake correlated with amyloid imag- is not as yet any validated PET probe specific 389 340 ing only in one of the studies and not in the other for ␣-synuclein. Studies available to date have 390 341 [78, 79]. Therefore, if molecular imaging of A␤ and also displayed discrepancies regarding CSF total ␣- 391 342 tau is showing anatomically that there are A␤ and synuclein. Thus, some studies have found no 392 343 tau lesions in the brains of PD and DLB patients and differences in CSF total ␣-synuclein between synu- 393 344 PET and CSF findings are significantly correlated, it cleinopathies (PD and DLB) and AD [87–89], 394 345 is reasonable to presume that CSF and PET A␤ and whereas others have shown an association between 395 346 tau markers are reflecting, at least partly, the under- low CSF total ␣-synuclein levels in AD and scores of 396 347 lying pathology. Few reports of autopsy findings in a global cognition test such as the mini mental state 397 348 patients, having previously undergone CSF or PET examination test, suggesting that it constituted a gen- 398 349 studies, would also support this notion [68, 80, 81], eral marker of synapse loss [8]. Yet, several published 399 350 but caution is still needed with tau imaging, as a recent reports have pointed towards increased levels of CSF 400 351 autopsy report has shown the presence of off-target total ␣-synuclein in AD [90–93], linking it to aggres- 401 352 binding (neuromelanin, choroid plexus, haemor- sive neurodegeneration in this condition, in a similar 402 353 rhages) for the tau PET tracer 18F-AV-1451 [82]. way to high levels of CSF tau and 14-3-3 proteins 403 354 In summary, to date the published CSF and PET in the setting of aggressive neuronal death as seen in 404 355 studies are overall in keeping with the aforemen- Creutzfeldt-Jakob disease or AD itself. 405 356 tioned neuropathological studies in that a remarkable Regarding CSF indicators of synaptic dysfunc- 406 357 proportion of PD patients have conjoint Lewy and tion in AD, besides the already discussed possibility 407 358 Alzheimer pathologies, and that these clinically cor- that it can be captured by proteins that accumulate 408 359 relate with cognitive impairment. in PD and AD, synaptic proteins partly overlap- 409 360 This leaves open the question for specific mark- ping with those above referenced to PD have been 410 361 ers of synaptic dysfunction in PD. In this area, the assessed in AD as well, in fact before and more 411 362 evidence is very limited, with the available infor- extensively than in PD. Hence, there are several 412 363 mation to date coming from proteomic approaches studies which reported increased CSF levels of neu- 413 364 and hypothesis-driven studies [83–86]. Hence, in a rogranin [94–96], synaptotagmin [97], and contactin 414 365 CSF proteomic study synaptic markers, among other [98] in AD both in its clinically manifest phase and 415 366 proteins, were detected to differ between different its prodromal stage as reflected by mild cognitive 416 367 forms of atypical parkinsonism, PD and controls impairment with biological evidence of underlying 417 368 [83] and a subsequent meta-analysis of 27 proteomic AD (that is, CSF tau and A␤ abnormalities), suggest- 418 369 studies, which found a total of 500 differentially ing these might be independent and complementary 419 370 expressed proteins, concluded that presynaptic pro- biomarkers of AD [99–101] Accordingly, a recent 420 371 teins involved in vesicle membrane fusion such as meta-analysis supports including neurogranin to the 421 372 SNAP25 could potentially be used as biomarkers for panel of AD biomarkers [102] Nevertheless, there are 422 373 PD [84]. In this vein, a post-mortem study has found outstanding issues regarding specificity, since as hap- 423 374 associations of cognitive decline in DLB and AD pens with proteins such as tau, increased CSF levels 424 375 with Rab3 in the inferior parietal lobe and SNAP25 neurogranin might merely reflect neuronal damage 425 376 in the prefrontal cortex, respectively [85]. The same in aggressive conditions such as Creutzfeldt-Jakob 426 377 research group recently published a study of these disease [103]. 427 378 proteins in CSF and found increasedUncorrected CSF levels of As for synaptic Author CSF makers Proof in PD, recently CSF 428 379 SNAP25 and neurogranin in relation to cognitive and levels of neurogranin have been assessed in parkin- 429 380 motor symptom severity [86]. sonian disorders, with the finding that these were 430 381 A summary of published sensitivities and speci- reduced in PD, PDD, MSA and PSP relative to AD 431 382 ficities of ␣-synuclein markers is provided in Supple- and controls, not correlating with motor or cognitive 432 mentary Table 1. measures, though [104]. By contrast, in another study 433 10 Y. Compta and T. Revesz / Neuropathological and Biomarker Findings in Parkinson’s Disease and Alzheimer’s Disease

Table 3 Putative correspondence between neuropathological and biomarker similarities in Parkinson’s disease and Alzheimer’s disease Neuropathology Biomarker finding Loss of pre and/or postsynaptic integrity, including dendritic spines CSF levels of specific synaptic proteins (SNAP25, synaptotagmin, neurogranin) Small protein aggregates with non-conventional approaches as PET CSF levels of ␣-synuclein or A␤ or phosphorylated tau blot, PAF assay or array tomography Larger protein aggregates by traditional immunohistochemistry PET imaging of A␤ Neuromelanin and other potential off-target binding structures to be PET imaging of tau (PET imaging of ␣-synuclein when it becomes considered available?) A␤, amyloid-␤; CSF, cerebrospinal fluid; PAF assay, protein aggregate filtration assay; PET blot, paraffin-embedded tissue blot; PET imaging, positron emission tomography imaging.

434 increased neurogranin CSF levels mirrored reduced in PD and, vice versa, ␣-synuclein Lewy-type 469 435 CSF A␤ in PD and in this case a significant correlation aggregates are frequent findings in AD. Modern non- 470 436 with cognition (as measured by MMSE) was reported conventional techniques overcoming limitations of 471 437 [105]. Hence more studies are needed to elucidate routine immunohistochemical techniques are promis- 472 438 the actual associations of these synaptic markers in ing as to take further our knowledge of the impact 473 439 degenerative parkinsonian disorders. of these disease-associated proteinaceous aggregates 474 440 Currently these markers are being explored not beyond the neurons’ soma, down to their presynaptic 475 441 only in CSF, but also in blood exosomes, which would and postsynaptic terminals, with potential mechanis- 476 442 provide a more accessible source relative to CSF tic and even future therapeutic implications. 477 443 [106]. An even greater challenge is translating this knowl- 478 444 An overview of published sensitivities and speci- edge to the clinic. CSF and PET markers of A␤ and 479 445 ficities of τ and A␤ markers is summarized in Supple- tau work reasonably well in the AD field, but their 480 446 mentary Table 1. counterparts in PD are far from being equally reli- 481 able, with new promising approaches being those of 482 aggregometric techniques such as real time quaking 483 447 OTHER BIOMARKERS IN AD AND PD induced conversion (RT-QuIC)[114]. In terms of PET 484 448 RESEARCH markers, beside the fact that there is no PET probe 485 available for ␣-synuclein yet, the AD PET markers 486 449 Although it is not in the scope of this review, the range from consistent evidence of their specificity 487 450 increasing interest in neurofilaments and markers of (amyloid imaging) to greater uncertainty of their 488 451 neuroinflammation as biomarkers in both AD and PD, reliability due to off-target binding (tau imaging). 489 452 needs also to be mentioned. Neurofilament has been CSF synaptic markers are attractive, but evidence 490 453 identified as a marker of disease progression or prog- is still scarce and most probably these will be non- 491 454 nostic marker in several neurological conditions from specific markers of disease progression. For all of 492 455 multiple sclerosis [107] to amyotrophic lateral scle- these CSF and PET markers, one should remember 493 456 rosis [108] and, importantly also in both AD [109] that ‘markers are not always makers’, and therefore 494 457 and PD [110]. A major breakthrough in the research caution is needed when interpreting associations as 495 458 of this biomarker has been the demonstration that causative. 496 459 its levels in plasma significantly correlate with those In summary and coming back to the question raised 497 460 in the CSF [111], making it a much more accessi- in the title of this review (what are the relevant simi- 498 461 ble biomarker. As for markers of neuroinflammation, larities between PD and AD? the protein aggregates? 499 462 there is research of both neuronal-specific (YKL-40 synaptic dysfunction? or both?), from a neuropatho- 500 463 [112]) and non-specific markers (cytokines [113]) as logical point of view protein aggregates are there 501 464 diagnostic and progression biomarkers in AD and PD both at the soma and the synapse. Thus, a number 502 Uncorrectedof CSF and Author PET biomarkers Proof might capture these 503 465 CONCLUSIONS different faces of protein-related neurodegeneration. 504 More specifically, CSF ␣-synuclein, tau and A␤ lev- 505 466 There is compelling evidence that PD and AD els might reflect beside underlying protein aggregates 506 467 share neuropathological hallmarks in that A␤ and also the soluble fractions of these proteins at the 507 468 tau lesions of the Alzheimer-type are common synapse level (Table 3). Y. Compta and T. Revesz / Neuropathological and Biomarker Findings in Parkinson’s Disease and Alzheimer’s Disease 11

508 ACKNOWLEDGMENTS [8] Ohrfelt A, Grognet P, Andreasen N, Wallin A, Vanmeche- 558 len E, Blennow K, Zetterberg H (2009) Cerebrospinal fluid 559 alpha-synuclein in neurodegenerative disorders-a marker 560 509 YC institution receives support from the CERCA of synapse loss? Neurosci Lett 450, 332-335. 561 510 Programme of the Generalitat de Catalunya (Barce- [9] Hakim AM, Mathieson G (1979) Dementia in Parkinson’s 562 511 lona, Catalonia). TR is supported by a research grant disease: A neuropathological study. Neurology 29, 1209- 563 1214. 564 512 from the Karin & Sten Mortstedt CBD Solutions [10] Boller F, Mitzutani T, Roessman U, Gambetti P (1980) 565 513 (grant code: 512385). This research was partly sup- Parkinson disease, dementia and Alzheimer disease: Clin- 566 514 ported by the National Institute for Health Research icopathological correlations. Ann Neurol 7, 329-335. 567 515 (NIHR) Queen Square Biomedical Research Unit in [11] Jendroska K, Lees AJ, Poewe W, Daniel SE (1996) Amy- 568 loid beta-peptide and the dementia of Parkinson’s disease. 569 516 Dementia based at University College London Hos- Mov Disord 11, 647-53. 570 517 pitals (UCLH), University College London (UCL). [12] Mattila PM, Roytt¨ a¨ M, Torikka H, Dickson DW, Rinne JO 571 518 The views expressed are those of the authors and (1998) Cortical Lewy bodies and Alzheimer-type changes 572 519 not necessarily those of the NHS, the NIHR or the in patients with Parkinson’s disease. Acta Neuropathol 95, 573 576-582. 574 520 Department of Health. [13] Spillantini MG, Crowther RA, Jakes R, Hasegawa M, 575 Goedert M (1998) alpha-Synuclein in filamentous inclu- 576 sions of Lewy bodies from Parkinson’s disease and 577 521 CONFLICT OF INTEREST dementia with Lewy bodies. Proc Natl Acad Sci U S A 578 95, 6469-6473. 579 522 The authors have no conflict of interest to report. 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