The SARS-CoV2 pandemic has impacted the life of the population globally from 2020.The association amongst the new viral infection besides pathogenesis of various neurodegenerative diseases (NDD) got evaluated in different studies .In this review our objective was to carry out assessment, of the available publications regarding Parkinson’s disease (PD) and the COVID19 pandemic for provision of association amongst, the crossing of viral infection along with neurodegeneration regarding the present issue . Here we emphasize the SARS-CoV2 neurotropism, neuropathology, along with our belief regarding the association amongst infection, neurodegeneration in addition to the psychosocial influence of the pandemic in PD patients. Despite the corroboration of SARS-CoV2 pandemic in this review pointing towards a greater incidence of NDD in the future. Still existence of lot of controversies are there’re garding enough outcomes for corroboration of COVID19 possessing the capacity of either result in stimulation of generation of new or exacerbation of the the existent NDDs.

With the initiation    of COVID19 certain doubts were raised regarding the central nervous system (CNS) involvement. Thus, here we had the objective   of provision   of a summary in the context of association amongst COVID19, other viral infections   as well as Parkinson’s diseases subsequent to reviewing varios aspects of Coronavirus disease (COVID19) besides various neuro degenerative diseases [1-8]. Hence variable modes by which SARS-CoV2 viruses might impact various cerebral functions  besides result in   induction of neurodegeneration   need to be taken into account. i) the direct neurotoxic action of the virus   that result secondary to neuro invasion is   feasible in addition to actions due to systemic inflammatory changes. Initially we deal with   the information with regards to SARS-CoV2   neurotropism, neuropathology, neuroinflammation along  with   alterations  in  the amounts of biomarkers   which  have been  found  in  the course  of  infection .ii) subsequently we  describe in  brief   the association amongst   other viral infections   along  with   neurodegenerative diseases(NDD), with our concentration being mainly on  neurodegeneration, with    attention centred  on  Parkinson’s disease(PD)  in addition to  cognitive impairment / Alzheimer’s disease (PD/ AD).iii)Finally  we detail the impact of the pandemic on  symptoms  as well as psychosocial   angle in case of patients with  PD along   with           stress on  the  considerable   influence    of   the infection  in  particular on   individuals  possessing prior  neurological  disorders  in addition to   disabilities.

Methods

Here we conducted a narrative review utilizing search engine pubmed, google scholar; web of science: embase   Cochrane  review library utilizing the MeSH terms like SARS-CoV2; COVID19; other viral infections; neurodegenerative diseases (NDD); Parkinson’s diseases; AD; from 1991 till 2021 till date from 1990 to 2022 till date.

Results 

We found a total of 300 articles out of which we selected 124 articles for this review. No meta-analysis was done.

The etiological  agent of the present  pandemic   is a member of the   family  Coronaviridae[1 rev by us].The earlier  species of Corona viridae  (like HCoV  -OC43), HCoV   -229E, SARS-CoV, MERSCoV) were observed   in  human brain  samples ,that corroborated   their  neurotropism along   with   them  possessing the  capacity of   resulting in  indelible infections of  central nervous system(CNS)[9].As early  as   1999 it was   illustrated that neuroblastoma, neuroglioma along  with   glial cells   possessed a proneness  towards infection    with human Coronaviridae  in addition to the information    that  this virus possessed  the capacity of   lingering around  for a minimum  of 130  days of culture duration[9].In   case  of animal models, this ineffaceable  infection resulted   in     elimination  of neurons   in addition to   long term  consequences like reduction in action,besides volume of hippocampal    neurons in the  form of neurodegenerative phenotype [10-12].

A controversy is existent regarding SARS-CoV2 possessing the capacity of  entering along   with           being indelible in cerebral structures. Actually, certain results that corroborated   the posit of SARS-CoV2 neurotropism are detailed here. regarding

The Identification of angiotensin converting enzyme (ACE2) receptor was the maximum common receptors observed for   its entry [7]. Nevertheless, its expression is less prevalent   in the brain in contrast to other  tissues[13].In Consists   expression  was illustrated  on glial cells(astrocytes),capillary  endothelium, monocyte/ macrophages,   along  with    neurons[14].In contrast to  this greater expression of  ACE2) receptor   was seen in the brain stem that  resulted   in the posit   that   invasion by  SARS-CoV2  in brain stem structures might  result in  their  impairment that are implicated in controlling CVS functions [15] . An infection of the ACE2 receptor in transgenic mice resulted   in   expression of viral antigen in neurons, in particular in thalamus, brain stem, cerebrum, whereas cerebellum    continues tobe unafflicted [11]. The influence brain regions illustrated  neuronal depletion as well as microglial activation without     any inflammatory signs [11].

Conversely  escalated  proof  existed regarding  ACE2 receptor   might not be the primary viral invasion  approach into the central  nervous system(CNS).Rather other receptors   might  be implicated like neurolipin  1(NRP1)might aid considerably in SARS-CoV2 entry in cerebral structures[16-18].Abundant NRP1 expression  was observed  in  neurons along   with   astrocytes[17].

Three major routes had been suggested to result in SARS-CoV2 invasion in CNS are detailed hereafter. [15,16,19].

The initial probable  mode being, the trans neural method initiated in the nasal epithelium along   with   olfactory nerve propagateng  into brain through  axonal    transportation[14].This route of SARS-CoV2  neurotropism got  illustrated for SARS-CoV2 along   with HCov-OC-43   subsequent to intranasal infection [10,20].In transgenic    mice expressing  ACE2 receptor, SARS-CoV2  intranasal infection  led to neuronal10,20] . Furthermore, the mouse equivalent of the human Coronavirus, the mouse hepatitis virus gained entry into brain   through olfactory nerve following intranasal inoculation [21].

It was corroborated that   neurotropism is the common mode that caused occurrence of olfactory impairment (OI)in COVID-19. Broad variable incidence of   OI correlated with COVID-19(5-98%) was seen basically secondary to no   objective evaluation [22]. Utilizing  objective smell  evaluation in 60   Iranian COVID-19 patients it got documented  that 98% of them illustrated  anosmia,  however just 35% had subjective  realization   of their   OI , emphasizing the significance of objective evaluation regarding  this symptomatology[23].Gustatory impairment  is frequent  too in COVID-19   resulting in diagnostic  dilemma with olfactory impairment [24]. Apparently OI   is   an early presentation during COVID-19 course[25].Generally  2 modes might cause OI i)blockade of the olfactory cleft  via swelling or rhinnorrhoea that  might not have been  picked up in COVID-19 patients[23,24,26].ii)defective sensorineural transmission   might result  in  dysfunctional sense of  smell[24].With  utilization of CT along   with    MRI imaging  study in details in COVID-19  patients  with protracted  OI  (least 1 mth) documented reduction  in  olfactory bulb volumes(43.5%)  along   with olfactory sulci  being  shallow (60.9%),thus  corroborating this pathogenesis for OI in COVID-19[26] . Nevertheless,  there is lack of ACE2 receptor   in olfactory  sensory  neurons along   with    their observation in  supporting cells,  sustenacular  cells besides horizontal   basal   cells (alias reserve Stem Cells )in the olfactory along   with respiratory epithelium[22].This  OI   is usually a frequent  symptom  in  elder patients occurrence of OI   is  in 10%of individuals >65 yrs  along  with in 62-80%in  >80yrs[24] .OI   is further realized to be a symptom of Alzheimer’s disease(AD) as well as  Parkinson’s disease(PD) [24]. Intriguingly OI  in COVID-19 takes place  more frequently in   younger  patients possessing inverse association with demise[27].This corroborates with  the  posit that is in contrast regarding  OI   being a sign of defense against the virus for avoidnce of the   arrival of the virus in the  cerebral  structures instead ofjust avoidance of entry in the CNS[28].

b) The other alternate transneural method of invasion approach in CNS by SARS-CoV2 implicates the trigeminal or vagal nerve has further got described.

ii)) The second route suggested for CNS viral invasion is the hamatogenous route that gets followed by crossing of the blood brain barrier (BBB)/choroid plexus infections [15,16,19]. This has been   detailed regarding other viruses like HIV, HSV, HCMV besides   enteroviruses [12].

In this particular route endothelial cells in   blood vessels   besides choroid plexus might be the   invasion  target in view of expression of ACE2 receptor demonstrated in them [16]. Furthermore the spike protein of SARS-CoV2   might cross along   with result in   impairment of the BBB   by stimulation of  an inflammatory  response   amongst the microvascular  endothelium[29].
The other mode  validating this route  might be   enhanced permeability of  BBB secondary  to escalation of interleukin-6( IL-6) amounts, existent  in acute  COVID-19 disease[19,30].

iii)The third probability regarding pathway of SARS-CoV2 neurotropism is what is referred to as the ‘’Trojan horse mode’’-detailing the viral infection of    immune cells (neutrophils, monocyte, macrophages, CD4+ lymphocytes) that arrive in the CNS via blood stream followed by migration into cerebral structure   by diapedesis [15-17]. On arrival   in the cerebral tissue, the virus/viral particles might get liberated    by these  immune cells [16]

2.1 Neuropathology   of SARS-CoV2 

Usually Neuropathological   cornerstone of COVID-19 autopsy patients reveal generalized oedema, gliosis with microglial along   with astrocytes activation, ischemic damage, intracranial bleeding, arteriosclerosis, hypoxic ischemic damage, encephalitis /meningitis along   with diffuse inflammation [31]. COVID-19 patients presenting with robust disease illustrated   decreased neuronal amounts besides escalated activated microglial along   with astrocytes amounts in addition to greaterproinflammatory cytokines as estimated by qPCR [32].

 In parallel with posit of hematogenous route of invasion brain, Paniz Mondolfi etal. isolated this virus in capillary endothelium along   with neurons from frontal lobe tissue in COVID-19 patients [16,33]. In vivo virus   was not observed in glial cells [16]. Akin observation was of SARS-CoV2    preference in CNS endothelial cells by identification of ACE2 receptor expression in smooth muscle of blood   vesse [34]. In5/9 patients small blood   vessel  disease     was seen in autopsy patients; Nevertheless, SARS-CoV2     was found in a lone case with utilization of Immunohistochemistry [35]. Utilization of PCR in brain for estimation of SARS-CoV2    was tough as well; maximum viral   load was seen in the olfactory bulb, whereas SARS-CoV2 PCR was negativecontinuously in the substania nigra [28,34,36]. Nevertheless, observation of viral existence was occasional in viral encephalitis   usually (like herpes virus, arbo virescent virus stimulated encephalitis) [12].

COVID-19 brains on   autopsy patients revealed microglial activation in olfactory bulb, frontal, hippocampus with maximum load seen in the brain stem, while no activation of lymphocytes was visualized apparently [35]. Intriguingly, patients with history of delirium at the time of COVID-19 illustrated greater microglial activation in the hippocampus [35]. Those patients whose    presentationwas with/ without sepsis was not feasible neuropathologically that   countered the usual posit of neuropathology generation secondary to a cytokinestorm at the time of septic disease [35].

2.2 SARS-CoV2    Neuroinflammation along   with Biomarker   

 Besides direct impact of SARS-CoV2   on brain by CNS   invasion, the   remaining actions on cerebral functions secondary to systemic   change in the disease   course have been broadly described. Brain tissue along   with biofluids   investigations besides the systemic  response demonstrated a neuro(inflammatory) reaction initiated   by COVID-19. Escalation   of numerous cytokines in the blood at the time of acute COVID-19 were seen, whereas enhanced proinflammatory markers amounts   were   not found in the cerebrospinal fluid (CSF) [37]. Serum amounts of IL-4, IL-10, IL-6, along   with IL-1β were escalated in patients of COVID-19[29,38]. Knowledge is existent regarding IL-1β as well as IL-6, possessing the capacity of stimulating neuro inflammation [14].
Common   determination of SARS-CoV2   COVID-19 patients was observed despite its    incapacity of corroborating intrathecal antibody generation [37,39,40], Determination of virus by the 

quantitative polymerase chain reaction(qPCR) from CSF was not feasible in maximum   patients [41,44,5], Description of sporadic positive outcomes obtained    in SARS-CoV2 PCR from   CSF was documented rarely by authors in patients with robust cerebral symptoms [41].

Evaluation of markers pointing to CNS    injuries documented escalated amounts of   neurofilament light chain (NfL) along   with glial fibrillary acidic protein (GFAP)in plasma of patients with moderate to robust COVID-19[17,49]. Moreover  3/8 patients  with robust  COVID-19 displayed signs of break   down in blood brain barrier,  one possessed particular  intrathecal antibody  generation ,while 4 illustrated positivity  for14-3-3in the CSF[44].The outcomes of CNS pleocytosis  were contradictory  thus far.In acase series comprising of 15 patients  besides  a review described CSF WBC  counts in 409 COVID-19 patients presenting   with neurological symptoms found commonly pleocytosis (by  definition>5 cells /μL)  in  36% of 15  along   with 17% of 409 patients [30,50]. Conversely acase series comprising of 13 patients with COVID-19 as well as encephalopathies / convulsions documented CSF pleocytosis in a single patient only akin to a study comprising of 18 patients of COVID-19 along   with neurological complications   observed pleocytosis in 4patients   besides documenting that all 4 were most probably secondary to blood contamination [51.2].

Assessment of cargo of   neuronal –enrichment of extra cellular vesicles (ECV’s)was conducted by Sun etal. Intriguingly they found enhanced NfL, amyloid –β, neurogranin, tau as well as phosphorylated   tau in   COVID-19 patients pointing to a neurodegenerative    event [42].

Other than the COVID-19 pandemic, a wide epidemiological corroboration  associating other viral infections with neurodegenerative diseases (NDD), particularly of PD as well as AD exists.

The thought that viral infections possess the capacity of facilitating neurodegeneration was initially generated   with encephalitis   lethargica subsequent, to Spanish flu epidemic at the initiation of 20th   century. Following that an association amongst infections with NDD got assumed repetitively.

A meta-analysis  of 287,773 patients with PD along   with7,102,901 controls documented that the patients with documented infections earlier possessed escalated risk for PD (odds ratio,1:20) [44]. Bacterial infections  were believed  to be  implicated   for these actions[44].In agreement another recent  study observed a ‘’greater  infectious  burden ‘’,that by definition was the presence of greater antibodies against various viruses  along   with bacteria  in blood   of PD patients[45] .With in  particular PD risk was demonstrated  to be   escalated subsequent  to VZV infections (adjusted hazard ratio[HR],1:17) as well as PD patients possessed seropositivity with  greater probability   for EBV[46].HCV has been  a well-documented  factor for PD ,like HSV1infection   for AD  generation [47, 48].

Influenza viruses were further   correlated with PD,as  encephalitis  lethargica possessed a  Parkinsonian   phenotype along   with Influenza virus was posited  to be  the etiological agent regarding Spanish flu[53]. Moreover, H1N1 infection resulted   in continuous microglial activation in the form of chronic   neuroinflammation in case of wild kinds of mice [49]. H1N1 thus caused microglial activation along   with α-synuclein accrual in mice leading to dopaminergic neuronal depletion in the substania nigra, which is believed to be the pathological landmark of PD [50]. Additionally, Influenza virus was observed in the autopsy of PD patients in substania nigra [51]. Utilization of outcomes of a recent case control study from the results of a Danish National patient registry illustrated    that there was a correlation amongst diagnosis of Influenza with the generation of PD upto 10yrs subsequently (OR1.73) [52]. Thus, this robust correlation existence   however requires greater evaluation.

Japanese encephalitis virus   results in Parkinsonian phenotype at the time of acute   disease, however continued Parkinsonism   with MRI wounds in the substania nigra was seen 3-5 yrs subsequent to the Viral Infection [53].

Induction of Parkinsonism   by West Nile virus is feasible at the time of  acute   infection.In post mortem evaluation  escalated  α-synuclein amounts  were  seen in patients  infected  with West Nile virus [46,54].An Intriguing  posit regarding  α-synuclein  function was generated  in an  α-synuclein  knockout mouse model   subsequent to the West Nile infection[54].The lack of α-synuclein    in this model  resulted  in dramatic propagation of the  disease pointing to α-synuclein  confers protection against Viral Infection[46,54].The posit given was entrapment of  viral particle   by α-synuclein  in the form of a cellular  defense mode,that  continues subsequent to the infection resulting    in its pathological  accrual followed by  neurotoxic actions. The   akin mode was posited for β-amyloid that  possess the  capacity of  entrapment of HSV1 besides  hampering its viral replication along   with entry in vivo as well as in vitro[55].Disease risk factor was attributed to HSV1 infection greater  in AD however in   PD as well in variable in vivo as well as in vitro evaluation [56].Enhancement   by2.56  times  risk factor  for dementia  generation was documented   in  a retrospective cohort study, comprising of 8362 patients  with acute  HSV1 or HSV2 infection[48].A  phase 2   study evaluating if  acyclovir possesses  the capacity of reduction of propagationn  of  AD in patients with HSV1 is presently continuing (Clinical trials.gov NCT03282916)[55].

Various studies   are existent pointing to implication of adaptive immunesystem in the generation of neurodegeneration. Genome wide association studies(GWAS) observed correlation of particular major histocompatibility complex II gene alleles with PD as well asT cells of   patients with PD were illustrated   to react with α-synuclein epitope [57].  Demonstration of Th17 Tcells aiding in PD pathogenesis in a cell culture with utilization of induced      pluripotent  Stem Cells(iPSCs)was doneby another group [58]. Recently Tcells were observed to be neighbouring   the Lewy bodies in addition to dopaminergic neurons in brains of   Lewy bodies dementia   patients along   with    stimulating CD4+ T cells with a phosphorylated α-synuclein epitope caused   escalation of IL17 generation as a sign of Th17reaction [59].

The earlier described mode of viral neurotropism along  with neuroinflammation stimulate a query regarding long term neurodegeneration    has   to be anticipated subsequent to COVID-19 disease.

SARS-CoV2   along  with pathogenic      proteins  possessing the  potential of impacting neurodegeneration have been correlated in various studies.It was  found that spike  protein receptor binding  domain binds to heparin  as well as heparin  binding proteins inclusive of,  -amyloid β, α-synuclein,tau,prion besides   TDP-43 which  might precipitate the  pathological accrual  of these proteins leading to  neurodegeneration [60].  Akin mode has been detailed regarding HSV1 that catalyzes   the accrual of amyloid β in vivo, as well as in vitro, having been well documented risk factor for AD [60]. Recent illustration was that viral   particles (inclusive of SARS-CoV2    spike protein) promoted the transmission of protopathic seeds by changing  intercellular cargo transport [61].

 Variable approaches utilized for    snatching the regulation of host cellular functions like disrupting autophagy besides mitochondrial or lysosomal function that are responsible for generation of NDD also [62]. i SARS-CoV2     changes autophagy besides mitochondrial or lysosomal function in lungs that are infected [63].

Moreover, viral    alterations of proteastasis in the host cell can result in escalated aging   of the infected tissue that might further accelerate the neurodegenerative event, often visualized in senescent cells [62]

Ferrosenescence represents an iron modulated premature aging event of cells causing iron stimulated disturbance   of DNAhealng that gets followed by neurodegeneration [64]. This represents an intriguing capacity of virus of inducing ferro senescence in host cells causing facilitation of viral replication [64].

4.1 COVID19 along   with potential modes associated with Parkinson’sdisease

There are various correlations amongst COVID19 along   with the generation of PD described further.

That the mouse hepatitis virus (isolated as a murine analogue of human Coronaviridae) was found to result in    mild encephalitis besides viral   antigen got deposited mainly in the nucleus                    subthalamicus as well as substania nigra [65]. Following gliosis in these areas was pointing to acorrelation amongst the virus along   with PD doorpost encephalitic Parkinsonism [65]. Escalation of antibodies against Corona viridae were observed   in the CSF of patients with PD in contrast to controls by 1992 itself [66]. 

The documentation of 3 case reports of PD initiation    at well-timed association with COVID19 disease. Nevertheless, no clear-cut etiological association could be found [67].

2 patients generating COVID19 correlated encephalitis with propagating atypical parkinsonism as well as FDG-PETchanges reminding of post encephalitic Parkinsonism got published [68].

Numerous   modes by which COVID19 might aid in the generation of PD got reviewed; i) Vascular injuries in the nigro striatum mightoccur following Parkinsonism [69]. Moreover, the cytokine storm correlated with robust COVID19induced neuroinflammation, followed by neurodegeneration [30,69]. Systemic amount of IL-6 was enhanced with a small prospective observational study showed a greater amount of IL-6 is correlated with an escalation of generating   PD [70].

The other plausible mode of PD induction might be viral neurotropism leading to direct neuronal injury in important regions. IPSC obtained  mid brain dopaminergic   neurons were     illustrated to be prone to SARS-CoV2   infection, that initiated an inflammatory response followed by cellular senescence in vitro[89].RNA sequencing evaluation of  the ventral   mid brain tissue of COVID19 patients illustrated an akin phenotype of   neurons which were inflamed  besides Identification  of low amounts of SARS-CoV2    transcripts [71].These outcomes emphasized regarding     particular proneness  to  SARS-CoV2   of  specifically  susceptible mid brain areas  implicated in the   generation of PD.

The usual proneness of CNS structures to SARS-CoV2     was illustrated by Ramani etal.  where brain       organoids  were infected besides  observation of viral  entering in particular in neurons .The infections stimulated  changed  organization along   with hyperphosphorylation of   tau      followed by neuronal  demise[72].

An association amongst    nuclear factor κB(NFκB) along   with PD have been   illustrated earlier since NFκB was enhanced in the substania nigra of mice who received MPTP treatment [73]. MPTP treatment is usually employed in an animal model of   PD since the neurotoxin resulted in    nigro striatal degeneration in addition to depletion of dopaminergic   neurons [73]. In this model NFκB suppression caused avoidance of dopaminergic   neuronal    degeneration [73]. Treatment of   dopaminergic   neurons in an in vitro model with 6-OHDA caused activation of NFκB along   with caspase   besides apoptotic demise that got avoided by hampering NFκB [74]. SARS-CoV2   activates NFκB   through   pattern  recognition   receptors, that might initiate neurodegeneration [74].

Other  intriguing  issue is  the common involvement  of  dopamine- angiotensin –aldosterone system  in   COVID19 along   with  PD. generation  of   Angiotensinogenn   occurs in  astrocytes in the form of local renin-angiotensin –aldosterone System(RAAS) [75].Pathological   over activation  of  this(which further occurs secondary   to  dopaminergic  neurons degeneration  ) resulting     in  Oxidative stress( OS) as well as inflammation  while hampering  it was  believed to   be an approach  regarding treatment in  various neurodegenerative diseases inclusive of PD as well asAD[76],In view of  utilization of   ACE2 receptor  for entering host cells,it causes disturbance   in RAAS  also[15].

A prior found   association amongst H1N1 Influenza virus   along   with  α-synuclein accrual might probably  possess importance  for  SARS-CoV2  as well. H1N1 resulted    in accrual of endogenous  α-synuclein     in LUHMEScells[98]. The   explanation   for the pathological  α-synuclein accrual subsequent  to H1N1 infection dysfunction of autophagosomes of   infected  LUHMEScells was posited[77]. Intriguingly α-synuclein accrual was visualized in the olfactory bulb subsequent to intranasal delivery of H1N1[77]. 

Early symptomatology of PD is olfactory along   with vegetative impairment inclusive of obstipation in addition to prodrome syndrome REMsleep behaviour disorders (RBD). Olfactory  impairment is a frequent  early symptom of COVID19 along   with olfactory route is described as a   way of entering CNS[21,25].Hence apparently     it is a probability regarding COVID19  impacting the pathogenesis of PD since SARS-CoV2   might use a route  for spread as described in generating  neuropathogenesis of PD [78].

Polysomnographic evaluation in 11 patients subsequent to 4 mths of originating infection with SARS-CoV2 documented REMsleep events without atonia in 4 patients that is a typical (prodromal)sign of RBD.

Other intriguing   issue is the association of gut microbiota (GM) along   with its dysbiosis in the generation of PD [79]. SARS-CoV2 results in dysbiosis as well as   intestinal inflammation   pointed by escalated fecal calprotectin in COVID19 correlated diarrhea, that posits a probable association with PD [80]. In around 50% of patients with COVID19 SARS-CoV2    RNAwas observed in the faeces, corroborating the posit of intestinal infection [81]. 

Molecular  evaluations have corroborated  association amongst COVID19 along   with PD concentrating  on protein  crosstalk .In toto 44 proteins  in CNS responsible for  PD were observed to crosstalk with 24 host proteins  from the lung which crosstalk with SARS-CoV2  viral   proteins[106].The 2 maximum  attractive crosstalk candidate proteins  were Rab7a along   with  NUP62[82]. Rab7a represents   a lysosomal protein which decreased the percentage of cells with α-synuclein particles along with α-synuclein toxicity while NUP62 is implicated in autophagosomes generation [82].  The contrasting of transcriptomic manipulation induction by SARS-CoV2 along with PD further displayed important overlap   in various pathways [83]. 

    Conversely part of α-synuclein in  conferring protection  from COVID19 was posited as α-synuclein like amyloid β are upregulated  on the arrival of virus infections besides limiting  viral replication in the form of a defense mode in the brain [84].Prior to the COVID19  pandemic,a Japanese retrospective cohort  study illustrated  that patients of  PD that were hospitalized  possessed lesser probability of demise from  pneumonia in contrast to    others[85].

In case of α-synuclein upregulation in viral infections in the form of a defense mode it might be resulting in continued inflammation along with neuronal demise that triggers the generation of PD in long time, the way   illustrated for West Nile virus infections [69].

Intriguingly,a posit regarding association amongst COVID19 along with atypical Parkinsonism  might be drawn   despite restricted   results thus far.It got illustrated regarding atypical Parkinsonism   like atrophy of numerous systems as well as propagating supranuclear palsy are correlated with microglial activation in the form of signs of neuroinflammation besides microglial activation aiding in neurodegeneration[86].That microglial activation can get  observed  with utilization of PET imaging which  might work like a biomarker  for tauropathies[87]. Microglial activation along with neuroinflammation are observed in COVID19(already detailed) that makes an association amongst Parkinsonism along with COVID19[35].

4.2 Alzheimer’sdisease, Cognitive deficiencies along with COVID19

Proof that   have been     accumulated illustrated an intricate association amongst cognitive interference along with COVID19. A prospective longitudinal, study documented that cognitive reduction as determined by Montreal Cognitive Assessment (MOCA)was found in 21% of mild COVID19 patients vis a vis 2%of seronegative persons [88]. In a different study pathological MOCA outcomes were observed in 18/26 COVID19 patients along with FDG-PET- aberrations (frontoparietal hypo metabolism) in 10 patients which matched the clinical deficiencies [40].

Besides observation of cognitive reduction at the time of acute infection document ation were further revealing of continued cognitive dysfunction subsequent to recovering from COVID19 sinice MOCA aberrations were found in a group of patients in the post COVID19 durationn for a minimum of1mth subsequent to release from hospital [89]. Akin to that 46/57 COVID19 patients undergoing   recovery (81%) revealed signs of cognitivedysfunction [18,90]. Intriguingly continued memory along with concentration abnormalities were further observed subsequent to SARS-CoV1 as well assumers’ infection in 15-20% patients [91].

Utilization of transcranial magnetic stimulation for assessment of patients recovering from COVID19who had developed robust COVID19 infection needing ICU admission in addition to    neurological complications   documented fatigue besides illustrated aberrant scores in the frontal evaluation battery at the timeof subacutephase [92].  This transcranial magnetic stimulation documented dysfunctional GABAergic intracortical circuits   whereas glutamatergic transmission was alright [92]. GABAergic dysfunctions are generally frequent in frontotemporal dementia along with executive impairment [92]. Nevertheless, noticeably cognitive dysfunction is frequent subsequent to acute respiratory distress syndrome (ARDS)that might possess numerous explanations rather than COVID19[89,93]. Subsequent to ARDS cognitive  impairment continued in long time follow up in around 10% of patients [89]. In other different studies cognitive deficiencies along with psychiatric abnormalities (basically depression as well as anxiety)iwere found in uptill 60% of patients  who survived following    ARDS subsequent  to  12mths[94]. 

Dementia was   observed to be the maximum robust risk factor for COVID19 along with correlated with greater mortality [95,96]. As such dementia patients face problems regarding hygiene sustenance, mask needs, behavioural directive along with rules   regarding maintaining distance inview of cognitive deficiencies [93]. Usually, dementia patients are placed in nursing homes with a greater risk factor for acquisition of   infection in numerous areas [93]. COVID19 disease in patients with dementia usually seemed to have atypical presentation mainly with delirium/confusion along with occasional symptom regarding infection [96]. Confusion along with mood as well as behavioural   impairment   continued in 19.2% survivors [96].

An assessment of the network’s dependent association regarding gene/ protein setups amongst virus as well as host factors along with various neurological diseases in an interactome model illustrated intricate association amongst COVID19 along with cognitive reduction besides PD as well as AD [18].

Post mortem studies illustrated that expression of ACE2 was escalated in brains of   patients with AD.     In particular in robust dementia expression of ACE2 was escalated that might result in greater    proneness to COVID19 [93].

Injury of white matter (WM), that is ischemic, taking   place early in AD aids in thepropagationof dementia. Induction of vascular damages is feasible with COVID19 in view of hypercoagulability besides can be anticipated   to cause exaggeration of disease propagationnin patients of AD [97].

It got posited that amyloid β, the protein   responsible for AD generation   represents an antimicrobial peptide implicated in avoidance, of cerebral SARS-CoV2 infection as detailed   regarding α-synuclein, for PD [98]. It might be pointed that there is upregulation of amyloid β in the form of a defense mode at the time of infection resulting in overactivation of   besides pathological amyloid β getting deposited in the longer time duration [98].

Additionally, Apoε4 is a corroborated risk factor for AD was further believed to be a significant risk factor for COVID19 probably associating the 2 pathophysiological conditions [99]. Greater proneness to SARS-CoV2 infection in human induced      pluripotent  Stem Cells(iPSCs) models possessing Apoε4, genotypes neurons along   with astrocytes   had greater pronenessto SARS-CoV2 infection in contrast to   non Apoε4cells beside brain    organoids[17].

  An alternate overlapping mode is IL-6 which was illustrated to be escalated in COVID19 along with believed to be a biomarker possessing prognostic importance in AD [49,100].

  Probably SARS-CoV2   causes interference with autonomic functions in vagal control centers in the brain stem [95]. Autonomic functions   are dysfunctional in AD  as greater cardiac sympathetic functions along   with lesser parasympathetic functions have been documented in patients [95]. Thus, non auricular vagal stimulation has been   detailed in the form of therapeutic approach for AD, besides robust COVID19, as a downregulation of inflammatory pathways (decreased IL-6 amounts) is anticipated secondary to that [95].  Corroboration of this posit transauricular vagal stimulation possessed the capacity of decreasing cognitive impairment in a pre clinical murine model of AD [101].

AD causes   changes in calcium homeostasis  in the brain; akin mode is utilized by RNA viruses for    promoting viral      replication .Thus viral      replication might be simpler  in   AD patients   ,           possessing aberrant calcium homeostasis   beforehand[102].A  correlation  is  amongst Diabetes type  II along with AD that escalates   the risk for AD generation[102]. 

The action of the pandemic regarding day to day life was  significant  worldwide besides  patients with chronic diseases(required   continued   care were in particular influenced .A detailed assessment   of global studies (with n=210,419enrolled patients) illustrated    that the acute care regarding neurological  situations were  interfered  with secondary  to the pandemic in 47.1% of subjects. Differential influence on PD patients was detailed   since particular   issues took place as a link amongst pandemic correlated limitations. Psychological problems besides issues correlated with care along with medicines   dissemination were observed    to be maximum taxing regarding this cohort [103].

COVID19 possesses   the capacity of changing the pharmacodynamics of levodopa further secondary to diarrhea, a usual symptom of COVID19[141].This   resulted in motor variations in PD patients which were infected [104]. PD patients   afflicted with COVID-19 frequently generated a post COVID syndrome (85.2%) presenting   with deteriorated motor functions along with escalated levodopa dosage needs, fatigue, reduction in concentration in addition to interference with sleep [105].  

Nevertheless, subjective deteriorateation of motor besides non motor symptoms of PD patients were not influenced by   COVID19 at the time of the pandemic was further documented   in various studies [106, 107]. Furthermore, new behavioural  symptoms were seen in 26% of PD patients in an Italian  crosssectional study [107]. Loneliness feeling as well as feeling of deprivation beside lack of interactions with the treating doctor was felt [106]. 

It was posited that dopamine-based adapting is needed regarding tackling situation successfully hence PD patients possess lesser   flexibility besides encountering greater problems for adapting to the new  milieu [145,6]. Hence the pandemic   might    result in stress in PD patients having to cope with adaptation to a new milieu rapidly. Psychological stress was   illustrated to cause deterioration of PD symptoms besides the effectiveness of dopaminergic medicines in particular regarding the tremor [108]. This might be the reason for the exaggeration of symptoms in the PD patients at the time of   the pandemic.

It was the observation that 103 patients of PD   documented 4 major difficulties at the time of   the initial lockdown i) scared of acquisition of COVID19ii) decreased physical activity iii) incapacity of acquisition of support services besides the clinics iv) decreased socialization [109]. An objective decrease in   physical activity as determined  with  the utilization of a smart phone application in view of maximum PD patients  we’re not able to perform     30’ of  daily activity[110].More  exacerbation was seen in 44%  at the time of  being confined .That physical activity as well as training is a significant treatment  approach  for sustenance  of motor symptoms as well as independence, thus   physical activity avoidance at the time of    lockdown can be  anticipated  to  cause symptoms propagation besides   deletion of independence[110].

Furthermore,in 66% of PD patients  from a large cohort from the Colombia University  documented mood along   with sleep  interference during  pandemic ,  depression     as well as insomnia were the commonest documented  in numerous other studies also[111,112].A Chinese study  displayed that PD patients  presentation   was greater sleep  interferences along   with anxiety in contrast to   healthy controls besides   these  symptoms having independent  correlation   with acceleration  of other   PD symptoms [112]. Sleep   issues were further correlated with a bad quality of life (QOL) [111]. 

Interventions dependent on mindfulness were illustrated to result in reduction of depression along   with   anxiety, besides enhancement of motor symptoms [108]. In view of achieving this feasible with virtual means apparently    it might work out as an attractive therapeutic approach currently besides in future [108].

The numbers of hours correlated with   care provision enhanced markedly at the time of   the pandemic. Family members were the major   providers of care [113]. In the COVID19 period pressure of care provision enhanced comiserably [107]. Intriguingly, Montanaro etal. as well as others illustrated   that depression along   with anxiety were common in PD patients besides their providers of care [114]. In 35% of PD patients depression  existed besides in 21.7%of  care providers,while 37% of PD patients along   with40% of  care providers  presented with anxiety[114].Thus  greater support was the requirement for  care providers  in particular at the time of   the  pandemic   for tackling their ownenhanced tensions besides  the neuropsychiatric issues  of their relatives[115].

Nevertheless  COVID19 by itself had  no influence  on  PD symptoms it was further described   regarding prior existent PD  possesses the  capacity of escalating the risk of mortality/case fatality onSARS-CoV2 infection  despite contradictory   result regarding this issue[116].The time period of ICU        stay/hospitalization  besides  ventilation further we’re   not    variable    in PD patients besides non PD  COVID-19 PD patients    in a large assessment of COVID-19  German  inpatients[117].The Italian study  contrasted  COVID-19 patients with   PD  to COVID-19 patients without  PD, observing no variation in  mortality(5.7% for PD COVID-19 patients expiring vs 7.6% non PD  COVID-19 patients ) [118].

This tendency might be corroborated by the posit regarding amantadine besides entacapone might confer protection   against COVID-19    that was pointed by various studies [119]. Nevertheless a systematic review  regarding 1061 greater in COVID-19 patients corroborated  greater  hospitalization rate, case fatality as well as mortality rates for these in contrast to   non  PD   COVID-19 patients [120].The short come of this study was no matched age ,that is  anticipated to impact  the  outcomes in view of age being a confirmed  risk factor case fatality as well as mortality rates for regarding COVID-19  [120].An American study  contrasted  78,355 non PD COVID-19 patients with 694 COVID-19 patients with PD, observed escalated  mortality   despite adjustment as well as  match for age along   with sex[121].A muticentric  German study   illustrated    that both prevalence as well as  mortality of COVID-19 patients  was  greater  in PD in contrast to   non PD  COVID-19 patients[122].

These results seem to not yield if these PD COVID-19 patients are at a greater risk for robust COVID-19 infection   can not be decided at this juncture. Noticeably PD patients suffering from COVID-19 have greater    chances of presentation    with    atypical symptom like mood alterations, fatigue, joint ache as well as acceleration  of PD   symptoms that might add complexity regarding the diagnosis of SARS-CoV2 infection [123]. 

Parkinsonism symptoms secondary to the generation of COVID-19 are occasional with proof associating COVID-19 to generating PD presently   is simply a posit. Goerttler etal.[124], scanned the literature regarding    the description of newer onset PD that correlated with COVID-19, observing 6 patients with new Parkinsonism motor symptoms, of which 5 presented with corroborated dysfunctional dopaminergic uptake in the basal ganglia subsequent to nuclear imaging. (see figure1)

Figure 1: Courtesy ref no- 124-Schematic diagram of the potentially harmful pathway in COVID-19 and Parkinson’s disease (PD): (a) the SARS-CoV-2 virus enters the brain via the olfactory bulb, binding to the ACE receptors. From there, it spreads via non-myelinated nerves into the brain. (b) In PD, there are two hypotheticals, not yet fully understood, routes that the viral pathogen can use to enter the brain, either via the olfactory bulb (“brain-first” theory) or via the gastrointestinal mucosa (“body-first” theory), spreading into the brain via the vagal nerve.

Nuclear imaging (with the utilization of FP-CIT-SPECT besides F-DOPA-PET in   5 of the patients displayed proof regarding the implication of   basal ganglia   with chronic dysfunction of dopaminergic     transmission secondary to nigro striatal degeneration that was responsible for motor symptoms [rev in 124]. In  a patient  FDG- PET   imaging  documented diffuse hypometabolism with considerable hypometabolism in  the praecuneus ,that had maximum probability  of being correlated with  Alzheimer’s disease[rev in 124].Correspondingly ,this subject illustrated Cognitive reduction at the time of propagation  of COVID-19, however, further illustrated comparative hypermetabolism in the basal ganglia, like commonly  seen in PD patients[rev in 124]. Acute encephalitis patients further displayed hypermetabolism in the impacted brain   regions followed by hypometabolism subsequent to recovery [rev in 124]. Hence in this patient hypermetabolism in the basal ganglia had maximum probability of being an encephalopathic   event. 2 patients responded well to dopaminergic medicines pointing to the dysfunction possessing the capacity of responding to substituting dopamine, that corresponded to nuclear imaging observations.

Absence of follow up for outcomes in these patients did not corroborate the existence of a propagateng Neurodegenerative disease. Nevertheless, a minimum of 1 patient achieved full remission of the PD symptoms [rev in 124], pointing to the feasibility of the existenceof     an acute reversible disorder. Conversely nuclear imaging illustrated dysfunctional dopaminergic tramission in all the patients studied. Moreover, in a patient antecedent symptom (like constipation) existed [rev in 124], pointing to the existence of prior PD not having been diagnosed   has to be taken account despite constipation might not be a particular aantecedent symptoms, which might be secondary to other etiologies.

Thus the restriction was  maximum studies were conducted with outcomes regarding PD patients along   with COVID-19 were collected just for the initial 6 mths  of the pandemic  with uptill 2500 patients  cohort &none to minimum follow up further inext fewmths/yrs. Simultaneously millions of COVID-19,   patients documented globally  with  anticipation  of similar enhancement of PD patientsto rise .This gap requires filling for drawing any meaningful association amongst PD& COVID-19,   .

Regarding the 2nd restriction was that maximum evaluated studies on PD along   with SARS-CoV2 usually had investigated patients with idiopathic Parkinson’s disease however no proof regarding the atypical Parkinson’s disease were observed. 

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