The aims of this study were to investigate the association between clinical and CSF biomarker data in suspected NPH, prognostic determinants of neurodegeneration and long-term outcome, and differential and concurrent diagnosis between iNPH and parkinsonian syndromes. Parkinsonism and parkinsonian syndrome occur in suspected NPH and further research into this relationship is needed.
Parkinsonian Syndromes
Despite ongoing research into protecting against the onset or reversing the progression of the neurodegenerative process of iPB, no prophylactic, regenerative, or curative treatment for iPB has been developed. DLB is the most common form of atypical parkinsonism and, after AD, one of the most important forms of neurodegenerative dementia.
Relationship between Normal Pressure Hydrocephalus and Parkinsonian Syndromes
Secondary Parkinson's syndromes include vascular Parkinson's disease resulting from cerebrovascular diseases (strategic infarctions or chronic vascular degeneration) and drug-induced parkinsonism caused by medication (especially neuroleptics) [1]. Overall, the prospective cohort study of the Kuopio NPH registry on suspected NPH demonstrates cases of Parkinsonian syndromes mimicking and matching iNPH and vice versa suggesting that the overlap, differential diagnosis and comorbidity between iNPH and Parkinsonian syndromes is challenging for awareness [8] .
From neuropathology to CSF biomarkers
- Beta-amyloid
- Tau proteins
- Alpha-synuclein
- Combinations
As previously mentioned, alpha-synuclein inclusions are the pathological hallmark of synucleinopathies (iPD [5] , DLB [6] , [7] and MSA [6] , [7] ). In Parkinsonian syndromes, CSF alpha-synuclein (aSyn) is equally reduced in synucleinopathies iPD and DLB, while it is lower in synucleinopathies compared to tauopathy PSP and CBD [66] , [67] .
Objectives for subsequent research
Considering iNPH, perturbation of CSF dynamics may predispose aging brain to accumulation of alpha-synuclein in addition to beta-amyloid or tau proteins. Then, comparing iNPH and Parkinsonian syndromes, lower aSyn distinguishes the synucleinopathies iPD and DLB, also MSA, from iNPH, while there are no differences between iNPH and the tauopathic PSP and CBD [67].
2 Materials and methods
Kuopio NPH registry and research group
Further to the protocol, "possible iNPH" cases suggestive of shunt surgery are identified with the CSF dynamics test. Clinical data from initial and follow-up outpatient clinic visits and follow-up data from standardized questionnaires were prospectively recorded in the NPH registry by the research group.
Present study
- Participants
- Follow-up
- CSF samples and biomarker analyses
- Statistical analysis
- Ethics statement
Baseline and endpoint cognitive status was determined with the MMSE, and neurologists confirmed the clinical diagnosis of mild cognitive impairment (MCI) and dementia using the CDR classification. Statistically, baseline and endpoint cognition was assessed using the MMSE and clinical diagnosis: scores above 25 and no clinical diagnosis of dementia were classified as “no cognitive impairment”, scores between 20 and 25 and/or a clinical diagnosis of MCI as. Final diagnoses were determined from the last available patient follow-up data, and the primary diagnosis accounting for symptoms giving rise to the suspicion of NPH was determined.
In final statistical analyses, endpoint diagnoses were classified as nine neurodegenerative diseases (NPH (idiopathic and secondary), AD, AD+VAD, VAD, NPH+AD, NPH+VAD, FTLD, DLB, PD), other neurological disease (PSP), MCI , dementia NAS, alcohol dementia, possible neurodegenerative disease, psychiatric disease, epilepsy, polyneuropathy or vertigo NAS), musculoskeletal disease (arthrosis, spinal stenosis, trauma) or no diagnosis explaining NPH-related occurrence. Biomarker analyzes were performed in the validated AD biomarker laboratory of the University of Eastern Finland in Kuopio [96] in three different sets. All test and control measurements were performed in duplicates, and variation within duplicates followed the same principles as mentioned above.
Abeta1-42 antibody affinity was approximately 10% higher in later assays versus earlier assays, so Abeta1-42 concentrations measured in the first set were weighted by a factor of 1.1. For continuous variables, parametric tests were performed with the Levene's Test for Equality of Variance and the Kolmogorov-Smirnof Independent Samples Test (comparing two groups) or Levene's Test of Homogeneity of Variance (comparing several groups). All statistical analyzes were performed with IBM SPSS Statistics 25 for Windows (version 25.0.0.0, IBM Corporation, Armonk, NY, USA) and graphs made with GraphPad Prism 9 for Windows (version 9.3.1, GraphPad Software Inc, San Diego , CA , USA).
3 Results
Baseline characteristics, shunt treatment and follow-up outcome
Written informed consent was provided in advance by the study participants or, in the event that dementia could have prevented them from making reliable decisions, requested from their proxies or caregivers. A tap test was performed in almost every patient, and as expected, non-shunted patients showed a response that was rarer than shunted patients (p<0.001, Chi-square). In addition, patients with a shunt who did not respond to the shunt had a positive response to the tap test even more often than patients with a shunt response (83 vs. 68.
Also, the mean concentration of aSyn differed between groups. p=0.017, Kruskall-Wallis), but the small number of aSyn measurements in bypass patients may confound the analysis. The mean baseline MMSE score was significantly lower among patients with no shunt response compared to the shunt responder group (p=0.014, LSD). The mean MMSE endpoint score was lowest for patients with unresponsive shunts (relative to non-shunted p=0.037 and responders p<0.001, post-hoc LSD), whereas non-shunted patients had a significantly higher mean score lower than shunt-responding patients (p=0.034, LSD post-hoc).
At the end of follow-up, the prevalence of dementia differed between groups (p=0.003, Chi-square), being higher for non-shunted and shunted but non-responding patients (52 and 54%) than for shunt -responding patients (34.
Clinical and CSF biomarker data
The tap test was more likely to be positive in patients with gait difficulty (60% responders) and tremor/rigidity (56% responders), while results were mostly negative in patients with cognitive dysfunction (60% no response). There was no statistical significance in the differences in shunt status between the subgroups (p=0.401, Chi-square), but frequency of shunting and. There were significant correlations between CSF p-tau and t-tau, p-tau and aSyn, and t-tau and aSyn.
Considering Abeta1-42, there was no statistically significant difference between the groups (p=0.144, ANOVA) but on average, there was an increasing concentration trend from memory deficits to walking difficulties and finally to parkinsonian symptoms (Figure 2a). On the contrary, mean p-tau and t-tau levels (Figure 2b and c) were higher for patients with memory problems compared to those with difficulty walking (both p<0.001, post-hoc LSD) and tremor or rigidity (p -tau p=0.060, t-tau p=0.015, post-hoc LSD). For aSyn (Figure 2d) there were no differences between groups (p=0.133, ANOVA), although a low number of measurements may confound this comparison.
End-point diagnoses and prognostic determinants for neurodegeneration
Considering the prevalence of memory impairment and gait impairment, there were clear differences between groups (p=0.003, p=0.011, respectively, Kendall's tau-b). About half of patients who later develop VAD, VAD+AD and FTLD (54, 44 and 50 %, respectively) had memory deficits at baseline, while almost half of patients had other. More than half of VAD patients (56%) had previously suffered from gait impairment, whereas less than half of AD and AD+VAD patients (43 and 39%, respectively) presented with gait problems at baseline.
Considering the occurrence of parkinsonian symptoms, there were no statistically significant differences between the groups (p=0.118, Kendall's tau-b). Less than half of patients with VAD, other neurological diagnoses and musculoskeletal disease respectively) responded. Almost half of NPH patients developed MCI or dementia (35 and 9 %, respectively), whereas only one in five PD patients (20 %) had cognitive decline and progressed to dementia during follow-up.
Considering the distribution of shunt treatment and response, there were differences between diagnostic groups (p<0.001, Kendall's tau-b). About half of the patients who developed AD or VAD had previously been shunted (57% and 44%, respectively), and vice versa: of the patients who had previously undergone a shunt, 16% developed AD and/or 4% VAD. Exceptionally, 83% of DLB and FTLD patients had undergone shunt surgery, while more than half of them (80% and 60%, respectively) had benefited from the treatment.
4 Discussion
- Supporting previous studies on suspected NPH
- Enhancing recent findings on Parkinsonian Syndromes
- Strengths and limitations
- Further questions
Almost all the patients underwent a tap test, and the shunt treatment exclusion or inclusion decision was largely based on the response (more than half of the patients with positive and less than half of the patients with a negative result were shunted). Baseline cognitive impairment (memory deficit as a predominant symptom, lower MMSE) was less common in shunted than non-shunted patients, but when present, less benefit from shunt therapy is expected. The occurrence of parkinsonian features (bradykinesia, tremor, rigidity, postural imbalance) was rare but present: 7% of patients had at least one of the main symptoms at baseline, half of them dominant.
After careful diagnostic procedure, most of the patients in our group who had Parkinsonian features were shunted (by definition as probable iNPH) and all benefited (confirmed definite iNPH). Considering the effects of differential or comorbid diagnoses on shunt surgery outcome [ 8 ], most of the PD and DLB patients in our group who underwent shunting benefited from the treatment. In addition, we analyzed CSF aSyn levels of subgroups of the entire cohort, and found a wide range within and wide overlap between diagnostic groups, inconsistent with the.
Conversely, cohort and data heterogeneity resulted in various confounding factors in the analyses. However, the presence of both separate symptoms of Parkinson's disease should be noted. bradykinesia, rigidity, tremor and postural instability) and full-blown parkinsonism (bradykinesia and at least one of the other core symptoms) could increase the precision of the analyses. Elucidating the differential and concurrent diagnosis between iNPH and neurodegenerative diseases such as AD and determining prognostic factors of long-term outcome could guide the clinical practice of prevention, detection, treatment and follow-up.
5 Conclusion
Future research on suspected NPH is essential and longer follow-up cohort studies are needed. Investigation of the occurrence, characteristics and prognostic value of Parkinson's symptoms or parkinsonism in suspected NPH could assist the physician in making the diagnosis. Comparing baseline clinical data and biomarker data with long-term diagnoses of suspected NPH patients could improve differential diagnostic procedures between iNPH and Parkinson's syndrome.
Determining the prevalence of Parkinson's syndrome in iNPH will improve the theories of relationship between disturbed CSF circulation dynamics, neurodegeneration and neuronal dysfunction. Comprehensive clinical examination is essential, while CSF biomarker data (Abeta1-42, p-tau and t-tau, additionally aSyn) can support the evaluation. Therefore, long-term follow-up is necessary regardless of undergoing shunt surgery or response to treatment.
However, patients shunted for iNPH may respond to treatment despite parkinsonian symptoms or prodromal iPD or DLB.
6 References
