Safety and Usefulness of Lumbar Puncture for the Diagnosis and Management of Young-Onset Cognitive Disorders

Abstract

Background:

Young-onset cognitive disorders (YOCD) often manifests with complex and atypical presentations due to underlying heterogenous pathologies. Therefore, a biomarker-based evaluation will allow for timely diagnosis and definitive management.

Objective:

Here, we evaluated the safety and usefulness of cerebrospinal fluid (CSF) sampling through lumbar puncture (LP) in YOCD patients in a tertiary clinical setting.

Methods:

Patients with mild cognitive impairment (MCI) and mild dementia with age of onset between 45-64 years were evaluated. Patients underwent magnetic resonance imaging and their medial temporal lobe atrophy (MTA) was rated. LP side-effects and the impact of the CSF findings on diagnosis and management were analyzed.

Results:

142 patients (53 (37.32%) MCI, 51 (35.92%) dementia of the Alzheimer’s disease [DAT] type, and 38 (26.76%) non-AD type dementia) who underwent LP between 2015 to 2021 were analyzed. Using post-LP results and MTA ratings, 74 (52.11%) patients met the AT(N) criteria for AD. 56 (39.44%) patients (28 out of 53 (50.0%) MCI, 12 out of 51 (21.43%) DAT, and 16 out of 38 (28.57%) non-AD dementia) had a change in diagnosis following LP. 13 (9.15%) patients developed side-effects post-LP (11 (84.62%) patients had headache, 1 (7.69%) patient had backache, and 1 (7.69%) patient had headache and backache). 32 (22.54%) patients had a change in management post-LP, 24 (75.0%) had medication changes, 10 (31.30%) had referrals to other specialists, and 3 (9.40%) was referred for clinical trial with disease modifying interventions.

Conclusion:

LP is well-tolerated in YOCD and can bring about relevant clinical decisions with regards to the diagnosis and management of this complex clinical condition.

Keywords

Alzheimer’s disease biomarkers cerebrospinal fluid dementia lumbar puncture mild cognitive impairment post-LP complications young-onset cognitive disorders

INTRODUCTION

Alzheimer’s disease (AD) is the most common cause of dementia [1] and is a fast-growing public health epidemic [2]. The accumulation of both extraneuronal amyloid-β (Aβ) plaques and intraneuronal tau neurofibrillary tangles (NFTs) are the two core changes that occur in AD brains [2]. These pathologies in the brain lead to widespread neuronal loss and subsequent cognitive impairment and dementia [2, 3]. AD is a slow progressive disease that usually transits from an asymptomatic preclinical phase to the mild cognitive impairment (MCI) stage where clinical symptoms first appear, followed by AD dementia [1, 2]. The key to altering the devastating trajectory of AD is early diagnosis as late diagnosis only allows for symptomatic treatment [4]. Therefore, the timely detection of Aβ and tau in the diagnosis of AD is crucial [3] to utilize disease-modifying drugs effectively.

There are two main methods of in vivo quantification of Aβ and tau; imaging and fluid biomarkers [5]. Although amyloid-PET allows for accurate diagnosis and is approved for clinical use, the disadvantages include high costs, radiation related health risks and inaccessibility to PET scans [5].

The most commonly studied fluid biomarkers for cognitive disorders include blood and cerebrospinal fluid (CSF) [5, 6]. Blood biomarkers are not as intrusive as CSF collection, however, blood biomarkers are less sensitive and specific due to the filtering mechanism of the blood-brain barrier, which prevents the diffusion of substances into the blood [5]. However, emerging evidence has demonstrated great promise for blood-based biomarkers for AD and more work will be required to establish their utility in clinical trials and clinical practice [4].

On the other hand, sampling CSF by lumbar puncture (LP) is the most direct way to measure biomarkers as a surrogate of the pathology in the brain. CSF analysis is shown to be accurate in detecting cerebral Aβ and tau pathology as CSF flows in the subarachnoid space and ventricular system of the brain and spinal cords and hence reflect biochemical changes that occur in the brain [3]. In this regard, CSF Aβ has been demonstrated to be specific for the diagnosis of AD and may even precede changes in amyloid PET [7, 8].

While CSF Aβ_1 - 42 and p-tau are useful biomarkers for neurodegenerative disorders, most patients may not be comfortable undergoing a LP due to the invasive nature of the LP procedure. However, the rate of complications, including post-LP headache (PLPH), bleeds or infections are generally low [9]. A study of memory clinic patients found a relatively low rate of PLPH (2.6%) [10]. In another large multicenter study evaluating side-effects of LP, 31% of patients reported post-LP complaints that were mostly mild in nature [11]. 17% reported backache, 19% reported headache, 9% reported PLPH, and 0.7% required hospitalization [11]. Procedural related risk factors for back pain was the number of LP attempts and risk factors for severe headache was the use of a large needle diameter (< 22-gauge) [11].

The use of biomarkers is crucial for the early detection of dementia in general and the case for biomarkers is particularly relevant for patients with young-onset cognitive disorders (YOCD). YOCD refers to cognitive impairment manifesting between the ages of 45 to 64 and there is evidence for growing prevalence of YOCD as reported in a systematic review that 3.9 million people in the world aged 30 to 64 live with young-onset dementia, with the global prevalence for that age group to be 119 per 100 thousand population [12]. Clinicians struggle to diagnose YOCD in a timely manner as there is often a delay in seeking help for YOCD which impedes medical intervention [13]. Furthermore, YOCD poses greater complexity for an accurate diagnosis as it often presents with atypical cognitive symptoms such as a dysexecutive problem, language impairment, or agnosia [14]. YOD may also present with non-cognitive behavioral changes [15], such as mild behavioral impairment [16]. Therefore, an accurate diagnosis of YOCD will be critical as it affects prognosis and management, given that early diagnosis may allow for medical and social interventions which could improve quality of life of patients and caregivers [17]. As YOCD are more likely inherited [18], achieving accurate diagnosis can facilitate referral to geneticists so that patients and family members can make decisions around career, family planning, lasting power of attorney and health insurance [18].

The rationale for this study is to evaluate the safety profile of LP specifically in YOCD and the usefulness of CSF analyses in the diagnostic pathway as well as in the management of YOCD. We hypothesized that LP will be associated with mild side-effects in YOCD. Furthermore, given the heterogeneity and complexity of YOCD, we hypothesized that CSF analyses will bring about meaningful clinical benefits in the diagnosis and management of YOCD.

MATERIALS AND METHODS

Study participants

Consecutive patients attending the memory clinic of the National Neuroscience Institute of Singapore between August 2015 and July 2021 with a diagnosis of MCI or mild dementia and having an age of symptom onset between 45 to 65 years were offered evaluation with lumbar puncture as part of their diagnostic work-up. Diagnosis of MCI and dementia was made by cognitive neurologists based on Petersen’s criteria [19], DSM V criteria for minor neurocognitive diseases and major neurocognitive disorder [20]. Individuals with MCI presented with a predominant memory or non-memory deficits but had normal ability to perform daily functions and did not meet criteria for diagnosis of dementia. Patients with MCI were further classified as MCI of the AD type if they met the NIA-AA criteria [21]. Patients with dementia were further categorized into dementia of the Alzheimer’s type (DAT) or dementia of the non-Alzheimer’s type. Patients with DAT met the NIA-AA criteria [22]. Those with dementia of the non-Alzheimer’s type included those with a diagnosis of frontotemporal dementia, autoimmune dementia, vascular dementia, primary progressive aphasia, and Parkinson’s disease dementia. Autoimmune dementia was diagnosed based on the Sechi criteria [23], primary progressive aphasia was diagnosed based on Gorno-Tempini criteria [24], Parkinson’s disease dementia was diagnosed based on the Emre criteria [25], vascular dementia was diagnosed based on the NINDS-AIREN criteria [26], and frontotemporal dementia was diagnosed based on the Raskovsky criteria [27]. Mild dementia included patients with a Clinical Dementia Rating score of 1 [28].

For each patient, neurologists determined a pre-LP and post-LP diagnosis that included both a clinical syndrome (dementia, MCI) and a suspected etiology (AD or non-AD). Information on initial clinical diagnosis, pharmacological management (initial and change in cognitive enhancer medication), non-pharmacological management (referral for participation in clinical trials, referral for cognitive rehabilitation, referral to other clinical specialties), side effects experienced following LP, and unscheduled hospital visits to manage side-effects of LP were traced from the patient’s medical records. Patients wherein the diagnosis following the CSF analyses changed from DAT to non-AD dementia or vice versa and those where MCI of the AD type changed to MCI of the non-AD type or vice versa were considered to have a change in diagnosis. Patients wherein cognitive enhancer medication was added or changed following the LP or whom were referred to a clinical trial, cognitive rehabilitation program, or a different clinical specialty (i.e., psychiatry) were considered to have a change in management.

Ethics approvals and patient consent

Informed consent was obtained from all patients according to the Declaration of Helsinki and local clinical research regulations, and procedures used in the study were in accordance with ethical guidelines. The study was granted approval by CIRB number 2015/2218 and 2019/2173.

Lumbar puncture assessment

LP was performed by neurologists or residents who were all trained and accredited in the procedure. LP was performed in the ambulatory day care service without the use of fluoroscopy guided techniques in the morning with the patient in lateral recumbent position as the preferred position. A local anesthetic was administered before the procedure and the procedure was carried out in the L3-4 or L4-5 interspace with a cutting-edge Quincke spinal needle (20 and 22-gauge). Following puncture of the dura, the stylet was removed, opening pressure was measured and 10 to 15 milliliters of CSF was collected using the drip method into a polypropylene tube [29]. Patients remained supine for a brief period and were encouraged to drink fluids. Patient was kept under observation for side-effects post-LP such as bleeding from puncture side or acute headaches (i.e., 1–2 h). CSF was analyzed for its biochemistry, cell count, Aβ_1 - 42, p-tau, and total tau (t-tau). CSF biomarker analysis was performed with Innogenetics immunosorbent assays (ELISAs) using a standardized protocol by the same staff for all the samples [30].

Neuroimaging

Magnetic resonance imaging (MRI) scans were performed on a 3T Prisma fit System (Siemens, Erlangen, Germany). Each participant had high resolution T1-weighted MPRAGE (Magnetization Prepared Rapid Gradient Echo: 192 continuous sagittal sli-ces, TR/TE/TI = 2300/2.28/900 ms, flip angle = 8°, FOV = 256×240 mm², matrix = 256×240, isotro-pic voxel size = 1.0×1.0×1.0 mm³, bandwidth =200 Hz/pixel) and FLAIR (Fluid Attenuated Inversion Recovery) sequences (192 continuous sagittal slices, TR/TE/ TI = 5000/387.0/1800 ms, flip angle =120°, FOV = 256×256 mm², matrix = 256×256, isotropic voxel size = 1.0×1.0×1.0 mm³, bandwidth = 750 Hz/pixel). In the year 2018, there was a change in the 3T scanner for research participants and the subsequent scans were performed using the 3T Ingenia System.

Using the 3T Ingenia System (Philips Medical Systems), each participant had high resolution T1-weighted MPRAGE (Magnetization Prepared Rapid Gradient Echo: 180 continuous sagittal slices, TR/TE = 7.46/3.4 ms, flip angle = 8°, FOV = 256×256mm², matrix = 256×256, isotropic voxel size = 1.0×1.0×1.0 mm³) and FLAIR sequences (200 continuous sagittal slices, TR/TE/ TI = 4800/378.15/1650 ms, flip angle = 90°, FOV = 240×240 mm², matrix = 240×240, isotropic voxel size = 1.0×1.0×2.0 mm³).

Scan images were reviewed at acquisition and participants with motion artifacts and gross pathological findings were excluded. All scans were visually rated by a trained rater after they have completed required training and obtained a weighted kappa of at least 0.80 for medial temporal atrophy (MTA). The raters were blinded for clinical diagnosis and visual rating of MTA was performed on oblique coronal T1-weighted images according to the 5-point (range 0-4) Schelten’s scale from the average score of the left and right sides [31].

AT(N) criteria for AD

Results of Aβ_1 - 42, t-tau, and p-tau and t-tau were recorded. To determine the cut-off values for AT(N) criteria for AD, we followed the recommended values by Delmotte and colleagues (2021) for AT(N) [32], and the recommended values by Ramusino (2019) for MTA [33]. A cut off score for Aβ_1 - 42 798 pg/ml and below and p-tau of 87 pg/ml were used to define A and T criteria of AT(N). For N criteria, a total tau of 465 pg/ml or a MTA average score of 1 and below for ages below 60, or MTA 2 and above for ages 60 and above was used to define AT(N) criteria for AD [32 –34].

Post-LP side effects

Follow-up was performed within 2 weeks after LP by a research staff. Patients were asked about side effects post-LP by phone. Post-LP side effects including PLPH, back pain, and any other complication were recorded in detail. The treatment for the side effects were also recorded (emergency department visit, visit to the doctor or hospitalization). The onset and duration of the side effects and days of hospitalization was recorded.

Statistical analysis

Baseline characteristics were compared among the total cohort, and between cohorts with a change in diagnosis and without a change in diagnosis using two independent sample t-test and chi-square test for continuous and categorical variables, respectively. Statistical analysis was performed using the IBM SPSS Statistics for Macintosh, Version 25.0 (IBM SPSS Statistics for Macintosh, IBM Corporation, Armonk, NY, USA).

Data availability statement

The dataset analyzed during the current study are not publicly available but is available upon request from the corresponding author.

RESULTS

Between August 2015 and July 2021, 69 patients with MCI aged between 45-64 years and 106 patients with mild dementia aged between 45–64 years were managed in the dementia clinic. Of these, 33 (18.86%) of the patients who were offered LP declined to go for LP for personal or medical reasons, including the use of anti-coagulants. 142 (81.14%) of the patients who underwent LP had initial clinical diagnosis of MCI (n = 53), DAT (n = 51), and non-AD type dementia (n = 38). Among those who underwent LP, there were more females than males (75 (52.82%) versus 67 (47.18%)), the mean number of years of education was 12.31±4.08 and the mean Mini-Mental State Examination (MMSE) score was 23.06±6.47. The mean MTA rating score was 1.83±0.94. The mean protein count was 0.41±0.21 mg/mL and mean glucose count was 3.83±1.05 mmol/L (Table 1).

Table 1

Descriptive statistics of patients who underwent lumbar puncture

	Total cohort	No change in	Change in diagnosis
	(N = 142)	diagnosis	(n = 56)
		(n = 86)
Demographics
Age, y (SD)	59.06 (6.49)	58.69 (6.24)	59.63 (6.88)
Sex, Male (%)	67 (47.18)	42 (48.84)	25 (44.64)
Education, y (SD)	12.31 (4.08)	12.65 (3.96)	11.78 (4.26)
MMSE, mean (SD)	23.06 (6.47)	22.76 (6.66)	23.55 (6.20)
MTA score, mean (SD)	1.83 (0.94)	1.89 (0.89)	1.74 (1.01)
Initial diagnosis				New diagnosis	Met AT(N) criteria
					for AD (n = 31)
MCI, n (%)	53 (37.32)	25 (29.07)	28 (50.00)	15 (53.57) Non-AD MCI to AD type MCI	15 (48.39)
				13 (46.43) AD type MCI to non-AD type MCI	0
Dementia of the AD type, n (%)	51 (35.92)	39 (45.35)	12 (21.43)	6 (50.00) FTD	0
				1 (8.33) Psychiatric disorder	0
				5 (41.67) Non-AD type dementia	0
Non-AD type dementia, n (%)	38 (26.77)	22 (25.58)	16 (28.57)
Frontotemporal dementia, n (%)	16 (42.11)	10 (45.45)	6 (37.50)	6 (37.50)	6 (19.35)
				AD dementia
Autoimmune dementia, n (%)	7 (18.42)	5 (22.73)	2 (12.50)	2 (12.50)	2 (6.45)
				AD dementia
Parkinson’s disease dementia, n (%)	3 (7.89)	2 (9.09)	1 (6.25)	1 (6.25)	1 (3.23)
				AD dementia
Vascular dementia, n (%)	5 (13.16)	2 (9.09)	3 (18.75)	3 (18.75)	3 (9.68)
				AD dementia
Primary progressive aphasia, n (%)	5 (13.16)	3 (13.64)	2 (12.50)	2 (12.50)	2 (6.45)
				AD dementia
Psychiatric illness, n (%)	1 (2.63)	0	1 (6.25)	1 (6.25)	1 (3.23)
				AD dementia
Lewy body dementia, n (%)	1 (2.63)	0	1 (6.25)	1 (6.25)	1 (3.23)
				AD dementia
CSF results
Protein mg per mL, mean (SD)	0.41 (0.21)	0.42 (0.25)	0.40 (0.13)
Glucose mmol/L, mean (SD)	3.83 (1.05)	3.78 (1.08)	3.90 (1.01)
Met AT(N) criteria for AD, n (%)	74 (52.11)	43 (50.00)	31 (55.36)
Change in management
Change in management, n (%)	32 (22.54)	NA	32 (57.14)
Medication change, n (%)	20 (62.50)	NA	20 (62.50)
Specialist referral, n (%)	6 (18.75)	NA	6 (18.75)
Clinical trial referral, n (%)	1 (3.13)	NA	1 (3.13)
Medication + Clinical trial referral, n (%)	1 (3.13)		1 (3.13)
Medication change + Specialist referral, n (%)	3 (9.38)	NA	3 (9.38)
Specialist referral + Clinical trial, n (%)	1 (3.13)	NA	1 (3.13)
Side effects
Developed side effects, n (%)	13 (9.15)	6 (6.97)	7 (12.50)
Headache, n (%)	11 (84.62)	6 (100.00)	5 (71.43)
Backache, n (%)	1 (7.69)	0	1 (14.29)
Headache and backache, n (%)	1 (7.69)	0	1 (14.29)
Day of headache onset, median (q1-q3)	1 (0.25-1)	1 (0-1)	1 (0.5-1.5)
Days of headache, days, median (q1-q3)	3 (2-5)	3 (2-5)	3 (2.5-5)
Doctor consults due to side effects, n (%)	2 (1.4)	2 (2.33)	0
Hospitalization due to side effects, n (%)	4 (2.8)	3 (3.49)	1 (1.79)
Days of hospitalization, median (q1-q3)	3 (3-3.75)	3 (3-3)	3 (3-3)

MCI, mild cognitive impairment; AD, Alzheimer’s disease; CSF, cerebrospinal fluid; q1, quartile 1; q3, quartile 3; NA, not applicable.

The number of patients who met the AT(N) criteria for AD was 74 patients (52.11%). (Table 2). Patients who met AT(N) criteria for AD were comparable in age (58.75±6.56 versus 59.41±6.45, p = 0.548), had less males (39.20 % versus 55.90%, p = 0.047), lower years of education (11.44±3.75 versus 13.24±4.24, p = 0.012) and lower baseline MMSE scores (20.44±6.66 versus 25.85±4.97, p < 0.001) compared to patients who did not meet the AT(N) criteria for AD (Table 2).

Table 2

Demographic differences between patients who met AT(N) criteria for AD profile and patients who did not meet AT(N) criteria for AD

	Met AT(N) criteria for AD (n = 74)	Did not meet AT(N) criteria for AD (n = 68)	p ^*
Age, y (SD)	58.75 (6.56)	59.41 (6.45)	0.548
Sex, Male (%)	29 (39.20)	38 (55.90)	0.047
Education, y (SD)	11.44 (3.75)	13.24 (4.24)	0.012
MMSE, mean (SD)	20.44 (6.66)	25.85 (4.97)	< 0.001

^*Two independent sample t-test and chi-square test for continuous and categorical variables, respectively. AT(N), amyloid tau neurodegeneration; AD, Alzheimer’s disease; MMSE, Mini-Mental State Examination.

Change in clinical diagnosis and management

A total of 56 (39.44%) patients, (28 (50.00%) MCI, 12 (21.43%) DAT, and 16 (28.57%) non-AD dementia) had a change in initial clinical diagnosis following LP. Among these 56 patients with change in diagnosis, 31 (55.36%) had a AT(N) AD profile while 25 (44.64%) did not have a AT(N) AD profile. The remaining 86 (60.56%) patients had no change in diagnosis (Table 1, Fig. 1). Among the 28 MCI patients, the diagnosis changed from non-AD MCI to AD type MCI in 15 (53.57%) patients and from AD type MCI to non-AD MCI in 13 (46.43%) patients. Of the 12 DAT patients with a change in diagnosis, 6 (50.00%) patients had a change from DAT to FTD, 1 (8.33%) patient from DAT to a primary psychiatric disorder, and 5 (41.67%) patients from DAT to non-AD dementia. Of the 16 non-AD dementia patients, 6 (37.50%) patients had a change from FTD to AD dementia, 3 (18.75%) patients had a change from vascular dementia to AD dementia, 2 (12.50%) from autoimmune dementia to AD dementia, 2 (12.50%) patients had a change from primary progressive aphasia to AD dementia, 1 (6.25%) patient had a change from primary psychiatric disorder to AD dementia, 1 (6.25%) patient from Lewy body dementia to AD dementia, and 1 (6.25%) patient had a change from Parkinson’s disease dementia to AD dementia.

Fig. 1

Percentage of patients with change in diagnosis, change in management, and side effects.

A total of 32 (22.54%) patients had a change in management post-LP (Table 1, Fig. 1). 20 (62.50%) of them had medication changes, 1 (3.13%) were referred for clinical trial with anti-amyloid disease modifying drugs, 6 (18.75%) had referrals to other specialist or allied health professionals, 1 (5.88%) had medication changes and clinical trial referrals, 3 (9.38%) had both medication changes and referrals to other specialist of allied health professionals, and 1 (3.13%) had both referral to clinical trial with anti-amyloid disease modifying drugs and referral to other specialist or allied health professionals (Table 1, Fig. 2A).

Fig. 2A

Proportion of patients with change in management.

Fig. 2B

Proportion of patients with side effects.

Side effects related to lumbar puncture

13 patients (9.15%) developed side effects post-LP. Of the 13 patients, 11 (84.62%) patients had only headache, 1 (7.69%) patient had only backache, and 1 (7.69%) patient had both headache and backache. Among those with headaches, the median onset of headache was 1-day post-LP and the median duration of days of headache was 3 days (Table 1, Fig. 2B).

2 patients (1.4%) required an unscheduled doctor’s appointment due to the side effects developed post-LP. 4 patients (2.8%) required hospitalization for management of headaches and the median duration of hospitalization was 3 days (Table 1).

DISCUSSION

While LPs are routinely performed for neurological diseases, clinicians are reluctant to perform LPs for patients with dementia due to concerns with safety and clinical usefulness. In this study, we demonstrate that LP performed in a cohort of patients with YOCD is well-tolerated with about 9.15% developing mild side-effects of headaches and backaches. Furthermore, LP in this cohort has important clinical utility, with 39.44% having a change in diagnosis and 22.54% having a change in management of their cognitive disorder.

One of the most common complications of LP is post-LP headache. The typical post-LP headache related to dural puncture is postural in nature, worsens with upright position, and improves with going supine [35]. The majority of post-LP headache begins within 48-72 h of LP [36]. The incidence of post-LP headache ranges from 1-40%, and specifically for diagnostic LP, the rate may be as high as 36% [37]. Factors that influence incidence of post-LP headache include needle gauge, operator experience, and age of patients [36]. In the present study, the incidence of post-LP headache is 8.45%, which is relatively low and may be related to the mean age of the cohort being younger at 59.06 years. Also, the procedure was carried out by clinicians trained and accredited to perform LP. These findings are reassuring and support the use of LP as a diagnostic test for YOCD.

While the diagnosis of dementia remains a clinical diagnosis, with the recent US Food and Drug Authority approval of aducanumab for MCI and dementia due to AD, as well as other potential disease modifying drugs for AD in the pipeline, there is growing clinical need to establish a biomarker-based diagnosis of dementia. In this respect, the CSF obtained from LP can provide information on Aβ_1 - 42 levels, P-tau levels, and T-tau levels, which allow for a biomarker based diagnosis if AD MCI and AD dementia [22]. Together with the MTA ratings obtained from MRI, this allows for a AT(N) biomarker diagnosis of AD [22]. We demonstrate that there can be discrepancy between clinical diagnosis and AT(N) biomarker-based diagnosis in patients with YOCD. From the AT(N) biomarker grouping, 52.11% of our patients met AT(N) criteria for AD, 55.36% of the patients had a positive change (non-AD to AD), and 44.64% had a negative change (AD to non-AD). This finding further highlights the importance of using biomarker-based criteria when offering patients disease modifying therapies or when recruiting for clinical trials.

In this study of YOCD having a mean MMSE score of 23.06, CSF amyloid and tau quantification together with MTA ratings from MRI resulted in a change in diagnosis in 39.44% of patients. In a previous study of unselected memory clinic patients by Wilde et al., with a mean MMSE score of 25, amyloid testing with amyloid PET, resulted in a change in diagnosis in 25.0% of patients [38]. The findings from the study by Wilde et al. in terms of proportion of patients who received a change in diagnosis following amyloid PET is comparable with our study using LP to determine amyloid status. In another study which included only complex patients with dementia, the use of amyloid PET imaging resulted in 66.80% having a change in diagnosis [39]. It is likely that the higher proportion of patients having a change in diagnosis observed in this study by Ceccaldi et al. was related to inclusion of patients with complex diagnosis including atypical dementia and those with a rapid progression [39]. Furthermore, the use of amyloid PET was per a hierarchical implementation workflow, wherein amyloid PET was used in cases where the managing clinician opted for cerebrospinal evaluation, but LP was not performed for various reasons. Our finding that LP can bring about a change in diagnosis in about 40.0% of unselected patients with YOCD, which is comparable or slightly higher than that reported with the use of amyloid PET will hopefully encourage clinicians to consider LP for their patients with cognitive disorders, especially those with younger age of onset.

In addition to potentially resulting in a revised diagnosis, we also demonstrate that 22.54% of YOCD received a change in management following the LP. This is consistent with the findings from Wilde et al., wherein 24.0% of patients also received a change in management post amyloid PET [38]. In our cohort of younger patients, among those wherein there was a change in management, 62.50% had changes related to medications only, which included addition or change in type of cognitive enhancer therapy. In addition, 3.13% were recruited into clinical trials only with disease modifying therapy for AD, while 18.75% were referred to other clinical specialties or for cognitive rehabilitation only. The remaining 15.62% had a combination of medication change, clinical trial referral, and referrals to other clinical specialists. Referral to psychiatrists for management of primary psychiatric conditions were commonly observed among patients with subtle or atypical cognitive symptoms having concomitant psychiatric symptoms when the CSF finding was suggestive of non-AD profile.

In a large multicenter prospective study, clinicians were shown to heavily rely on CSF AD biomarkers when clinical symptoms and biomarkers results were discordant, to improve the confidence in making the final diagnosis [40]. Overall, the clinical diagnosis and CSF biomarker results were concordant in about two thirds of the cases. However, in this study, it was shown that a reclassification performed at the beginning of the follow-up could be beneficial for the patient. Thus, future studies of younger patients with dementia should look into the reclassification performed at the beginning of follow-up and the concordant between clinical diagnosis to the diagnosis based on CSF biomarker results [40].

The main limitations of this study include the relatively small sample size. However, given that this is the first report of the usefulness of LP in YOCD, we believe that this paper provides useful insights to clinicians managing patients with YOCD. The detailed pre-LP and post-LP diagnosis as well as the availability of data on post-LP management are also strengths. The change in diagnosis in 39.44% of our patients brought about changes in clinical management; however, quality of life change was not measured. The positive and negative changes in diagnosis (non-AD to AD and vice versa) will likely have different effects on quality of life and the ratio of benefit versus risks of LP. The impact of a change in diagnosis on mental well-being will also need to be carefully studied. Future studies should look into how change in diagnosis impacts mental well-being, quality of life, and ratio of benefit versus risks of the procedure.

This study is the first to report the usefulness and safety of LP in a cohort of patients with YOCD. YOCD is known to have a higher atypical clinical presentation and these patients will benefit from a detailed biomarker characterization. Our findings provide evidence with regards to safety as well as the usefulness of LP in the differential diagnosis and management of YOCD.

Footnotes

ACKNOWLEDGMENTS

We thank the participants, Ministry of Education, Singapore, under its MOE AcRF Tier 3 Award MOE2017-T3-1-002, National Medical Research Council (NMRC) Singapore, under its Clinician Scientist Award (MOH-CSAINV18nov-0007) and Clinician Scientist Individual Research Grant (NMRC/CIRG/14MAY025) for supporting our study.

Authors’ disclosures available online ().

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