Increased expression of pathological markers in Parkinson's disease dementia post-mortem brains compared to dementia with Lewy bodies.

BACKGROUND: Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are common age-related neurodegenerative diseases comprising Lewy body spectrum disorders associated with cortical and subcortical Lewy body pathology. Over 30% of PD patients develop PD dementia (PDD), which describes dementia arising in the context of established idiopathic PD. Furthermore, Lewy bodies frequently accompany the amyloid plaque and neurofibrillary tangle pathology of Alzheimer's disease (AD), where they are observed in the amygdala of approximately 60% of sporadic and familial AD. While PDD and DLB share similar pathological substrates, they differ in the temporal onset of motor and cognitive symptoms; however, protein markers to distinguish them are still lacking. METHODS: Here, we systematically studied a series of AD and PD pathogenesis markers, as well as mitochondria, mitophagy, and neuroinflammation-related indicators, in the substantia nigra (SN), temporal cortex (TC), and caudate and putamen (CP) regions of human post-mortem brain samples from individuals with PDD and DLB and condition-matched controls. RESULTS: We found that p-APPT668 (TC), α-synuclein (CP), and LC3II (CP) are all increased while the tyrosine hydroxylase (TH) (CP) is decreased in both PDD and DLB compared to control. Also, the levels of Aß42 and DD2R, IBA1, and p-LRRK2S935 are all elevated in PDD compared to control. Interestingly, protein levels of p-TauS199/202 in CP and DD2R, DRP1, and VPS35 in TC are all increased in PDD compared to DLB. CONCLUSIONS: Together, our comprehensive and systematic study identified a set of signature proteins that will help to understand the pathology and etiology of PDD and DLB at the molecular level.

NOTCH2NLC GGC Repeat Expansions Are Associated with Sporadic Essential Tremor: Variable Disease Expressivity on Long-Term Follow-up.

We screened 662 subjects comprising 462 essential tremor (ET) subjects (285 sporadic, 125 with family history, and 52 probands from well-characterized ET pedigrees) and 200 controls and identified pathogenic NOTCH2NLC GGC repeat expansions in 4 sporadic ET patients. Two patients were followed up for >1 decade; one with 90 repeats remained an ET phenotype that did not evolve after 40 years, whereas another patient with 107 repeats developed motor symptoms and cognitive impairment after 8 to 10 years. Neuroimaging in this patient revealed severe leukoencephalopathy; diffusion-weighted imaging hyperintensity in the corticomedullary junction and skin biopsy revealed intranuclear inclusions suggestive of intranuclear inclusion body disease (NIID). No GGC repeats of >60 units were detected in familial ET cases and controls, although 4 ET patients carried 47 to 53 "intermediate" repeats. NOTCH2NLC GGC repeat expansions can be associated with sporadic ET. Carriers presenting with a pure ET phenotype may or may not convert to NIID up to 4 decades after initial tremor onset. ANN NEUROL 2020;88:614-618.

The splenial angle: a novel radiological index for idiopathic normal pressure hydrocephalus.

OBJECTIVES: To evaluate the utility of the splenial angle (SA), an axial angular index of lateral ventriculomegaly measured on diffusion tensor MRI color fractional anisotropy maps, in differentiating NPH from Alzheimer's disease (AD), Parkinson's disease (PD), and healthy controls (HC), and post-shunt changes in NPH, compared to Evans' index and callosal angle. METHODS: Evans' index, callosal angle, and SA were measured on brain MRI of 76 subjects comprising equal numbers of age- and sex-matched subjects from each cohort of NPH, AD, PD, and HC by two raters. Receiver operating characteristics (ROC) and multivariable analysis were used to assess the screening performance of each measure in differentiating and predicting NPH from non-NPH groups respectively. Temporal changes in the measures on 1-year follow-up MRI in 11 NPH patients (with or without ventriculoperitoneal shunting) were also assessed. RESULTS: Inter-rater and intra-rater reliability were excellent for all measurements (intraclass correlation coefficients > 0.9). Pairwise comparison showed that SA was statistically different between NPH and AD/PD/HC subjects (p < 0.0001). SA performed the best in predicting NPH, with an area under the ROC curve of > 0.98, and was the only measure left in the final model of the multivariable analysis. Significant (p < 0.01) change in SA was seen at follow-up MRI of NPH patients who were shunted compared to those who were not. CONCLUSIONS: The SA is readily measured on axial DTI color FA maps compared to the callosal angle and shows superior performance differentiating NPH from neurodegenerative disorders and sensitivity to ventricular changes in NPH after surgical intervention. KEY POINTS: • The splenial angle is a novel simple angular radiological index proposed for idiopathic normal pressure hydrocephalus, measured in the ubiquitous axial plane on DTI color fractional anisotropy maps. • The splenial angle quantitates the compression and stretching of the posterior callosal commissural fibers alongside the distended lateral ventricles in idiopathic normal pressure hydrocephalus (NPH) using tools readily accessible in clinical practice and shows excellent test-retest reliability. • Splenial angle outperforms Evans' index and callosal angle in predicting NPH from healthy, Parkinson's disease, and Alzheimer's disease subjects on ROC analysis with an area under the curve of > 0.98 and is sensitive to morphological ventricular changes in NPH patients after ventricular shunting.

Phenotypic bases of NOTCH2NLC GGC expansion positive neuronal intranuclear inclusion disease in a Southeast Asian cohort.

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder associated with GGC repeats of >60 to 500 copies in the 5'-untranslated region of NOTCH2NLC. The clinical and genetic characterization of NIID outside of East Asia remains unknown. We identified twelve patients who underwent genetic testing using long-read sequencing or repeat primed polymerase chain reaction. All were positive for a GGC repeat expansion; the median repeat length was 107 (range 92-138). Ten were Chinese and two of Malay ethnicity. Age at onset ranged from 50 to 69 years. Eight (66.7%) patients had dementia, while four (33.3%) patients were oligosymptomatic, without typical NIID symptoms of dementia, Parkinsonism, or muscle weakness. GGA interruptions within the GGC expansion were present in four patients; the number of GGA interruptions was highest (6.71%) in the patient with the earliest age at onset (50 years). Median plasma neurofilament light level was 47.3 pg/mL in seven patients (range 26-380 pg/mL). The highest level (380 pg/mL) was found in one patient who experienced an encephalitic episode. Overall, we describe a cohort of genetically confirmed NIID patients from Southeast Asia and provide further information that the presence of GGA interruptions within GGC repeat expansions may serve as a potential genetic modifier in NIID.

Patient attitudes towards brain donation across both neurodegenerative and non-neurodegenerative neurological disorders.

Brain donations are imperative for research; understanding possible barriers to entry is required to improve brain donation rates. While a few surveys have studied attitudes towards brain banking in patients with neurodegenerative disorders, none have surveyed patients with chronic neurological disorders but without neurodegeneration. This cross-sectional study was conducted on 187 participants, with both neurodegenerative (n = 122) and non-neurodegenerative disorders (n = 65), to compare their attitudes and preferences towards brain donation. Encouragingly, patients with non-neurodegenerative disorders were just as likely to consider brain donation as those with neurodegenerative diseases. Approximately half of each group were willing to consider brain donation, and majority of participants across both groups would not be offended if asked to participate in brain donation (71%). Across both groups, altruistic reasons such as desire to advance medical knowledge and benefit to other patients were the main motivating factors for brain donation, while perceived stress for family members, fears of body disfigurement and religious reasons were the main reasons against brain donation. Of note, nearly two-thirds of all participants were agreeable to allow their family to decide on their behalf. Overall, participants with non-neurodegenerative disorders appeared equally likely to consider brain donation as participants with neurodegenerative disorders. This is an important finding as they represent a significant population seen in specialist neurology clinics who may be overlooked in brain donor recruitment and awareness efforts. Healthcare professionals involved in brain banking should consider actively approaching these potential donors and involving their family members in these discussions.

SNCA Rep1 promoter variability influences cognition in Parkinson's disease.

BACKGROUND: While the association between alpha-synuclein gene promoter (Rep1) variability and risk of PD is well established, its association with cognition is unclear. OBJECTIVES: To investigate the association between Rep1 and motor and cognitive outcomes in PD. METHODS: Rep1 allele lengths were determined in 172 PD patients who were grouped into "long" and "short" carriers according to previous methods. Multivariable regression analysis was performed to investigate the effect of Rep1 length on cognitive and motor scores. RESULTS: Long Rep1 allele carriers had significantly lower MMSE (P = 0.010) and higher UPDRS Part III (P = 0.026) and H & Y (P = 0.008) scores compared to short allele carriers (controlled for age, sex, and disease duration). Interaction analyses of Rep1 with apolipoprotein 4 revealed no significant effect on clinical outcomes. CONCLUSIONS: PD patients carrying long Rep1 alleles are more impaired on cognitive and motor function independent of apolipoprotein 4 genotype. © 2019 International Parkinson and Movement Disorder Society.

Attitudes of Asian Parkinson patients towards brain donation.

Histopathological examination of brain tissue is required for better understanding of neurodegenerative conditions such as Parkinson's disease and related disorders. However, patient willingness remains the greatest hurdle hampering participation in brain donation for research. While there is extensive research being conducted on the subject in West, to the best of our knowledge, there are no studies done in this regard in Asia. This cross-sectional survey was conducted on 105 Parkinson's disease patients to assess their knowledge, beliefs and attitude towards brain donation in an Asian population. The majority of the participants (78%) acknowledged the importance of donation of brain for research, and 70% believed that their donated brain samples would be handled professionally. Fifty percent participants were willing to consider donating their brain for research. Motivating factors for brain donation included altruism (87%) and contribution to advance medical knowledge (80%). Common reasons for unwillingness towards brain donation were stress for family (30%), disfigurement of body (25%), and having a conservative mindset (23%). About one-third of the participants preferred to be approached for brain donation after their first clinic visit. Most patients preferred either their treating neurologists (66%) or research staff (18%) to discuss brain donation with. Participation for brain donation may be increased further with greater patient and public education to overcome misconceptions and change mindsets.

Intermediate C9orf72 alleles in neurological disorders: does size really matter?

C9orf72 repeat expansions is a major cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) worldwide. Sizes of <20 hexanucleotide repeats are observed in controls, while up to thousands associate with disease. Intermediate C9orf72 repeat lengths, however, remain uncertain. We systematically reviewed the role of intermediate C9orf72 alleles in C9orf72-related neurological disorders. We identified 49 studies with adequate available data on normal or intermediate C9orf72 repeat length, involving subjects with FTD, ALS, Parkinson's disease (PD), atypical parkinsonism, Alzheimer's disease (AD) and other aetiologies. We found that, overall, normal or intermediate C9orf72 repeat lengths are not associated with higher disease risk across these disorders, but intermediate allele sizes appear to associate more frequently with neuropsychiatric phenotypes. Intermediate sizes were detected in subjects with personal or family history of FTD and/or psychiatric illness, parkinsonism complicated by psychosis and rarely in psychiatric cohorts. Length of the hexanucleotide repeat may be influenced by ethnicity (with Asian controls displaying shorter normal repeat lengths compared with Caucasians) and underlying haplotype, with more patients and controls carrying the 'risk' haplotype rs3849942 displaying intermediate alleles. There is some evidence that intermediate alleles display increased methylation levels and affect normal transcriptional activity of the C9orf72 promoter, but the 'critical' repeat size required for initiation of neurodegeneration remains unknown and requires further study. In common neurological diseases, intermediate C9orf72 repeats do not influence disease risk but may associate with higher frequency of neuropsychiatric symptoms. This has important clinical relevance as intermediate carriers pose a challenge for genetic counselling.

Plasma Soluble ST2 Levels Are Higher in Neurodegenerative Disorders and Associated with Poorer Cognition.

BACKGROUND: Suppressor of tumorgenicity 2 (ST2) is highly expressed in brain tissue and is a receptor for interleukin 33 (IL-33). ST2 exists in two forms, a transmembrane receptor (ST2L) and a soluble decoy receptor (sST2). IL-33 binds to ST2L, triggering downstream signaling pathways involved in amyloid plaque clearance. Conversely, sST2 binds competitively to IL-33, attenuating its neuroprotective effects. High sST2 levels have been reported in mild cognitive impairment (MCI) and Alzheimer's disease (AD), suggesting that the IL-33/ST2 signaling pathway may be implicated in neurodegenerative diseases. OBJECTIVE: To investigate plasma sST2 levels in controls and patients with MCI, AD, frontotemporal dementia (FTD), and Parkinson's disease (PD). METHODS: Plasma sST2 levels were measured using ELISA in 397 subjects (91 HC, 46 MCI, 38 AD, 28 FTD, and 194 PD). Cerebrospinal fluid (CSF) levels of sST2 were measured in 22 subjects. Relationship between sST2 and clinical outcomes were analyzed. RESULTS: Plasma sST2 levels were increased across all disease groups compared to controls, with highest levels seen in FTD followed by AD and PD. Dementia patients with higher sST2 had lower cross-sectional cognitive scores in Frontal Assessment Battery and Digit Span Backward. At baseline, PD-MCI patients had higher sST2, associated with worse attention. In the longitudinal PD cohort, higher sST2 significantly associated with decline in global cognition and visuospatial domains. Plasma sST2 levels correlated with CSF sST2 levels. CONCLUSION: Plasma sST2 is raised across neurodegenerative diseases and is associated with poorer cognition. Higher baseline sST2 is a potential biomarker of disease severity in neurodegeneration.

Feasibility, comprehensibility and acceptability of the VISION-Cog, a novel tool to assess cognitive impairment in visually impaired older adults: a cross-sectional pilot study in Singapore.

OBJECTIVES: We pilot-tested the VISually Independent test battery Of NeuroCOGnition (VISION-Cog) to determine its feasibility, comprehensibility and acceptability in evaluating cognitive impairment (CI) in visually impaired older Asian adults. DESIGN: The VISION-Cog was iteratively fine-tuned through pilot studies and expert-panel discussion. In the first pilot study (Stage 1), we recruited 15 visually impaired and cognitively normal participants aged ≥60 years to examine the pilot VISION-Cog's feasibility (length of time to administer), comprehensibility (clarity of instructions) and acceptability (participant burden). We then presented the pilot results to the expert panel (Stage 2) who decided via agreement on a revised version of the VISION-Cog. Subsequently, we conducted a second pilot study (Stage 3) on another four participants to ascertain improvement in feasibility, comprehensibility and acceptability of the revised version. SETTING: Singapore Eye Research Institute. PARTICIPANTS: Nineteen Asian adults aged ≥60 years with visual impairment (defined as near visual acuity worse than N8) were recruited. OUTCOME MEASURE: Revised VISION-Cog. RESULT: The VISION-Cog was deemed feasible, taking approximately 60 min to complete on average. All participants agreed that the test instructions were clear, and the battery did not cause undue discomfort or frustration. The data collector rated all tests as very user-friendly (score of 5/5). Minor modifications to the pilot VISION-Cog were suggested by the panel to improve its safety, clarity of instructions and content validity, which were incorporated and iteratively tested in the second pilot study until no further issues emerged. CONCLUSIONS: Using an iterative mixed-methods process, we have developed a feasible, comprehensible and acceptable 5-domain and 9-item visually independent VISION-Cog test battery suitable to assist CI diagnosis in older adults with visual impairment. We will assess its diagnostic potential against clinician-based assessment of CI in subsequent phases.

Content development of the VISION-Cog: a novel tool to assess cognitive impairment in visually impaired older adults in Singapore.

OBJECTIVES: Current cognitive screening and diagnostic instruments rely on visually dependent tasks and are, therefore, not suitable to assess cognitive impairment (CI) in visually impaired older adults. We describe the content development of the VISually Independent test battery Of NeuroCOGnition (VISION-Cog)-a new diagnostic tool to evaluate CI in visually impaired older Singaporean adults. DESIGN: The content development phase consisted of two iterative stages: a neuropsychological consultation and literature review (stage 1) and an expert-panel discussion (stage 2). In stage 1, we investigated currently available neuropsychological test batteries for CI to inform constructions of our preliminary test battery. We then deliberated this battery during a consensus meeting using the Modified Nominal Group technique (stage 2) to decide, via agreement of five experts, the content of a pilot neuropsychological battery for the visually impaired. SETTING: Singapore Eye Research Institute. PARTICIPANTS: Stakeholders included researchers, psychologists, neurologists, neuro-ophthalmologists, geriatricians and psychiatrists. OUTCOME MEASURE: pilot VISION-Cog. RESULTS: The two-stage process resulted in a pilot VISION-Cog consisting of nine vision-independent neuropsychological tests, including the modified spatial memory test, list learning, list recall and list recognition, adapted token test, semantic fluency, modified spatial analysis, verbal subtests of the frontal battery assessment, digit symbol, digit span forwards, and digit span backwards. These tests encompassed five cognitive domains-memory and learning, language, executive function, complex attention, and perceptual-motor abilities. The expert panel suggested improvements to the clarity of test instructions and culturally relevant test content. These suggestions were incorporated and iteratively pilot-tested by the study team until no further issues emerged. CONCLUSIONS: We have developed a five-domain and nine-test VISION-Cog pilot instrument capable of replacing vision-dependent diagnostic batteries in aiding the clinician-based diagnosis of CI in visually impaired older adults. Subsequent phases will examine the VISION-Cog's feasibility, comprehensibility and acceptability; and evaluate its diagnostic performance.

Unique Clinical, Radiological and Histopathological Characteristics of a Southeast Asian Cohort of Patients with Limb-Girdle Muscular Dystrophy 2G/LGMD-R7-Telethonin-Related.

AIM: We describe a cohort of five patients with limb-girdle muscular dystrophy (LGMD) 2G/LGMD-R7 in a South-east Asian cohort. BACKGROUND: LGMD2G/LGMD-R7-telethonin-related is caused by mutations in the TCAP gene that encodes for telethonin. METHODS: We identified consecutive patients with LGMD2G/LGMD-R7-telethonin-related, diagnosed at the National Neuroscience Institute (NNI) and National University Hospital (NUH) between January 2000 and June 2021. RESULTS: At onset, three patients presented with proximal lower limb weakness, one patient presented with Achilles tendon contractures, and one patient presented with delayed gross motor milestones. At last follow up, three patients had a limb girdle pattern of muscle weakness and two had a facioscapular humeral pattern of weakness. Whole body muscle MRI performed for one patient with a facioscapular-humeral pattern of weakness showed a pattern of muscle atrophy similar to facioscapular-humeral dystrophy. One patient had histological features consistent with myofibrillar myopathy; electron microscopy confirmed the disruption of myofibrillar architecture. One patients also had reduced staining to telethonin antibody on immunohistochemistry. CONCLUSION: We report the unique clinical and histological features of a Southeast Asian cohort of five patients with LGMD2G/LGMD-R7-telethonin-related muscular dystrophy and further expand its clinical and histopathological spectrum.

C9orf72 expansions are the most common cause of genetic frontotemporal dementia in a Southeast Asian cohort.

OBJECTIVE: Frontotemporal dementia (FTD) encompasses a spectrum of neurodegenerative disorders, including behavioural variant FTD (bvFTD), semantic variant primary progressive aphasia (svPPA) and non-fluent variant PPA (nfvPPA). While a strong genetic component is implicated in FTD, genetic FTD in Asia is less frequently reported. We aimed to investigate the frequency of Southeast Asian FTD patients harbouring known genetic FTD variants. METHODS: A total of 60 FTD-spectrum patients (25 familial and 35 sporadic) from Singapore and the Philippines were included. All underwent next-generation sequencing and repeat-primed PCR for C9orf72 expansion testing. Neurofilament light chain (NfL) levels were measured in a subset of patients. RESULTS: Overall, 26.6% (16/60 cases) carried pathogenic or likely pathogenic variants in a FTD-related gene, including: MAPT Gln351Arg (n = 1); GRN Cys92Ter (n = 1), Ser301Ter (n = 2), c.462 + 1G > C (n = 1); C9orf72 expansion (35-70 repeats; n = 8); TREM2 Arg47Cys (n = 1); and OPTN frameshift insertion (n = 2). Genetic mutations accounted for 48% (12/25) of patients with familial FTD, and 11.4% (4/35) of patients with sporadic FTD. C9orf72 repeat expansions were the most common genetic mutation (13.3%, 8/60), followed by GRN (6.7%, 4/60) variants. Within mutation carriers, plasma NfL was highest in a C9orf72 expansion carrier, and CSF NfL was highest in a GRN splice variant carrier. INTERPRETATION: In our cohort, genetic mutations are present in one-quarter of FTD-spectrum cases, and up to half of those with family history. Our findings highlight the importance of wider implementation of genetic testing in FTD patients from Southeast Asia.

Longitudinal Study of SNCA Rep1 Polymorphism on Executive Function in Early Parkinson's Disease.

The alpha-synuclein gene promoter (SNCA-Rep1) is associated with Parkinson's disease (PD), but its relationship with performance across individual cognitive domains in early PD is unknown. This study aims to investigate Rep1 polymorphism and longitudinal change in cognition in early PD. In this longitudinal study, Rep1 allele lengths ("long" and "short") were determined in 204 early PD patients. All participants underwent annual neuropsychological assessments and followed up for 3 years. Linear-mixed model was performed to investigate the association of Rep1 status and longitudinal change in individual cognitive domains. At 3 years, significant decline in executive function was observed in long Rep1 allele carriers vs short allele carriers, controlling for potential confounders. This is the first longitudinal study demonstrating that long Rep1 allele carriers are at higher risk for executive dysfunction in early PD.

Plasma Neurofilament Light Concentration Is Associated with Diffusion-Tensor MRI-Based Measures of Neurodegeneration in Early Parkinson's Disease.

BACKGROUND: Neurofilament light is a marker of axonal degeneration, whose measurement from peripheral blood was recently made possible by new assays. OBJECTIVE: We aimed to determine whether plasma neurofilament light chain (NfL) concentration reflects brain white matter integrity in patients with early Parkinson's disease (PD). METHODS: 137 early PD patients and 51 healthy controls were included. Plasma NfL levels were measured using ultrasensitive single molecule array. 3T MRI including diffusion tensor imaging was acquired for voxelwise analysis of association between NfL and both fractional anisotropy (FA) and mean diffusivity (MD) in white matter tracts and subcortical nuclei. RESULTS: A pattern of brain microstructural changes consistent with neurodegeneration was associated with increased plasma NfL in most of the frontal lobe and right internal capsule, with decreased FA and increased MD. The same clusters were also associated with poorer global cognition. A significant cluster in the left putamen was associated with increased NfL, with a significantly greater effect in PD than controls. CONCLUSION: Plasma NfL may be associated with brain microstructure, as measured using diffusion tensor imaging, in patients with early PD. Higher plasma NfL was associated with a frontal pattern of neurodegeneration that also correlates with cognitive performance in our cohort. This may support a future role for plasma NfL as an accessible biomarker for neurodegeneration and cognitive dysfunction in PD.

Ipsilateral stroke in a patient with horizontal gaze palsy with progressive scoliosis and a subcortical infarct.

BACKGROUND AND PURPOSE: horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare congenital disorder caused by mutation in the ROBO3 gene. It is characterized by absent horizontal eye movements with progressive scoliosis developing in childhood and adolescence. To our knowledge, both diffusion tensor imaging evaluation in HGPPS patients who present with stroke and truncating stop codon mutation in the ROBO3 gene have yet to be reported. SUMMARY OF CASE: we present a man with HGPPS who experienced a left pure motor stroke as a result of a left corona radiata infarct on diffusion-weighted imaging. Diffusion tensor imaging tractography confirmed the presence of uncrossed corticospinal tracts, accounting for the ipsilateral deficit. He was also found to possess a novel ROBO3 stop codon mutation on genetic testing. CONCLUSIONS: patients with HGPPS may present with stroke symptoms on the ipsilateral side of the infarct in view of uncrossed corticospinal tracts. Truncating mutation in ROBO3 may provide additional pathophysiologic insights.

Altered Cerebrospinal Fluid Exosomal microRNA Levels in Young-Onset Alzheimer's Disease and Frontotemporal Dementia.

BACKGROUND: micro-RNAs (miRNAs) are stable, small, non-coding RNAs enriched in exosomes. Their variation in levels according to different disease etiologies have made them a promising diagnostic biomarker for neurodegenerative diseases such as Alzheimer's disease (AD). Altered expression of miR-320a, miR-328-3p, and miR-204-5p have been reported in AD and frontotemporal dementia (FTD). OBJECTIVE: To determine their reliability, we aimed to examine the expression of three exosomal miRNAs isolated from cerebrospinal fluid (CSF) of patients with young-onset AD and FTD (< 65 years), correlating with core AD biomarkers and cognitive scores. METHODS: Exosomes were first isolated from CSF samples of 48 subjects (8 controls, 28 AD, and 12 FTD), followed by RNA extraction and quantitative PCR to measure the expression of miR-320a, miR-328-3p, and miR-204-5p. RESULTS: Expression of all three markers (miR-320a (p = 0.005), miR-328-3p (p = 0.049), and miR-204-5p (p = 0.036)) were significantly lower in AD versus controls. miR-320a was reduced in FTD versus controls (p = 0.049) and miR-328-3p was lower in AD versus FTD (p = 0.054). Notably, lower miR-328-3p levels could differentiate AD from FTD and controls with an AUC of 0.702, 95% CI: 0.534- 0.870, and showed significant correlation with lower CSF Aß42 levels (r = 0.359, p = 0.029). Pathway enrichment analysis identified potential targets of miR-328-3p implicated in the AMPK signaling pathway linked to amyloid-ß and tau metabolism in AD. CONCLUSION: Overall, we demonstrated miR-320a and miR-204-5p as reliable biomarkers for AD and FTD and report miR-328-3p as a novel AD biomarker.