Early Alzheimer's disease pathology in human cortex involves transient cell states.

Cellular perturbations underlying Alzheimer's disease (AD) are primarily studied in human postmortem samples and model organisms. Here, we generated a single-nucleus atlas from a rare cohort of cortical biopsies from living individuals with varying degrees of AD pathology. We next performed a systematic cross-disease and cross-species integrative analysis to identify a set of cell states that are specific to early AD pathology. These changes-which we refer to as the early cortical amyloid response-were prominent in neurons, wherein we identified a transitional hyperactive state preceding the loss of excitatory neurons, which we confirmed by acute slice physiology on independent biopsy specimens. Microglia overexpressing neuroinflammatory-related processes also expanded as AD pathology increased. Finally, both oligodendrocytes and pyramidal neurons upregulated genes associated with ß-amyloid production and processing during this early hyperactive phase. Our integrative analysis provides an organizing framework for targeting circuit dysfunction, neuroinflammation, and amyloid production early in AD pathogenesis.

Utility of the INECO Frontal Screening and the Frontal Assessment Battery in detecting executive dysfunction in early-onset cognitive impairment and dementia.

OBJECTIVE: The INECO Frontal Screening (IFS) and the Frontal Assessment Battery (FAB) are executive dysfunction (ED) screening tools that can distinguish patients with neurodegenerative disorders from healthy controls and, to some extent, between dementia subtypes. This paper aims to examine the suitability of these tests in assessing early-onset cognitive impairment and dementia patients. METHOD: In a memory clinic patient cohort (age mean = 57.4 years) with symptom onset at ≤65 years, we analyzed the IFS and the FAB results of four groups: early-onset dementia (EOD, n = 49), mild cognitive impairment due to neurological causes (MCI-n, n = 34), MCI due to other causes such as depression (MCI-o, n = 99) and subjective cognitive decline (SCD, n = 14). Data were gathered at baseline and at 6 and 12 months. We also studied the tests' accuracy in distinguishing EOD from SCD patients and ED patients from those with intact executive functioning. Correlations with neuropsychological measures were also studied. RESULTS: The EOD group had significantly (p < .05) lower IFS and FAB total scores than the MCI-o and SCD groups. Compared with the FAB, the IFS showed more statistically significant (p < .05) differences between diagnostic groups, greater accuracy (IFS AUC = .80, FAB AUC = .75, p = .036) in detecting ED and marginally stronger correlations with neuropsychological measures. We found no statistically significant differences in the EOD group scores from baseline up to 6- or 12-months follow-up. CONCLUSIONS: While both tests can detect EOD among memory clinic patients, the IFS may be more reliable in detecting ED than the FAB.

Gut Microbiome Changes in Patients With Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: The gut microbiome is a complex system within the human gastrointestinal tract. The bacteria play a significant role in human health, and some can promote inflammation and pathologic processes through chemical interactions or metabolites. Gut microbiome dysbiosis has been linked to some neurological and other diseases. Here we aimed to examine microbiome differences between patients with a progressive neurological disorder, idiopathic normal pressure hydrocephalus (iNPH), compared with healthy controls (CO). METHODS: We recruited 37 neurologically healthy CO and 10 patients with shunted iNPH. We evaluated these participants' cognition using the CERAD-NB test battery and CDR test, and collected a variety of information, including about dietary habits and health. We also collected fecal samples, which were subjected to 16S amplicon sequencing to analyze differences in gut microbiome composition. RESULTS: We found that the iNPH group exhibited significantly different abundances of 10 bacterial genera compared with the CO group. The Escherichia/Shigella and Anaeromassilibacillus genera were most remarkably increased. Other increased genera were Butyrivibrio , Duncaniella , and an unidentified genus. The decreased genera were Agathobaculum , Paramuribaculum , Catenibacterium , and 2 unidentified genera. CONCLUSIONS: Here we report the first identified microbiome differences in iNPH patients compared with healthy controls.

Exposure to urban particulate matter alters responses of olfactory mucosal cells to SARS-CoV-2 infection.

Respiratory viruses have a significant impact on health, as highlighted by the COVID-19 pandemic. Exposure to air pollution can contribute to viral susceptibility and be associated with severe outcomes, as suggested by recent epidemiological studies. Furthermore, exposure to particulate matter (PM), an important constituent of air pollution, is linked to adverse effects on the brain, including cognitive decline and Alzheimer's disease (AD). The olfactory mucosa (OM), a tissue located at the rooftop of the nasal cavity, is directly exposed to inhaled air and in direct contact with the brain. Increasing evidence of OM dysfunction related to neuropathogenesis and viral infection demonstrates the importance of elucidating the interplay between viruses and air pollutants at the OM. This study examined the effects of subacute exposure to urban PM 0.2 and PM 10-2.5 on SARS-CoV-2 infection using primary human OM cells obtained from cognitively healthy individuals and individuals diagnosed with AD. OM cells were exposed to PM and subsequently infected with the SARS-CoV-2 virus in the presence of pollutants. SARS-CoV-2 entry receptors and replication, toxicological endpoints, cytokine release, oxidative stress markers, and amyloid beta levels were measured. Exposure to PM did not enhance the expression of viral entry receptors or cellular viral load in human OM cells. However, PM-exposed and SARS-CoV-2-infected cells showed alterations in cellular and immune responses when compared to cells infected only with the virus or pollutants. These changes are highly pronounced in AD OM cells. These results suggest that exposure of human OM cells to PM does not increase susceptibility to SARS-CoV-2 infection in vitro, but it can alter cellular immune responses to the virus, particularly in AD. Understanding the interplay of air pollutants and COVID-19 can provide important insight for the development of public health policies and interventions to reduce the negative influences of air pollution exposure.

Human-derived air-liquid interface cultures decipher Alzheimer's disease-SARS-CoV-2 crosstalk in the olfactory mucosa.

BACKGROUND: The neurological effects of the coronavirus disease of 2019 (COVID-19) raise concerns about potential long-term consequences, such as an increased risk of Alzheimer's disease (AD). Neuroinflammation and other AD-associated pathologies are also suggested to increase the risk of serious SARS-CoV-2 infection. Anosmia is a common neurological symptom reported in COVID-19 and in early AD. The olfactory mucosa (OM) is important for the perception of smell and a proposed site of viral entry to the brain. However, little is known about SARS-CoV-2 infection at the OM of individuals with AD. METHODS: To address this gap, we established a 3D in vitro model of the OM from primary cells derived from cognitively healthy and AD individuals. We cultured the cells at the air-liquid interface (ALI) to study SARS-CoV-2 infection under controlled experimental conditions. Primary OM cells in ALI expressed angiotensin-converting enzyme 2 (ACE-2), neuropilin-1 (NRP-1), and several other known SARS-CoV-2 receptor and were highly vulnerable to infection. Infection was determined by secreted viral RNA content and confirmed with SARS-CoV-2 nucleocapsid protein (NP) in the infected cells by immunocytochemistry. Differential responses of healthy and AD individuals-derived OM cells to SARS-CoV-2 were determined by RNA sequencing. RESULTS: Results indicate that cells derived from cognitively healthy donors and individuals with AD do not differ in susceptibility to infection with the wild-type SARS-CoV-2 virus. However, transcriptomic signatures in cells from individuals with AD are highly distinct. Specifically, the cells from AD patients that were infected with the virus showed increased levels of oxidative stress, desensitized inflammation and immune responses, and alterations to genes associated with olfaction. These results imply that individuals with AD may be at a greater risk of experiencing severe outcomes from the infection, potentially driven by pre-existing neuroinflammation. CONCLUSIONS: The study sheds light on the interplay between AD pathology and SARS-CoV-2 infection. Altered transcriptomic signatures in AD cells may contribute to unique symptoms and a more severe disease course, with a notable involvement of neuroinflammation. Furthermore, the research emphasizes the need for targeted interventions to enhance outcomes for AD patients with viral infection. The study is crucial to better comprehend the relationship between AD, COVID-19, and anosmia. It highlights the importance of ongoing research to develop more effective treatments for those at high risk of severe SARS-CoV-2 infection.

Incidence and Risk Factors of Transient Global Amnesia.

INTRODUCTION: Transient global amnesia (TGA) is a spontaneously resolving, anterograde amnesia that lasts mostly <24 h and often occurs with retrograde amnesia. The etiology of TGA remains unclear, although in recent decades, many risk factors and preceding events have been identified. There are few up-to-date reports on the TGA incidence in Northern Europe. In this study, we report the incidence and risk factors associated with TGA in Finland. MATERIALS AND METHODS: The study included all patients with suspected TGA that were referred to Kuopio University Hospital (KUH) in 2017. The hospital catchment area included 246,653 individuals. Risk factors and demographic data were collected from medical records. The TGA incidence rates were calculated as the number of patients with TGA divided by the number of individuals at risk in different age groups. RESULTS: In 2017, 56 patients were treated for TGA at KUH. Of these, 46 had a first-ever TGA. The most common event preceding TGA was physical effort (n = 28, 50%), followed by emotional stress (n = 11, 19.6%) and water contact or a temperature change (n = 11, 19.6%). The most common comorbidities were hypercholesterolemia (n = 22, 39.3%), hypertensive disease (n = 21, 37.5%), hypothyroidism (n = 11, 19.6%), coronary artery disease (n = 8, 14.3%), and migraine (n = 7, 12.5%). TGA occurred most often in December (n = 9, 16.0%), March (n = 8, 14.3%), or October (n = 8, 14.3%), and least often in November and May (n = 2, 3.6% in both months). The crude incidence of a first TGA in Eastern Finland was 18.6/100,000 inhabitants, and when standardized to the European population in 2010, it was 14.3/100,000 inhabitants. Therefore, the TGA incidence was higher than previously reported in European countries. DISCUSSION: The most common precipitating factors for TGA were physical effort, emotional stress, and water contact/temperature change. The incidence of TGA was high in the Eastern Finnish population.

Computer-based Eye-tracking Analysis of King-Devick Test Differentiates Persons With Idiopathic Normal Pressure Hydrocephalus From Cognitively Unimpaired.

BACKGROUND: Functional defects in eye movements and reduced reading speed in neurodegenerative diseases represent a potential new biomarker to support clinical diagnosis. We investigated whether computer-based eye-tracking (ET) analysis of the King-Devick (KD) test differentiates persons with idiopathic normal pressure hydrocephalus (iNPH) from cognitively unimpaired [control (CO)] and persons with Alzheimer's disease (AD). METHODS: We recruited 68 participants (37 CO, 10 iNPH, and 21 AD) who underwent neurological examination, the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological test battery (CERAD-NB), and a Clinical Dementia Rating interview. The KD reading test was performed using computer-based ET. We analyzed the total time used for the reading test, number of errors, durations of fixation and saccade, and saccade amplitudes. RESULTS: The iNPH group significantly differed from the CO group in the KD test mean total time (CO 69.3 s, iNPH 87.3 s; P ≤0.009) and eye-tracking recording of the mean saccade amplitude (CO 3.6 degree, iNPH 3.2 degree; P ≤0.001). The AD group significantly differed from the CO group in each tested parameter. No significant differences were detected between the iNPH and AD groups. CONCLUSION: For the first time, we demonstrated altered reading ability and saccade amplitudes in patients with iNPH.

Incidence of first-ever transient ischemic attack in Eastern Finland.

OBJECTIVES: The incidence of stroke has been declining in Finland, as well as in Europe. However, it is unclear whether the incidence of transient ischemic attack (TIA) is also decreasing. In fact, the TIA incidence in the Finnish population has never been reported. Therefore, here we investigated the incidence of TIA in the Eastern Finnish population in 2017. MATERIALS AND METHODS: All patients with suspected TIA, from a defined catchment area, were referred to a neurological emergency unit at Kuopio University Hospital (KUH) in the Northern Savonia region of Eastern Finland, which had a population of 246,653 in 2017. The original study population comprised TIA patients diagnosed based on the WHO TIA criteria in 2017. Incidence rates were calculated by dividing the number of TIA cases by the number of people in different age groups. RESULTS: Among 432 patients with a suspected TIA referred to the neurological emergency unit at Kuopio University Hospital in 2017, 293 were living in Northern Savonia and were ultimately diagnosed with TIA after neurological examinations. The number of first-ever TIAs was 211. The crude incidence of all TIA was 122/100,000 inhabitants, and of first-ever TIA was 86/100,000. The age-standardized incidence (European population 2010) of the first-ever TIA was calculated to be 64/100,000. The mean age of first-ever TIA patients was 70 years: 72 years for women versus 68 years for men. CONCLUSIONS: We found a high incidence of TIA in Eastern Finland.

Pet ownership supports quality of life in home-dwelling people with Alzheimer's disease.

OBJECTIVES: Human-animal interactions have beneficial psychosocial and psychophysiological effects on individuals in both the presence and absence of medical health conditions. No previous prospective studies with long follow-up have investigated the effects of domestic pets on individuals with Alzheimer's disease (AD) who live at home. We examined the effects of pets on quality of life (QoL) and general well-being during a 5-year follow-up of home-dwelling persons with AD. METHODS: In a prospective study including 223 patients with very mild (Clinical Dementia Rating Scale [CDR] 0.5) or mild (CDR 1) AD at baseline who participated in the ALSOVA study, 40 (18%) had a pet. Self- and proxy-rated QoL in AD quality of life-AD (QoL-AD), 15D, and self-rated visual analogic scale (VAS) were assessed annually for 3 years and after 5 years. The Mini-Mental State Examination, Neuropsychiatric Inventory, and CDR sum of boxes (CDR sum of boxes) were measured at the same visits. RESULTS: A significant positive effect of pet ownership (p = 0.003, proxy-rated QoL-AD) on QoL was found over the entire follow-up. However, self-rated QoL-AD, 15D, and VAS did not significantly differ between pet owners and non-pet owners. CONCLUSIONS: The findings suggest that having a pet may support QoL in home-dwelling persons with AD. Self-rated or general QoL or well-being measurements are not an accurate method for studying QoL in individuals with dementia over time due to a lack of insight. Adding proxy-rated evaluations to this kind of study is recommended.

Treatment initiation for parkinson's disease in Australia 2013-2018: a nation-wide study.

BACKGROUND: Guidelines highlight the importance of an individualized approach to treatment initiation for Parkinson's disease. Our aim was to investigate initiation of anti-Parkinson medication in Australia from 2013-2018, and to determine factors predicting choice of initial treatment. METHODS: Cohort of new-users (N = 4,887) of anti-Parkinson medication aged ≥ 40 years were identified from a 10% random representative sample of national medication dispensing data from July-2013 to June-2018. Changes in treatment initiation were examined across the whole cohort and stratified by age and sex. RESULTS: Treatment initiation was most frequent with levodopa followed by non-ergot dopamine agonists (DAs) and anticholinergics. Two thirds initiated with levodopa across the study period. Initiation with non-ergot DAs increased from 22 to 27% (rate ratio, RR 1.23, 95% confidence interval, CI 1.02-1.47) and initiation with anticholinergics decreased from 6.9% to 2.4% (RR 0.34, 95% CI 0.21-0.55) from 2013-2018. Among persons aged ≥ 65 years, one third of women and one fourth of men initiated on levodopa. Among women aged < 65 years, rates of treatment initiation with DAs (37%) and levodopa (37%) were similar in 2013/2014 but initiation with DA exceeded levodopa thereafter. Among men aged < 65 years, treatment initiation with levodopa (44%-49%) remained more frequent than initiation with DAs (29%-32%) throughout the study period. CONCLUSIONS: Treatment initiation with levodopa was most frequent among persons aged ≥ 65 years, consistent with current guidelines. Whilst the value of levodopa sparing strategies is unclear, treatment initiation with DA has become increasingly common relative to levodopa among women but not among men aged < 65 years.

Biometal Dyshomeostasis in Olfactory Mucosa of Alzheimer's Disease Patients.

Olfactory function, orchestrated by the cells of the olfactory mucosa at the rooftop of the nasal cavity, is disturbed early in the pathogenesis of Alzheimer's disease (AD). Biometals including zinc and calcium are known to be important for sense of smell and to be altered in the brains of AD patients. Little is known about elemental homeostasis in the AD patient olfactory mucosa. Here we aimed to assess whether the disease-related alterations to biometal homeostasis observed in the brain are also reflected in the olfactory mucosa. We applied RNA sequencing to discover gene expression changes related to metals in olfactory mucosal cells of cognitively healthy controls, individuals with mild cognitive impairment and AD patients, and performed analysis of the elemental content to determine metal levels. Results demonstrate that the levels of zinc, calcium and sodium are increased in the AD olfactory mucosa concomitantly with alterations to 17 genes related to metal-ion binding or metal-related function of the protein product. A significant elevation in alpha-2-macroglobulin, a known metal-binding biomarker correlated with brain disease burden, was observed on the gene and protein levels in the olfactory mucosa cells of AD patients. These data demonstrate that the olfactory mucosa cells derived from AD patients recapitulate certain impairments of biometal homeostasis observed in the brains of patients.

Different Trajectories of Depressive Symptoms in Alzheimer's Disease Caregivers - 5-Year Follow-Up.

OBJECTIVES: The care of individuals with Alzheimer's disease (AD) relies on family caregivers (FCs) who face increasing demands. This study aimed to identify trajectories of depressive symptoms in FCs. METHODS: 226 FCs and individuals with AD were followed up for 5 years as a part of the ALSOVA study. Depressive symptoms in FCs were measured with the Beck Depression Inventory from the time of the AD diagnosis to the 5-year follow-up. We compared the trajectory of groups regarding age, education, and sex of both FC distress and AD symptoms. RESULTS: We identified three trajectories of FC depressive symptoms throughout follow-up: (1) declining (7.5% of FCs), (2) minor (59.7% of FCs), and (3) increased (32.7% of FCs). These groups exhibited differences in demographic variables, FC distress, and individuals with AD neuropsychiatric symptoms. CONCLUSIONS: The present study showed that FC depressive symptoms existed, and one-third of caregivers experienced increasing depressive symptoms over five years. CLINICAL IMPLICATIONS: Family caregivers' health should be followed in clinical practice, and those at risk of depression could be recognized early in caregiving.

GFAP as a biomarker in frontotemporal dementia and primary psychiatric disorders: diagnostic and prognostic performance.

BACKGROUND: Frontotemporal lobar degeneration (FTLD) and primary psychiatric disorders (PPD) are characterised by overlapping clinical features but different aetiologies. Here, we assessed for the first time the potential of blood glial fibrillar acidic protein (GFAP), marker of astrogliosis, as a discriminative and prognostic tool in FTLD and PPD. METHODS: The levels of GFAP in serum (sGFAP) of patients with FTLD (N=107) and PPD (N=44) and GFAP in whole blood samples (bGFAP) from FTLD (N=10), PPD (N=10) and healthy controls (N=18) were measured. We evaluated whether the sGFAP levels associate with C9orf72 repeat expansion, survival of FTLD and PPD patients, and brain atrophy assessed cross-sectionally and longitudinally by structural T1W MRI. We also examined the correlation between sGFAP and bGFAP levels in a subset of patients. RESULTS: sGFAP and bGFAP levels were elevated in the FTLD group compared with the PPD or control groups. Receiver operating characteristic analysis indicated an excellent diagnostic performance between FTLD and PPD (the area under the curve (AUC)=0.820, 95% CI 0.745 to 0.896). sGFAP and bGFAP levels showed a strong correlation and elevated sGFAP levels significantly associated with atrophy rate in the temporal cortex and predicted shorter survival time in patients with FTLD. No association with C9orf72 repeat expansion was detected. CONCLUSIONS: sGFAP enabled differentiation of patients with FTLD and PPD and associated with shorter survival and more severe brain atrophy rate in patients with FTLD. These results suggest that blood-based GFAP represents a minimally invasive and useful biomarker in the differential diagnostics between patients with FTLD and PPD and in evaluating disease progression and astrogliosis in FTLD.

Biomarker counseling, disclosure of diagnosis and follow-up in patients with mild cognitive impairment: A European Alzheimer's disease consortium survey.

OBJECTIVES: Mild cognitive impairment (MCI) is associated with an increased risk of further cognitive decline, partly depending on demographics and biomarker status. The aim of the present study was to survey the clinical practices of physicians in terms of biomarker counseling, management, and follow-up in European expert centers diagnosing patients with MCI. METHODS: An online email survey was distributed to physicians affiliated with European Alzheimer's disease Consortium centers (Northern Europe: 10 centers; Eastern and Central Europe: 9 centers; and Southern Europe: 15 centers) with questions on attitudes toward biomarkers and biomarker counseling in MCI and dementia. This included postbiomarker counseling and the process of diagnostic disclosure of MCI, as well as treatment and follow-up in MCI. RESULTS: The response rate for the survey was 80.9% (34 of 42 centers) across 20 countries. A large majority of physicians had access to biomarkers and found them useful. Pre- and postbiomarker counseling varied across centers, as did practices for referral to support groups and advice on preventive strategies. Less than half reported discussing driving and advance care planning with patients with MCI. CONCLUSIONS: The variability in clinical practices across centers calls for better biomarker counseling and better training to improve communication skills. Future initiatives should address the importance of communicating preventive strategies and advance planning.

A novel CT-based automated analysis method provides comparable results with MRI in measuring brain atrophy and white matter lesions.

PURPOSE: Automated analysis of neuroimaging data is commonly based on magnetic resonance imaging (MRI), but sometimes the availability is limited or a patient might have contradictions to MRI. Therefore, automated analyses of computed tomography (CT) images would be beneficial. METHODS: We developed an automated method to evaluate medial temporal lobe atrophy (MTA), global cortical atrophy (GCA), and the severity of white matter lesions (WMLs) from a CT scan and compared the results to those obtained from MRI in a cohort of 214 subjects gathered from Kuopio and Helsinki University Hospital registers from 2005 - 2016. RESULTS: The correlation coefficients of computational measures between CT and MRI were 0.9 (MTA), 0.82 (GCA), and 0.86 (Fazekas). CT-based measures were identical to MRI-based measures in 60% (MTA), 62% (GCA) and 60% (Fazekas) of cases when the measures were rounded to the nearest full grade variable. However, the difference in measures was 1 or less in 97-98% of cases. Similar results were obtained for cortical atrophy ratings, especially in the frontal and temporal lobes, when assessing the brain lobes separately. Bland-Altman plots and weighted kappa values demonstrated high agreement regarding measures based on CT and MRI. CONCLUSIONS: MTA, GCA, and Fazekas grades can also be assessed reliably from a CT scan with our method. Even though the measures obtained with the different imaging modalities were not identical in a relatively extensive cohort, the differences were minor. This expands the possibility of using this automated analysis method when MRI is inaccessible or contraindicated.

Total cost of care increases significantly from early to mild Alzheimer's disease: 5-year ALSOVA follow-up.

INTRODUCTION: We studied the costs of formal and informal care in relation to Alzheimer's disease (AD) progression. METHODS: 231 persons with AD with a family caregiver were followed up for 5 years. The Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) was used to measure AD progression. Health and social care unit costs were used for formal care costs. An opportunity cost method for lost leisure time was applied to analyse the cost of informal care. RESULTS: Total cost of care in early stage AD (CDR-SB ≤ 4) was 16,448€ (95% CI 13,722-19,716) annually. In mild (CDR-SB 4.5-9), moderate (CDR-SB 9.5-15.5) and severe (CDR-SB ≥ 16) AD, the total costs were 2.3, 3.4 and 4.4 times higher, respectively. A one-unit increase in CDR-SB increased the total, formal and informal costs by 15, 11 and 18%, respectively. CONCLUSIONS: Compared to early AD, the costs of total, formal and informal care are remarkably higher already in mild AD. This finding emphasises early diagnosis, interventions and family support for persons with AD and their caregivers.

Upper limb dysfunction and activities in daily living in idiopathic normal pressure hydrocephalus.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a neurodegenerative disease with a characteristic symptom triad of gait disturbance, cognitive decline, and incontinence. Recently, also dysfunctions in upper limbs have been described in iNPH and reported to improve after shunt surgery. We aim to describe the role of upper limb motor function in the clinical assessment of iNPH patients and its influence on activities of daily living (ADL). METHODS: Seventy-five consecutive patients with probable iNPH were studied pre-operatively and at 3 and 12 months after shunt surgery. The pre-operative evaluation included lumbar drainage of cerebrospinal fluid (tap test). Motor functions were assessed in upper and lower limbs with Grooved Pegboard Test (GPT), Box & Block Test (BBT), Total Score of Gait (TSG), and balance test. ADL was assessed with Barthel's index and cognition in accordance with the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). RESULTS: Patients showed improvement in all motor tests and ADL at 3 months after shunt surgery. The improvement remained stable during the 12-month post-operative follow-up. The motor function tests correlated with each other and with ADL. CONCLUSIONS: A 3-month follow-up period after shunt surgery is adequate to show improvement in motor tasks, and a positive outcome will last for at least 12 months. A shunt-responsive dysfunction of upper limb motor performance plays a major role in ADL of iNPH patients. Therefore, we suggest an evaluation of upper limb motor performance to be included in routine evaluation of iNPH patients.

Comparison of Prodromal Symptoms of Patients with Behavioral Variant Frontotemporal Dementia and Alzheimer Disease.

INTRODUCTION: Behavioral variant frontotemporal dementia (bvFTD) is the most common clinical subtype of frontotemporal lobar degeneration. bvFTD is often characterized by changes in behavior and personality, frequently leading to psychiatric misdiagnoses. On the other hand, substantial clinical overlap with other neurodegenerative diseases, such as Alzheimer disease (AD), further complicates the diagnostics. OBJECTIVE: Our aim was to identify the main differences in early symptoms of bvFTD and AD in the prodromal stages of the diseases. In addition, patients with bvFTD were analyzed separately according to whether they carry the C9orf72repeat expansion or not. METHODS: Patient records of bvFTD (n = 75) and AD (n = 83) patients were analyzed retrospectively for memory and neuropsychiatric symptoms, sleeping disorders, and somatic complaints before the setting of the accurate diagnosis. RESULTS: A total of 84% of bvFTD patients (n = 63) and 98.8% of AD patients (n = 82) reported subjective memory disturbances in the prodromal phases of the disease. bvFTD patients presented significantly more often with sleeping disorders, headache, inexplicable collapses, transient loss of consciousness, somatization, delusions, and hallucinations, suicidality, changes in oral behaviors, and urinary problems. In addition, poor financial judgement was frequently detected in patients with prodromal bvFTD. Aberrant sensations in the nose and throat without any physical explanation, regarded as somatizations, emerged only in bvFTD patients with the C9orf72 repeat expansion. CONCLUSIONS: Subjective reporting of impaired episodic memory is a poor indicator in differentiating bvFTD from AD. Sleeping disturbances, delusions, hallucinations, and unexplained somatic complaints in a patient with cognitive disturbances should prompt the clinicians to consider bvFTD as a possible diagnostic option behind these symptoms. The spectrum of symptoms in the prodromal stages of bvFTD may be more diverse than the latest criteria suggest.

Neuropsychiatric symptoms and activities of daily living in Alzheimer's disease: ALSOVA 5-year follow-up study.

BACKGROUND: Neuropsychiatric symptoms (NPSs) in Alzheimer's disease (AD) are related to activities of daily living (ADLs), but longitudinal studies are sparse. OBJECTIVES: We investigated which NPSs were related to decline in instrumental ADLs (IADLs) and basic ADLs (BADLs) in a 5-year follow-up of individuals with AD. METHODS: ALSOVA 5-year follow-up study data of 236 individuals with very mild or mild AD at baseline and their caregiver were analyzed. IADLs and BADLs were assessed with Alzheimer's Disease Cooperative Study ADL inventory, and NPSs with Neuropsychiatric Inventory at annual follow-up visits. Generalized estimating equations (GEEs) were used for longitudinal data analysis, and NPS-ADL networks were estimated to demonstrate symptom interactions. RESULTS: Apathy [rate ratio (RR) 1.23, 95% CI 1.06-1.44, p = 0.007], aberrant motor behavior (RR 1.24, 95% CI 1.07-1.44, p = 0.005), and appetite disturbances (RR 1.22, 95% CI 1.06-1.41, p = 0.005) were related to impairment in BADLs, and the same symptoms (RR 1.13, 95% CI 1.07-1.21, p < 0.001; RR 1.13, 95% CI 1.07-1.20, p < 0.001; RR 1.14; 95% CI 1.08-1.21, p < 0.001, for apathy, aberrant motor behavior, and appetite disturbances, respectively), in addition to delusions (RR 1.09, 95% CI 1.03-1.15, p = 0.004), were related to IADL impairment. Symptom networks varied at different time points. CONCLUSION: As AD progresses, common (apathy) and uncommon NPSs (aberrant motor behavior, appetite disturbances, delusions) seem to be related to ADLs through various symptom interactions. Previous literature suggests that frontal pathology could underlie these relationships.

Prevalence of C9ORF72 Expansion in a Large Series of Patients with Idiopathic Normal-Pressure Hydrocephalus.

BACKGROUND/AIMS: The C9ORF72 expansion is known to cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We aim to identify the prevalence of the C9ORF72 expansion in idiopathic normal pressure hydrocephalus (iNPH). METHODS: We analysed the C9ORF72 expansion in a large cohort of patients with possible iNPH (n = 487) and cognitively intact elderly controls (n = 432; age > 65 years). RESULTS: While the C9ORF72 expansion was detected in 1.6% (n = 8/487) of cases with possible iNPH, no control subject was found to carry the mutation. The mean age at onset of symptoms of C9ORF72 expansion carriers was 59 years (range: 52-67 years), 11 years less than non-carriers (p = 0.0002). The most frequent initial/main symptom pertained to gait difficulties. Despite identified mutation, only 3 of the patients fulfilled the criteria for the FTLD-ALS spectrum. Clinically significant shunt response was detected in 6 out of 7 shunted C9ORF72 expansion carriers. CONCLUSION: This is the first study cohort identifying the underlying C9ORF72 expansion in patients with iNPH providing evidence for the potential comorbidity between iNPH and the FTLD-ALS spectrum. Analysis of the C9ORF72 expansion should be considered for patients with probable iNPH presenting with frontal atrophy and personality changes or other severe psychiatric symptoms.