High Risk of Dementia in Ventricular Enlargement with Normal Pressure Hydrocephalus Related Symptoms 1

Abstract

Background: Differential diagnosis of ventricular enlargement with normal pressure hydrocephalus (NPH) related symptoms is challenging. Patients with enlarged ventricles often manifest cognitive deterioration but their long-term outcome is not well known.

Objectives: We aim to evaluate long-term cognitive outcome in patients with enlarged ventricles and clinically suspected NPH.

Methods: A neurologist and a neurosurgeon clinically evaluated 468 patients with enlarged ventricles and suspected NPH using radiological methods, intraventricular pressure monitoring, and frontal cortical brain biopsy. The neurologist confirmed final diagnoses after a median follow-up interval of 4.8 years.

Results: Altogether, 232 patients (50%) with enlarged ventricles did not fulfill the criteria for shunt surgery. The incidence of dementia among patients with enlarged ventricles, and at least one NPH-related symptom with adequate follow-up data (n = 446) was high, varying from 77 (iNPH, shunt responders) to 141/1000 person-years (non-shunted patients with enlarged ventricles). At the end of the follow-up, 59% of all these patients were demented. The demented population comprised 73% of non-shunted patients with enlarged ventricles, 63% of shunted iNPH patients that did not respond to treatment, and 46% of iNPH patients that were initially responsive to shunting. The most common cause of dementia was Alzheimer’s disease (n = 94, 36%), followed by vascular dementia (n = 68, 26%).

Conclusions: One-half of patients with enlarged ventricles and clinically suspected NPH were not shunted after intraventricular pressure monitoring. Dementia caused by various neurodegenerative diseases was frequently seen in patients with ventricular enlargement. Thus, careful diagnostic evaluation in collaboration with neurologists and neurosurgeons is emphasized.

Keywords

Alzheimer’s disease cognition dementia memory normal pressure hydrocephalus prognosis vascular dementia ventricular enlargement

INTRODUCTION

Ventricular enlargement accompanied by gait apraxia, cognitive deterioration, or urinary incontinence represents a differential diagnostic challenge for neurologists and raises suspicion of normal pressure hydrocephalus (NPH) [1, 2]. The incidence rate for clinically suspected idiopathic NPH (iNPH) is up to 15/100,000 person-years in a population older than 50 years of age and prevalence increases with aging [3 –6]. One-half of the patients with clinically suspected iNPH will not be shunted after neuroradiological and cerebrospinal fluid (CSF) dynamics evaluations [3 , 8] emphasizing rigorous differential diagnosis [9].

Reports of cognitive response after shunt surgery in cases of verified iNPH are inconsistent [2 , 10] and comorbidities hamper the outcome [11]. We reported previously that after 4.7 years median follow-up, 46% of shunt-responsive iNPH patients (the same original population with the current study) were eventually demented due to various neurodegenerative diseases [7]. On the basis of the previous reports, NPH may account for up to 5% of all dementia cases [12].

Most of the previous follow-up studies focus on shunted patients [13 –16] but the long-term cognitive outcome of patients with enlarged ventricles and NPH-related symptoms that are not shunted or not initially responsive to shunt surgery is not well known. Outcome appears to be poor based on a review of six studies that evaluate outcome in a total of 102 non-shunted individuals with iNPH [17]. The cognitive function of only a minority of non-shunted individuals with iNPH improved during long-term follow-up [17] and without treatment symptoms seem to progress [18].

We aimed to evaluate long-term cognitive outcome and final clinical diagnosis in patients with enlarged ventricles and clinically suspected NPH, emphasizing the outcome of patients not responding to the shunt or not fulfilling the criteria for shunt.

MATERIALS AND METHODS

Study participants

The Kuopio University Hospital Neurosurgery NPH Registry (http://www.uef.fi/nph) consists of 468 consecutive patients from a defined catchment population (851,000 in 2006) in Eastern Finland who were evaluated clinically, neuroradiologically, and using 24-h intracranial pressure (ICP) monitoring between 1991 and 2006 because of enlarged ventricles with at least one NPH related clinical symptom (Fig. 1) [19]. A cortical biopsy (2 to 5 mm ×3 to 7 mm) was obtained during ICP catheter insertion, and samples were analyzed for the presence of amyloid-β (Aβ) and hyperphosphorylated tau [7, 19]. The registry contains clinical baseline and follow-up data from all hospitals in Kuopio University Hospital catchment area, medications, causes of death, and radiological and biopsy findings.

After primary examination by neurologists, patients were referred for additional evaluation described above. All patients had one to three symptoms potentially related to NPH (impaired cognition, impaired gait, or urinary continence), with enlarged brain ventricles (Evans’ index >0.30) disproportionate to the size of the sulci of cerebral convexities [20] according to computed tomography or magnetic resonance imaging.

Indications for the shunt in iNPH were (1) a basal ICP >10 mmHg continuously, or when the basal pressure was below 10 mmHg and (2) the presence of any A-waves or >30% B-waves during 24-h ICP monitoring [21]. The initial response to the shunt (improvement, no change, or deterioration in the patient’s gait, memory, or urinary continence) was evaluated by clinical examination and interviewing patient (and caregiver when appropriate) at the outpatient clinic 2 to 3 months after the surgery [7]. Patients that did not undergo shunt insertion were referred back to neurologists for differential diagnostic examinations.

After differential diagnostic examinations and possible shunt therapy, clinical follow-up was continued. The patients’ primary care physicians maintained detailed medical records at local hospitals. In cases of suspected shunt malfunction or cognitive decline, patients were referred for neurological and neurosurgical (if a shunt had been inserted) re-evaluation. Patients without adequate follow-up data were excluded from the analyses.

Follow-up and evaluation of cognition

All study patients (n = 468) were followed for a median period of 4.8 years (range 0–17). During follow-up period, 267 patients died. Follow-up data was collected from the hospitals’ archives, and causes of death were obtained from the national registries. Sufficient information to evaluate clinical and cognitive status retrospectively (systematically registered time course, nature, and progression of symptoms) was available from 446 patients with suspected NPH (Fig. 1).

Neurologists performed evaluations for memory disorder according to the dementia criteria [8]. Follow-up data of all study patients was re-evaluated and the final clinical diagnoses (including iNPH) of neurodegenerative brain diseases were confirmed by a neurologist specialized in memory disorders (AMK). Clinical data concerning cognitive impairment (e.g., Mini-Mental State Examination (MMSE) scores [22], neuropsychological tests), changes in daily ability, and the clinical course recorded by neurologists, neurosurgeons, and primary care physicians, were carefully evaluated.

Alzheimer’s disease (AD), vascular dementia (VaD), and other forms of dementia were diagnosed according to the established criteria [23 –27]. During re-evaluation, revised AD criteria and a newly available concept of vascular impairment were used to support final AD and VaD diagnoses [28, 29]. Previously described possible iNPH-related dementia [7] was defined as progressive neuropsychological symptoms (apathy, psychomotor slowing, lack of spontaneity, inattention, forgetfulness, and impaired executive functions) combined with motor impairment and incontinence, in spite of possible early response to the shunt. Probable iNPH-related dementia was defined when no co-morbidities were observed during the re-evaluation of clinical (AMK and VL), radiological (AS), and brain biopsy (JR) data. Mild cognitive impairment (MCI, both amnestic and non-amnestic) was diagnosed if a decline was registered in at least one domain of cognition, but abilities in daily function were maintained and the patient did not fulfill the criteria for any type of dementia [30]. MMSE scores were converted to dementia staging in accordance to the Clinical Dementia Rating (CDR) [31]: no dementia (MMSE 30, CDR 0), questionable dementia (MMSE 26-29, CDR 0.5), mild dementia (MMSE 21-25, CDR 1), moderate dementia (MMSE 11-20, CDR 2), and severe dementia (MMSE 0-10, CDR 3).

Statistical analysis

Between-group differences were analyzed using analysis of variance (ANOVA, for continuous variables) or the Chi-squared test (for categorical variables). Cox regression analysis was used to investigate the cause-specific hazards of MCI and dementia. Confidence intervals for the dementia incidence rate were calculated as exact Poisson confidence intervals. SPSS version 19.0 statistical software was used.

Ethical issues

The Kuopio University Hospital Research Ethical Committee, the Finnish National Supervisory Authority for Welfare and Health, and the Finnish Ministry of Social Affairs and Health approved this study.

RESULTS

Characteristics of the patients are shown in Table 1. Those patients with enlarged ventricles who did not meet criteria for shunt surgery were more likely to have AD-related brain pathology in biopsy and early cognitive impairments when compared to patients that underwent shunt surgery (p < 0.001, Table 1). Shunted iNPH patients more frequently suffered from early gait problems (p < 0.001, ANOVA, Table 1).

Altogether 232 patients with suspected iNPH did not undergo shunt surgery on the basis of ICP monitoring (Fig. 1). Non-shunted patients had higher mortality than the shunted patients (Table 1).

Long-term cognitive outcome in patients with enlarged ventricles and NPH related symptoms

At the end of the follow-up, clinical dementia was observed in 264 (59%) and MCI in 97 (22%) of all the patients with adequate data (n = 446) (Fig. 1). The number of patients with dementia in each study group and between-group comparisons is presented in Table 1.

The incidence of dementia among patients with enlarged ventricles and at least one NPH-related clinical symptom was 141 cases/1000 person-years (95% CI, 121–165) in non-shunted patients, 114/1000 person-years (95% CI, 71–173) in shunted but non-responsive iNPH patients, and 77/1000 person-years (95% CI, 60–99) in shunt-responsive iNPH patients.

Baseline characteristics and risk of poor outcome in non-shunted patients with enlarged ventricles

In univariate analysis, several factors correlated significantly with dementia in the non-shunted patients (Table 2). However, in the adjusted multivariate regression model, only memory deficit as the first symptom correlated with MCI (OR 6.15, p < 0.008) and dementia (OR 13.1 and p < 0.001) diagnosed during follow-up (Table 3). Non-shunted patients with dementia died more often than the non-shunted patients with MCI (p < 0.001; Table 2). For comparison, the baseline risk factors for cognitive deterioration in all studied patients are provided in Table 4.

Wide range of dementia syndromes in patients with enlarged ventricles and suspected NPH

Several different neurodegenerative diseases were diagnosed in demented patients (n = 264 out of 446): possible or probable AD in 94 (36%), VaD in 68 (26%), probable iNPH-related dementia in 36 (14%), and other or unspecified dementia in 66 (25%) (Fig. 1).

Both AD and VaD were significantly more common among non-shunted than shunted patients with suspected NPH (AD cases in non-shunted versus shunted patients: 69 of 226 versus 26 of 220, p < 0.001; VaD cases of non-shunted versus shunted patients: 41 of 226 versus 12 of 220, p < 0.001). In many cases (25 of 165 non-shunted with dementia) the specific diagnosis of dementia was still unclear (dementia NOS). We also observed nine demented, non-shunted patients with iNPH-related symptoms and signs; however, they did not fulfill the criteria for shunt surgery, or for any dementia-causing disease other than iNPH.

Among all shunted iNPH patients (n = 193), possible or probable iNPH was the most common cause of dementia (45% of both shunted responders and non-responders), although often other neurodegenerative diseases were present (Fig. 1).

DISCUSSION

We had a unique opportunity to evaluate the long-term cognitive outcome in patients with enlarged ventricles and NPH related symptoms in the largest reported population-based follow-up study in this era (n = 446, an average follow-up time of 4.8 years). The specific clinical diagnosis of dementia was made by specialists using all available medical data according to uniform diagnostic criteria. Finland’s well-organized, integrated public health care system and systematically maintained medical records were essential in this retrospective follow-up study, enabling us to evaluate the development of clinical dementia from the first symptom. One might argue that the retrospective approach was a limitation; however, it provided more reliable knowledge about patients’ final cognitive status than cross-sectional studies or short-term prospective follow-up.

We report in this study that 50% of cases with ventricular enlargement and suggestive NPH in clinical and neuroradiological examinations did not meet the criteria for shunt surgery on the basis of 24-h ICP monitoring. Furthermore, comparable to the previous reports [8, 15] 19% of shunted iNPH patients did not exhibit any improvement after shunt surgery.

Clinical diagnosis of iNPH is challenging: NPH-type triad of clinical symptoms is observed with a prevalence of 4.4% in the aged (>66 years) population [32], not always related to NPH and, only one-half of the patients with diagnosed NPH present with all of these symptoms [12]. Furthermore, single symptoms (e.g., impaired gait) are common, often due to other etiology than NPH. Gait disorder alone affects 20% to 50% of aged persons [33], and 3.8% to 6.4% of populations older than 60 years of age in Europe and North America are demented [34]. Disproportion between ventricular and sulcal CSF volume is associated with gait and cognitive impairment [32], and diagnostic accuracy regarding NPH is increased when gait difficulty is the predominant clinical feature [35]. If shunt surgery were performed exclusively on the basis of clinical and neuroradiological examinations, 46% to 61% of patients would not benefit from shunt placement [5, 36]. In agreement with the previous reports, our findings confirm that the diagnosis of iNPH is difficult to establish using only clinical profile and imaging findings. Evaluation of CSF dynamics (e.g., by ICP monitoring) increases diagnostic accuracy [8 , 37] and new methods like measuring postural balance may assist in clinical differential diagnostic between cerebral atrophy and iNPH [38].

Whether the employment of a widely used clinical test of patients’ response to shunt insertion (gait improvement) is enough to verify iNPH has been a point of critique [39]. In this study, at 2 to 3 months of follow-up, a neurosurgeon examined gait and interviewed shunted patients and their caregivers regarding memory and ability in daily functions, as well as incontinence complaints. However, beyond often available follow-up MMSEs, as a limitation we lack systematic quantitative measures of the outcome.

Differential diagnosis of NPH versus other neurodegenerative diseases may be challenging [1, 9]. Twenty-two of 35 patients who did not respond to the shunt therapy had concomitant neurodegenerative disease (Fig. 1).

Long-term cognitive outcome in patients with enlarged ventricles and suspected NPH

Enlargement of brain ventricles and white matter lesions, which are also observed in suspected NPH, are related to the impairment of cognitive functions [32 , 41]. The incidence rates of dementia in patients with enlarged brain ventricles and clinically suspected NPH have not been reported previously.

In this study, the incidence of dementia among patients with enlarged ventricles and at least one NPH-related symptom was high, varying from 77 to 141/1000 person-years depending on the etiology. Fifty-nine percent of the study patients became demented; the highest proportion (73%) and incidence (141/1000 person-years) were among non-shunted patients with enlarged ventricles and initially suspected iNPH, followed by patients lacking an initial shunt response (63%; 114/1000 person-years).

In the current study, only 11% of non-shunted patients with previously suspected NPH and with varying neurodegenerative diseases exhibited no cognitive deterioration (MCI or dementia) at a median follow-up time of 4.8 years. In a review of six studies with a total of 102 non-shunted iNPH patients (9–27 patients per study), poor outcome was reported in both short-term and long-term evaluations [17]. Cognitive function improved in 0% to 9% of non-shunted iNPH patients during long-term follow-up [17]. Additionally, shunt-responsive iNPH patients do not often exhibit long-term cognitive improvement, as discussed previously [7].

Differential diagnosis of cognitive deterioration in patients with enlarged ventricles

In all, the proportion of AD (36%) was lower and the proportion of VaD (26%)—as expected—was higher than generally observed in the demented population, and 14% had probable NPH-related dementia. Among non-shunted patients with enlarged ventricles and dementia (n = 226), 15% did not receive any specific dementia diagnosis owing to atypical symptoms and signs. Nine (4%) patients did not exhibit any neurodegenerative disease other than iNPH, which might reflect misdiagnosed cases by ICP monitoring.

In iNPH, cognitive impairment or lack of cognitive response after shunt therapy has often been explained mostly by co-existing degenerative brain disease [7, 11]. AD is the most common cause of dementia [42]; it may have overlapping symptoms and signs with iNPH, and they may exist in mixed form [7 , 43].

Careful anamnesis assists in differential diagnosis. In typical AD, impaired episodic memory is an early symptom, while motor impairment manifests during advanced AD. Psychometric tests, brain imaging, and other biomarkers (e.g., CSF Aβ₄₂, CSF tau, and positron emission tomography examinations) are recommended in differential diagnosis of early AD [28]. A small cortical brain biopsy (obtained during catheter insertion for ICP monitoring in cases of suspected iNPH) may also assist in differential diagnosis between iNPH and other neurodegenerative diseases [7, 19].

The association of iNPH with cerebrovascular diseases has been speculated [44]. Differential diagnosis of vascular cognitive impairment is challenging for clinicians because motor system impairment, cognitive impairment, and ventricular enlargement are often observed in VaD [45] (at least in the late stage) as well as in iNPH.

In agreement with a previous report [3], various other neurodegenerative diseases (e.g., dementia with Lewy bodies, Parkinson disease, and other extrapyramidal syndromes) were observed in the patients with enlarged ventricles and suspected NPH. The occurrence of these diseases, as well as occurrence of iNPH, increases with age.

Among the 446 patients with enlarged ventricles, NPH related symptoms, and sufficient follow-up data we identified 36 with clinical dementia not matching the current criteria for any neurodegenerative disorder other than iNPH. Interestingly, 19 of the 36 patients were non-shunted, or exhibited no shunt response after treatment. Furthermore, 16 patients exhibited predominantly iNPH-related cognitive symptoms, but with comorbidities potentially influencing their cognition. Altogether, 33% of shunted patients underwent shunt revision indicating active follow-up and low threshold for re-evaluation in case of no response or later deterioration.

Recent findings suggest that iNPH may be an independent disease with distinct biology [46, 47], and iNPH patients may develop dementia without degenerative conditions other than iNPH [7]. Frontal lobe executive functions may deteriorate early in iNPH patients, with irreversible pathological changes related to iNPH itself [48]. Still, clinical diagnostic criteria and the neuropathological classification of iNPH-related dementia as an independent cognitive disorder lack systematic description and standardization requiring further study. Unfortunately, we lack autopsy verification of the dementia diagnosis in the majority of the patients [44].

Clinical findings predicting dementia in patients with enlarged ventricles and iNPH-related symptoms

Memory deficit as the first symptom was the most significant predictor of dementia in all patients. This is reasonable since impaired episodic memory is an early symptom of AD [24, 28] and many of the current patients were diagnosed with AD. Also patients with vascular cognitive impairment have deteriorated learning skills deteriorating memory, although impairment of episodic memory is not as profound and clear as in AD.

Demented, non-shunted patients were older at the time of symptom onset and diagnostic evaluations. They exhibited poor performance in MMSE testing, and had more frequently AD-related biopsy findings than the other non-shunted patients (i.e., no cognitive impairment or MCI at the end of follow-up). These findings were expected because aging is the most important risk factor for dementia and higher age at shunting reportedly increases the risk of dementia [49]. It has been suggested that poor prognosis in NPH is related to cortical atrophy and longstanding symptoms [11]. The risk factors for dementia in shunt-responsive iNPH patients have been discussed previously [7].

Need for systematic cognitive follow-up of patients with enlarged ventricles and suspected NPH-related symptoms

These results warrant systematic multidisciplinary (neurological, neurosurgical, neuropsychological, neuroradiological, and sometimes urological) examinations to improve diagnostic accuracy in ventricle enlargement with suspected iNPH. Furthermore, repeated long-term neurological and neuropsychological evaluations of patients with enlarged brain ventricles and suspected iNPH-related symptoms are needed. Those patients are at high risk of developing dementia, and these evaluations would enable early diagnosis of specific neurodegenerative disease, thereby increasing the likelihood that patients will receive adequate therapy and support. An interesting issue remains for further study whether disproportionately enlarged subarachnoid-space hydrocephalus [50, 51] has an effect on the final diagnosis of patients with primarily suspected iNPH.

In conclusion, one-half of the patients with enlarged ventricles and clinically suspected NPH have a disorder likely other than iNPH and are not shunted. Progressive dementia is frequently observed in patients with enlarged ventricles and NPH-like symptoms, especially in non-shunted patients. These patients have various neurodegenerative diseases, most frequently AD, VaD, and NPH-related dementia. Once NPH has been suspected or verified, careful differential diagnostic evaluation and cognitive follow-up using validated measurements must be organized for these patients at high risk of a variety of progressive neurodegenerative diseases.

Footnotes

ACKNOWLEDGMENTS

The study was supported by research grants from the Kuopio University Hospital EVO Fund (5252614), the Finnish Medical Foundation, and the Emil Aaltonen Foundation.

We thank Marita Voutilanen, RN, for maintenance of the Kuopio NPH Registry and The Statistics and Registers of Finland for supplying the certificates of death and Lotta Salo, MSc, for technical help in manuscript preparation.

Authors’ disclosures available online ().

References

Relkin

, Marmarou

, Klinge

, Bergsneider

, Black

(2005) Diagnosing idiopathic normal-pressure hydrocephalus. Neurosurgery 57(3 Suppl), S4–S16.

Vanneste

(2000) Diagnosis and management of normal-pressure hydrocephalus. J Neurol 247, 5–14.

Klassen

, Ahlskog

(2011) Normal pressure hydrocephalus. How often does the diagnosis hold water? Neurology 77, 1119–1125.

Jaraj

, Rabiei

, Marlow

, Jensen

, Skoog

, Wikkelsø

(2014) Prevalence of idiopathic normal-pressure hydrocephalus. Neurology 82, 1449–1454.

Brean

, Eide

(2008) Prevalence of probable idiopathic normal pressure hydrocephalus in a Norwegian population. Acta Neurol Scand 118, 48–53.

Martín-Láez

, Caballero-Arzapalo

, López-Menéndez

LÁ

, Arango-Lasprilla

, Vázquez-Barquero

(2015) Epidemiology of idiopathic normal pressure hydrocephalus: A systematic review of the literature. World Neurosurg 84, 2002–2009.

Koivisto

, Alafuzoff

, Savolainen

, Sutela

, Rummukainen

, Kurki

, Jääskeläinen

, Soininen

, Rinne

, Leinonen

(2013) Poor cognitive outcome in shunt-responsive idiopathic normal pressure hydrocephalus. Neurosurgery 72, 1–8.

Eide

, Sorteberg

(2010) Diagnostic intracranial pressure monitoring and surgical management in idiopathic normal pressure hydrocephalus: A 6-year review of 214 patients. Neurosurgery 66, 80–91.

Williams

, Relkin

(2013) Diagnosis and management of idiopathic normal-pressure hydrocephalus. Neurol Clin Pract 3, 375–385.

10.

Thomas

, McGirt

, Woodworth

, Heidler

, Rigamonti

, Hillis

, Williams

(2005) Baseline neuropsychological profile and cognitive response to cerebrospinal fluid shunting for idiopathic normal pressure hydrocephalus. Dement Geriatr Cogn Disord 20, 163–168.

11.

Meier

, Kiefer

, Neumann

, Lemcke

(2006) On the optimal opening pressure of hydrostatic valves in cases of idiopathic normal-pressure hydrocephalus: A prospective randomized study with 123 patients. Acta Neurochir Suppl 96, 358–363.

12.

Malm

, Graff-Radford

, Ishikawa

, Kristensen

, Leinonen

, Mori

, Owler

, Tullberg

, Williams

, Relkin

(2013) Influence of comorbidities in idiopathic normal pressure hydrocephalus - research and clinical care. A report of the ISHCSF task force on comorbidities in INPH. Fluids Barriers CNS 10, 22.

13.

Mirzayan

, Luetjens

, Borremans

, Regel

, Krauss

(2010) Extended long-term (>5 years) outcome of cerebrospinal fluid shunting in idiopathic normal pressure hydrocephalus. Neurosurgery 67, 295–301.

14.

Poca

, Solana

, Martínez-Ricarte

, Romero

, Gándara

, Sahuquillo

(2012) Idiopathic normal pressure hydrocephalus: Results of a prospective cohort of 236 shunted patients. Acta Neurochir Suppl 114, 247–253.

15.

Toma

, Papadopoulos

, Stapleton

, Kitchen

, Watkins

(2013) Systematic review of the outcome of shunt surgery in idiopathic normal-pressure hydrocephalus. Acta Neurochir (Wien) 155, 1977–1980.

16.

Gölz

, Ruppert

, Meier

, Lemcke

(2014) Outcome of modern shunt therapy in patients with idiopathic normal pressure hydrocephalus 6 years postoperatively. J Neurosurg 121, 771–775.

17.

Toma

, Stapleton

, Papadopoulos

, Kitchen

, Watkins

(2011) Natural history of idiopathic normal-pressure hydrocephalus. Neurosurg Rev 34, 433–439.

18.

Andrén

, Wikkelsø

, Tisell

, Hellström

(2014) Natural course of idiopathic normal pressure hydrocephalus. J Neurol Neurosurg Psychiatry 85, 806–810.

19.

Leinonen

, Koivisto

, Savolainen

, Rummukainen

, Tamminen

, Tillgren

, Vainikka

, Pyykkö

, Mölsä

, Fraunberg

, Pirttilä

, Jääskeläinen

, Soininen

, Rinne

, Alafuzoff

(2010) Amyloid and tau proteins in cortical brain biopsy and Alzheimer’s disease. Ann Neurol 68, 446–453.

20.

Shprecher

, Schwalb

, Kurlan

(2008) Normal pressure hydrocephalus: Diagnosis and treatment. Curr Neurol Neurosci Rep 8, 371–476.

21.

Savolainen

, Hurskainen

, Paljarvi

, Alafuzoff

, Vapalahti

(2002) Five-year outcome of normal pressure hydrocephalus with or without a shunt: Predictive value of the clinical signs, neuropsychological evaluation and infusion test. Acta Neurochir 144, 515–523.

22.

Folstein

, Folstein

, McHugh

(1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12, 189–198.

23.

American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders. 4th ed. American Psychiatric Association, Washington DC.

24.

McKhann

, Drachman

, Folstein

, Katzman

, Price

, Stadlan

(1984) Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34, 939–944.

25.

Román

, Tatemichi

, Erkinjuntti

, Cummings

, Masdeu

, Garcia

, Amaducci

, Orgogozo

, Brun

, Hofman

, et al. (1993) Vascular dementia: Diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 43, 250–260.

26.

Neary

, Snowden

, Gustafson

, Passant

, Stuss

, Black

, Freedman

, Kertesz

, Robert

, Albert

, Boone

, Miller

, Cummings.

, Benson

(1998) Frontotemporal lobar degeneration: A consensus on clinical diagnostic criteria. Neurology 51, 1546–1554.

27.

McKeith

, Galasko

, Kosaka

, Perry

, Dickson

, Hansen

, Salmon

, Lowe

, Mirra

, Byrne

, Lennox

, Quinn

, Edwardson

, Ince

, Bergeron

, Burns

, Miller

, Lovestone

, Collerton

, Jansen

, Ballard

, de Vos

, Wilcock

, Jellinger

, Perry

(1996) Consensus guidelines for the clinical and pathological diagnosis of dementia with Lewy bodies (DLB): Report of the consortium on DLB international workshop. Neurology 47, 1113–1124.

28.

Dubois

, Feldman

, Jacova

, Dekosky

, Barberger-Gateau

, Cummings

, Delacourte

, Galasko

, Gauthier

, Jicha

, Meguro

, O’brien

, Pasquier

, Robert

, Rossor

, Salloway

, Stern

, Visser

, Scheltens

(2007) Research criteria for the diagnosis of Alzheimer’s disease: Revising the NINCDS-ADRDA criteria. Lancet Neurol 6, 734–746.

29.

Erkinjuntti

, Gauthier

(2009) The concept of vascular cognitive impairment. Front Neurol Neurosci 24, 79–85.

30.

Petersen

, Roberts

, Knopman

, Boeve

, Geda

, Ivnik

, Smith

, Jack

Jr (2009) Mild cognitive impairment: Ten years later. Arch Neurol 66, 1447–1455.

31.

Perneczky

, Wagenpfeil

, Komossa

, Grimmer

, Diehl

, Kurz

(2006) Mapping scores onto stages: Mini-mental state examination and clinical dementia rating. Am J Geriatr Psychiatry 14, 139–144.

32.

Palm

, Saczynski

, van der Grond

, Sigurdsson

, Kjartansson

, Jonsson

, Eiriksdottir

, Gudnason

, Admiraal-Behloul

, Launer

, van Buchem

, Age, Gene/Environment Susceptibility-Reykjavik Study (2009) Ventricular dilation: Association with gait and cognition. Ann Neurol 66, 485–493.

33.

Rubenstein

, Josephson

, Robbins

(1994) Falls in the nursing home. Ann Intern Med 121, 442–451.

34.

Ballard

, Gauthier

, Corbett

, Brayne

, Aarsland

, Jones

(2011) Alzheimer’s disease. Lancet 377, 1019–1031.

35.

Factora

, Luciano

(2006) Normal pressure hydrocephalus: Diagnosis and new approaches to treatment. Clin Geriatr Med 22, 645–657.

36.

Hebb

, Cusimano

(2001) Idiopathic normal pressure hydrocephalus: A systematic review of diagnosis and outcome. Neurosurgery 49, 1166–1184.

37.

Hellström

, Edsbagge

, Blomsterwall

, Archer

, Tisell

, Tullberg

, Wikkelsø

(2008) Neuropsychological effects of shunt treatment in idiopathic normal pressure hydrocephalus. Neurosurgery 63, 527–536.

38.

Czerwosz

, Szczepek

, Sokolowska

, Jurkiewicz

, Czernicki

(2013) Posturography in differential diagnosis of normal pressure hydrocephalus and brain atrophy. Adv Exp Med Biol 755, 311–324.

39.

Stein

, Burnett

, Sonnad

(2006) Shunts in normal-pressure hydrocephalus: Do we place too many or too few? J Neurosurg 105, 815–822.

40.

Breteler

, van Amerongen

, van Swieten

, Claus

, Grobbee

, van Gijn

, Hofman

, van Harskamp

(1994) Cognitive correlates of ventricular enlargement and cerebral white matter lesions on magnetic resonance imaging. The Rotterdam Study. Stroke 25, 1109–1115.

41.

Apostolova

, Babakchanian

, Hwang

, Green

, Zlatev

, Chou

, DeCarli

, Jack

Jr , Petersen

, Aisen

, Cummings

, Toga

, Thompson

(2013) Ventricular enlargement and its clinical correlates in the imaging cohort from the ADCS MCI donepezil/vitamin E study. Alzheimer Dis Assoc Disord 27, 174–181.

42.

Fratiglioni

, Launer

, Andersen K Breteler

, Copeland

, Dartigues

, Lobo

, Martinez-Lage

, Soininen

, Hofman

(2000) Incidence of dementia and major subtypes in Europe: A collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology 54(Suppl 5), S10–S15.

43.

Cabral

, Beach

, Vedders

, Sue

, Jacobson

, Myers

, Sabbagh

(2011) Frequency of Alzheimer’s disease pathology at autopsy in patients with clinical normal pressure hydrocephalus. Alzheimers Dement 7, 509–513.

44.

Leinonen

, Koivisto

, Savolainen

, Rummukainen

, Sutela

, Vanninen

, Jääskeläinen

, Soininen

, Alafuzoff

(2012) Post-mortem findings in 10 patients with presumed normal-pressure hydrocephalus and review of the literature. Neuropathol Appl Neurobiol 38, 72–86.

45.

Bennett

, Gilley

, Lee

, Cochran

(1994) White matter changes: Neurobehavioral manifestations of Binswanger’s disease and clinical correlates in Alzheimer’s disease. Dementia 5, 148–152.

46.

Takahashi

, Kawanami

, Nagasawa

, Iseki

, Hanyu

, Kato

(2011) Familial normal pressure hydrocephalus (NPH) with an autosomal-dominant inheritance: A novel subgroup of NPH. J Neurol Sci 308, 149–151.

47.

McGirr

, Cusimano

(2012) Familial aggregation of idiopathic normal pressure hydrocephalus: Novel familial case and a family study of the NPH triad in an iNPH patient cohort. J Neurol Sci 321, 82–88.

48.

Iddon

, Pickard

, Cross

, Griffiths

, Czosnyka

, Sahakian

(1999) Specific patterns of cognitive impairment in patients with idiopathic normal pressure hydrocephalus and Alzheimer’s disease: A pilot study. J Neurol Neurosurg Psychiatry 67, 723–732.

49.

Golomb

, Wisoff

, Miller

, Boksay

, Kluger

, Weiner

, Salton

, Graves

(2000) Alzheimer’s disease comorbidity in normal pressure hydrocephalus: Prevalence and shunt response. J Neurol Neurosurg Psychiatry 68, 778–781.

50.

Kitagaki

, Mori

, Ishii

, Yamaji

, Hirono

, Imamura

(1998) CSF spaces in idiopathic normal pressure hydrocephalus: Morphology and volumetry. AJNR Am J Neuroradiol 19, 1277–1284.

51.

Mori

, Ishikawa

, Kato

, Kazui

, Miyake

, Miyajima

, Nakajima

, Hashimoto

, Kuriyama

, Tokuda

, Ishii

, Kaijima

, Hirata

, Saito

, Arai

, Japanese Society of Normal Pressure Hydrocephalus (2012) Guidelines for management of idiopathic normal pressure hydrocephalus: Second edition. Neurol Med Chir (Tokyo) 52, 775–809.