**8. Our experience**

As reported in our recent review [96] the classic definition "fronto- subcortical dementia" is reductive, because it cannot completely describe the entire clinical spectrum. It is now known that patients with iNPH actually present impairment in broader cognitive domains: attention, working memory, episodic memory, visuoperceptual, and visuospatial functions [50, 63–65].

Jingami et al. [93] studied 55 iNPH patients, 20 Alzheimer's disease patients, 11 patients with cortico-basal syndrome, and 7 patients with spino-cerebellar degeneration. Tau levels were significantly decreased in iNPH in respect to AD especially in tap test responders patients; the authors concluded that CSF tau can be considered useful for differentiation iNPH from AD.

Pyykkö et al. [77] performed both cortical biopsy and CSF sampling in a population of 53 patients with iNPH, 26 with AD, and 23 with other diagnosis. In iNPH Aβ load in the brain biopsy showed a negative correlation with CSF levels of Aβ-42, no differences in markers of neuro-inflammation and neuronal damage were found in both iNPH and Alzheimer's patients. No differences between CSF Aβ levels or tau biomarkers in shunt-responding and non-responding iNPH patients have been reported, the non-responding patients were how-

The results of a recent meta-analysis [94] suggest that iNPH may be associated with significantly reduced levels of CSF Aβ42, t-tau and p-tau compared to normal controls, while compared to AD both t-tau and p-tau were significantly decreased in iNPH, but CSFAβ42 is slightly increased. The data cannot be considered definitive and helpful for the diagnosis and the authors conclude that prospective studies are needed to further assess the clinical utility of these and other biomarkers in assisting in the diagnosis of iNPH and differentiating it from

Actually iNPH CSF profile seems to be different from AD, in particular most studies report low CSF tau levels which are in contrast with elevated CSF tau levels in AD. However, the results from the literature cannot be considered conclusive. With particular regard to the data pre- and post-shunt Graff-Radford [95] observe that CSF biomarkers cannot be considered helpful in distinguishing patients with iNPH from those with comorbid AD and rather can provide misleading information. The author suggests that the pre-shunt low CSF Aβ42 (and other APP fragments) are not necessarily related to Aβ brain deposition similar to what happens in AD, but rather could be result from impaired clearance; the data of pre-shunt low tau proteins levels may have the same explanation. In iNPH in fact the brain is compressed and therefore a decrease in interstitial space and APP protein fragment drainage into the CSF may be impeded, resulting in low levels of all CSF proteins. Shunting decompresses the brain and creates more room for the interstitial space to increase and protein waste fragments to drain into the CSF; CSF proteins increase after shunting in fact has been reported. On the other hand Graff-Radfford [95] remarks that this hypothesis does not exclude the hypothesis proposed by Jeppsson et al. [89] about a reduced periventricular metabolism; prospective amyloid PET studies could be needed in order to determine whether this procedure is able to distinguish

As reported in our recent review [96] the classic definition "fronto- subcortical dementia" is reductive, because it cannot completely describe the entire clinical spectrum. It is now known

ever older.

60 Hydrocephalus: Water on the Brain

AD and other neurodegenerative disorders.

iNPH from comorbid AD.

**8. Our experience**

Here we report the results of our experience [97] to confirm this hypothesis. We evaluated retrospectively the cognitive profile and its relationship with disease variables in a group of subjects with iNPH. We retrospectively studied clinical charts collected from January 2010 to December 2014, at the Parkinson's Disease and Movement Disorders Unit of the Istituto Neurologico Nazionale "C. Mondino" of Pavia, Italy. A case series of 64 subjects with diagnosis of "probable" iNPH was collected. All recruited patients were referred with primary diagnoses of "parkinsonism".

The diagnosis of iNPH was made on the basis of clinical, neuropsychological and neuroimaging features [1]. In particular, as regard neuroimaging, we followed the criteria previously reported: ventricular enlargement not entirely attributable to cerebral atrophy or congenital enlargement (Evans Index >0.3) and the absence of macroscopic obstruction to CSF flow. These main aspects had to be accompanied by at least one of the following supportive features: enlargement of the temporal horns of the lateral ventricles not entirely attributable to hippocampus atrophy; narrowing of the sulci and subarachnoid spaces over the high convexity/midline surface; callosal angle of 40° or more; evidence of altered brain water content, including periventricular signal changes on CT and MRI not attributable to microvascular ischemic changes or demyelination; an aqueductal or fourth ventricular flow void on MRI.

Evidence of an antecedent event such as head trauma, intracerebral hemorrhage, meningitis, or other known causes of secondary hydrocephalus has been excluded as well as other neurologic, psychiatric, or general medical conditions sufficient to explain symptoms.

Fifty-eight healthy elderly, matched for age, sex, and education, recruited among hospitalized patients and/or patients' relatives without neurological disorder or cognitive impairment, represented the normal control group (NC). All patients and NC were examined by a neurologist and tested by a neuropsychologist.

Motor symptoms have been evaluated by the Unified Parkinson's Disease Rating Scale Part III (UPDRS III); this scale has been currently applied to measure the motor impairment due to parkinsonism and is administered by the clinician [98, 99].

The following neuropsychological tests were administered to evaluate various domains of cognition:


Age-, gender-, and education-corrected scores were calculated from the raw scores; the corrected score then were transformed into equivalent scores, ranging from 0 (pathological) to 1 (lower limit of normal) and 2, 3, 4 (normal).

When considering the different cognitive domains involved and on the basis of equivalent

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• Group 1 (G1): 27 patients (42%) with global cognitive impairment, characterized by global

• Group 2 (G2): 15 patients (24%) with typical deficit in attention and executive abilities

• Group 3 (G3): 11 patients (17%) with mild cognitive impairment (MCI), single domain (isolated deficit of a single cognitive domain, i.e. memory, attention, visuospatial abilities).

In **Table 3**, the clinical, demographic, and motor characteristics of the different groups are

In G1 the patients were older, with significantly longer disease duration and a more severe motor impairment in respect to the other groups (p < 0.00001). UPDRS III total score showed significant differences between G2 versus G3 and G4 patients (p < 0.02 and p < 0.0001, respec-

The results of this study show that, when comparing with controls, our iNPH whole population was impaired in almost all neuropsychological measures; the extent of statistical significant varied from test to test, being more pronounced in logical and executive functions. Only episodic memory was relatively preserved; these data seem to suggest that memory impairment in iNPH is generally milder in respect to the deficit in other functions, executive

However, when we consider the different cognitive domains involved, we can identify subgroups of patients with different cognitive profiles: about an half of the subjects (42%) in fact presented an overall diffuse impairment which can be framed as dementia of mild to moderate

**G3**

**(11 pts)**

20.6 ± 8.4 range 29–10

**MCI single domain** 

**G4**

**No cognitive impairment (11pts)**

21.4 ± 2.3 range 24–16

**G2**

Sex M/F 13/14 10/5 7/4 5/6 Age (years) 79.3 ± 1.9\* 73.7 ± 7.5 70.4 ± 4.2 69.9 ± 3.2

**Fronto-cortical dysfunction (15 pts)**

26.3 ± 3.1°+ range 29–22

**Table 3.** Demographic and clinical characteristics of the different iNPH groups (M ± SD) (ANOVA).

54.2 ± 16.8\* 40.0 ± 31.0 33.3 ± 13.2 32.4 ± 11.3

scores, we subdivided the entire iNPH population in the following subgroups:

deficit of cognitive functions, or anyway by widespread deficit.

• Group 4 (G4): 11 patients (17%) with no cognitive impairment.

tively). No differences were found between G3 and G4 groups.

(fronto-cortical dysfunction).

reported (Chi square test).

in particular [46].

Disease duration (months)

\*

UPDRS III 36.6 ± 10.0\*

**G1**

**Global cognitive impairment (27 pts)**

range 47–27

G1 vs. G2, G3 and G4: p < 0.00001; °G2 vs. G3: p < 0.02; +G2 vs. G4: p < 0.0001.

As reported in **Table 2**, compared to normal group, iNPH patients showed a worst cognitive performances in almost all neuropsychological tests, except for Rey's 15-word test, immediate recall, and Logical memory test, which were within the normal range (ANOVA).


**Table 2.** Demographic and neuropsychological profiles: Comparisons between iNPH and NC groups (M ± SD) (ANOVA)].

When considering the different cognitive domains involved and on the basis of equivalent scores, we subdivided the entire iNPH population in the following subgroups:


• Frontal Assessment Battery (FAB): fronto-executive functioning

Age-, gender-, and education-corrected scores were calculated from the raw scores; the corrected score then were transformed into equivalent scores, ranging from 0 (pathological) to 1

As reported in **Table 2**, compared to normal group, iNPH patients showed a worst cognitive performances in almost all neuropsychological tests, except for Rey's 15-word test, immediate

recall, and Logical memory test, which were within the normal range (ANOVA).

**Test/subtest iNPH NC P value**

Education (years) 8 ± 5 8 ± 5 NS

(range 66–81)

(range 8–71) MMSE 21.8 ± 4.9 28.5 ± 1.5 0.000000001 Digit span forward 4.4 ± 0.7 5.1 ± 1.3 0.0008 Word span 3.8 ± 0.7 4.2 ± 0.9 0.01 Spatial span (Corsi's test) 3.4 ± 1.0 5.0 ± 1.3 0.00000002

> 31.2 ± 7.5 4.7 ± 3.6

> 19.9 ± 9.2 12.1 ± 3.4

Constructive Apraxia 10.9 ± 2.6 12.1 ± 1.9 0.009

**Table 2.** Demographic and neuropsychological profiles: Comparisons between iNPH and NC groups (M ± SD) (ANOVA)].

Logical Memory test 6.9 ± 4.3 8.2 ± 3.4 NS Raven's Colored Matrices 47 21.0 ± 6.6 25.1 ± 5.3 0.0007 Weigl's Sorting Test 5.9 ± 2.9 7.2 ± 2.1 0.01 Frontal Assessment Battery (FAB) 11.5 ± 3.6 15.6 ± 1.8 0.00000008 Attentive matrices 34.8 ± 12.1 42 ± 6.9 0.0003

76.0 ± 5.8 (range 71–81)

33.1 ± 2.4 7.1 ± 2.3

23.1 ± 4.3 14.0 ± 2.6 NS

NS 0.0001

0.02 0.002

• Phonological and semantic fluency: lexical magazine

• Constructive Apraxia: copying and visuospatial abilities.

Subjects F/M 64 29/35 58 26/32

• Attentive matrices: selective attention

62 Hydrocephalus: Water on the Brain

(lower limit of normal) and 2, 3, 4 (normal).

Age (years) 73.7 ± 7.5

Disease duration (months) 40.1 ± 31.8

Rey's 15-word test • Immediate recall • Delayed recall

Verbal fluency: • Phonological • Semantic

In **Table 3**, the clinical, demographic, and motor characteristics of the different groups are reported (Chi square test).

In G1 the patients were older, with significantly longer disease duration and a more severe motor impairment in respect to the other groups (p < 0.00001). UPDRS III total score showed significant differences between G2 versus G3 and G4 patients (p < 0.02 and p < 0.0001, respectively). No differences were found between G3 and G4 groups.

The results of this study show that, when comparing with controls, our iNPH whole population was impaired in almost all neuropsychological measures; the extent of statistical significant varied from test to test, being more pronounced in logical and executive functions. Only episodic memory was relatively preserved; these data seem to suggest that memory impairment in iNPH is generally milder in respect to the deficit in other functions, executive in particular [46].

However, when we consider the different cognitive domains involved, we can identify subgroups of patients with different cognitive profiles: about an half of the subjects (42%) in fact presented an overall diffuse impairment which can be framed as dementia of mild to moderate


**Table 3.** Demographic and clinical characteristics of the different iNPH groups (M ± SD) (ANOVA).

degree, out of not demented patients, only 24% was characterized by fronto-cortical dysfunction and we also found a subgroup with impairment in a single cognitive domain and even patients without any neuropsychological deficit.

The great variability of clinical pictures in iNPH has to be interpreted also taking into account the role of the "cognitive reserve" phenomenon [100]; even partially, this aspect can also con-

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65

Clinical and neuroimaging data are crucial for the diagnosis and the literature has provided guidelines and precise neuroradiological diagnostic criteria. However, there is no general agreement about the neuropsychological measures to employ in assessing the condition, as the studies reported in the literature used different cognitive tests; this aspect is obviously relevant to the post-shunt follow-up, too. The neuropsychological assessment has to include sensitive and exhaustive measures investigating the different cognitive domains; also patients' quality of life and caregivers' point of view have to be investigated in particular after shunt

Another important issue is represented by the difficulty to establish with precision the different stages in the disease. The studies reported in the literature have been conducted in patients with different disease durations and therefore with different degrees of disease severity; this makes it difficult to compare the different results and obviously the results after shunt placement may well be negatively affected in patients with more severe or longer lasting disease. In particular as regards the shunt procedure, reliable indices predictive of a good response to surgery are still lacking; in the studies analyzed different outcome measures were employed

We can conclude that there is a need for further studies with a better standardization; longer follow-ups and closer interaction among the different professionals involved are also requested.

, Marta Picascia2

1 Alzheimer's Disease Assessment Unit/Laboratory of Neuropsychology, C. Mondino

2 Parkinson's Disease and Movement Disorders Unit, C. Mondino National Neurological

3 Neuroradiology Unit and Brain MRI 3T Mondino Research Center, C. Mondino National

[1] Williams MA, Relkin NR. Diagnosis and management of idiopathic normal-pressure hydrocephalus. Neurology Clinical Practice. 2013;**3**:375-385. DOI: 10.1212/CPJ.0b013e3182a78f6b

, Nicolò Gabriele Pozzi2

,

tribute to the differences of the response to shunt surgery.

surgery in order to obtain a more global and sensitive evaluation.

\*, Claudio Pacchetti<sup>2</sup>

National Neurological Institute, Pavia, Italy

Neurological Institute, Pavia, Italy

 and Paolo Vitali3 \*Address all correspondence to: elena.sinforiani@mondino.it

in different follow-up periods.

**Author details**

Elena Sinforiani<sup>1</sup>

Massimiliano Todisco2

Institute, Pavia, Italy

**References**

Therefore our results are in agreement with the data of the literature about a wide range of cognitive pictures in iNPH [50, 63–65, 94]; in particular, the heading of "fronto-subcortical dysfunction" is reductive as it cannot completely encompass the different cognitive profiles.

The second important finding of our study is represented by a positive correlation between cognition and disease progression; in fact, though cognitive impairment may be absent in early cases, its severity undoubtedly increases with older age, disease duration and severity of motor disturbances, hypothesizing an underlying common physiopathological mechanism. In this view, as our data can suggest, an early shunt surgery could contain not only the progression of motor disturbances but also the advance of cognitive impairment in these patients.

Our sample was enrolled on the basis of the presence of gait disturbances/parkinsonism and because of these symptoms the patients were referred to our Unit; this aspect may represent a weakness of the study in term of patient's enrollment. On the other hand it is well-known that motor disorders are the leading presentation of iNPH [1].

In this study, we have administered an exhaustive neuropsychological evaluation in order to investigate different cognitive domains; this is crucial to obtain a more detailed cognitive profile, as suggested by different authors [64–66]. In our opinion an accurate cognitive characterization before shunt is relevant in terms of outcome measures. Enrolling homogeneous population of iNPH may improve the prediction of response to shunt surgery; a longer follow-up period and a closer interaction among the different professionals are needed.
