**7. iNPH and Alzheimer's disease**

As above reported iNPH can mimic other neurological diseases variously characterized by gait disturbances and cognitive impairment, namely vascular dementia with small vessel disease, dementia with Lewy bodies, Parkinson's disease and other parkinsonisms. The diagnostic differentiation can be difficult. In this regard, clinical and neuroimaging data are crucial; also the lack of response of iNPH patients to antiparkinsonian drugs can help in the diagnosis.

As regard AD, the matter is fairly complex and challenging. Motor disturbances are usually absent in AD, at least in the early stages. As for cognitive impairment, as explained in the previous section, impairment of frontal lobe-related functions is not frequent in AD, even if a "frontal" variant has been described [84]; all types of memory are impaired in AD, while recognition memory is relatively preserved in iNPH. On the other hand, an overlapping of the two diseases cannot be excluded, this is particularly important when considering the response to shunt surgery. From this perspective, many studies have tried to identify biological markers both for improving the diagnosis and predicting shunt efficacy.

Savolainen et al. [76] performed cortical biopsy in 223 iNPH patients; 66 subjects presented normal brain tissue, while Alzheimer pathology (neuritic plaques) was present in over 40% of patients. The authors suggest that these data may explain the unsuccessful recovery of many patients after shunt surgery. The presence of positive biopsies for neuritic plaques was also reported by Golomb et al. [75]; 81/117 patients with possible iNPH received a structured psychiatric interview, out of these 81, 77 were cognitively impaired (Global Deterioration Scale- GDS, ≥ 3), out of these 77, 56 received cortical biopsy. Twenty-three patients presented neuritic plaques; these subjects with positive biopsies were more cognitively impaired (higher GDS and lower MMSE scores) as well as more gait impaired than patients with negative biopsies. The prevalence of neuritic plaques increased in parallel with dementia severity from 18% for patients with GDS = 3–75% for patients with GDS scores >6. However, in this study the concomitant Alzheimer pathology did not strongly influence the clinical response to shunt surgery independently by the severity.

On the contrary, the degree of Alzheimer pathology is reported to be important in predicting the response to surgery in the study by Hamilton et al. [85]; out of 37 patients 12 showed a negative biopsy, the remaining 25 subjects showed a high percentage (above 60%) not only of neuritic plaques but also of neurofibrillary tangles, which indicates the presence of tau pathology. Patients with moderate-to-severe Aβ and tau pathology showed more severe baseline cognitive impairment and poorer performance postoperatively on NPH symptom severity scales and measures of cognition, while patients with mild Alzheimer pathology responded well to shunting. The authors suggest that some patients may be relatively unimpaired by the presence of cortical Alzheimer pathology; the different results obtained in respect to previous studies are explained by the different methods employed.

independence in daily life was measured using scales evaluating activities of daily living, gait, urinary incontinence, cognition (the modified Rankin scale, the Krauss scale, the Larsson categorization system, the Stein-Langfitt scale); a relationship between functional data and clinical assessment was found only after surgery, not before, while changes both in FDG uptake and in global cognitive functioning measured by MMSE were reported in 3 out of 19 subjects. A further study by the same authors [82] confirmed these data. In an earlier study, Dumarey et al. [83] observed an improvement of regional blood flow in the bilateral dorsolateral frontal and left mesiotemporal cortex in patients who had previously seen to be clinical responders to the spinal tap test. All these data show that functional changes occur early than morphological ones and seem to suggest a prompt metabolic response by neuronal cells possibly related to neuronal plasticity. As yet, however, functional imaging does not seem to provide prognostic information making it possible to identify patients who will benefit from surgery.

As above reported iNPH can mimic other neurological diseases variously characterized by gait disturbances and cognitive impairment, namely vascular dementia with small vessel disease, dementia with Lewy bodies, Parkinson's disease and other parkinsonisms. The diagnostic differentiation can be difficult. In this regard, clinical and neuroimaging data are crucial; also the lack of response of iNPH patients to antiparkinsonian drugs can help in the diagnosis. As regard AD, the matter is fairly complex and challenging. Motor disturbances are usually absent in AD, at least in the early stages. As for cognitive impairment, as explained in the previous section, impairment of frontal lobe-related functions is not frequent in AD, even if a "frontal" variant has been described [84]; all types of memory are impaired in AD, while recognition memory is relatively preserved in iNPH. On the other hand, an overlapping of the two diseases cannot be excluded, this is particularly important when considering the response to shunt surgery. From this perspective, many studies have tried to identify biologi-

Savolainen et al. [76] performed cortical biopsy in 223 iNPH patients; 66 subjects presented normal brain tissue, while Alzheimer pathology (neuritic plaques) was present in over 40% of patients. The authors suggest that these data may explain the unsuccessful recovery of many patients after shunt surgery. The presence of positive biopsies for neuritic plaques was also reported by Golomb et al. [75]; 81/117 patients with possible iNPH received a structured psychiatric interview, out of these 81, 77 were cognitively impaired (Global Deterioration Scale- GDS, ≥ 3), out of these 77, 56 received cortical biopsy. Twenty-three patients presented neuritic plaques; these subjects with positive biopsies were more cognitively impaired (higher GDS and lower MMSE scores) as well as more gait impaired than patients with negative biopsies. The prevalence of neuritic plaques increased in parallel with dementia severity from 18% for patients with GDS = 3–75% for patients with GDS scores >6. However, in this study the concomitant Alzheimer pathology did not strongly influence the clinical response to shunt

cal markers both for improving the diagnosis and predicting shunt efficacy.

**7. iNPH and Alzheimer's disease**

58 Hydrocephalus: Water on the Brain

surgery independently by the severity.

Leinonen et al. [86] evaluated the predictive value of brain biopsy for the long-term outcome of iNPH in 468 patients with possible iNPH; the presence of beta-amyloid was detected in 197 (42%) patients, and together with tau pathology in 44 cases (9%), but it did not affect the survival.

On the other hand, Alzheimer pathology as neuritic plaques can be present also in the brain of normal healthy individuals [87]; therefore, in order to ameliorate the differentiation of diagnosis, also CSF biological markers have been investigated. The specific combination of both low CSF beta-amyloid (Aβ)-42 and elevated CSF phosphorylated tau (P-tau) in fact is considered the biological signature of Alzheimer's disease, where low Aβ levels reflect amyloid deposition and high tau levels indicate a prevalent non specific neuronal damage [88].

In 2007, Kapaki et al. [89] studied 85 patients subdivided in 67 with AD and 18 with iNPH, and 72 healthy controls. Aβ-42 levels were significantly decreased in both diseases as compared with controls, while P-tau levels were significantly increased only in Alzheimer's patients; therefore the authors concluded that P-tau may be a useful marker in the differentiation of iNPH from Alzheimer's disease.

In the same year Agren-Wilsson et al. [90] studied 62 iNPH patients, 26 patients with subcortical vascular encephalopathy and 23 healthy controls. The CSF concentration of neurofilament light protein was elevated in iNPH and vascular encephalopathy compared with the controls, levels of total tau (T-tau), P-tau, and Aβ-42 were lower in iNPH compared with vascular encephalopathy and controls; all markers except Aβ-42 were significantly elevated after shunt surgery. These results lead the authors to conclude that not a specific marker but the combined pattern of more markers can distinguish iNPH from vascular patients and controls.

Lower CSF levels of both T-tau and P-tau and amyloid precursor protein have been reported also by Jeppsson et al. [91] in 28 iNPH patients compared with 20 healthy controls, while neurofilament light protein was elevated. After surgery there was an increase; these data have been interpreted as due to a reduced periventricular metabolism and axonal degeneration rather than to a major cortical damage.

Kang et al. [92] found lower CSF Aβ-42 levels and lower P-tau levels in 35 iNPH patients in respect to the control reference values; tau levels correlated with gait disturbance and CSF P-tau/Aβ ratios were significantly higher in patients who did not respond to shunt surgery.

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.

that patients with iNPH actually present impairment in broader cognitive domains: attention, working memory, episodic memory, visuoperceptual, and visuospatial functions [50, 63–65]. 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

Clinical and Cognitive Features of Idiopathic Normal Pressure Hydrocephalus

http://dx.doi.org/10.5772/intechopen.73273

61

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 neuro-

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

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

The following neuropsychological tests were administered to evaluate various domains of

• Mini-Mental State Examination (MMSE): general index of cognitive functioning

• Rey's 15-word test, both immediate and delayed recall: long-term verbal memory

• Logical memory test: long-term verbal memory for structured material

• Digit Span forward, Word Span and Spatial Span (Corsi's test) tests: working memory

logic, psychiatric, or general medical conditions sufficient to explain symptoms.

neurologist and tested by a neuropsychologist.

cognition:

parkinsonism and is administered by the clinician [98, 99].

• Raven's Colored Matrices 47: visuospatial reasoning • Weigl's Sorting Test: categorical abstract thinking

diagnoses of "parkinsonism".

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 however older.

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 AD and other neurodegenerative disorders.

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 iNPH from comorbid AD.
